Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents

Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America

Prepared by
Jonathan E. Kaplan, MD¹
Constance Benson, MD²
King K. Holmes, MD, PhD³
John T. Brooks, MD¹
Alice Pau, PharmD⁴
Henry Masur, MD^4
1CDC, Atlanta, Georgia
² University of California San Diego, San Diego, California
³University of Washington, Seattle, Washington
⁴National Institutes of Health, Bethesda, Maryland

Disclosure of Relationship

CDC, our planners, and our content specialists wish to disclose they have no financial interests or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters, with the exception of Constance Benson and King K. Holmes. Dr. Benson discloses being on the Advisory Board for Merck, GlaxoSmithKline, and Boehringer Ingelheim; being a grant recipient for Gilead; and being a Data Safety Monitoring Board (DSMB) member for Achillion and JJR Australia. Her spouse also is a consultant for Merck, Gilead, Achillion, Monogram, and Vertex. Dr. Holmes discloses being a DSMB member of Merck, receiving an honorarium at the 2005 Infectious Diseases Society of America Conference, and serving on the Mycology Research Laboratories scientific advisory board. Presentations will not include any discussion of the unlabeled use of a product or a product under investigational use.

The material in this report originated in the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Kevin Fenton, MD, Director.
Corresponding preparer: John T. Brooks, M.D., Division of HIV/AIDS Prevention, NCHHSTP, CDC, 1600 Clifton Road NE, MS E-45, Atlanta, GA 30333, Telephone: 404-639-3894, Fax: 404-639-6127, Email: zud4@cdc.gov.

Summary

This report updates and combines earlier versions of guidelines for the prevention and treatment of opportunistic infections (OIs) in HIV-infected adults (i.e., persons aged >18 years) and adolescents (i.e., persons aged 13--17 years), last published in 2002 and 2004, respectively. It has been prepared by the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and the HIV Medicine Association (HIVMA) of the Infectious Diseases Society of America (IDSA). The guidelines are intended for use by clinicians and other health-care providers, HIV-infected patients, and policy makers in the United States. These guidelines address several OIs that occur in the United States and five OIs that might be acquired during international travel. Topic areas covered for each OI include epidemiology, clinical manifestations, diagnosis, prevention of exposure; prevention of disease by chemoprophylaxis and vaccination; discontinuation of primary prophylaxis after immune reconstitution; treatment of disease; monitoring for adverse effects during treatment; management of treatment failure; prevention of disease recurrence; discontinuation of secondary prophylaxis after immune reconstitution; and special considerations during pregnancy.

These guidelines were developed by a panel of specialists from the United States government and academic institutions. For each OI, a small group of specialists with content-matter expertise reviewed the literature for new information since the guidelines were last published; they then proposed revised recommendations at a meeting held at NIH in June 2007. After these presentations and discussion, the revised guidelines were further reviewed by the co-editors; by the Office of AIDS Research, NIH; by specialists at CDC; and by HIVMA of IDSA before final approval and publication.

The recommendations are rated by a letter that indicates the strength of the recommendation and a Roman numeral that indicates the quality of evidence supporting the recommendation, so that readers can ascertain how best to apply the recommendations in their practice environments.

Major changes in the guidelines include 1) greater emphasis on the importance of antiretroviral therapy for the prevention and treatment of OIs, especially those OIs for which no specific therapy exists; 2) information regarding the diagnosis and management of immune reconstitution inflammatory syndromes; 3) information regarding the use of interferon-gamma release assays for the diagnosis of latent Mycobacterium tuberculosis (TB) infection; 4) updated information concerning drug interactions that affect the use of rifamycin drugs for prevention and treatment of TB; 5) the addition of a section on hepatitis B virus infection; and 6) the addition of malaria to the list of OIs that might be acquired during international travel.

This report includes eleven tables pertinent to the prevention and treatment of OIs, a figure that pertains to the diagnois of tuberculosis, a figure that describes immunization recommendations, and an appendix that summarizes recommendations for prevention of exposure to opportunistic pathogens.

Introduction

Before the widespread use of potent combination antiretroviral therapy (ART), opportunistic infections (OIs), which have been defined as infections that are more frequent or more severe because of immunosuppression in HIV-infected persons, were the principal cause of morbidity and mortality in this population. In the early 1990s, the use of chemoprophylaxis, immunization, and better strategies for managing acute OIs contributed to improved quality of life and improved survival (1). However, the widespread use of ART starting in the mid-1990s has had the most profound influence on reducing OI-related mortality in HIV-infected persons in those countries in which these therapies are accessible and affordable (1--8).

Despite the availability of ART in the United States and other industrialized countries, OIs continue to cause considerable morbidity and mortality for three primary reasons: 1) many patients are unaware of their HIV infection and seek medical care when an OI becomes the initial indicator of their disease; 2) certain patients are aware of their HIV infection, but do not take ART because of psychosocial or economic factors; and 3) certain patients are prescribed ART, but fail to attain adequate virologic and immunologic response because of factors related to adherence, pharmacokinetics, or unexplained biologic factors (4,9,10). Thus, although hospitalizations and deaths have decreased since the implementation of ART, OIs remain a leading cause of morbidity and mortality in HIV-infected persons (11--19). Clinicians must be knowledgeable about optimal strategies for prevention and management of OIs to provide comprehensive high-quality care for these patients.

Recognizing that the relation between OIs and HIV infection is bidirectional is important. HIV leads to immunosuppression that allows opportunistic pathogens to cause disease in HIV-infected persons. OIs and other coinfections that might be common in HIV-infected persons, such as sexually transmitted infections, can also have adverse effects on the natural history of HIV infection. Certain OIs are associated with reversible increases in circulating viral load (20--25), and these increases could lead to accelerated HIV progression or increased transmission of HIV (26). Thus, although chemoprophylaxis and vaccination directly prevent pathogen-specific morbidity and mortality, they might also contribute to reduced rate of progression of HIV disease. For instance, randomized trials using trimethoprim-sulfamethoxazole (TMP-SMX) have documented that chemoprophylaxis can both decrease OI-related morbidity and improve survival. The survival benefit is likely to be partially attributable to reduced progression of HIV infection (27--31). Reduced progression of HIV infection would also indirectly delay or reduce the occurrence of subsequent OIs.

History of the Guidelines

In 1989, the Guidelines for Prophylaxis against Pneumocystis carinii Pneumonia for persons infected with the human immunodeficiency virus became the first HIV-related treatment guideline published by the U.S. Public Health Service (32). This report was followed by a guideline on prevention of Mycobacterium avium complex (MAC) disease in 1993 (33). In 1995, these guidelines were expanded to include the prevention of all HIV-related OIs and the Infectious Diseases Society of America (IDSA) joined as a cosponsor (34). These prevention guidelines were revised in 1997, 1999, and 2002 and have been published in MMWR (35--37), Clinical Infectious Diseases (38--40), the Annals of Internal Medicine (41,42), American Family Physician (43,44), and Pediatrics (45); accompanying editorials have appeared in the Journal of the American Medical Association (46,47).

In 2004, CDC, the National Institutes of Health (NIH), and the HIV Medicine Association (HIVMA) of the IDSA published a new guideline including recommendations for treating HIV-infected adults and adolescents with OIs (48). Companion guidelines were published for HIV-infected children (49).

Responses to these guidelines (e.g., numbers of requests for reprints, website contacts, and observations from health-care providers) have demonstrated that these guidelines have served as valuable references for HIV health-care providers. Because the guidelines include ratings indicating the strength of each recommendation and the quality of supporting evidence, readers have been able to assess the importance of each recommendation. The present report includes recommendations for both prevention and treatment of OIs in HIV-infected adults and adolescents; an accompanying report includes recommendations for HIV-exposed and -infected children.

These guidelines are intended for clinicians, other health-care providers, HIV-infected patients, and policy makers residing in the United States; guidelines pertinent to other regions of the world, especially countries with limited resources, might differ regarding the spectrum of OIs of interest and their diagnostic and therapeutic capacity.

Guidelines Process

These guidelines were prepared by the Opportunistic Infections Working Group under the auspices of the Office of AIDS Research Advisory Council (OARAC) of NIH. Group leaders and team members with expertise in specific OIs were selected from the membership of the Working Group; each group reviewed the literature since the last publication of the prevention and treatment guidelines, conferred for several months, and produced draft revised guidelines. Recommendations were reviewed and discussed by the Working Group at a meeting in Bethesda, Maryland, on June 25--26, 2007. A draft version of these recommendations was posted at AIDSInfo (http://aidsinfo.nih.gov/contentfiles/Adult_OI.pdf) on June 18, 2008. Since the June 18, 2008 posting, the draft recommendations were reviewed and updated for this report by Working Group members and subject matter experts. Suggested updates were reviewed by the co-editors, who amended the report, as warranted. The final version of the report was further reviewed by the co-editors, the Office of AIDS Research, NIH; experts at CDC; and the HIVMA of IDSA before final approval and publication.

The current guidelines share key features with prior versions. They are labeled as guidelines, indicating that the recommendations should be considered in the context of the individual patient situation and the community where the patient is being managed. They are evidence based. For each recommendation, the strength and quality of the evidence supporting it are indicated using a revised version of the rating system of the IDSA. As noted above, they have been developed by a broadly based panel that included representatives from academic medical centers, federal governmental agencies, community-based practices, and consumer advocates; representatives from Europe, Latin America, and Asia also took part in the process. The guidelines are available in print media and on the Internet. They are written for physicians and other health-care providers who care for HIV-infected persons in the United States and Western Europe where access is available to a full range of up-to-date medical services; however, these recommended strategies might not be feasible or appropriate in all settings where the spectrum of HIV-related complications and diagnostic capacity differ from those observed in the United States and Western Europe. Final versions of the guidelines were reviewed by respective members of each panel to ensure the recommendations were complete and appropriate. They are endorsed by CDC, the NIH, and the HIVMA of the IDSA. They are intended to complement more comprehensive textbooks, journals, and other relevant informational materials. Information is summarized in 11 tables.

Major Changes in Guidelines Since Last Publication

Major changes include 1) additional emphasis on the importance of ART for prevention and treatment of OIs, especially those for which specific chemoprophylaxis and treatment do not exist; 2) information on diagnosis and management of immune reconstitution inflammatory syndromes (IRIS); 3) information on interferon-gamma release assays (IGRAs) for the detection of latent Mycobacterium tuberculosis infection; 4) updated information on drug interactions affecting use of rifamycin drugs for prevention and treatment of tuberculosis (TB); 5) addition of a section on hepatitis B virus (HBV) infection; and 6) addition of a section on malaria to the OIs of geographic interest.

How to Use the Information in this Report

For each of the OIs discussed in this report, recommendations are provided that address 1) preventing exposure to opportunistic pathogens, 2) preventing disease, 3) discontinuing primary prophylaxis after immune reconstitution, 4) treating patients with disease, 5) monitoring for adverse effects (including IRIS), 6) managing treatment failure, 7) preventing disease recurrence ("secondary prophylaxis" or chronic maintenance therapy), 8) discontinuing secondary prophylaxis after immune reconstitution, and 9) special considerations during pregnancy. Recommendations are rated by a revised version of the IDSA rating system (Box). In this system, the letters A--E signify the strength of the recommendation for or against a preventive or therapeutic measure, and Roman numerals I--III indicate the quality of evidence supporting the recommendation. The guidelines include eleven tables pertinent to the prevention and treatment of OIs (Tables 1--11), a figure that pertains to the diagnosis of tuberculosis (Figure 1), a figure that describes immunization recommendations (Figure 2), and an appendix that summarizes recommendations pertinent to prevention of exposure to opportunistic pathogens.

Effect of ART on the Management of OIs

Clinicians treating HIV-infected patients often have to consider two questions related to OIs and ART: 1) when to initiate ART in ART-naïve persons who experience an acute OI, and 2) how ART should be managed for persons who are on ART but who experience an acute OI.

Initiation of ART in the Setting of an Acute OI (Treatment-Naïve Patients)

When an acute OI is present, initiation of ART is usually expected to improve immune function and contribute to faster resolution of the OI. Initiation of ART has been documented to be effective for OIs for which effective therapy does not exist; cryptosporidiosis, microsporidiosis, and progressive multifocal leukoencephalopathy (PML) might resolve or at least stabilize after the institution of effective ART (50--52). For Kaposi's sarcoma (KS), initiation of ART has been documented to lead to resolution of lesions in the absence of specific therapy for the sarcoma (53). The initiation of ART in the setting of an acute OI also has preventive benefit; a second OI is less likely to occur if ART is started promptly rather than delaying the initiation of ART.

Starting ART in the setting of an acute OI has several potential disadvantages. Severely ill patients might not absorb ART drugs, leading to subtherapeutic serum levels and the development of antiretroviral drug resistance. ART toxicities might be confused with disease manifestations or toxicities associated with drugs used for treating patients with an OI. Drug-drug interactions among ART and anti-OI drugs might be difficult to manage. Renal or hepatic dysfunction during acute OIs might make dosing of ART drugs difficult to estimate. Finally, IRIS events can occur and cause manifestations that are difficult to distinguish from other clinical conditions.

The term IRIS has been used to describe a group of clinical syndromes associated with immune reconstitution that have been observed most commonly for mycobacterial infections (TB and disseminated MAC disease), but also for other OIs, including Pneumocystis jirovecii pneumonia (PCP), toxoplasmosis, hepatitis B and hepatitis C viruses, cytomegalovirus (CMV) infection, varicella-zoster virus (VZV) infection, cryptococcal infection, histoplasmosis, and PML (54--65). IRIS manifestations are diverse and have not been defined precisely; they are usually characterized by fever and worsening of the clinical manifestations of the underlying OI. These clinical manifestations might be at the site of previously recognized opportunistic disease or might "unmask" disease at new sites not previously known to be infected by the pathogen. They also might represent a response to a previously unrecognized additional pathogen. The majority of patients who manifest IRIS do so within the first 4--8 weeks after starting ART, and have had high viral loads and low CD4⁺ T-lymphocyte (CD4⁺) counts. However, IRIS has occurred weeks after ART was started and in sequestered sites such as bone.

Diagnosis of IRIS is clinically challenging and involves differentiation from progression of the initial OI (including the possibility of antimicrobial resistance and treatment failure), development of a new OI, unrelated organ dysfunction, or drug toxicity. Therapy for IRIS has been empiric. No well-controlled trials exist to help decide when nonsteroidal drugs or corticosteroids are needed or when ART should be suspended. The inflammation might take weeks or months to subside. IRIS does not appear to have favorable or unfavorable implications about patient survival, with the possible exception of IRIS associated with cryptococcal meningitis (66, 67).

For these reasons, no consensus has been reached concerning the optimal time to start ART in the setting of a recently diagnosed OI. However, one recently completed randomized clinical trial has demonstrated a clinical and survival benefit of starting ART early, within the first 2 weeks, of initiation of treatment for an acute OI, excluding TB (68). The majority of OIs represented in this study were PCP and invasive bacterial infections, although cryptococcal, other fungal diseases, and disseminated MAC disease occurred in substantial numbers; the results suggest that unless other individual compelling contraindications are present, early initiation of ART near the time of initiating OI treatment should be considered for most patients with an acute OI, excluding TB. Other elements that should be considered when making this decision are degree of immunosuppression, availability of effective therapy for the OI, risk for drug interactions, overlapping drug toxicities, risk for the consequences of the development of IRIS, and willingness of the patients to adhere to their drug regimens. In cases of cryptosporidiosis, microsporidiosis, PML, KS, PCP, and invasive bacterial infections, the early benefits of ART outweigh increased risk related to these other factors and ART should be started as soon as possible. In the setting of TB disease, awaiting a response to OI therapy might be warranted before initiating ART.

Management of Acute OIs in Patients Receiving ART

OIs that occur after patients have been started on ART can be categorized into three groups. The first group includes OIs that occur shortly after initiating ART (within 12 weeks). These cases might be subclinical infections that have been unmasked by early immune reconstitution or simply OIs that occurred because of advanced immunosuppression and are not considered to represent early failure of ART. Many of these cases represent IRIS (54,56,69--72).

The second group includes OIs that occur >12 weeks after initiation of ART among patients with suppressed HIV ribonucleic acid (RNA) levels and sustained CD4⁺ counts >200 cells/µL (73,74). Determining whether these represent a form of IRIS rather than incomplete immunity with the occurrence of a new OI is difficult. The third group includes OIs that occur among patients who are experiencing virologic and immunologic failure while on ART. These represent clinical failure of ART.

When an OI occurs within 12 weeks of starting ART, treatment for the OI should be started and ART should be continued. When an OI occurs despite complete virologic suppression (i.e., late OI), therapy for the OI should be initiated and ART should be continued. If the CD4⁺ response to ART has been suboptimal, modification of the ART regimen may be considered, although no evidence exists to indicate that changing the ART regimen in this setting will improve the CD4⁺ response. When an OI occurs in the setting of virologic failure, OI therapy should be started, antiretroviral resistance testing should be performed, and the ART regimen should be modified, if possible, to achieve better virologic control.

Special Considerations During Pregnancy

No large studies have been conducted concerning the epidemiology or manifestations of HIV-associated OIs among pregnant women. No data demonstrate that the spectrum of OIs differs from that among nonpregnant women with comparable CD4⁺ counts.

Physiologic changes during pregnancy can complicate the recognition of OIs and complicate pharmacokinetics. Factors to consider include the following (75):

• Increased cardiac output by 30%--50% with concomitant increase in glomerular filtration rate and renal clearance.
• Increased plasma volume by 45%--50% while red cell mass increases only by 20%--30%, leading to dilutional anemia.
• Tidal volume and pulmonary blood flow increase, possibly leading to increased absorption of aerosolized medications. The tidal volume increase of 30%--40% should be considered if ventilatory assistance is required.
• Placental transfer of drugs, increased renal clearance, altered gastrointestinal absorption, and metabolism by the fetus might affect maternal drug levels.
• Limited pharmacokinetic data are available; use usual adult doses based on current weight, monitor levels if available, and consider the need to increase doses if the patient is not responding as expected.

Fetal risk is not increased with cumulative radiation doses below 5 rads; the majority of imaging studies result in radiation exposure to the fetus that is lower than the 5-rad recommended limit. In humans, the primary risks associated with high-dose radiation exposure are growth restriction, microcephaly, and developmental disabilities. The most vulnerable period is 8--15 menstrual weeks of gestation with minimal risk before 8 weeks and after 25 weeks. The apparent threshold for development of mental retardation is 20--40 rads, with risk of more serious mental retardation increasing linearly with increasing exposures above this level. Among children, risk for carcinogenesis might be increased approximately 1 per 1,000 or less per rad of in utero radiation exposure (76). Therefore, pregnancy should not preclude usual diagnostic evaluation when an OI is suspected (76--78). Abdominal shielding should be used when feasible to further limit radiation exposure to the fetus. Experience with use of magnetic resonance imaging (MRI) in pregnancy is limited, but no adverse fetal effects have been noted (76).

Other procedures necessary for diagnosis of suspected OIs should be performed in pregnancy as indicated for nonpregnant patients. A pregnant women who is >20 weeks of gestation should not lie flat on her back but should have her left hip elevated with a wedge to displace the uterus off the great vessels and prevent supine hypotension. Oxygenation should be monitored when pregnant patients are positioned such that ventilation or perfusion might be compromised.

For pregnant women who have had an OI diagnosed and are not on ART, immediate initiation of ART with OI therapy should be encouraged to minimize the risk for perinatal transmission of HIV (79). Decisions about immediate versus delayed initiation of ART in pregnancy should include consideration of gestational age, maternal HIV RNA levels and clinical condition, and potential toxicities and interactions between ART and OI drugs.

After first-trimester exposure to agents of uncertain teratogenic potential, a detailed ultrasound examination at 18--20 weeks should be conducted to detect possible major anomalies. For women who receive drugs that have not been extensively evaluated during pregnancy, an ultrasound should be conducted every 4--6 weeks to assess fetal growth and fluid volume, with antepartum testing if growth lag or decreased fluid are noted. Women in the third trimester of pregnancy should be instructed in daily fetal movement counting to detect decreased activity that might indicate fetal compromise (80).

Disease Specific Recommendations

Pneumocystis Pneumonia

Epidemiology

Pneumocystis pneumonia (PCP) is caused by Pneumocystis jirovecii, a ubiquitous organism that is classified as a fungus but that also shares biologic characteristics with protozoa. The taxonomy of the organism has been changed; Pneumocystis carinii now refers only to the pneumocystis that infects rodents, and Pneumocystis jirovecii refers to the distinct species that infects humans. The abbreviation PCP is still used to designate Pneumocystis pneumonia. Initial infection with P. jirovecii usually occurs in early childhood; two thirds of healthy children have antibody to P. jirovecii by age 2--4 years (81). Rodent studies and case clusters among immunosuppressed patients suggest that Pneumocystis spreads by the airborne route. Disease probably occurs by new acquisition of infection and by reactivation of latent infection (82--84). Before the widespread use of primary PCP prophylaxis and ART, PCP occurred in 70%--80% of patients with AIDS (85); the course of treated PCP was associated with a mortality of 20%--40% in persons with profound immunosuppression. Approximately 90% of cases occurred among patients with CD4⁺ counts of <200 cells/µL. Other factors associated with a higher risk for PCP included CD4⁺ cell percentage <14%, previous episodes of PCP, oral thrush, recurrent bacterial pneumonia, unintentional weight loss, and higher plasma HIV RNA (86,87).

Incidence of PCP has declined substantially with widespread use of prophylaxis and ART; recent incidence among patients with AIDS in Western Europe and the United States is 2--3 cases per 100 person-years (88). The majority of cases occur among patients who are unaware of their HIV infection or are not receiving ongoing HIV care (89) or among those with advanced immunosuppression (CD4⁺ counts <100 cells/µL) (90).

Clinical Manifestations

The most common manifestations of PCP among HIV-infected persons are the subacute onset of progressive dyspnea, fever, nonproductive cough, and chest discomfort that worsens within days to weeks. The fulminant pneumonia observed among non-HIV-infected patients is less common (91,92).

In mild cases, pulmonary examination is usually normal at rest. With exertion, tachypnea, tachycardia, and diffuse dry ("cellophane") rales might be observed (92). Oral thrush is a common coinfection. Fever is apparent in the majority of cases and might be the predominant symptom among some patients. Extrapulmonary disease is rare but can occur in any organ and has been associated with use of aerosolized pentamidine prophylaxis.

Hypoxemia, the most characteristic laboratory abnormality, might range from mild (room air arterial oxygen [pO2] of >70 mm Hg or alveolar-arterial O2 difference, [A-a] DO2 <35 mm Hg) to moderate ([A-a] DO2 >35 and <45 mm Hg) to severe levels ([A-a] DO2 >45 mm Hg). Oxygen desaturation with exercise is indicative of an abnormal A-a gradient but is nonspecific (93). Elevation of lactate dehydrogenase levels to >500 mg/dL is common but nonspecific (94). The chest radiograph typically demonstrates diffuse, bilateral, symmetrical interstitial infiltrates emanating from the hila in a butterfly pattern (92); however, patients with early disease might have a normal chest radiograph (95). In addition, atypical presentations with nodules, blebs and cysts, asymmetric disease, upper lobe localization, and pneumothorax occur. Pneumothorax in a patient with HIV infection should raise the suspicion of PCP (96,97). Cavitation, intrathoracic adenopathy, and pleural effusion are uncommon in the absence of other pulmonary pathogens or malignancy, and their presence might indicate an alternative diagnosis. Approximately 13%--18% of patients with documented PCP have another concurrent cause of pulmonary dysfunction (e.g., TB, KS, or bacterial pneumonia) (98,99).

Thin-section computerized tomography (CT) demonstrating patchy ground-glass attenuation (100,101) or a gallium scan indicating increased pulmonary uptake (102) increases the likelihood that a diagnostic study such as bronchoscopy would demonstrate PCP in patients with mild-to-moderate symptoms and a normal chest radiograph and might be useful as adjunctive studies.

Diagnosis

Because the clinical presentation, blood tests, or chest radiographs are not pathognomonic for PCP and the organism cannot be cultivated routinely, histopathologic demonstration of organisms in tissue, bronchoalveolar lavage fluid, or induced sputum samples (98,99,103,104) are required for a definitive diagnosis. Spontaneously expectorated sputum has low sensitivity and should not be submitted to the laboratory to diagnose PCP. Giemsa, Diff-Quik, and Wright stains detect both the cyst and trophozoite forms but do not stain the cyst wall; Gomori methenamine silver, Gram-Weigert, cresyl violet, and toluidine blue stain the cyst wall. Certain laboratories prefer direct immunofluorescent staining. Nucleic acid tests have greater sensitivity but less specificity than colorimetric or immunologic stains and can be combined with noninvasive samples such as induced sputum or oral wash samples; however, their availability is limited (105--107). (1→3)ß-D-glucan (a component of fungal cell walls) might be elevated in patients with PCP, but the sensitivity and specificity of this assay to establish a diagnosis of PCP has not been adequately evaluated. (108).

Previous studies of stained respiratory tract samples obtained by various methods indicate the following relative diagnostic sensitivities: induced sputum <50%-->90% (the sensitivity and specificity depend on the quality of the specimens and the experience of the microbiologist or pathologist), bronchoscopy with bronchoalveolar lavage 90%--99%, transbronchial biopsy 95%--100%, and open lung biopsy 95%--100%.

Because of the potential for certain processes to have similar clinical manifestations, a specific diagnosis of PCP should be sought rather than relying on a presumptive diagnosis, especially in patients with moderate-to-severe disease. Treatment can be initiated before making a definitive diagnosis because organisms persist in clinical specimens for days or weeks after effective therapy is initiated (104).

Preventing Exposure

Certain authorities might recommend that persons who are at risk for PCP not share a hospital room with a patient who has PCP, a recommendations based on animal studies and anecdotal human experience. Data are insufficient to support this recommendation as standard practice (CIII).

Preventing Disease

Initiating Primary Prophylaxis

HIV-infected adults and adolescents, including pregnant women and those on ART, should receive chemoprophylaxis against PCP if they have a CD4⁺ count of <200 cells/µL (AI) or a history of oropharyngeal candidiasis (AII) (32,85,86). Persons who have a CD4⁺ cell percentage of <14% or a history of an AIDS-defining illness, but do not otherwise qualify, should be considered for prophylaxis (BII) (32,85,86). When monitoring CD4⁺ counts frequently (e.g., every 1--3 months) is not possible, initiating chemoprophylaxis at a CD4⁺ count of >200, but <250 cells/µL, also should be considered (BII) (86).

TMP-SMX is the recommended prophylactic agent (AI) (32,109--111). One double-strength tablet daily is the preferred regimen (AI). However, one single-strength tablet daily (111) also is effective and might be better tolerated than one double-strength tablet daily (AI). One double-strength tablet three times weekly also is effective (BI) (112). TMP-SMX at a dose of one double-strength tablet daily confers cross-protection against toxoplasmosis (113) and selected common respiratory bacterial infections (109,114). Lower doses of TMP-SMX also likely confer such protection. For patients who have an adverse reaction that is not life threatening, chemoprophylaxis with TMP-SMX should be continued if clinically feasible; for those who have discontinued such therapy because of an adverse reaction, reinstituting TMP-SMX should be strongly considered after the adverse event has resolved (AII). Patients who have experienced adverse events, including fever and rash, might better tolerate reintroduction of the drug with a gradual increase in dose (i.e., desensitization), according to published regimens (BI) (115,116) or reintroduction of TMP-SMX at a reduced dose or frequency (CIII); as many as 70% of patients can tolerate such reinstitution of therapy (114).

If TMP-SMX cannot be tolerated, alternative prophylactic regimens include dapsone (BI) (109), dapsone plus pyrimethamine plus leucovorin (BI) (117--119), aerosolized pentamidine administered by the Respirgard II nebulizer (manufactured by Marquest, Englewood, Colorado) (BI) (110), and atovaquone (BI) (120,121). Atovaquone is as effective as aerosolized pentamidine (120) or dapsone (BI) (121) but is substantially more expensive than the other regimens. For patients seropositive for Toxoplasma gondii who cannot tolerate TMP-SMX, recommended alternatives to TMP-SMX for prophylaxis against both PCP and toxoplasmosis include dapsone plus pyrimethamine plus leucovorin (BI) (117--119) or atovaquone with or without pyrimethamine plus leucovorin (CIII).

Oral pyrimethamine plus sulfadoxine also has activity in preventing PCP (CIII) (122--124). This combination should not be used in patients with hypersensitivity to sulfonamides. Pyrimethamine plus sulfadoxine has an increased risk for severe cutaneous reactions, including Stevens-Johnson syndrome (125), and the long half-life of both pyrimethamine and sulfadoxine will result in a delayed clearance when the drug is stopped. Largely because TMP-SMX has superior safety, widespread availability, and is low cost, oral pyrimethamine plus sulfadoxine should be used rarely in the United States (CIII).

The following regimens cannot be recommended as alternatives because data regarding their efficacy for PCP prophylaxis are insufficient:

• Aerosolized pentamidine administered by other nebulization devices
• Intermittently administered parenteral pentamidine
• Oral clindamycin plus primaquine.

However, clinicians might consider using these agents in unusual situations in which the recommended agents cannot be administered (CIII).

Discontinuing Primary Prophylaxis

Primary pneumocystis prophylaxis should be discontinued for adult and adolescent patients who have responded to ART with an increase in CD4+ counts to >200 cells/µL for >3 months (AI). In observational and randomized studies supporting this recommendation, the majority of patients were taking antiretroviral regimens that included a protease inhibitor (PI), and the majority had a CD4+ count of >200 cells/µL for >3 months before discontinuing PCP prophylaxis (88,126--134). The median CD4+ count at the time prophylaxis was discontinued was >300 cells/µL, most had a CD4+ cell percentage of >14 %, and many patients had a sustained suppression of HIV plasma RNA levels below detection limits of the assay employed. Median follow-up was 6-- -- 19 months.

Discontinuing primary prophylaxis among these patients is recommended because prophylaxis adds limited disease prevention (i.e., for PCP, toxoplasmosis, or bacterial infections) (127,133) and because discontinuing drugs reduces pill burden, potential for drug toxicity, drug interactions, selection of drug-resistant pathogens, and cost.

Prophylaxis should be reintroduced if the CD4⁺ count decreases to <200 cells/µL (AIII).

Treatment of Disease

TMP-SMX is the treatment of choice (AI) (135,136). The dose must be adjusted for abnormal renal function. Multiple randomized clinical trials indicate that TMP-SMX is as effective as parenteral pentamidine and more effective than other regimens. Adding leucovorin to prevent myelosuppression during acute treatment is not recommended because of questionable efficacy and some evidence for a higher failure rate (DII) (137). Oral outpatient therapy of TMP-SMX is highly effective among patients with mild-to-moderate disease (AI) (136).

Mutations associated with resistance to sulfa drugs have been documented, but their effect on clinical outcome is uncertain (138--140). Patients who have PCP despite TMP-SMX prophylaxis are usually effectively treated with standard doses of TMP-SMX (BIII).

Patients with documented or suspected PCP and moderate-to-severe disease, as defined by room air pO₂ <70 mm Hg or arterial-alveolar O₂ gradient >35 mm Hg, should receive adjunctive corticosteroids as early as possible, and certainly within 72 hours after starting specific PCP therapy (AI) (141--146). If steroids are started at a later time, their benefits are unclear, although the majority of clinicians would use them in such circumstances for patients with moderate-to-severe disease (BIII). Methylprednisolone at 75% of the respective prednisone dose can be used if parenteral administration is necessary.

Alternative therapeutic regimens for mild-to-moderate disease include 1) dapsone and TMP (BI) (136,147) (this regimen might have similar efficacy and fewer side effects than TMP-SMX but is less convenient because of the number of pills), 2) primaquine plus clindamycin (BI) (148--150) (the clindamycin component can be administered intravenously for more severe cases; however, primaquine is only available orally), and 3) atovaquone suspension (BI) (135,151) (this is less effective than TMP-SMX for mild-to-moderate disease but has fewer side effects). Patients should be tested for G6PD deficiency whenever possible before administration of primaquine. Alternative therapeutic regimens for patients with moderate-to-severe disease include clindamycin-primaquine or intravenous (IV) pentamidine (AI) (150,152,153) (usually the drug of second choice for severe disease). Certain clinicians prefer IV pentamidine because of convincing data regarding its high degree of efficacy. Other clinicians prefer clindamycin-primaquine because this combination is better tolerated than pentamidine, although data regarding efficacy are not as robust as the data supporting pentamidine. Aerosolized pentamidine should not be used for the treatment of PCP because of limited efficacy and more frequent relapse (DI) (152,154,155). Trimetrexate is no longer available commercially.

The recommended duration of therapy for PCP is 21 days (AII) (91). The probability and rate of response to therapy depend on the agent used, number of previous PCP episodes, severity of illness, degree of immunodeficiency, and timing of initiation of therapy.

Although the overall prognosis of patients whose degree of hypoxemia requires intensive care unit (ICU) admission or mechanical ventilation remains poor, survival in up to 50% of patients requiring ventilatory support has been reported in recent years (156--158). Because long-term survival is possible for patients in whom ART is effective, certain patients with AIDS and severe PCP should be offered intensive care unit (ICU) admission or mechanical ventilation when appropriate (e.g., when they have reasonable functional status) (AII).

Because of the potential for additive or synergistic toxicities associated with anti-PCP and antiretroviral therapies, certain health-care providers delay initiation of ART until after the completion of anti-PCP therapy, or until at least 2 weeks after initiating anti-PCP therapy, despite some suggestion of potential benefit of early ART in the treatment of PCP (CIII) (157,159).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Careful monitoring during therapy is important to evaluate response to treatment and to detect toxicity as soon as possible. Follow-up after therapy includes assessment for early relapse, especially when therapy has been with an agent other than TMP-SMX or was shortened for toxicity. PCP prophylaxis should be initiated immediately upon completion of therapy and maintained until the CD4⁺ count is >200 cells/µL.

Adverse reaction rates among patients with AIDS are high for TMP-SMX (20%--85%) (135,136,147,149,153,161--165). Common adverse effects are rash (30%--55%) (including Stevens-Johnson syndrome), fever (30%--40%), leukopenia (30%--40%), thrombocytopenia (15%), azotemia (1%--5%), hepatitis (20%), and hyperkalemia. Supportive care for common adverse effects should be attempted before discontinuing TMP-SMX (AIII). Rashes can often be "treated through" with antihistamines, nausea can be controlled with antiemetics, and fever can be managed with antipyretics.

The most common adverse effects of alternative therapies include methemoglobinemia and hemolysis with dapsone or primaquine (especially in those with G6PD deficiency); rash and fever with dapsone (136,147); azotemia, pancreatitis, hypo- or hyperglycemia, leukopenia, electrolyte abnormalities, and cardiac dysrhythmia with pentamidine (151--153,164); anemia, rash, fever, and diarrhea with primaquine and clindamycin (136,148,149); and headache, nausea, diarrhea, rash, and transaminase elevations with atovaquone (135,163).

IRIS has been reported following PCP. Most cases have occurred within weeks of the episode of PCP. Reported cases are not sufficient to provide guidance on the optimal time to start ART following a mild or severe case of PCP (160,166).

Management of Treatment Failure

Clinical failure is defined as lack of improvement or worsening of respiratory function documented by arterial blood gases (ABGs) after at least 4--8 days of anti-PCP treatment. Treatment failure attributed to treatment-limiting toxicities occurs in up to one third of patients (136). Switching to another regimen is the appropriate management for treatment-related toxicity (BII). Failure attributed to lack of drug efficacy occurs in approximately 10% of those with mild-to-moderate disease. No convincing clinical trials exist on which to base recommendations for the management of treatment failure attributed to lack of drug efficacy. Clinicians should wait at least 4--8 days before switching therapy for lack of clinical improvement (BIII). In the absence of corticosteroid therapy, early and reversible deterioration within the first 3--5 days of therapy is typical, probably because of the inflammatory response caused by antibiotic-induced lysis of organisms in the lung. Other concomitant infections must be excluded as a cause for clinical failure (98,99); bronchoscopy with bronchoalveolar lavage should be strongly considered to evaluate for this possibility, even if it was conducted before initiating therapy.

If TMP-SMX has failed or must be avoided for toxicity in moderate-to-severe disease, the common practice is to use parenteral pentamidine or primaquine combined with clindamycin (BII) (149,153,165). As noted above, trimetrexate is no longer available commercially. For mild disease, atovaquone is a reasonable alternative (BII). Although one meta-analysis concluded that the combination of clindamycin and primaquine might be the most effective regimen for salvage therapy (150), no prospective clinical trials have evaluated the optimal approach to patients who experience a therapy failure with TMP-SMX.

Preventing Recurrence

Patients who have a history of PCP should be administered chemoprophylaxis for life (i.e., secondary prophylaxis or chronic maintenance therapy) with TMP-SMX unless immune reconstitution occurs as a result of ART (167) (AI). For patients who are intolerant of TMP-SMX, alternatives are dapsone, dapsone combined with pyrimethamine, atovaquone, or aerosolized pentamidine.

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)

Secondary prophylaxis should be discontinued for adult and adolescent patients whose CD4⁺ count has increased from <200 cells/µL to >200 cells/µL for >3 months as a result of ART (BII). Reports from observational studies (126,132,168,169) and from two randomized trials (133,170) and a combined analysis of eight European cohorts being followed prospectively (171) support this recommendation. In these studies, patients had responded to ART with an increase in CD4⁺ counts to >200 cells/µL for >3 months. The majority of patients were taking PI-containing regimens. The median CD4⁺ count at the time prophylaxis was discontinued was >300 cells/µL and most had a CD4⁺ cell percentage of >14%. The majority of patients had sustained suppression of plasma HIV RNA levels below the detection limits of the assay employed; the longest follow-up was 40 months. If the episode of PCP occurred at a CD4⁺ count of >200 cells/µL, continuing PCP prophylaxis for life, regardless of how high the CD4⁺ count rises as a consequence of ART, would be prudent (CIII); however, data regarding the most appropriate approach in this setting are limited.

Discontinuing secondary prophylaxis for patients is recommended because prophylaxis adds limited disease prevention (i.e., for PCP, toxoplasmosis, or bacterial infections) and because discontinuing drugs reduces pill burden, potential for drug toxicity, drug interactions, selection of drug-resistant pathogens, and cost.

Prophylaxis should be reintroduced if the CD4⁺ count decreases to <200 cells/µL (AIII). If PCP recurs at a CD4⁺ count of >200 cells/µL, lifelong prophylaxis should be administered (CIII).

Special Considerations During Pregnancy

PCP diagnostic considerations for pregnant women are the same as for nonpregnant women. Indications for therapy are the same as for nonpregnant women. The preferred initial therapy during pregnancy is TMP-SMX, although alternate therapies can be used if patients are unable to tolerate or are unresponsive to TMP-SMX (172) (AI). In case-control studies, trimethoprim has been associated with an increased risk for neural tube defects and cardiovascular, urinary tract, and multiple anomalies after first-trimester exposure (173--175). Epidemiologic data suggest that folic acid supplementation might reduce this risk (174,175), but no controlled studies have been done. In a small study, an increased risk for birth defects among infants born to women receiving antiretrovirals and folate antagonists, primarily trimethoprim, was reported, whereas no increase was observed among those with either antiretroviral or folate antagonist exposure alone (176). Although first-trimester exposure to trimethoprim might be related to a small increased risk for birth defects, pregnant women in their first trimester with PCP should be treated with TMP-SMX (AIII). Although folic acid supplementation of 0.4 mg/day is routinely recommended for all pregnant women (177), data do not indicate if higher levels of supplementation, such as the 4 mg/day recommended for pregnant women with a previous infant with a neural tube defect, would provide added benefit in this situation. Follow-up ultrasound to assess fetal anatomy at 18--20 weeks is recommended (BIII).

Neonatal-care providers should be informed of maternal sulfa or dapsone therapy if used near the delivery date because of the theoretical increased risk for hyperbilirubinemia and kernicterus (178).

Pentamidine is embryotoxic but not teratogenic among rats and rabbits (179). Adjunctive corticosteroid therapy should be used as indicated in nonpregnant adults (180--183) (AIII). Maternal fasting and postprandial glucose levels should be monitored closely when corticosteroids are used in the third trimester because the risk for glucose intolerance is increased.

Rates of preterm labor and preterm delivery are increased with pneumonia during pregnancy. Pregnant women with pneumonia after 20 weeks of gestation should be monitored for evidence of contractions (BII).

Chemoprophylaxis for PCP should be administered to pregnant women the same as for other adults and adolescents (AIII). TMP-SMX is the recommended prophylactic agent; dapsone is an alternative. Because of theoretical concerns regarding possible teratogenicity associated with drug exposures during the first trimester, health-care providers might withhold prophylaxis during the first trimester. In such cases, aerosolized pentamidine can be considered because of its lack of systemic absorption and the resultant lack of exposure of the developing embryo to the drug (CIII).

Toxoplasma gondii Encephalitis

Toxoplasmic encephalitis (TE) is caused by the protozoan Toxoplasma gondii. Disease appears to occur almost exclusively because of reactivation of latent tissue cysts (184--187). Primary infection occasionally is associated with acute cerebral or disseminated disease.

Epidemiology

Seroprevalence varies substantially among different communities (e.g., approximately 15% in the United States and 50%--75% in certain European countries) (187,188). In the pre-ART era, for patients with advanced immunosuppression who were seropositive for T. gondii and not receiving prophylaxis with drugs active against T. gondii, the 12-month incidence of TE was approximately 33%. The incidence of toxoplasmosis in patients who are seronegative for T. gondii is low. If well-documented cases did occur among seronegative patients, they would presumably represent either primary infection, reactivation of latent disease in patients unable to produce detectable antibody, or patients who were tested with insensitive assays. The incidence and associated mortality in Europe and the United States have decreased substantially with the initiation of ART and the broad use of prophylaxis regimens active against T. gondii (189,190).

Clinical disease is rare among patients with CD4⁺ counts >200 cells/µL. The greatest risk occurs among patients with a CD4⁺ count <50 cells/µL (184--186,190). Primary infection occurs after eating undercooked meat containing tissue cysts or ingesting oocysts that have been shed in cat feces and have sporulated in the environment (sporulation requires at least 24 hours). No transmission of the organism occurs by person-to-person contact.

Clinical Manifestations

The most common clinical presentation of T. gondii infection among patients with AIDS is focal encephalitis with headache, confusion, or motor weakness and fever (184--186). Physical examination might demonstrate focal neurological abnormalities, and in the absence of treatment, disease progression results in seizures, stupor, and coma. Retinochoroiditis, pneumonia, and evidence of other multifocal organ system involvement can be observed after dissemination of infection but are rare manifestations in this patient population. CT scan or MRI of the brain will typically show multiple contrast-enhancing lesions, often with associated edema (184,185,191--193). However, toxoplasmosis also can manifest as single lesions in the brain.

Diagnosis

HIV-infected patients with TE are almost uniformly seropositive for anti-toxoplasma immunoglobulin G (IgG) antibodies (184--186,194). The absence of IgG antibody makes a diagnosis of toxoplasmosis unlikely but not impossible. Anti-toxoplasma immunoglobulin M (IgM) antibodies are usually absent. Quantitative antibody titers are not diagnostically useful.

Definitive diagnosis of TE requires a compatible clinical syndrome; identification of one or more mass lesions by CT, MRI, or other radiographic testing; and detection of the organism in a clinical sample. For TE, this requires a brain biopsy, which is most commonly performed by a stereotactic CT-guided needle biopsy. Organisms are demonstrable with hematoxylin and eosin stains, although immunoperoxidase staining by experienced laboratories might increase sensitivity (195). Detection of T. gondii by polymerase chain reaction (PCR) in cerebrospinal fluid (CSF) has produced disappointing results; although specificity is high (96%--100%), sensitivity is low (50%) and the results usually are negative once specific anti-toxoplasma therapy has been started (196,197).

The differential diagnosis of focal neurological disease in patients with AIDS includes central nervous system (CNS) lymphoma; mycobacterial infection (especially TB); fungal infection (e.g., cryptococcosis); Chagas disease; bacterial abscess; and rarely PML, which can be distinguished on the basis of imaging studies (PML lesions typically involve white matter rather than gray matter, are noncontrast enhancing, and produce no mass effect).

The majority of clinicians rely initially on an empiric diagnosis, which can be established as an objective response, on the basis of clinical and radiographic improvement, to specific anti-T. gondii therapy in the absence of a likely alternative diagnosis. Brain biopsy is reserved for patients who fail to respond to specific therapy. In patients with contrast-enhancing mass lesions, detection of Epstein-Barr virus (EBV) by PCR in CSF is highly suggestive of CNS lymphoma (198,199). Positron emission tomography (PET) (192) or single-photon emission computed tomography (SPECT) scanning (193) might be helpful for distinguishing between TE and primary CNS lymphoma, but no imaging technique is completely specific.

Preventing Exposure

HIV-infected persons should be tested for IgG antibody to Toxoplasma soon after the diagnosis of HIV infection to detect latent infection with T. gondii (BIII).

HIV-infected persons, including those who lack IgG antibody to Toxoplasma, should be counseled regarding sources of Toxoplasma infection. To minimize risk for acquiring toxoplasmosis, HIV-infected persons should be advised not to eat raw or undercooked meat, including undercooked lamb, beef, pork, or venison (BIII). Specifically, lamb, beef, venison, and pork should be cooked to an internal temperature of 165ºF--170ºF (200); meat cooked until it is no longer pink inside usually has an internal temperature of 165ºF--170ºF and therefore, from a more practical perspective, satisfies this requirement. To minimize the risk for acquiring toxoplasmosis, HIV-infected persons should wash their hands after contact with raw meat and after gardening or other contact with soil; in addition, they should wash fruits and vegetables well before eating them raw (BIII). If the patient owns a cat, the litter box should be changed daily, preferably by an HIV-negative, nonpregnant person; alternatively, patients should wash their hands thoroughly after changing the litter box (BIII). Patients should be encouraged to keep their cats inside and not to adopt or handle stray cats (BIII). Cats should be fed only canned or dried commercial food or well-cooked table food, not raw or undercooked meats (BIII). Patients need not be advised to part with their cats or to have their cats tested for toxoplasmosis (EII).

Preventing Disease

Initiating Primary Prophylaxis

Toxoplasma-seropositive patients who have a CD4⁺ count of <100 cells/µL should be administered prophylaxis against TE (AII) (113). The double-strength tablet daily dose of TMP-SMX recommended as the preferred regimen for PCP prophylaxis also is effective against TE and is therefore recommended (AII) (113). TMP-SMX, one double-strength tablet three times weekly, is an alternative (BIII). If patients cannot tolerate TMP-SMX, the recommended alternative is dapsone-pyrimethamine plus leucovorin, which is also effective against PCP (BI) (117--119). Atovaquone with or without pyrimethamine/leucovorin also can be considered (CIII). Prophylactic monotherapy with dapsone, pyrimethamine, azithromycin, or clarithromycin cannot be recommended on the basis of available data (DII). Aerosolized pentamidine does not protect against TE and is not recommended (EI) (109,113).

Toxoplasma-seronegative persons who are not taking a PCP prophylactic regimen known to be active against TE (e.g., aerosolized pentamidine) should be retested for IgG antibody to Toxoplasma when their CD4⁺ counts decline to <100 cells/µL to determine whether they have seroconverted and are therefore at risk for TE (CIII). Patients who have seroconverted should be administered prophylaxis for TE as described previously (AII).

Discontinuing Primary Prophylaxis

Prophylaxis against TE should be discontinued among adult and adolescent patients who have responded to ART with an increase in CD4⁺ counts to >200 cells/µL for >3 months (AI). Multiple observational studies (126,132,201) and two randomized trials (127,202) have reported that primary prophylaxis can be discontinued with minimal risk for developing TE among patients who have responded to ART with an increase in CD4⁺ count from <200 cells/µL to >200 cells/µL for >3 months. In these studies, the majority of patients were taking PI-containing regimens and the median CD4⁺ count at the time prophylaxis was discontinued was >300 cells/µL. At the time prophylaxis was discontinued, the majority of patients had sustained suppression of plasma HIV RNA levels below the detection limits of available assays; the median follow-up was 7--22 months. Although patients with CD4⁺ counts of <100 cells/µL are at greatest risk for having TE, the risk for TE occurring when the CD4⁺ count has increased to 100--200 cells/µL has not been studied as rigorously as an increase to >200 cells/µL. Thus, the recommendation specifies discontinuing prophylaxis after an increase to >200 cells/µL. Discontinuing primary TE prophylaxis is recommended because prophylaxis at CD4⁺ count >200 cells/ µL adds limited disease prevention for toxoplasmosis and because discontinuing drugs reduces pill burden, potential for drug toxicity, drug interaction, selection of drug-resistant pathogens, and cost. Prophylaxis for TE should be reintroduced if the CD4⁺ count decreases to <100--200 cells/µL (AIII).

Treatment of Disease

The initial therapy of choice for TE consists of the combination of pyrimethamine plus sulfadiazine plus leucovorin (AI) (203--206). Pyrimethamine penetrates the brain parenchyma efficiently even in the absence of inflammation (207). Use of leucovorin reduces the likelihood of the hematologic toxicities associated with pyrimethamine therapy (208,209). The preferred alternative regimen for patients with TE who are unable to tolerate or who fail to respond to first-line therapy is pyrimethamine plus clindamycin plus leucovorin (AI) (203,204).

TMP-SMX was reported in a small (77 patients) randomized trial to be effective and better tolerated than pyrimethamine-sulfadiazine (210). On the basis of less in vitro activity and less experience with TMP-SMX, treatment with this drug may be considered an option (BI). For patients who cannot take an oral regimen, no well-studied options exist. No parenteral formulation of pyrimethamine exists; the only widely available parenteral sulfonamide is the sulfamethoxazole component of TMP-SMX. Certain specialists will treat severely ill patients initially requiring parenteral therapy for TE with parenteral TMP-SMX or oral pyrimethamine plus parenteral clindamycin (CIII).

The following regimens have been show to be effective in the treatment of TE in at least two nonrandomized, uncontrolled trials, although their relative efficacy compared with the previous regimens is unknown: atovaquone (with meals or oral nutritional supplements) plus either pyrimethamine plus leucovorin or sulfadiazine or, for patients intolerant of both pyrimethamine and sulfadiazine, as a single agent (BII) (211--214) (if atovaquone is used alone, clinicians should be aware that different patients experience a high variability of absorption of the drug; plasma levels of >18.5 µg/mL are associated with an improved response rate but measurements are not routinely available) (212--214); and azithromycin plus pyrimethamine plus leucovorin daily (BII) (215,216).

The following regimens have been reported to have activity in the treatment of TE in small cohorts of patients or in case reports of one or several patients: clarithromycin plus pyrimethamine (CIII) (217); 5-fluorouracil plus clindamycin (CIII) (218), dapsone plus pyrimethamine plus leucovorin (CIII) (219); and minocycline or doxycycline combined with either pyrimethamine plus leucovorin, sulfadiazine, or clarithromycin (CIII) (220,221). Although the clarithromycin dose used in the only published study was 1g twice a day, doses >500 mg have been associated with increased mortality in HIV-infected patients treated for disseminated MAC. Doses >500 mg twice a day should not be used (DIII).

Acute therapy for TE should be continued for at least 6 weeks, if there is clinical and radiologic improvement (BII) (184--187). Longer courses might be appropriate if clinical or radiologic disease is extensive or response is incomplete at 6 weeks. CNS lesions must not have contrast enhancement on CT/MRI. Adjunctive corticosteroids (e.g., dexamethasone) should be administered to patients with TE when clinically indicated only for treatment of a mass effect associated with focal lesions or associated edema (BIII). Because of the potential immunosuppressive effects of corticosteroids, they should be discontinued as soon as clinically feasible. Patients receiving corticosteroids should be monitored closely for the development of other OIs, including cytomegalovirus (CMV) retinitis and TB disease.

Anticonvulsants should be administered to patients with TE who have a history of seizures (AIII), but should not be administered as prophylactics to all patients (DIII). Anticonvulsants, if administered, should be continued at least through the period of acute therapy.

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Changes in antibody titers are not useful for monitoring responses to therapy. Patients with TE should be monitored routinely for adverse events and clinical and radiologic improvement (AIII). Common pyrimethamine toxicities include rash, nausea, and bone marrow suppression (neutropenia, anemia, and thrombocytopenia) that can often be reversed by increasing the dose of leucovorin to 50--100 mg/day administered in divided doses (CIII).

Common sulfadiazine toxicities include rash, fever, leukopenia, hepatitis, nausea, vomiting, diarrhea, and crystalluria. Common clindamycin toxicities include fever, rash, nausea, diarrhea (including pseudomembranous colitis or diarrhea related to Clostridium difficile toxin), and hepatotoxicity. Common TMP-SMX toxicities include rash, fever, leukopenia, thrombocytopenia, and hepatotoxicity. Drug interactions between anticonvulsants and antiretroviral agents should be evaluated carefully and doses adjusted according to established guidelines.

Several cases of neurologic disease have been attributed to immune reconstitution and toxoplasmosis, but more data are needed to verify that such cases are IRIS related to T. gondii (222).

Management of Treatment Failure

A brain biopsy, if not previously performed, should be strongly considered for patients who fail to respond to initial therapy for TE (BII) as defined by clinical or radiologic deterioration during the first week despite adequate therapy or lack of clinical improvement within 2 weeks. For those who undergo brain biopsy and have confirmed histopathologic evidence of TE, a switch to an alternative regimen as previously described should be considered (BIII). Recurrence of disease during secondary maintenance therapy following an initial clinical and radiographic response is unusual if patients adhere to their regimens.

Preventing Recurrence

Patients who have completed initial therapy for TE should be administered lifelong suppressive therapy (i.e., secondary prophylaxis or chronic maintenance therapy) (AI) (203,204) unless immune reconstitution occurs as a consequence of ART, in which case discontinuation of treatment is indicated. The combination of pyrimethamine plus sulfadiazine plus leucovorin is highly effective as suppressive therapy for patients with TE (AI) and provides protection against PCP (AII). Although sulfadiazine is routinely dosed as a four times a day regimen, a pharmacokinetic study suggests bioequivalence when using the same total daily dose in a twice a day or four times a day regimen (223), and limited clinical experience suggests that twice a day dosing is effective (224). A commonly used regimen as suppressive therapy for patients with TE who cannot tolerate sulfa drugs is pyrimethamine plus clindamycin (BI). Because of the high failure rate observed with lower doses (203), a dose of 600 mg clindamycin every 8 hours is recommended (CIII). However, this regimen does not provide protection against PCP (AII), and thus an additional agent (e.g., aerosol pentamidine) must be used. Atovaquone with or without pyrimethamine or sulfadiazine is also active against both TE and PCP (BII) but is substantially more expensive (121). A small uncontrolled study in patients who had been receiving ART for a median of 13 months suggested that TMP-SMX could be used as a suppressive regimen to reduce pill burden (225).

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)

Adult and adolescent patients receiving secondary prophylaxis (i.e., chronic maintenance therapy) for TE are at low risk for recurrence of TE when they have successfully completed initial therapy for TE, remain asymptomatic with regard to signs and symptoms of TE, and have a sustained increase in their CD4⁺ counts of >200 cells/µL after ART (e.g., >6 months) (132,168,202,226). Although the numbers of patients who have been evaluated in observational studies and in one randomized clinical trial remain limited, and occasional recurrences have been reported, on the basis of these observations and inference from more extensive cumulative data indicating the safety of discontinuing secondary prophylaxis for other OIs during advanced HIV disease, discontinuing chronic maintenance therapy among such patients is a reasonable consideration (BI). Certain specialists recommend obtaining an MRI of the brain as part of their evaluation to determine whether discontinuing therapy is appropriate by assessing whether the brain lesions had resolved.

Secondary prophylaxis (chronic maintenance therapy) for TE should be reintroduced if the CD4⁺ count decreases to <200 cells/µL (AIII).

Special Considerations During Pregnancy

Documentation of maternal T. gondii serologic status should be obtained during pregnancy. Indications for treatment of T. gondii during pregnancy should be based on confirmed or suspected symptomatic disease in the mother. Pediatric-care providers should be informed if the HIV-infected mother is seropositive for T. gondii infection to allow evaluation of the neonate for evidence of congenital infection. Pregnant HIV-infected women with suspected or confirmed primary T. gondii infection during pregnancy should be managed in consultation with a maternal-fetal medicine or other appropriate specialist (BIII) (227).

Treatment should be the same as in nonpregnant adults (BIII). Although pyrimethamine has been associated with birth defects in animals, limited human data have not suggested an increased risk for defects and, therefore, it can be administered to pregnant women (228--230). Pediatric providers should be notified if sulfadiazine is continued until delivery because its use might increase the risk for neonatal hyperbilirubinemia and kernicterus (230).

Although perinatal transmission of T. gondii normally occurs only with acute infection in the immunocompetent host, case reports have documented occurrences of transmission with reactivation of chronic infection in HIV-infected women with severe immunosuppression (229,231). Pregnant, HIV-infected women who have evidence of primary toxoplasmic infection or active toxoplasmosis, including TE, should be evaluated and managed during pregnancy in consultation with appropriate specialists (BIII). Because the risk for transmission with chronic infection appears low, routine evaluation of the fetus for infection with amniocentesis or cordocentesis is not indicated. Detailed ultrasound examination of the fetus specifically evaluating for hydrocephalus, cerebral calcifications, and growth restriction should be done for HIV-infected women with suspected primary or symptomatic reactivation of T. gondii during pregnancy.

TMP-SMX can be administered for primary prophylaxis against TE as described for PCP (AIII). Secondary prophylaxis should be provided using the same indications as for nonpregnant women. The risks of TMP-SMX in the first trimester, as discussed for PCP, must be balanced against the risk for recurrent TE.

Cryptosporidiosis

Epidemiology

Cryptosporidiosis is caused by various species of the protozoan parasite Cryptosporidium, which infect the small bowel mucosa, and in immunosuppressed persons, the large bowel and extra-intestinal sites. Persons at greatest risk for disease have advanced immunosuppression, typically CD4⁺ counts of <100 cells/µL (232). The three most common species infecting humans are C. hominis, C. parvum, and C. meleagridis. Infections are usually caused by one species but might be mixed (233).

In developed countries with low rates of environmental contamination where potent ART is widely available, cryptosporidiosis occurs at an incidence of <1 per 100 person-years among persons with AIDS. Infection occurs through ingestion of Cryptosporidium oocysts. Viable oocysts in feces can be transmitted directly through contact with infected humans or animals, particularly those with diarrhea. Oocysts can contaminate recreational water sources (e.g., swimming pools, lakes) and public water supplies and might persist despite standard chlorination (see Appendix: Food and Water-Related Exposures). Person-to-person transmission is common, especially among sexually active men who have sex with men (MSM). Young children with cryptosporidial diarrhea might infect adults during diapering and cleaning after defecation.

Clinical Manifestations

Patients with cryptosporidiosis most commonly have acute or subacute onset of profuse, nonbloody, watery diarrhea, accompanied often by nausea, vomiting, and lower abdominal cramping (234). Fever is present in approximately one third of patients and malabsorption is common. The epithelium of the biliary tract and the pancreatic duct can be infected with Cryptosporidium, leading to sclerosing cholangitis and to pancreatitis secondary to papillary stenosis, particularly among patients with prolonged disease and low CD4⁺ counts (235--238). Pulmonary infections also have been reported (239,240).

Diagnosis

Cryptosporidium species can be cultivated in vitro, but not as a routine diagnostic procedure. Diagnosis of cryptosporidiosis can be made by microscopic identification of the oocysts in stool or tissue. Acid-fast staining methods, with or without stool concentration, are most frequently used in clinical laboratories. Oocysts stain varying intensities of red with a modified acid-fast technique, permitting their differentiation from yeasts, which are of similar size and shape but are not acid fast. Cryptosporidium oocysts also can be detected by direct immunofluorescence, which offers the greatest sensitivity and specificity, or by enzyme-linked immunosorbent assays (ELISAs) (241). Molecular methods such as PCR are predicted to enhance sensitivity further. Cryptosporidial enteritis also can be diagnosed from small intestinal biopsy sections. The organism, which appears basophilic with hematoxylin and eosin staining, occurs alone or in clusters in various developmental stages on the brush border of the mucosal epithelial surfaces.

Among persons with profuse diarrheal illness, a single stool specimen is usually adequate for diagnosis. Among persons with milder disease, repeat stool sampling is recommended, although no controlled studies have demonstrated the utility of three consecutive stool samples as is the case in Giardia duodenalis infection.

Preventing Exposure

HIV-infected persons should be educated and counseled concerning the different ways that Cryptosporidium can be transmitted (BIII). Modes of transmission include having direct contact with infected adults, diaper-aged children, and infected animals; coming into contact with contaminated water during recreational activities; drinking contaminated water; and eating contaminated food.

Scrupulous handwashing can reduce the risk for diarrhea in HIV-infected persons, including diarrhea caused by Cryptosporidium (242). HIV-infected persons should be advised to wash their hands after potential contact with human feces (including after diapering small children) and after the following activities: handling pets or other animals, gardening or other contact with soil, before preparing food, before eating, and before and after sex (BIII). HIV-infected persons should avoid unprotected sex practices, especially practices that could lead to direct (e.g., oral-anal) or indirect (e.g., penile-anal) contact with feces. Patients should be advised to use barriers during sex to reduce such exposures (e.g., condoms, dental dams) (BIII).

HIV-infected persons (particularly those with CD4⁺ counts < 200 cells/µL), should avoid direct contact with diarrhea or stool from pets, particularly any stray pets, or dogs and cats aged <6 months (BIII). Gloves should be worn when handling feces or cleaning areas that might have been contaminated by feces from pets (BIII). HIV-infected persons should limit or avoid direct exposure to calves and lambs (e.g., farms, petting zoos) (BII). Paying attention to hygiene and avoiding direct contact with stool are important when visiting premises where these animals are housed or exhibited.

HIV-infected persons should not drink water directly from lakes or rivers (AIII). Waterborne infection also can result from swallowing water during recreational activities. HIV-infected persons should be aware that lakes, rivers, and salt water beaches and some swimming pools, recreational water parks, and ornamental water fountains might be contaminated with human or animal waste that contains Cryptosporidium. They should avoid swimming in water that is likely contaminated and should avoid swallowing water while swimming or playing in recreational water (BIII).

Outbreaks of cryptosporidiosis have been linked to drinking water from municipal water supplies. During outbreaks or in other situations that impose a community advisory to boil water, boiling water for at least 3 minutes will eliminate the risk for cryptosporidiosis (AIII). Using submicron personal-use water filters (home/office types) or bottled water might also reduce the risk for infection from municipal and well water (CIII).

The magnitude of the risk for acquiring cryptosporidiosis from drinking water in a non-outbreak setting is uncertain, and available data are inadequate to recommend that all HIV-infected persons boil water or avoid drinking tap water in non-outbreak settings. However, HIV-infected persons who wish to take independent action to reduce the risk for waterborne cryptosporidiosis might take precautions similar to those recommended during outbreaks. Persons who opt to use a personal-use filter or bottled water should be aware of the complexities involved in selecting appropriate products, the lack of enforceable standards for the destruction or removal of oocysts, the costs of the products, and the logistic difficulty of using these products consistently.

Persons who take precautions to avoid acquiring cryptosporidiosis from drinking water should be advised that ice made from contaminated tap water also can be a source of infection. Such persons also should be aware that fountain beverages served in restaurants, bars, theaters, and other places also might pose a risk because these beverages, and the ice they contain, are usually made from tap water. Nationally distributed brands of bottled or canned carbonated soft drinks are safe to drink. Commercially packaged noncarbonated soft drinks and fruit juices that do not require refrigeration until after they are opened (i.e., can be stored unrefrigerated on grocery shelves) are also safe. Nationally distributed brands of frozen fruit juice concentrate are safe if the user reconstitutes them with water from a safe water source. Fruit juices that must be kept refrigerated from the time they are processed to the time of consumption might be either fresh (i.e., unpasteurized) or heat-treated (i.e., pasteurized); only those juices labeled as pasteurized should be considered free of risk from Cryptosporidium. Other pasteurized beverages and beers also are considered safe to drink.

HIV-infected persons should avoid eating raw oysters because cryptosporidial oocysts can survive in oysters for >2 months and have been found in oysters taken from certain commercial oyster beds (BIII). In a hospital, standard precautions (i.e., use of gloves and handwashing after removal of gloves) should be sufficient to prevent transmission of cryptosporidiosis from an infected patient to a susceptible HIV-infected person (BIII). However, because of the potential for fomite transmission, some specialists recommend that HIV-infected persons, specifically persons who are severely immunocompromised, should not share a room with a patient with cryptosporidiosis (CIII).

If HIV-infected persons travel in developing countries, they should be warned to avoid drinking tap water or using tap water to brush their teeth (BIII). Ice that is not made from bottled water also should be avoided. Raw fruits or vegetables that might have been washed in tap water also should be avoided (BIII). HIV-infected persons also should avoid other sources of Cryptosporidium oocytes as much as possible (BIII). These include working directly with people with diarrhea; with farm animals, cattle, and sheep; and with domestic pets that are very young or have diarrhea. If exposure is unavoidable, then the use of gloves and good hand hygiene is recommended.

Preventing Disease

Because chronic cryptosporidiosis occurs primarily in persons with advanced immunodeficiency, appropriate initiation of ART before the patient becomes severely immunosuppressed should prevent this disease (AIII). Rifabutin (RIF) or clarithromycin, when taken for MAC prophylaxis, have been found to protect against cryptosporidiosis (243,244). However, data are insufficient to warrant a recommendation for using rifabutin or clarithromycin as chemoprophylaxis for cryptosporidiosis.

Treatment of Disease

In the setting of severe immunosuppression, ART with immune restoration to a CD4⁺ count >100 cells/µL leads to resolution of clinical cryptosporidiosis (50,245) and is the mainstay of treatment. Therefore, patients with cryptosporidiosis should be offered ART as part of the initial management of their infection (AII). Management should include symptomatic treatment of diarrhea (AIII). Rehydration and repletion of electrolyte losses by either the oral or IV route are important. Severe diarrhea can exceed >10 L/day among patients with AIDS, often requiring intensive support. Oral rehydration should be pursued aggressively with oral rehydration solutions (AIII).

Multiple agents have been investigated in small randomized controlled clinical trials of HIV-infected adults, including nitazoxanide, paromomycin, spiramycin, bovine hyperimmune colostrum, and bovine dialyzable leukocyte extract. No pharmacologic or immunologic therapy directed specifically against C. parvum has been shown to be consistently effective when used without ART (246,247).

Nitazoxanide is an orally administered nitrothiazole benzamide with in vivo activity against a broad range of helminths, bacteria, and protozoa (248--250). It has been approved by the Food and Drug Administration (FDA) for treatment of C. parvum in children and adults. When administered for 3 days at 500 mg twice daily to HIV-uninfected adults with cryptosporidiosis, nitazoxanide resulted in higher rates of diarrhea resolution and oocyst-free stools than placebo (248). HIV-infected adults with cryptosporidiosis with CD4⁺ >50 cells/µL treated with 500--1,000 mg twice daily of nitazoxanide for 14 days experienced substantially higher rates of parasitological cure and resolution of diarrhea than persons receiving placebo treatment (249). Data from a compassionate use program before the advent of combination ART, which included primarily white male adults with a median CD4⁺ count <50 cells/µL, reported that a majority of patients experienced some degree of clinical response (reduction in frequency of total stool and of liquid stools), usually within the first week of treatment (251). Adverse events associated with nitazoxanide are limited and typically mild, and no important drug-drug interactions have been reported. Because of the clinical significance of cryptosporidiosis, a trial of nitazoxanide in conjunction with ART, but never instead of ART, may be considered (CIII).

Paromomycin is a nonabsorbable aminoglycoside indicated for the treatment of intestinal amebiasis but not specifically approved for cryptosporidiosis. It is effective in high doses for the treatment of cryptosporidiosis in animal models (252). A meta-analysis of 11 published studies of paromomycin in humans reported a response rate of 67%; however, relapses were common, with long-term success rates of only 33%. A Cochrane review and a meta-analysis of the two randomized controlled trials comparing paromomycin with placebo among patients with AIDS found the drug was no more effective than placebo at reducing diarrheal frequency or parasite burden (246,247,253,254). In persons with CD4⁺ counts <100 cells/µL, a substantial clinical response to paromomycin is rare. Therefore, data do not support a recommendation for the use of paromomycin for cryptosporidiosis (DII).

Treatment with antimotility agents (e.g., loperamide, tincture of opium) can palliate symptoms by reducing diarrheal frequency and volume, but these agents are not consistently effective (BIII). Octreotide, a synthetic octapeptide analog of naturally occurring somatostatin that is approved for the treatment of secreting tumor-induced diarrhea, is no more effective than other oral antidiarrheal agents and is usually not recommended (DII) (250).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Patients should be monitored closely for signs and symptoms of volume depletion, electrolyte and weight loss, and malnutrition. Total parenteral nutrition might be indicated in certain patients (CIII).

IRIS has not been described in association with treatment of cryptosporidiosis.

Management of Treatment Failure

Supportive treatment and optimizing ART to achieve full virologic suppression are the only feasible approaches to the management of treatment failure (AIII).

Preventing Recurrence

No pharmacologic interventions are known to be effective in preventing the recurrence of cryptosporidiosis.

Special Considerations During Pregnancy

As with nonpregnant women, initial treatment should rely on rehydration and initiation of ART (AII). Pregnancy should not preclude the use of ART. Nitazoxanide is not teratogenic in animals but human data on use in pregnancy are not available. Nitazoxanide may be used in pregnancy after the first trimester in severely symptomatic pregnant women (CIII).

Microsporidiosis

Epidemiology

Microsporidia are protists related to fungi, defined by the presence of a unique invasive organelle consisting of a single polar tube that coils around the interior of the spore (255,256). They are ubiquitous organisms and are likely zoonotic and/or waterborne in origin (257,258). The microsporidia reported as pathogens in humans include Encephalitozoon cuniculi, Encephalitozoon hellem, Encephalitozoon (syn Septata) intestinalis, Enterocytozoon bieneusi, Trachipleistophora hominis, Trachipleistophora anthropophthera, Pleistophora species, P. ronneafiei, Vittaforma (syn Nosema) corneae, Microsporidium sp., Nosema ocularum, Anncaliia (syns Brachiola/Nosema) connori, Anncaliia (syn Brachiola) vesicularum, and Anncaliia (syns Brachiola/Nosema) algerae (255--257,259--262). In the pre-ART era, reported prevalence rates of microsporidiosis varied between 2% and 70% among HIV-infected patients with diarrhea, depending on the diagnostic techniques employed and the patient population described (255--257,259). The incidence of microsporidiosis has declined with the widespread use of effective ART, but is still being detected in HIV-infected persons unable to access or continue with ART. Among non-HIV-infected persons, microsporidiosis is being increasingly recognized in children, travelers, organ transplant recipients, and the elderly. In the immunosuppressed host, clinical signs related to microsporidiosis are most commonly observed when the CD4⁺ count is <100 cells/µL (255-257,259).

Clinical Manifestations

The most common manifestation of microsporidiosis is gastrointestinal tract infection with diarrhea; however, encephalitis, ocular infection, sinusitis, myositis, and disseminated infection also are described (255--257,259).

Clinical syndromes can vary by infecting species. E. bieneusi is associated with malabsorption, diarrhea, and cholangitis. E. cuniculi is associated with hepatitis, encephalitis, and disseminated disease. E. intestinalis is associated with diarrhea, disseminated infection, and superficial keratoconjunctivitis. E. hellem is associated with superficial keratoconjunctivitis, sinusitis, respiratory disease, prostatic abscesses, and disseminated infection. Nosema, Vittaforma, and Microsporidium are associated with stromal keratitis following trauma in immunocompetent hosts. Pleistophora, Anncaliia, and Trachipleistophora are associated with myositis. Trachipleistophora is associated with encephalitis and disseminated disease.

Diagnosis

Although microsporidia belonging to the genera Encephalitozoon, Anncaliia, Vittaforma, and Trachipleistophora have been cultivated in vitro, E. bieneusi has not been successfully cultivated in vitro. Effective morphologic demonstration of microsporidia by light microscopy can be accomplished by staining methods that produce differential contrast between the spores of the microsporidia and the cells and debris in clinical samples (e.g., stool). In addition, because of the small size of the spores (1--5 mm), adequate magnification (e.g., 1,000X) is required for visualization. Chromotrope 2R, calcofluor white (a fluorescent brightener), and Uvitex 2B (a fluorescent brightener) are useful as selective stains for microsporidia in stool and other body fluids (262).

In biopsy specimens, microsporidia can be visualized with Giemsa, tissue Gram stains (Brown-Hopps Gram stain), calcofluor white or Uvitex 2B (fluorescent brighteners) staining, Warthin-Starry silver staining, hematoxylin and eosin, or Chromotrope 2A (262). In gastrointestinal disease, examination of three stools with chromotrope and chemofluorescent stains is often sufficient for diagnosis. If stool examination is negative and microsporidiosis is suspected, a small bowel biopsy should be performed. If the etiologic agent is Encephalitozoon or Trachipleistophora spp., examination of urine often also reveals the organism. Determination of the species of microsporidia causing disease can be made by the morphology of the organism demonstrated by transmission electron microscopy, by staining with species-specific antibodies, or by PCR using species- or genus-specific primers (262). Assistance of specialists familiar with the species differentiation of microsporidia should be sought.

Preventing Exposure

Patients with AIDS (e.g., CD4⁺ count <200 cells/µL) should avoid untreated water sources (AIII). Otherwise, other than general attention to handwashing and other personal hygiene measures, no precautions to reduce exposure to microsporidia are recommended.

Preventing Disease

No chemoprophylactic regimens are known to be effective in preventing microsporidiosis.

Treatment of Disease

ART with immune restoration (an increase of CD4⁺ count to >100 cells/µL) is associated with resolution of symptoms of enteric microsporidiosis, including that caused by E. bieneusi (245,263-265). All patients should be offered ART as part of the initial management of microsporidial infection (AII). Data suggest that following successful ART, immune reconstitution occurs and enables the patient's own defenses to eradicate microsporidia (245,264).

No specific therapeutic agent is available for E. bieneusi infection. A controlled clinical trial suggested that E. bieneusi might respond to oral fumagillin (60 mg/day), a water-insoluble antibiotic made by Aspergillus fumigatus (BII) (266,267), or to its synthetic analog TNP-470 (BIII) (268). However, fumagillin and TNP-470 are not available for systemic use in the United States. One report indicated that treatment with nitazoxanide for 60 days might resolve chronic diarrhea caused by E. bieneusi in the absence of ART (269); however, the effect appeared to be minimal among patients with low CD4⁺ counts. Therefore, this drug cannot be recommended with confidence (CIII).

Albendazole, a benzimidazole that binds to β-tubulin, has activity against many species of microsporidia, but it is not effective against Enterocytozoon infections or V. corneae. The tubulin genes of both E. bieneusi (270) and V. corneae (271) have amino acid residues associated with albendazole resistance. Therefore, albendazole is recommended for initial therapy of intestinal and disseminated microsporidiosis caused by microsporidia other than E. bieneusi and V. corneae (AII) (272--274).

Itraconazole might be useful in disseminated disease when combined with albendazole, especially in infections caused by Trachipleistophora or Anncaliia (CIII).

Ocular infections caused by microsporidia should be treated with topical Fumidil B (fumagillin bicylohexylammonium) in saline (to achieve a concentration of 70 µg/mL of fumagillin) (BII) (273). Topical fumagillin is the only formulation available for treatment in the United States and is investigational. Although clearance of microsporidia from the eye can be demonstrated, the organism often is still present systemically and can be detected in urine or in nasal smears. Therefore, the use of albendazole as a companion systemic agent to fumagillin is recommended in ocular infections (BIII).

Metronidazole and atovaquone are not active in vitro or in animal models and should not be used to treat microsporidiosis (DII). Fluid support should be offered if diarrhea has resulted in dehydration (AIII). Patients with malnutrition and wasting should be treated with nutritional supplementation (AIII). Antimotility agents can be used if required for diarrhea control (BIII).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Albendazole side effects are rare but hypersensitivity (rash, pruritis, fever), neutropenia (reversible), CNS effects (dizziness, headache), gastrointestinal disturbances (abdominal pain, diarrhea, nausea, vomiting), hair loss (reversible), and elevated hepatic enzymes (reversible) have been reported. Albendazole is not known to be carcinogenic or mutagenic. Topical fumagillin has not been associated with substantial side effects. Oral fumagillin has been associated with thrombocytopenia, which is reversible on stopping the drug.

An IRIS has not been described in association with treatment for E. bieneusi or non-E. bieneusi microsporidiosis.

Management of Treatment Failure

Supportive treatment and optimizing ART to attempt to achieve full virologic suppression are the only feasible approaches to the management of treatment failure (AIII).

Preventing Recurrence

Treatment for ocular microsporidiosis should be continued indefinitely because recurrence or relapse might follow discontinuation of treatment (BIII). Whether treatment of other manifestations can be safely discontinued after immune restoration with ART is unknown; however, such a practice is reasonable, based on experience with discontinuation of secondary prophylaxis (chronic maintenance therapy) for other OIs present during advanced HIV disease. Therefore, certain specialists recommend discontinuing chronic maintenance therapy if patients no longer have signs and symptoms of microsporidiosis and have a sustained (e.g., >6 months) increase in their CD4⁺ counts to levels >200 cells/µL after ART (BIII) (245).

Special Considerations During Pregnancy

The primary approach to treatment of microsporidiosis in pregnancy should be initiation of ART to restore immune function. Among animals (i.e., rats and rabbits), albendazole is embryotoxic and teratogenic at dosages of 20 mg/kg body weight. Therefore, albendazole is not recommended for use among pregnant women (DIII). However, well-controlled studies in human pregnancy have not been performed. Systemic fumagillin has been associated with increased resorption and growth retardation in rats. No data on use in human pregnancy are available. However, because of the antiangiogenic effect of fumagillin, this drug should not be used among pregnant women (EIII). Topical fumagillin has not been associated with embryotoxic or teratogenic effects among pregnant women and may be considered when therapy with this agent is appropriate (CIII).

Mycobacterium tuberculosis Infection and Disease

Epidemiology

The World Health Organization (WHO) estimates that TB is the cause of death for 13% of persons with AIDS (275). TB infection occurs when a susceptible person inhales droplet nuclei containing Mycobacterium tuberculosis organisms, generated when persons with pulmonary or laryngeal TB disease cough, sneeze, shout, or sing (276). Usually within 2--12 weeks after infection, the immune response limits multiplication of tubercle bacilli. However, viable bacilli persist for years, a condition referred to as latent TB infection (LTBI). Persons with LTBI are asymptomatic and are not infectious. TB disease can develop immediately after exposure (primary disease) or after reactivation of LTBI (reactivation disease). Primary disease accounts for one third or more of cases of TB disease in HIV-infected populations (277).

Overall case rates of TB in the United States are declining, with 4.4 new cases of TB disease per 100,000 population (a total of 13,299 cases) reported in 2007 (278) and an estimated 4.0% prevalence of LTBI in the general population (279). Similarly, health-care--associated outbreaks of TB are now uncommon in the United States, partly because of improved public health and hospital TB-control programs (280). The percentage of patients with TB and with known HIV infection also decreased from 15.0% in 2003 to 12.4% in 2006, although the percentage of TB cases with unknown HIV status increased from 28.7% in 2005 to 31.7% in 2006 (281), which might reflect either a lack of HIV testing or incomplete reporting of HIV test results (278).

The estimated annual risk for active TB among persons with LTBI in the general population is 12.9 per 1,000 person-years of observation. In contrast, rates of progression to active TB among HIV-infected persons with LTBI have ranged from 35 to 162 per 1,000 person-years of observation (282--284). Unlike other AIDS-related OIs, CD4⁺ count is not a reliable predictor of increased risk for TB disease in HIV-infected persons. In both TB-endemic and non-TB-endemic areas, patients can have relatively high CD4⁺ counts at the time HIV-related TB disease develops. As with HIV-uninfected persons, HIV-infected persons who live or work in high-risk congregate settings such as correctional facilities, health-care facilities, drug-treatment units, or homeless shelters are at increased risk for acquiring TB.

Clinical Manifestations

Persons with LTBI are, by definition, asymptomatic. Among HIV-infected persons, the presentation of active TB disease is influenced by the degree of immunodeficiency (285,286). In addition, early after initiating ART in severely immunosuppressed patients, previously unrecognized subclinical TB can be unmasked by reconstitution of the immune system (287,288).

In HIV-infected patients without pronounced immunodeficiency (e.g., CD4⁺ count >350 cells/µL), HIV-related TB clinically resembles TB among HIV-uninfected persons. The majority of patients have disease limited to the lungs, and common chest radiographic manifestations include upper lobe fibronodular infiltrates with or without cavitation (289). However, extrapulmonary disease is more common in HIV-infected persons than in HIV-uninfected persons, regardless of CD4⁺ counts, although clinical manifestations are not substantially different from those described in HIV-uninfected persons. TB must be ruled out in diseases of every organ (290) but especially those related to CNS or meningeal symptoms in which early TB treatment is essential to improve outcomes (291,292).

In advanced HIV disease, the chest radiographic findings of pulmonary TB are markedly different compared with those among patients with less severe immunosuppression. Lower lobe, middle lobe, interstitial, and miliary infiltrates are common and cavitation is less common (285,289,293). Marked mediastinal lymphadenopathy also can be found. Even with normal chest radiographs, patients with HIV infection and pulmonary TB might have acid fast bacilli (AFB)-positive sputum smear and culture results.

With increasing degrees of immunodeficiency, extrapulmonary TB (e.g., lymphadenitis, pleuritis, pericarditis, and meningitis), with or without pulmonary involvement, is more common, and found in the majority of TB patients with CD4⁺ counts <200 cells/µL. Among such patients, TB can be a severe systemic disease with high fevers, rapid progression, and sepsis syndrome.

Histopathologic findings also are affected by the degree of immunodeficiency. Patients with relatively intact immune function have typical granulomatous inflammation associated with TB disease. With progressive immunodeficiency, granulomas become poorly formed or can be completely absent (286).

In severely immunodeficient patients with a high mycobacterial load, TB disease may be subclinical or oligo-symptomatic. After initiation of ART, immune reconstitution might unmask active TB, resulting in pronounced inflammatory reactions at the sites of infection (294--298). This type of IRIS can manifest as early as 7 days after starting ART. Signs and symptoms include fever; weight loss; and signs of local inflammatory reactions such as lymphadenitis, pulmonary consolidation, infiltrates, nodules, and effusions. Histologically, a vigorous granulomatous reaction, with or without caseation, but with suppuration, necrotising inflammation, and AFB might be evident; cultures of this material are almost invariably positive for M. tuberculosis.

Diagnosis

Diagnosis of Latent Tuberculosis Infection (LTBI)

All persons should be tested for LTBI at the time of HIV diagnosis regardless of their TB risk category (AII). Persons with negative diagnostic tests for LTBI, advanced HIV infection (CD4⁺ count <200 cells/µL), and without indications for initiating empiric LTBI treatment should be re-tested for LTBI once they start ART and attain a CD4⁺ count >200 cells/µL (AIII). In general, annual testing for LTBI is recommended for HIV-infected persons who are or remain in a "high-risk" category for repeated or ongoing exposure to persons with active TB, i.e., persons who are or who have been incarcerated, live in congregate settings, are active drug users, or have other sociodemographic risk factors for TB (AIII). All HIV-infected persons with a positive diagnostic test for LTBI should undergo chest radiography and clinical evaluation to rule out active TB (AI).

Diagnosis of LTBI can be accomplished with one of two approaches. The tuberculin skin test (TST), placed by the Mantoux method, is considered positive in HIV-infected persons if induration of >5 mm is demonstrated 48--72 hours after the intradermal placement of 0.1 mL purified protein derivative (PPD). Recently, new in vitro assays that detect IFN-γ release in response to M. tuberculosis-specific peptides have been developed for diagnosing LTBI (299). Given the high risk for progression to active disease in HIV-infected persons, any HIV-infected person with reactivity on any of the current LTBI diagnostic tests should be considered infected with M. tuberculosis (Figure 1) (300).

Evidence suggests that the IGRAs have more consistent and higher specificity (92%--97%) compared with TST (56%--95%), better correlation with surrogate measures of exposure to M. tuberculosis, and less cross reactivity because of Bacillus Calmette-Guérin (BCG) vaccination or other nontuberculous mycobacteria exposure than the TST (299,301). Three IGRAs are FDA-approved and available in the United States: the QuantiFERON®-TB Gold and the QuantiFERON®-TB Gold In-Tube (Cellestis Limited), and the TSPOT™.TB test (Oxford Immunotec) is awaiting final FDA approval (Table 10). For both the TST and IGRAs, however, HIV-related immunosuppression might be associated with false-negative results (302). The frequency of false-negative and indeterminate IGRA results increases with advancing immunodeficiency (303,304).

Results from comparative studies of TST and IGRAs in HIV-infected patients indicate that concordance between the tests is not complete (305,306). The TST remains useful for diagnosing LTBI, particularly for patients who have not been vaccinated for BCG and in settings with cost constraints. The optimal application of IGRAs in HIV-infected persons will be better defined when the results of ongoing studies become available (301). IGRAs might be used in combination with TST to improve sensitivity and specificity for detection of LTBI (301).

Fibrotic lesions consistent with TB might be incidentally noted on a chest radiograph obtained for other reasons. Persons with fibrotic lesions should undergo diagnostic testing for LTBI and be evaluated for active disease. Unless the patient has a known history of prior adequate treatment for active TB, sputum samples for AFB smear and culture should be obtained even if the patient is asymptomatic. HIV-infected persons with CD4⁺ counts <200 cells/µL who have fibrotic lesions consistent with TB on a chest radiograph and no prior history of treatment should be considered as having M. tuberculosis infection irrespective of the results of LTBI diagnostic tests. In situations with moderate-to-high suspicion of active TB regardless of the results of LTBI tests, empiric treatment for active TB should be initiated while awaiting the results of further diagnostic tests (AII).

Diagnosis of Active Tuberculosis

The evaluation of suspected HIV-related TB should include a chest radiograph regardless of the possible anatomic site of disease. Sputum samples for AFB smear and culture should be obtained from patients with pulmonary symptoms and chest radiographic abnormalities. A normal chest radiograph does not exclude the possibility of active pulmonary TB and when suspicion for disease is high, sputum samples should still be obtained (289,307). Obtaining three unique specimens, preferably in the morning of different days, increases the yield for both smear and culture (308). TST and IGRAs should not be relied upon for the diagnosis of TB disease. Approximately one fourth of HIV-infected persons with pulmonary TB disease have false-negative results (301).

HIV serostatus does not affect the yield from sputum smear and culture examinations; positive smear results are more common in cavitary pulmonary disease (309). The yield of AFB smear and culture of specimens from extrapulmonary sites is greater among patients with advanced immunodeficiency compared with HIV-uninfected adults (310-312). Nucleic acid amplification (NAA) tests, also called "direct amplification tests," can be applied directly to clinical specimens such as sputum and help to evaluate persons with a positive AFB smear. A positive NAA result in an AFB smear-positive patient likely reflects active TB. In persons with AFB smear-negative sputum or extrapulmonary disease, however, NAA tests have lower sensitivity and negative predictive value and should be used and interpreted with caution (299).

For patients with signs of extrapulmonary TB, needle aspiration or tissue biopsy of skin lesions, lymph nodes, or pleural or pericardial fluid should be performed. Mycobacterial blood cultures might be helpful for patients with signs of disseminated disease or worsening immunodeficiency.

A positive AFB smear result in any specimen (sputum, needle aspirate, tissue biopsy) represents some form of mycobacterial disease but does not always represent TB. Because TB is the most virulent mycobacterial pathogen and can be spread from person to person, patients with smear-positive results should be considered to have TB disease until definitive mycobacterial species identification is made. Automated liquid media culture systems might indicate growth of M. tuberculosis within 1--3 weeks compared with 3--8 weeks in solid media.

Drug-susceptibility testing and adjustment of the treatment regimen based on results are critical to the successful treatment of patients with TB and to curbing transmission of drug-resistant M. tuberculosis. For all patients with TB disease, testing for susceptibility to first-line agents (isoniazid [INH], rifampin [RIF], ethambutol [EMB], and pyrazinamide [PZA]) should be performed, regardless of the source of the specimen. Drug susceptibility tests should be repeated if sputum cultures remain positive for M. tuberculosis after 3 months of treatment or become positive after 1 month or longer of negative cultures (308). Second-line drug susceptibility testing should be performed only in reference laboratories and should be limited to specimens from patients who 1) have had previous therapy, 2) are contacts of patients with drug-resistant TB disease, 3) have demonstrated resistance to RIF or to other first-line drugs, 4) have positive cultures after 3 months of treatment, or, 5) are from regions with a high prevalence of multiple drug-resistant (MDR) or extensively drug-resistant (XDR) TB (313).

Molecular beacons, phage-based assays, and line probe assays are three methods for rapidly detecting the presence of drug resistance, specifically to INH and RIF. These assays are expensive, require sophisticated laboratory support, need further study, and are not yet FDA-approved for use in the United States. Published results on the performance of the two assays suitable for direct use on samples, the INNO-LiPA Rif.TB kit (Innogenetics, Gent, Belgium) and FASTPlaque-TB (Biotec Laboratories Ltd., Ipswich, United Kingdom), have been inconsistent. Until results of ongoing validation and field testing of these rapid tests are available, conventional laboratory methods for culture and susceptibility testing should be pursued on all suspect clinical specimens.

Preventing Exposure

HIV-infected persons should be advised that time spent in congregate settings or other environments identified as possible sites of TB transmission (e.g., correctional facilities, homeless shelters, nursing homes) might increase the likelihood of contracting M. tuberculosis infection (BIII) (277). Factors known to increase contagiousness include anatomical site of TB disease (pulmonary or laryngeal), AFB smear-positive sputum, cavities evident on chest radiograph, and aerosolization by coughing or singing. HIV-infected patients who have pulmonary or laryngeal TB are, on average, as contagious as patients who are not HIV-infected. Exposure to patients with known TB, but who have AFB smear-negative sputum results, poses a lower but not nonexistent risk for M. tuberculosis transmission (276,314).

In health-care facilities and other environments with a high risk for transmission, all patients with known or presumed infectious TB should be physically separated from other patients, but especially from those with HIV infection (AII) (276). A patient with infectious TB returning to a congregate living setting or to any setting in which susceptible persons might be exposed should be receiving or should have completed treatment and have three consecutive negative AFB smear results from good quality sputum samples collected >8 hours apart (with one specimen collected during the early morning), be on adequate treatment for >2 weeks, and demonstrate clinical improvement before being considered noninfectious (AIII) (276,280,315). Certain specialists recommend that patients with MDR-TB have a negative sputum culture before returning to a congregate setting.

Treatment of LTBI is effective in reducing TB incidence among populations who reside in areas of low, medium, and high TB transmission (316--318). All possible strategies should be pursued to ensure that HIV-infected persons with risk factors for TB are tested for M. tuberculosis infection and those with LTBI receive and complete a course of LTBI treatment (AII) (319). Persons infected with HIV should be treated presumptively for LTBI when the history of TB exposure is substantial, regardless of the results of diagnostic testing for LTBI (BII) (276,282,283). Use of BCG vaccine is not recommended as a means to control TB in the United States because of the unproven efficacy of the vaccine in the U.S. population and the success of other measures in reducing TB incidence (319). BCG vaccination for HIV-infected persons is contraindicated because of its potential to cause disseminated disease (EII).

Preventing Disease (Treatment of LTBI)

All HIV-infected persons with suspected LTBI or who have symptoms indicating TB should promptly undergo chest radiography and clinical evaluation to rule out active TB regardless of the results of diagnostic tests for LTBI (320).

HIV-infected persons, regardless of age, should be treated for LTBI if they have no evidence of active TB and exhibit the following characteristics: 1) a positive diagnostic test for LTBI and no prior history of treatment for active or latent TB (AI); 2) a negative diagnostic test for LTBI but are close contacts of persons with infectious pulmonary TB (AII); and 3) a history of untreated or inadequately treated healed TB (i.e., old fibrotic lesions on chest radiography) regardless of diagnostic tests for LTBI (AII) (321).

The efficacy of LTBI treatment has not been documented for HIV-infected persons with negative diagnostic tests for LTBI without known exposure to M. tuberculosis. Persons from groups or geographic areas with a high prevalence of M. tuberculosis infection might be at increased risk for primary or reactivation TB and, in this situation, decisions to treat for LTBI must include consideration of CD4⁺ count and other factors (BIII) (282,283,320).

Treatment options for LTBI include INH daily (AII) or twice weekly (BII) for 9 months (282,283,322). Results from a randomized clinical trial comparing INH daily therapy for 9 months with 12 doses of once-weekly INH-rifapentine are pending (323). Because of an increased risk for fatal and severe hepatotoxicity, a 2-month regimen of daily RIF and PZA is not recommended for LTBI treatment regardless of HIV status (DI) (277). HIV-infected persons receiving INH should receive pyridoxine (BIII) to minimize the risk for developing peripheral neuropathy. Alternatives for persons who cannot take INH or who have been exposed to a known INH-resistant index patient include either RIF or rifabutin alone for 4 months (BIII). Decisions to use a regimen containing either RIF or rifabutin should be made after considering potential drug interactions (see the section on ART in the Management of TB Disease). For persons exposed to INH- and/or RIF-resistant TB, decisions to treat with one or two drugs other than INH, RIF, or rifabutin should be based on the relative risk for exposure to organisms broadly resistant to other antimycobacterial drugs and should be made in consultation with public health authorities (AII). Directly observed therapy (DOT) should be used with intermittent dosing regimens (AI) when otherwise feasible to maximize regimen-completion rates (282,283).

No evidence suggests that LTBI treatment should be continued beyond the recommended duration in persons with HIV infection. Therefore, LTBI treatment should be discontinued after completing the appropriate number of doses (AII).

Treatment of Disease

Considering the variability of yield from smear microscopy and NAA tests, empiric treatment should be initiated and continued in HIV-infected persons in whom TB is suspected until all diagnostic work-up (smears, cultures, or other identification results) is complete (AII). When active TB is diagnosed or suspected, a multi-drug anti-TB treatment regimen should be started immediately (AI). This approach promotes rapid killing of tubercle bacilli, prevents the emergence of drug resistance, and decreases the period of contagion (48). DOT is recommended for all patients with HIV-related TB (AII). Likelihood of treatment success is further enhanced by DOT with support for other social and medical needs of HIV-infected patients (BII) (enhanced DOT) (48). A treatment plan should be based on completion of the total number of recommended doses ingested rather than the duration of treatment administration (AIII) (277). The following text summarizes both duration-based and total number-based dosing recommendations.

Recommendations for anti-TB treatment regimens in HIV-infected adults follow the same principles as for adults without HIV infection (AI) (48). Treatment of drug-susceptible TB disease should include a 6-month regimen with an initial phase of INH, RIF or rifabutin, PZA, and EMB administered for 2 months, followed by INH and RIF (or rifabutin) for 4 additional months (AI). When drug-susceptibility testing confirms the absence of resistance to INH, RIF, and PZA, EMB may be discontinued before 2 months of treatment have been completed (AI) (277). For patients with cavitary lung disease and cultures positive for M. tuberculosis after completion of 2 months of therapy, treatment should be extended with INH and RIF for an additional 3 months for a total of 9 months (AII). All HIV-infected patients treated with INH should receive pyridoxine supplementation (BIII). For patients with extrapulmonary TB, a 6- to 9-month regimen (2 months of INH, RIF, PZA, and EMB followed by 4--7 months of INH and RIF) is recommended (AII). Exceptions to the recommendation for a 6- to 9-month regimen for extrapulmonary TB include CNS disease (tuberculoma or meningitis) and bone and joint TB, for which many experts recommend 9--12 months (AII) (277). Adjuvant corticosteroids should be added when treating CNS and pericardial disease (AII). Treatment with corticosteroids should be started intravenously as early as possible with change to oral therapy individualized according to clinical improvement (Table 3). Recommended corticosteroid regimens are dexamethasone 0.3--0.4 mg/kg tapered over 6--8 weeks (324) or prednisone 1 mg/kg for 3 weeks, then tapered for 3--5 weeks.

The optimal way to prevent relapse has not been determined. How the CD4⁺ count relates to likelihood of treatment failure and relapse remains uncertain. Some recent observational studies suggest that 9 months of therapy result in a lower rate of relapse than shorter or 6-month anti-TB regimens (325--327). While awaiting definitive results of randomized comparisons of treatment duration in HIV-infected patients with TB disease, 6 months of therapy are probably adequate for the majority of patients, but prolonged therapy (up to 9 months) is recommended (as in HIV-uninfected patients) for patients with a delayed response to therapy, with cavitary disease on chest radiograph, and for those with extrapulmonary or CNS disease (BII) (48).

Intermittent dosing (i.e., twice or thrice weekly) facilitates DOT by decreasing the number of encounters required, might provide more effective peak serum concentrations, and is preferable to complete the regimen. For HIV-infected patients, the initial 8-week phase of therapy should be administered daily by DOT (7 days per week for 56 doses or 5 days per week for 40 doses) (AII) or 3 times weekly by DOT for 24 doses (BII) (277). Because twice-weekly administration of the continuation phase of therapy is associated with an increased risk for relapse with acquired rifamycin-resistant M. tuberculosis strains (277,328--330), for patients with CD4⁺ counts <100 cells/µL the continuation phase of either 4 months or 7 months should be administered either daily or three times weekly by DOT (AIII). Twice-weekly continuation-phase therapy may be considered in patients with CD4⁺ counts >100 cells/µL (CIII). Once-weekly administration of INH-rifapentine in the continuation phase should not be used for any patient with HIV infection (EI).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Monitoring of LTBI Treatment

All patients with a diagnosis of LTBI should be counseled about risk for TB, adherence to treatment regimens, benefits and risks of treatment, interactions with other drugs, and an optimal follow-up plan. HIV-infected patients receiving treatment for LTBI also should have baseline laboratory testing, including an evaluation of hepatic function (serum aspartate aminotransferase [AST], bilirubin, and alkaline phosphatase) for patients treated with INH and a complete blood count and platelet count for patients taking RIF or rifabutin (282,283).

Patients being treated for LTBI should be monitored at least monthly with a history and physical assessment designed to detect hepatitis and neuropathy. Patients should be advised to stop treatment and promptly seek medical evaluation if symptoms suggesting hepatitis occur, such as nausea, vomiting, jaundice, or dark urine. Clinicians in all settings should consider dispensing no more than a 1-month supply of medication (331,332). Routine laboratory monitoring is indicated in HIV-infected patients with abnormal baseline liver-function tests, with chronic liver disease, or in those receiving treatment with ART (282,283,333).

Monitoring of Active TB Disease Treatment

A baseline evaluation and monthly follow-up consisting of clinical, bacteriologic, and periodic laboratory and radiographic evaluations are essential to ensure treatment success. Clinical history and baseline tests to evaluate hepatic function (AST, bilirubin, and alkaline phosphatase), renal function (serum creatinine), complete blood count (including platelet count), and CD4⁺ counts are recommended for all patients (277). HIV-infected patients being treated for active TB should have a clinic-based evaluation at least monthly. For patients with extrapulmonary TB, the frequency and types of evaluations will depend on the sites involved and the ease with which specimens can be obtained. For patients with pulmonary TB, at least one sputum specimen for AFB smear and mycobacterial culture should be obtained monthly until two consecutive specimens are culture negative. Sputum specimens should be obtained after 8 weeks of treatment to inform clinical decision-making about the duration of the continuation phase. For patients with positive AFB smears at initiation of treatment, follow-up smears may be obtained at more frequent intervals (e.g., every 2 weeks until two consecutive specimens are negative) to provide an early assessment of the treatment response (277).

For patients with positive M. tuberculosis cultures after 3 months of treatment, drug-susceptibility tests should be repeated on newly acquired sputum specimens. Patients with positive M. tuberculosis cultures after 4 months of treatment should be considered as treatment failures and managed accordingly (44). At each visit, patients should be questioned about adherence and possible adverse effects of anti-TB medications; those taking EMB should be asked about blurred vision or scotomata and tested for visual acuity and color discrimination. Routine laboratory monitoring during treatment, even when baseline laboratory abnormalities are not present, could be considered (333).

In HIV-infected persons with active TB, serum concentrations of the first-line anti-TB drugs are frequently lower than published normal ranges (334). However, routine drug-level monitoring is not recommended (277). For those with a slow response to treatment, drug concentration measurements might provide objective information on which to base modifications of treatment (335).

Management of Common Adverse Events

Although the reported frequency of anti-TB drug-related toxicity in patients with HIV infection varies, for most adverse events, rates are not different than for HIV-uninfected patients (333,336--339). Because alternative drugs often have less efficacy and more toxicities than first-line anti-TB drugs and diagnosing a drug reaction and determining the responsible agent can be difficult, the first-line drugs (especially INH, RIF, or rifabutin) should not be stopped permanently without strong evidence that the specific anti-TB drug was the cause of the reaction. In such situations, consultation with a specialist in treating LTBI or TB in persons with HIV infection is recommended (48).

Gastrointestinal reactions are common with many of the anti-TB medications (340). If gastrointestinal symptoms occur, AST and bilirubin should be measured, and if the AST level is less than three times the upper limit of normal (ULN) or the baseline for the patient, the symptoms are assumed not to be caused by hepatic toxicity. Typically, gastrointestinal symptoms should be managed without discontinuing TB medications; initial approaches should include either changing the hour of administration or administering drugs with food.

Skin rashes are common with all of the anti-TB drugs. If rash is minor, affects a limited area, or causes pruritis, antihistamines should be administered for symptomatic relief and all anti-TB medications continued. If the rash is severe, all TB medications should be stopped until the rash is substantially improved, and TB drugs restarted one by one at intervals of 2--3 days. RIF or rifabutin should be restarted first (because they are least likely to cause rash and their role in treatment is critical). If the rash recurs, the last drug added should be stopped. If a petechial rash thought to be caused by thrombocytopenia occurs, the RIF or rifabutin should be stopped permanently (341). If a generalized rash associated with either fever or mucous membrane involvement occurs, all drugs should be stopped immediately, the patient should be switched to alternative anti-TB agents, and LTBI or TB treatment should be managed in consultation with a specialist.

Fever in an HIV-infected patient who has been receiving effective TB therapy for several weeks might represent drug fever, a paradoxical reaction, or IRIS (342). If superinfection or worsening TB is excluded as a potential cause, all TB drugs should be stopped. Once the fever has resolved, the general guidelines described for restarting/stopping drugs in the presence of a rash should be followed.

An increase in AST concentration occurs in approximately 20% of patients treated with the standard four-drug anti-TB regimen (343). Drug-induced liver injury can be caused by INH, rifamycins, or PZA and is defined as an AST elevation to >3 times the ULN in the presence of symptoms, or >5 times the ULN in the absence of symptoms (344). In addition to AST elevation, disproportionate increases in bilirubin and alkaline phosphatase occur occasionally. This latter pattern is more consistent with rifamycin hepatotoxicity than with INH or PZA hepatotoxicity. In most patients, asymptomatic aminotransferase elevations resolve spontaneously.

In the absence of symptoms, elevations of AST <3 times ULN should not prompt changes of TB therapy, but the frequency of clinical and laboratory monitoring should be increased. If AST levels are >5 times the ULN regardless of symptoms, >3 times the ULN with symptoms, or if a significant increase in bilirubin and/or alkaline phosphatase occurs, hepatotoxic drugs should be stopped, and the patient should be evaluated immediately. For any substantial new transaminase or bilirubin elevation, serologic testing for hepatitis A, B, and C should be performed and the patient questioned regarding symptoms suggestive of biliary tract disease and exposures to alcohol and other hepatotoxins.

If anti-TB drugs must be stopped for hepatotoxicity, substituting >3 nonhepatotoxic anti-TB drugs is prudent until the specific cause of hepatotoxicity can be determined and an alternative longer-term regimen constructed. The suspected anti-TB medications should be restarted one at a time after the AST level returns to <2 times the ULN or to near baseline for patients with pre-existing abnormalities. Because the rifamycins are a critical part of the TB regimen and are less likely to cause hepatotoxicity than INH or PZA (343), they should be restarted first. If no increase in AST occurs after 1 week, INH may be restarted. PZA may be restarted 1 week after INH if AST does not increase. If symptoms recur or AST increases, the last drug added should be stopped. If RIF and INH are tolerated and hepatitis was severe, PZA should be assumed responsible and should be discontinued. In this last circumstance, depending on the number of doses of PZA taken, severity of disease, and bacteriological status, therapy might be extended to 9 months with RIF and INH alone.

For HIV-infected patients on LTBI therapy who have hepatotoxicity, most of the general guidelines described for restarting/stopping drugs for patients on therapy for active TB apply. The ultimate decision regarding resumption of therapy with the same or a different agent for LTBI treatment should be made after weighing the risk for additional hepatic injury against the benefit of preventing progression to TB disease (333) and always in consultation with an expert in treating LTBI in persons with HIV infection.

ART in the Management of TB Disease

The treatment of TB can be complicated by drug interactions with the rifamycins and overlapping toxicities associated with antiretrovirals (ARVs) and anti-TB drugs when therapy for both HIV and TB infections is concomitantly administered. Both RIF and rifabutin induce CYP3A enzymes, and although rifabutin is not as potent an inducer as RIF, it is a substrate, leading to drug interactions with the PIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) when these agents are concomitantly administered with the rifamycins; such administration might result in increased metabolism and suboptimal levels of ARVs (345).

Compared with PI-based regimens, NNRTI-based regimens have fewer interactions with RIF-based TB therapy (346). Rifabutin is an alternative to RIF and can be administered with PIs or NNRTIs with appropriate dose adjustments (346). Concomitant use of RIF with ritonavir-boosted PIs has been shown to result in subtherapeutic levels of the PI. Use of ritonavir-boosted saquinavir with RIF was associated with a high incidence of hepatotoxicity in a pharmacokinetic study using healthy volunteers (347). RIF should not be used in patients on PI-based regimens, with or without ritonavir-boosting (EII). For patients undergoing treatment for active TB, starting ART with either an efavirenz- or nevirapine-based regimen is preferred because these NNRTIs have fewer interactions with RIF (BII); dosage adjustments for these NNRTIs might be needed for persons weighing more than 60 kg (BII) (348,349). Delavirdine should not be used with either RIF or rifabutin (350).

If rifabutin is used in place of RIF, dosage reduction is required with boosted-PI regimens. Efavirenz decreases the levels of rifabutin, and the dose of the latter might have to be increased. Nevirapine does not affect the levels of rifabutin sufficiently to merit adjustment of the rifabutin dose. Underdosing of ARVs or rifabutin can result in selection of HIV drug-resistant mutants or acquired rifamycin resistance, respectively, whereas overdosing of rifabutin might result in dose-related toxicities such as neutropenia and uveitis. Because interpatient variations in the degree of enzyme induction or inhibition can occur, the use of therapeutic drug monitoring for levels of rifabutin, PIs, or NNRTIs might help to adjust dosing for individual patients.

HIV nucleos(tide) analogs and the fusion inhibitor enfuvirtide are not affected by the CYP enzymes and can be used with the rifamycins. Results of ongoing drug-drug interaction studies predict that the combination of RIF (and possibly rifabutin) will result in decreased levels of maraviroc, raltegravir, and elvitegravir. Until data are available to guide dose adjustment, these drugs in combination should be avoided or used with extreme caution. Available NNRTIs and PIs do not have clinically significant drug interactions with other first- and second-line anti-TB drugs; thus, when rifamycins cannot be administered because of toxicity or resistance (MDR or XDR M. tuberculosis strains), ART regimens should be selected on the basis of other factors appropriate to the patient (AIII).

Optimal Timing of Initiation of ART in ART-Naïve Patients with Active TB

For ART-naïve, HIV-infected persons who are diagnosed with active TB, anti-TB treatment must be started immediately (AIII). The optimal timing of initiation of ART in this setting is not clear. Options include simultaneous TB and ART or treatment of TB first with delay of ART by several weeks to months. A positive aspect of starting both regimens simultaneously is the possible prevention of progressive HIV disease and reduction in morbidity or mortality associated with TB or other OIs. A negative of this approach is the possibility of overlapping toxicities, drug interactions, a high pill burden, and the possibility of developing IRIS or a paradoxical reaction. These factors must be weighed carefully when choosing the best time to start ART in individual patients.

Several randomized clinical trials are under way to address the optimal timing of initiation of ART in persons being treated for active TB, but the results will not be known for several years. Pending these results, certain specialists determine when to start ART based on the immunologic status of the patients (339,351,352). For patients with a CD4⁺ count <100 cells/µL, ART should be started after >2 weeks of TB treatment (BII) to reduce confusion about overlapping toxicities, drug interactions (339), and the occurrence of paradoxical reactions or IRIS (353). For persons with a CD4⁺ count of 100--200 cells/µL, certain specialists would delay ART until the end of the 2-month intensive phase of anti-TB treatment (BII). In those with a sustained CD4⁺ count >200 cells/µL, ART could be started during the anti-TB maintenance phase and for those with a CD4⁺ count >350 cells/µL, after finishing anti-TB treatment (BII). In one study, paradoxical reactions occurred in almost all HIV-infected patients with TB and a CD4⁺ count <100 cells/µL who started ART within the first 30 days of TB therapy (222). However, other studies suggest this approach might prevent HIV disease progression or death (222,339,353). In a small, prospective, nonrandomized study of 49 HIV-infected patients from Brazil (348) treated with a RIF-based anti-TB regimen and efavirenz-based ART, morbidity and side effects of medications in patients who started ART 3 weeks after initiation of TB treatment were reduced, compared with those who started ART and anti-TB treatment simultaneously. Furthermore, simultaneous anti-TB and anti-HIV treatment did not reduce overall mortality.

When TB occurs in patients already on ART, treatment for TB must be started immediately (AIII), and ART should be modified to reduce the risk for drug interactions and maintain virologic suppression. When TB occurs in the setting of virologic failure, ART drug-resistance testing should be performed and a new ART regimen constructed to achieve virologic suppression and avoid drug interactions with the anti-TB regimen administered (AIII).

Immune Reconstitution and Paradoxical Reactions

IRIS or a paradoxical reaction occurring after the initiation of ART is thought to be the result of recovery of immune responses to previously recognized TB antigens, reconstituted by ART or by TB treatment itself (48). The immune response might be an exaggerated inflammatory response during TB treatment in a patient known to have TB, referred to as paradoxical TB-associated IRIS, or might unmask previously undiagnosed TB, referred to as unmasking TB-associated IRIS.

TB-associated paradoxical reactions or IRIS usually occur in the first 1--3 months after starting ART in patients receiving TB treatment (294). The risk for IRIS is greater when ART is started within the first 2 months of TB therapy (222,354) and when the CD4⁺ count is <100 cells/µL (295-298). Signs of a paradoxical reaction or IRIS can include, but are not limited to, high fevers, worsening respiratory status, increase in size and inflammation of involved lymph nodes or new lymphadenopathy, breakthrough meningitis or new or expanding CNS lesions, radiologic worsening of pulmonary parenchymal infiltrations, and increasing pleural effusions. Such findings should be attributed to a paradoxical or IRIS reaction only after a thorough evaluation has excluded other possible causes, especially failure of TB therapy.

IRIS or paradoxical reactions are usually self-limited but if symptoms are severe, supportive treatment might be required, depending on the nature of the complications. Typically, a paradoxical or IRIS reaction that is not severe should be treated symptomatically with nonsteroidal anti-inflammatory agents without a change in anti-TB treatment or ART (BIII). Approaches to the management of severe reactions (e.g., high fever, airway compromise from enlarging lymph nodes, enlarging serosal fluid collections, increased intracranial pressure [ICP], or sepsis syndrome) have not been studied but might require invasive interventions such as surgical decompression, and although no specific treatment is recommended for severe reactions, improvement has been observed with the use of prednisone or methylprednisolone used at a dose of approximately 1 mg/kg body weight gradually reduced after 1--2 weeks (BIII) (48).

Management of Treatment Failure

Drug-resistant TB continues to be a substantial clinical and public health problem. Predisposing factors include cavitary disease with a large bacillary load, use of an inadequate drug regimen, or a combined failure of both the patient and the provider to ensure compliance with the prescribed regimen (277). Ongoing transmission of drug-resistant strains is a source of new drug-resistant cases (355). The recommended treatment for drug-resistant TB is the same for HIV-infected as for non-HIV-infected patients (AII) (277,355). The optimal duration of treatment for highly resistant strains has not been established.

For patients with M. tuberculosis strains resistant to INH, INH should be discontinued and the patient treated with a 6-month regimen of RIF, PZA, and EMB, which is nearly as effective as the conventional INH-containing regimen (BII). A fluoroquinolone may be added for those with more severe or extensive disease (CIII). Alternatively, treatment with RIF and EMB for 12 months can be used, with PZA added during at least the initial 2 months (BII).

Treatment regimens for TB disease caused by RIF mono-resistant strains are less effective, and patients infected with these strains are at increased risk for relapse and treatment failure. A minimum of 12--18 months of treatment with INH, EMB, and a fluoroquinolone (e.g., levofloxacin, moxifloxacin) with PZA administered during the first 2 months is recommended (BIII). An injectable agent (e.g., amikacin or capreomycin) might be included in the first 2--3 months for patients with RIF mono-resistance and severe or extensive disease (CIII).

Patients with M. tuberculosis resistant to both INH and RIF (MDR-TB) are at high risk for treatment failure and further acquired resistance and require close follow-up during and after treatment. Treatment regimens for MDR-TB should be individualized based on drug-resistance test results, relative activities of available anti-TB agents, the extent of disease, potential interaction with ARVs, and presence of other comorbid conditions (AIII). Treatment regimens should consist of at least four effective drugs (AIII) (277,355). The management of MDR-TB is complex and should be undertaken only by an experienced specialist or in close consultation with specialized treatment centers (AIII).

Reports of highly resistant M. tuberculosis strains have occurred during the past two decades (356,357,358, 359,360). The emergence of M. tuberculosis with extensive drug resistance was first reported on a global level in 2006 (361). The WHO Emergency Global Task Force on XDR-TB has defined XDR-TB as resistance to at least INH and RIF among the first-line anti-TB drugs, and resistance to any fluoroquinolone and at least one of three injectable second-line drugs (kanamycin, amikacin, capreomycin) (362). XDR-TB has been reported in the United States and every region of the world (363--365). Community transmission of XDR-TB and a high and rapid mortality rate among HIV-infected patients with XDR-TB have been documented in South Africa (366). Poor TB treatment outcomes and high mortality among HIV-infected persons with XDR-TB also have been reported from New York City (367). Patients with M. tuberculosis resistant to RIF or any two first-line drugs should be tested for susceptibility to a full panel of anti-TB drugs (BIII). Repeat drug-susceptibility testing should be considered for HIV-infected patients with MDR-TB who are not responding to treatment to rapidly identify drug resistance that occurs during treatment (BIII). Contact investigation and strict infection- control precautions should be implemented according to national guidelines (BIII) (368). The management of XDR-TB should be undertaken only by an experienced specialist in close consultation with specialized treatment centers (AIII).

Preventing Recurrence

For patients with a low ongoing risk for exposure and transmission of M. tuberculosis infection, chronic suppressive therapy after successful completion of a recommended treatment regimen for LTBI or active TB is unnecessary (DII). However, recurrence of TB disease can result from either endogenous relapse or exogenous reinfection. Even in low TB burden countries, reinfection is a risk for HIV-infected residents of institutions that pose an ongoing high risk for exposure to M. tuberculosis (e.g., prisons, jails, and homeless shelters) (282,283). Recurrence of TB disease is also substantially increased in HIV-infected persons in geographic areas with a high TB burden (344,369--375). In these settings, treatment of LTBI resulting from presumed reinfection among persons previously treated for TB has been documented to reduce recurrence of TB disease (370,372,376). The reported incidence of TB disease for persons immigrating to the United States from settings with high TB burden (especially Sub-Saharan Africa and Asia) who have been in the United States <1 year is often greater than the estimated case rate in their country of origin (377). Recent molecular epidemiology studies suggest that the majority of TB cases among foreign-born persons in the United States are caused by or related to activation of latent infection (377--381). These findings suggest that recent immigrants might be at high risk for recent infection or reinfection in their countries of origin. Close monitoring of recent immigrants at such risk is necessary.

Special Considerations During Pregnancy

HIV-infected pregnant women who do not have documentation of a negative TST result during the preceding year should be tested during pregnancy. The frequency of anergy is not increased during pregnancy, and routine anergy testing for HIV-1-infected pregnant women is not recommended (382--385). No data are available on the performance of the IGRAs for diagnosis of LTBI in pregnant women.

The diagnostic evaluation for TB disease in pregnant women is the same as for nonpregnant adults. Chest radiographs with abdominal shielding result in minimal fetal radiation exposure. An increase in pregnancy complications and undesirable outcomes (including preterm birth), low birthweight, and intrauterine growth retardation might be observed among pregnant women with either pulmonary or extrapulmonary TB not confined to the lymph nodes, especially when treatment is not begun until late in pregnancy (382--389). Congenital TB infection of the infant might occur but appears to be rare (390).

Treatment of TB disease for pregnant women should be the same as for nonpregnant women, but with attention given to the following considerations (BIII):

• Although INH is not teratogenic in animals or humans, hepatotoxicity caused by INH might occur more frequently in pregnancy and the postpartum period (391). Monthly monitoring of liver transaminases during pregnancy and the postpartum period is recommended (CIII).
• RIF is not teratogenic in humans. Because of a potential increased risk for RIF-related hemorrhagic disease among neonates born to women who receive anti-TB therapy during pregnancy, prophylactic vitamin K, in a single 10 mg dose, should be administered to the neonate (BIII).
• PZA is not teratogenic among animals. Experience is limited with use in human pregnancy. Although WHO and the International Union Against Tuberculosis and Lung Diseases (392,393) have made recommendations for the routine use of PZA in pregnant women, it has not been recommended for general use during pregnancy in the United States because data characterizing its effects in this setting are limited (394). If PZA is not included in the initial treatment regimen, the minimum duration of TB therapy should be 9 months. The decision regarding whether to include PZA for treatment should be made after consultation among obstetricians, TB specialists, and women, taking into account gestational age and likely susceptibility pattern of the infecting strain (CIII).
• EMB is teratogenic among rodents and rabbits at doses that are much higher than those used among humans. No evidence of teratogenicity has been observed among humans. Ocular toxicity has been reported among adults taking EMB, but changes in visual acuity have not been detected in infants born after exposure in utero.

Experience with using the majority of the second-line drugs for TB during pregnancy is limited. MDR-TB in pregnancy should be managed in consultation with a specialist. Therapy should not be withheld because of pregnancy (AIII). The following concerns should be considered when selecting second-line anti-TB drugs for use among pregnant women:

• Streptomycin use has been associated with a 10% rate of VIII nerve toxicity in infants exposed in utero; its use during pregnancy should be avoided if possible (DIII).
• Hearing loss has been detected in approximately 2% of children exposed to long-term kanamycin therapy in utero; like streptomycin, this agent should typically be avoided if possible (DIII). The fetus is at a theoretical risk for ototoxicity with in utero exposure to amikacin and capreomycin, but this risk has not been documented and these drugs might be alternatives when an aminoglycoside is required for treatment of MDR-TB (CIII).
• Because arthropathy has been noted in immature animals exposed in utero to quinolones, quinolones are typically not recommended for pregnant women and among children aged <18 years (CIII). However, >400 cases of quinolone use in human pregnancies have been reported to various pregnancy registries, and use has not been associated with human arthropathy or birth defects after in utero exposure. Thus, quinolones can be used in pregnancy for drug-resistant TB, if they are required on the basis of susceptibility testing (CIII) (395).
• Para-aminosalicylic acid (PAS) is not teratogenic among rats or rabbits (394). In one study, a possible increase in limb and ear anomalies was reported among 143 infants delivered by woman who were exposed during the first trimester of their pregnancies (396). No specific pattern of defects and no increase in rate of defects have been detected among subjects in other human studies, indicating that this agent can be used with caution if needed (CIII).
• Ethionamide has been associated with an increased risk for several anomalies among mice, rats, and rabbits after high-dose exposure; no increased risk for defects was noted with doses similar to those used among humans, but experience is limited with use during human pregnancy. Thus, ethionamide should be avoided unless its use is necessary (CIII).
• No data are available from animal studies or reports of cycloserine use in humans during pregnancy.

If LTBI is diagnosed during pregnancy and active TB has been ruled out, treatment should be initiated during pregnancy whenever possible (BIII). If the woman is receiving ART only for prophylaxis of perinatal HIV transmission and will stop ARVs after delivery, deferral of treatment for LTBI until after delivery or use of a triple nucleoside regimen to allow use of RIF is reasonable. For women who require long-term ART for their own health, initiation of INH prophylaxis during pregnancy is recommended (BIII).

ART is indicated for all pregnant women either for treatment of maternal infection, or if not indicated for maternal therapy, for prevention of perinatal transmission of HIV (397). Pregnant women on ART who have a diagnosis of active TB should have their ARV regimens adjusted as needed to accommodate their TB drugs. For women whose diagnosis includes concurrent active TB and HIV infection during pregnancy, TB therapy should be initiated immediately and ART should be initiated as soon as possible thereafter, usually according to the principles described for nonpregnant adults. Efavirenz use is not recommended during the first trimester because of 1) substantial CNS and cleft defects seen in cynomolgous monkeys treated in the first trimester with efavirenz at doses similar to those used in humans and 2) because of case reports of neural tube defects in humans after first-trimester exposure. Efavirenz can be used after the first trimester, if indicated, to avoid drug interactions between anti-TB drugs and PIs. Initiation of nevirapine is not recommended for women with CD4⁺ counts >250 cells/µL because of an increased risk for potentially fatal liver toxicity. For women who require ART strictly for prophylaxis of perinatal HIV transmission, use of a triple nucleoside regimen, including abacavir, could be considered to avoid interactions with TB drugs.

Disseminated Mycobacterium avium Complex Disease

Epidemiology

Organisms of the Mycobacterium avium complex (MAC) are ubiquitous in the environment (398--400). M. avium is the etiologic agent in >95% of patients with AIDS who acquire disseminated MAC disease (398,401--406). An estimated 7%--12% of adults have been previously infected with MAC, although rates of disease vary in different geographic locations (398,402,405,406). Although epidemiologic associations have been identified, no environmental exposure or behavior has been consistently linked to a subsequent risk for developing MAC disease.

The mode of transmission is thought to be through inhalation, ingestion, or inoculation via the respiratory or gastrointestinal tract. Household or close contacts of those with MAC disease do not appear to be at increased risk for disease, and person-to-person transmission is unlikely.

In the absence of effective ART or chemoprophylaxis in those with AIDS-associated immunosuppression, the incidence of disseminated MAC disease is 20%--40% (407,408). For persons with a CD4⁺ count <100 cells/µL who are receiving effective prophylaxis or have responded to ART with a sustained increase in CD4⁺ count to levels >100--200 cells/µL, the overall incidence has been estimated at 2 cases per 100 person-years. MAC disease typically occurs among persons with CD4⁺ counts <50 cells/µL. Other factors that are associated with increased susceptibility to MAC disease are high plasma HIV RNA levels (>100,000 copies/mL), previous OIs, previous colonization of the respiratory or gastrointestinal tract with MAC, and reduced in vitro lymphoproliferative immune responses to M. avium antigens, possibly reflecting defects in T-cell repertoire.

Clinical Manifestations

In persons with AIDS not on ART, MAC disease is typically a disseminated multi-organ infection (409--412). Early symptoms might be minimal and might precede detectable mycobacteremia by several weeks. Symptoms include fever, night sweats, weight loss, fatigue, diarrhea, and abdominal pain (402).

Localized manifestations of MAC disease have been reported most frequently among persons who are receiving and have responded to ART. Localized syndromes include cervical or mesenteric lymphadenitis, pneumonitis, pericarditis, osteomyelitis, skin or soft tissue abscesses, genital ulcers, or CNS infection.

Laboratory abnormalities particularly associated with disseminated MAC disease include anemia (often out of proportion to that expected for the stage of HIV disease) and elevated liver alkaline phosphatase (398,399,401--408,413,414). Hepatomegaly, splenomegaly, or lymphadenopathy (paratracheal, retroperitoneal, para-aortic, or less commonly peripheral) might be identified on physical examination or by radiographic or other imaging studies. Other focal physical findings or laboratory abnormalities might occur in the context of localized disease.

IRIS, initially characterized by focal lymphadenitis with fever, has subsequently been recognized as a systemic inflammatory syndrome with signs and symptoms that are clinically indistinguishable from active MAC infection. Its occurrence with MAC disease is similar to IRIS or paradoxical reactions observed with TB disease (415--418). Bacteremia is absent. The syndrome has been described among patients with subclinical ("unmasking IRIS") or established MAC disease and advanced immunosuppression who begin ART and have a rapid and marked increase in CD4⁺ count (>100 cells/µL). As with TB, the syndrome might be benign and self-limited or might result in severe unremitting symptoms that are improved with the use of systemic anti-inflammatory therapy or corticosteroids in doses similar to those described for TB-associated IRIS.

Diagnosis

A confirmed diagnosis of disseminated MAC disease is based on compatible clinical signs and symptoms coupled with the isolation of MAC from cultures of blood, lymph node, bone marrow, or other normally sterile tissue or body fluids (408,411,419,420). Species identification should be performed using specific DNA probes, high performance liquid chromatography, or biochemical tests.

Other ancillary studies provide supportive diagnostic information, including AFB smear and culture of stool or tissue biopsy material, radiographic imaging, or other studies aimed at isolation of organisms from focal infection sites.

Preventing Exposure

MAC organisms commonly contaminate environmental sources (e.g., food and water). Available information does not support specific recommendations regarding avoidance of exposure.

Preventing Disease

Initiating Primary Prophylaxis

HIV-infected adults and adolescents should receive chemoprophylaxis against disseminated MAC disease if they have a CD4⁺ count of <50 cells/µL (AI). Azithromycin (421) or clarithromycin (399,422) are the preferred prophylactic agents (AI). The combination of clarithromycin and rifabutin is no more effective than clarithromycin alone for chemoprophylaxis, is associated with a higher rate of adverse effects than either drug alone, and should not be used (EI) (399). The combination of azithromycin with rifabutin is more effective than azithromycin alone; however, the additional cost, increased occurrence of adverse effects, potential for drug interactions, and absence of a survival difference compared with azithromycin alone do not warrant a routine recommendation for this regimen (CI) (421). Azithromycin and clarithromycin also each confer protection against respiratory bacterial infections (BII). If azithromycin or clarithromycin cannot be tolerated, rifabutin is an alternative prophylactic agent for MAC disease, although drug interactions might complicate the use of this agent (BI) (423,424). Before prophylaxis is initiated, disseminated MAC disease should be ruled out by clinical assessment, which might include obtaining a blood culture for MAC. Because treatment with rifabutin could result in RIF resistance among persons who have active TB, active TB also should be excluded before rifabutin is used for prophylaxis.

Although detecting MAC organisms in the respiratory or gastrointestinal tract might predict disseminated MAC infection, no data are available regarding efficacy of prophylaxis with clarithromycin, azithromycin, rifabutin, or other drugs among asymptomatic patients harboring MAC organisms at these sites in the presence of a negative blood culture. Therefore, routine screening of respiratory or gastrointestinal specimens for MAC is not recommended (DIII).

Discontinuing Primary Prophylaxis

Primary MAC prophylaxis should be discontinued among adult and adolescent patients who have responded to ART with an increase in CD4⁺ counts to >100 cells/µL for >3 months (AI). Two randomized, placebo-controlled trials and observational data have demonstrated that such patients can discontinue primary prophylaxis with minimal risk for acquiring MAC disease (126,425--428). Discontinuing primary prophylaxis among patients who meet these criteria is recommended to reduce pill burden, the potential for drug toxicity, drug interactions, selection of drug-resistant pathogens, and cost. Primary prophylaxis should be reintroduced if the CD4⁺ count decreases to <50 cells/µL (AIII).

Treatment of Disease

Initial treatment of MAC disease should consist of two or more antimycobacterial drugs to prevent or delay the emergence of resistance (AI) (400,405,406,429--436). Clarithromycin is the preferred first agent (AI); it has been studied more extensively than azithromycin in patients with AIDS and appears to be associated with more rapid clearance of MAC from the blood (400,429,431,435--437). However, azithromycin can be substituted for clarithromycin when drug interactions or clarithromycin intolerance preclude the use of clarithromycin (AII). Testing MAC isolates for susceptibility to clarithromycin or azithromycin is recommended for all patients (BIII) (438,439).

EMB is the recommended second drug (AI). Some clinicians add rifabutin as a third drug (CI). One randomized clinical trial demonstrated that the addition of rifabutin to the combination of clarithromycin and EMB improved survival, and in two randomized clinical trials, this approach reduced emergence of drug resistance (400,431) in persons with AIDS and disseminated MAC disease. These studies were completed before the availability of effective ART. The addition of a third or fourth drug should be considered in persons with advanced immunosuppression (CD4⁺ count <50 cells/µL), high mycobacterial loads (>2 log₁₀ colony forming units/mL of blood), or in the absence of effective ART, settings in which mortality is increased and emergence of drug resistance is most likely (CIII). On the basis of data in non-HIV-infected patients, the third or fourth drug might include an injectable agent such as amikacin or streptomycin (CIII) (438).

Patients who have disseminated MAC disease and have not been treated previously with or are not receiving effective ART should generally typically have ART withheld until after the first 2 weeks of antimycobacterial therapy have been completed to reduce risk for drug interactions, pill burden, and complications associated with the occurrence of IRIS (CIII). If ART has already been instituted, it should be continued and optimized unless drug interactions preclude the safe concomitant use of antiretroviral and antimycobacterial drugs (CIII).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

A repeat blood culture for MAC should be obtained 4--8 weeks after initiating antimycobacterial therapy only for patients who fail to have a clinical response to their initial treatment regimen. Improvement in fever and a decline in quantity of mycobacteria in blood or tissue can be expected within 2--4 weeks after initiation of appropriate therapy; however, for those with more extensive disease or advanced immunosuppression, clinical response might be delayed.

Adverse effects with clarithromycin and azithromycin include nausea, vomiting, abdominal pain, abnormal taste, and elevations of liver transaminase levels or hypersensitivity reactions. Doses of clarithromycin >1 g/day for treatment of disseminated MAC disease have been associated with increased mortality and should not be used (EI) (440). Rifabutin doses of >450 mg/day have been associated with higher risk for adverse drug interactions when used with clarithromycin or other drugs that inhibit cytochrome P450 isoenzyme 3A4 and might be associated with a higher risk for experiencing uveitis, arthralgias, or other adverse drug reactions (441,442).

Persons who develop moderate to severe symptoms typical of IRIS during ART, should receive initial treatment with nonsteroidal, anti-inflammatory agents (CIII). If IRIS symptoms do not improve, short-term (4--8 weeks) systemic corticosteroid therapy, in doses equivalent to 20--40 mg of oral prednisone daily, has been successful in reducing symptoms and morbidity (CIII) (416,443,444).

Rifabutin should not be administered to patients receiving certain PIs and NNRTIs because the complex interactions have been incompletely studied and the clinical implications of those interactions are unclear (423,424). PIs can increase clarithromycin levels, but no recommendation to adjust the dose of either clarithromycin or PIs can be made on the basis of existing data. Efavirenz can induce metabolism of clarithromycin. This can result in reduced serum concentration of clarithromycin but increased concentration of the 14-OH active metabolite of clarithromycin. Although the clinical significance of this interaction is unknown, the efficacy of clarithromycin for MAC prophylaxis could be reduced because of this interaction. Azithromycin metabolism is not affected by the cytochrome P450 (CYP450) system; azithromycin can be used safely in the presence of PIs or NNRTIs without concerns of drug interactions.

Management of Treatment Failure

Treatment failure is defined by the absence of a clinical response and the persistence of mycobacteremia after 4--8 weeks of treatment. Repeat testing of MAC isolates for susceptibility to clarithromycin or azithromycin is recommended for patients who relapse after an initial response. The majority of patients who experience failure of clarithromycin or azithromycin primary prophylaxis in clinical trials had isolates susceptible to these drugs at the time MAC disease was detected (400,405,406,429,445,446).

Because the number of drugs with demonstrated clinical activity against MAC is limited, results of susceptibility testing should be used to construct a new multi-drug regimen. The regimen should consist of at least two new drugs not used previously, to which the isolate is susceptible and selected from among the following: EMB, rifabutin, amikacin, or a quinolone (moxifloxacin, ciprofloxacin, or levofloxacin), although data supporting a survival or microbiologic benefit when these agents are added have not been compelling (CIII) (33,405,406,430-434,437,447--450). On the basis of data related to non-HIV-infected patients being treated for MAC, an injectable agent such as amikacin or streptomycin should be considered (CIII) (438). Whether continuing clarithromycin or azithromycin despite resistance provides additional benefit is unknown. Clofazimine should not be used because randomized trials have demonstrated lack of efficacy and an association with increased mortality (EII) (430,432,448). Other second-line agents (e.g., ethionamide, thiacetazone [not available in the United States], or cycloserine) have been anecdotally combined with clarithromycin and azithromycin as salvage regimens. However, their role in this setting is not well defined. Among patients whose initial treatment for MAC disease has not been successful or who have antimycobacterial drug-resistant MAC disease, optimizing ART is an important adjunct to second-line or salvage therapy for MAC disease (AIII).

Adjunctive treatment of MAC disease with immunomodulators has not been thoroughly studied, and data are insufficient to support a recommendation for use (DIII).

Preventing Recurrence

Adult and adolescent patients with disseminated MAC disease should receive lifelong secondary prophylaxis (chronic maintenance therapy) (AII), unless immune reconstitution occurs as a result of ART (425,426).

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)

Patients are at low risk for recurrence of MAC when they have completed a course of >12 months of treatment for MAC, remain asymptomatic with respect to MAC signs and symptoms, and have a sustained increase (e.g., >6 months) in their CD4⁺ counts to >100 cells/µL after ART. Although the numbers of patients who have been evaluated remain limited and recurrences could occur, based on the limited number of patients who have been evaluated and the inferences from more extensive data indicating the safety of discontinuing secondary prophylaxis for other OIs, discontinuing chronic maintenance therapy is reasonable (BII) (121,426,434,451). Secondary prophylaxis should be reintroduced if the CD4⁺ count decreases to <100 cells/µL (AIII).

Special Considerations During Pregnancy

Chemoprophylaxis for MAC disease should be administered to pregnant women the same as for nonpregnant women and adolescents (AIII). Because of an increased risk for birth defects evident in certain animal studies, clarithromycin is not recommended as the first-line agent for prophylaxis or treatment of MAC in pregnancy (DIII). Two studies, each with slightly more than 100 women with first-trimester exposure to clarithromycin, did not demonstrate an increase in or specific pattern of defects, although an increased risk for spontaneous abortion was noted in one study (452,453). Azithromycin did not produce defects in animal studies, but experience for use in humans during the first trimester is limited. Azithromycin is recommended for primary prophylaxis in pregnancy (BIII). For secondary prophylaxis (chronic maintenance therapy), azithromycin plus EMB are the preferred drugs (BIII).

Diagnostic considerations and indications for treatment of pregnant women are the same as for nonpregnant women. On the basis of animal data discussed previously, azithromycin is preferred over clarithromycin as the second agent with EMB (BIII). Use of EMB should minimize concerns regarding drug interactions, allowing initiation of ART as soon as possible during pregnancy to decrease the risk for perinatal transmission of HIV. Pregnant women whose treatment failed on their primary regimen should be managed in consultation with infectious disease and obstetrical specialists.

Bacterial Respiratory Disease

Epidemiology

Bacterial pneumonia is a common cause of HIV-associated morbidity. The incidence of bacterial pneumonia among HIV-infected persons is greater than that in the noninfected population (454). In the precombination ART era, the Pulmonary Complications of HIV Infection Study reported that the incidence of bacterial pneumonia ranged was 3.9--7.3 episodes per 100 person-years (455). In the current era, the incidence of bacterial pneumonia in HIV-infected persons has declined (4,456,457).

Bacterial pneumonia might be the first manifestation of underlying HIV infection and can occur at any stage of HIV disease and at any CD4⁺ count. The high rates of bacterial pneumonia in HIV-infected persons probably result from multiple factors, including qualitative B-cell defects that impair ability to produce pathogen-specific antibody, impaired neutrophil function or numbers or both, and factors (e.g., injection drug use) that are associated with underlying HIV infection. Risk factors associated with an increased risk for bacterial pneumonia, include low CD4⁺ count, injection-drug use, and cigarette smoking (454).

Similar to persons without HIV infection, Streptococcus pneumoniae and Haemophilus species are the most frequently identified causes of community-acquired bacterial pneumonia in HIV-infected persons (458--464). Similar to the noninfected population, drug-resistant Streptococcus pneumoniae is an increasing concern and is associated with increased mortality (465).

Although atypical bacterial pathogens such as Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila species have been reported as infrequent causes of community-acquired bacterial pneumonia in HIV-infected persons (461,466), they are important considerations in decisions regarding antibiotic treatment.

In contrast to the noninfected population, Pseudomonas aeruginosa and Staphylococcus aureus are both reported as community-acquired pathogens with an increased frequency among persons with HIV infection (462,467).

Compared with persons without HIV infection, HIV-infected persons have an increased incidence of bacteremia accompanying pneumonia, especially if they are infected with S.pneumoniae. (468--470). In one study, the estimated rate of pneumococcal bacteremia (9.4 cases per 1,000 patient-years) in AIDS patients was approximately 100-fold greater than in HIV-uninfected historical controls (468).

Bacterial pneumonia is associated with an increased mortality among HIV-infected persons (462,471,472). Among HIV-infected persons with community-acquired bacterial pneumonia, a prospective, multicenter study documented that a CD4⁺ count <100 cells/µL, radiographic progression of disease, and the presence of shock were independent predictors of increased mortality (473). In this study, multilobar infiltrates, cavitary infiltrates, and pleural effusion at baseline were all independent predictors of radiographic progression of HIV.

Clinical Manifestations

The clinical and radiographic presentation of bacterial pneumonia in HIV-infected persons is similar to that in persons without HIV infection. Persons with pneumonias caused by Streptococcus pneumoniae and Haemophilus species characteristically have an acute onset (3--5 days) of symptoms, including fevers, chills, rigors, chest pain, cough productive of purulent sputum, and dyspnea (92). On examination of vital signs, patients are often febrile. The presence of tachycardia or hypotension is an indicator of the systemic inflammatory response syndrome (SIRS). Tachypnea and decreased arterial oxygen saturation indicate moderate-to-severe pneumonia and clinicians should strongly consider hospitalizing such patients.

Persons with bacterial pneumonia typically have evidence of focal consolidation and/or pleural effusion on lung examination, as contrasted to persons with PCP, in which the lung examination is often normal or, if abnormal, reveals inspiratory crackles.

The white blood cell (WBC) count is usually elevated in persons with bacterial pneumonia. In persons with advanced HIV disease, the elevation might be relative to the persons's baseline WBC. A left shift also might be present.

Persons with bacterial pneumonia characteristically exhibit unilateral, focal, segmental, or lobar consolidation on chest radiograph. However, the frequency of these typical radiographic findings might depend on the underlying bacterial pathogen. HIV-infected persons might present with multifocal or multilobar involvement and with parapneumonic effusions more frequently than persons without HIV infection (474).

Diagnosis

Guidelines for the management of community-acquired pneumonia (CAP) in persons without HIV infection also apply to HIV-infected persons (475). Persons with clinical symptoms and signs suggestive of CAP should have a chest radiograph. When available, previous radiographs should be reviewed to assess for the presence of new findings. The clinical diagnosis of bacterial pneumonia requires a demonstrable infiltrate.

Given the increased incidence of Mycobacterium tuberculosis in HIV-infected persons, the diagnosis of TB should always be suspected in HIV-infected persons who have pneumonia. Those persons with a clinical and radiographic evidence suggestive of TB should be managed as potential TB (e.g., respiratory isolation if hospitalized), and three sputum specimens should be obtained for AFB smear and culture. Dual therapy for both bacterial pneumonia and TB is appropriate for patients for whom both of these diagnoses are considerations and where diagnostic studies are undertaken.

Standard recommendations for routine testing for bacterial pneumonia remain controversial (475). Usually, the differential diagnosis of pneumonia in HIV-infected persons is broad and a confirmed microbiologic diagnosis might allow clinicians to target the specific pathogen and to discontinue broad spectrum antibiotic therapy and/or empiric therapy that targets nonbacterial pathogens (e.g., empiric PCP therapy). The increased incidence of bacteremia in HIV-infected persons (especially at low CD4⁺ count) and the high specificity of blood cultures argue for their collection in HIV-infected persons. Although the low sensitivity of sputum and blood cultures and the infrequency that these results alter clinical management in HIV-uninfected patients with CAP argue against their routine collection, patients with HIV infection are at increased risk for infection with drug-resistant Streptococcus pneumococci (drug-resistant S. pneumoniae) and identification of this organism could lead to changes in management.

HIV-infected persons with suspected CAP should undergo investigation for specific pathogens that would significantly alter standard (empirical) management decisions when the presence of such pathogens is suspected on the basis of epidemiologic, clinical, or radiologic clues. Pseudomonas aeruginosa should be considered in HIV-infected persons with advanced HIV disease (i.e., CD4⁺ count <50 cells/µL); those with pre-existing lung disease (i.e., bronchiectasis); underlying neutropenia, corticosteroid therapy, or severe malnutrition; those who have been hospitalized within 90 days or reside in a health-care facility or nursing home; and those on chronic hemodialysis. Given the frequency of cavitary infiltrates in persons with P. aeruginosa, this radiographic finding should also prompt an investigation for this pathogen. Staphylococcus aureus should be considered in persons with recent viral (or influenza) infection; history of injection-drug use; or severe, bilateral, necrotizing pneumonia.

Routine diagnostic tests to identify an etiologic diagnosis are optional for persons with CAP who are well enough to be treated as outpatients, especially true if microbiologic studies cannot be performed promptly.

A pretreatment expectorated sputum specimen for Gram stain and culture and two blood cultures should be obtained from persons with CAP who are hospitalized, especially if intensive care is required. Gram stain and culture of expectorated sputum should be performed only if a good-quality specimen can be obtained and quality performance measures for collection, transport, and processing of samples can be met. Correlation of the sputum culture with the Gram stain can help in the interpretation of sputum culture data. For intubated patients, an endotracheal aspirate sample should be obtained. In addition to the above tests, urinary antigen tests for Legionella pneumophila and Streptococcus pneumoniae should be considered.

Diagnostic thoracentesis should be considered in any person with pleural effusion, especially if a concern exists for accompanying empyema, and a therapeutic thoracentesis should be performed to relieve respiratory distress secondary to a moderate- to large-sized effusion.

Preventing Exposure

No effective means exist to reduce exposure to Streptococcus pneumoniae and Haemophilus influenzae, which are common in the community.

Preventing Disease

HIV-infected adults and adolescents who have a CD4⁺ count of >200 cells/µL should be administered a single dose of 23-valent polysaccharide pneumococcal vaccine (PPV) unless they have received this vaccine during the previous 5 years (AII) (157,476--479). One randomized placebo-controlled trial of pneumococcal vaccine in Africa paradoxically determined that an increased risk for pneumonia was associated with vaccination (480). Follow-up of this cohort confirmed the increase in pneumonia in vaccinated subjects but also reported a decrease in all-cause mortality (481). In contrast, multiple observational studies of pneumococcal vaccine in the United States have reported benefits from vaccination (157,476--479,482). Studies also have documented that vaccination is associated with a lower risk for pneumococcal bacteremia (482,483). The majority of HIV specialists believe that the potential benefit of pneumococcal vaccination in the United States outweighs the risk.

HIV-infected adults and adolescents who have a CD4⁺ count of <200 cells/µL can be offered PPV (CIII). Clinical evidence has not confirmed efficacy in this group, but evidence documents the benefit for those who also start ART (482). Revaccination can be considered for persons who were initially vaccinated when their CD4⁺ counts were <200 cells/µL and whose CD4⁺ counts have increased to >200 cells/µL in response to ART (CIII).

The duration of the protective effect of primary pneumococcal vaccination is unknown; revaccination every 5 years may be considered (CIII) (479). No evidence confirms clinical benefit from revaccination. Nevertheless, the recommendation to vaccinate is increasingly pertinent because of the increasing incidence of invasive infections with drug-resistant (including TMP-SMX-, macrolide-, and ß-lactam-resistant) strains of S. pneumoniae.

The incidence of H. influenzae type b (Hib) infection among HIV-infected adults is low. Therefore, Hib vaccine is not usually recommended for adult use (DIII).

Several factors are associated with a decreased risk for bacterial pneumonia, including the use of combination ART and TMP-SMX used for PCP prophylaxis (472). The use of antimicrobial prophylaxis to prevent bacterial pneumonia has been explored. In many studies, TMP-SMX, when administered daily for PCP prophylaxis, reduces the frequency of bacterial respiratory infections (30, 114,454). This should be considered in selecting an agent for PCP prophylaxis (AII). However, indiscriminate use of this drug (when not indicated for PCP prophylaxis or other specific reasons) might promote development of TMP-SMX-resistant organisms. Thus, TMP-SMX should not be prescribed solely to prevent bacterial respiratory infection (DIII). Similarly, clarithromycin administered daily or azithromycin administered weekly for MAC prophylaxis might be effective in preventing bacterial respiratory infections (421,484). This should be considered in selecting an agent for prophylaxis against MAC (BII). However, these drugs should not be prescribed solely for preventing bacterial respiratory infection (DIII).

An absolute neutrophil count that is depressed because of HIV disease or drug therapy is associated with an increased risk for bacterial infections, including pneumonia. To reduce the risk for such bacterial infections, health-care providers might consider taking steps to reverse neutropenia, either by stopping myelosuppressive drugs (CII) or by administering granulocyte-colony stimulating factor (G-CSF) (CII).

Modifiable factors associated with an increased risk for bacterial pneumonia include smoking cigarettes and other drugs, injection-drug use (IDU), and alcohol use (138,454,485,486). Clinicians should encourage cessation of these behaviors, although no data exist to indicate that cessation decreases risk (CIII).

Inactivated influenza vaccine should be administered annually to all HIV-infected persons during influenza season (AIII). This recommendation is pertinent to prevention of bacterial pneumonia, which might occur as a complication of influenza illness. Live attenuated influenza vaccine is contraindicated for HIV-infected persons (EIII).

Treatment of Disease

The principles of the treatment of community-acquired bacterial pneumonia are the same for HIV-infected persons as for HIV-uninfected persons (475). Usually, collection of specimens for microbiologic studies should be performed before the initiation of antibiotic therapy. However, antibiotic therapy should be administered promptly, without waiting for the results of diagnostic testing.

An assessment of disease severity and arterial oxygenation should be performed in all persons with pneumonia. Noninvasive measurement of arterial oxygen saturation via pulse oximetry is an appropriate screening test. However, ABG analysis is indicated for persons with evidence of hypoxemia suggested by noninvasive assessment and for persons with tachypnea and/or respiratory distress. Criteria that were developed to assess CAP disease severity in HIV-uninfected persons have been found to be valid for HIV-infected persons (473). Unlike recommendations for CAP therapy in non-HIV patients, no HIV-infected patient should receive macrolide monotherapy because of the increased risk for drug-resistant Streptococcus pneumoniae in the HIV-infected patient.

Outpatient Treatment

HIV-infected persons who are being treated as outpatients should receive an oral beta-lactam plus an oral macrolide (AII). Preferred beta-lactams are high-dose amoxicillin and amoxicillin-clavulanate; cefpodoxime and cefuroxime are alternatives. Preferred macrolides are azithromycin and clarithromycin. Oral doxycycline is an alternative to the macrolide (CIII).

For persons who are allergic to penicillin or who have received a beta-lactam within the previous 3 months, an oral respiratory fluoroquinolone (moxifloxacin, levofloxacin [750 mg/day], or gemifloxacin) should be used (AII). Respiratory fluoroquinolones are active against Mycobacterium tuberculosis. Thus, persons with TB who are treated with fluoroquinolone monotherapy might respond initially, but this response might be misleading, might delay the diagnosis of TB and the initiation of appropriate multi-drug therapy, and might increase the risk for transmission of TB. Thus, fluoroquinolones should be used with caution in patients in whom TB is suspected but who are not being treated with concurrent standard four-drug TB therapy. Because HIV-infected persons have an increased incidence of TB and the presentation of TB can be varied in HIV-infected persons, fluoroquinolones should be used only when the presentation strongly suggests bacterial pneumonia.

Increasing pneumococcal resistance rates have suggested that empirical therapy with a macrolide alone cannot be routinely recommended (DIII). Patients who are receiving a macrolide for MAC prophylaxis should never receive macrolide monotherapy for empiric treatment of bacterial pneumonia.

Non-ICU Inpatient Treatment

HIV-infected persons who are being treated as inpatients should receive an IV beta-lactam plus a macrolide (AII). Preferred beta-lactams are ceftriaxone, cefotaxime, or ampicillin-sulbactam. Doxycycline is an alternative to the macrolide (CIII).

For persons who are allergic to penicillin or who have received a beta-lactam within the previous 3 months, an IV respiratory fluoroquinolone (moxifloxacin or levofloxacin [750 mg/day]) should be used (AII). Because of the activity of fluoroquinolones against Mycobacterium tuberculosis and the dangers of monotherapy in persons with TB, fluoroquinolones should be used with caution in patients in whom TB is suspected but is not being treated with concurrent standard four-drug TB therapy.

Increasing pneumococcal resistance rates have suggested that empirical therapy with a macrolide alone cannot be recommended routinely (DIII). Patients who are receiving a macrolide for MAC prophylaxis should never receive macrolide monotherapy for empiric treatment of bacterial pneumonia.

ICU Treatment

Persons with severe pneumonia who require intensive care should be treated with an IV beta-lactam plus either IV azithromycin (AII) or an IV respiratory fluoroquinolone (moxifloxacin or levofloxacin [750 mg/day]) (AII). Preferred beta-lactams are ceftriaxone, cefotaxime, or ampicillin-sulbactam.

For persons who are allergic to penicillin or who have received a beta-lactam within the previous 3 months, aztreonam plus an IV respiratory fluoroquinolone (moxifloxacin or levofloxacin [750 mg/day]) should be used (BIII).

Infections with the overwhelming majority of CAP pathogens will be treated adequately by use of the recommended empirical regimens. The increased incidence of P. aeruginosa and S. aureus as a cause of CAP is the exception. These pathogens occur in specific epidemiologic patterns with distinct clinical presentations, for which empirical antibiotic coverage might be warranted. Diagnostic tests (sputum Gram stain and culture) are likely to be of high yield for these pathogens, allowing early discontinuation of empirical treatment if results are negative.

Empiric Pseudomonas aeruginosa Treatment

If risk factors for Pseudomonas infection are present, an antipneumococcal, antipseudomonal beta-lactam plus either ciprofloxacin or levofloxacin (750 mg dose) should be used (BIII). Preferred beta-lactams are piperacillin-tazobactam, cefepime, imipenem, or meropenem. An antipneumococcal, antipseudomonal beta-lactam plus an aminoglycoside and azithromycin (BIII) or an antipneumococcal, antipseudomonal beta-lactam plus an aminoglycoside and an antipneumococcal fluoroquinolone (BIII) are alternatives. For persons who are allergic to penicillin or who have received a beta-lactam within the previous 3 months, aztreonam can be used in place of the beta-lactam (BIII).

Empiric Staphylococcus aureus Treatment

If risk factors for Staphylococcus aureus infection, including community-acquired methicillin-resistant S. aureus, are present, vancomycin (possibly in combination with clindamycin) or linezolid alone should be added to the antibiotic regimen (BIII).

Pathogen-Directed Therapy

When the etiology of pneumonia has been identified on the basis of reliable microbiological methods, antimicrobial therapy should be directed at that pathogen (BIII).

Switch from Intravenous to Oral Therapy

For patients with CAP who begin IV antibiotic therapy, switching to oral therapy should be considered when they are improving clinically, are able to swallow and tolerate oral medications, and have intact gastrointestinal function. Suggested criteria for clinical stability include oral temperature <37.8 °C, heart rate <100 beats/minute, respiratory rate <24 breaths/minute, systolic blood pressure >90 mm Hg, and room air oxygen saturation >90% or partial pressure of oxygen in arterial blood (PaO2) >60 mm Hg (475).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

The clinical response to appropriate antimicrobial therapy is similar in HIV-infected and non-HIV-infected persons (487). A clinical response (i.e., a reduction in fever and improvement in respiratory symptoms, physical findings, and laboratory studies) is typically observed within 48--72 hours after the initiation of appropriate antimicrobial therapy. Usually, radiographic improvement might lag behind clinical improvement. If a patient has progressive pneumonia in spite of therapy, leading to severe CAP, adjunctive therapy with corticosteroids might be appropriate to ameliorate the inflammatory reaction to killing bacteria in the lung parenchyma (CIII).

IRIS has not been described in association with bacterial respiratory disease and treatment with ART in HIV-infected persons.

Management of Treatment Failure

Persons who fail to respond to appropriate antimicrobial therapy should undergo further evaluation to search for other infectious and noninfectious causes of pulmonary dysfunction. The possibility of TB should always be considered in HIV-infected persons with pulmonary disease.

Preventing Recurrence

HIV-infected persons should receive pneumococcal and influenza vaccine as recommended. Clinicians can administer antibiotic chemoprophylaxis to HIV-infected patients who have frequent recurrences of serious bacterial respiratory infections (CIII). TMP-SMX, administered for PCP prophylaxis, and clarithromycin or azithromycin, administered for MAC prophylaxis, are appropriate for drug-sensitive organisms. However, health-care providers should be cautious when using antibiotics solely for preventing the recurrence of serious bacterial respiratory infections because of the potential development of drug-resistant microorganisms and drug toxicity.

Special Considerations During Pregnancy

The diagnosis of bacterial respiratory-tract infections among pregnant women is the same as for nonpregnant women, with appropriate shielding of the abdomen during radiographic procedures. Bacterial respiratory-tract infections should be managed as in nonpregnant women, with certain exceptions. Because of an increased risk for birth defects evident in some animal studies, clarithromycin is not recommended as the first-line agent among macrolides. Two studies, each involving at least 100 women with first-trimester exposure to clarithromycin, did not document a clear increase in or specific pattern of birth defects, although an increased risk for spontaneous abortion was noted in one study (452,453). Azithromycin did not produce birth defects in animal studies, but experience with human use in the first trimester is limited. Azithromycin is recommended when a macrolide is indicated in pregnancy (BIII). Arthropathy has been noted in immature animals exposed in utero to quinolones. However, approximately 400 cases of quinolone use in human pregnancies have been reported to various pregnancy registries, and use has not been associated with human arthropathy or birth defects after in utero exposure. Thus, quinolones can be used in pregnancy for serious respiratory infections when indicated (CIII) (395). Doxycycline is not recommended for use during pregnancy because of increased hepatotoxicity and staining of fetal teeth and bones. Beta-lactam antibiotics have not been associated with teratogenicity or increased toxicity in pregnancy. Aminoglycosides may be used as needed. Although a theoretical risk for fetal renal or eighth nerve damage can occur with exposure during pregnancy, this finding has not been documented in humans except with streptomycin (10% risk) and kanamycin (2% risk). Experience with linezolid in human pregnancy has been limited, but it was not teratogenic in mice, rats, and rabbits.

Rates for preterm labor and preterm delivery are increased with pneumonia during pregnancy. Pregnant women with pneumonia after 20 weeks of gestation should be monitored for evidence of contractions (BII).

Pneumococcal vaccine can be administered during pregnancy (AIII). Although its safety during the first trimester of pregnancy has not been evaluated, no adverse consequences have been reported among newborns whose mothers were inadvertently vaccinated during pregnancy. Inactivated influenza vaccine also can be administered during pregnancy, and influenza vaccine is recommended for all pregnant women who will be pregnant during influenza season (AIII). Live attenuated influenza vaccine should not be used during pregnancy (EIII). Because administration of vaccines might be associated with a transient rise in plasma HIV RNA levels, vaccination of pregnant women is recommended after ART has been initiated to minimize increases in plasma HIV RNA levels that might increase the risk for perinatal HIV transmission.

Bacterial Enteric Infections

Epidemiology

Incidence rates of gram-negative bacterial enteric infections are 20- to 100-fold higher among HIV-infected adults than in the general population (488-492). The most common causes among adults in the United States are Salmonella (particularly Salmonella serotypes Typhimurium and Enteritidis), Shigella, and Campylobacter. As with non-HIV-associated bacterial enteric infections, the probable source for most HIV-infected associated infections is ingestion of contaminated food or water (490). Sexual activity with the potential for fecal-oral exposure also increases risk for infections, especially with Shigella (493) and Campylobacter (494). Acquisition of enteric bacterial infections might be facilitated by HIV-associated gastric achlorhydria, by treatment with agents that decrease gastric acid secretion, and by HIV-associated alterations in mucosal immunity. Although diarrheagenic Escherichia coli, especially enteroaggregative E. coli, are a frequent cause of diarrhea among HIV-infected persons in resource-limited settings, they do not appear to cause more morbidity in HIV-infected patients than in other persons in more developed regions (495).

Clinical Manifestations

The three major clinical syndromes of infection with gram-negative enteric bacteria among HIV-infected patients include the following:

• Self-limited gastroenteritis;
• A more severe and prolonged diarrheal disease, associated with fever, bloody diarrhea, weight loss, and possible bacteremia (bloody diarrhea is more frequent with Shigella but also can occur with Campylobacter or Salmonella (496,497); and
• Septicemia, which can exhibit extra-intestinal involvement with or without concurrent or preceding gastrointestinal illness (498--501).

The risk for more profound illness increases with the degree of immunosuppression (488,490,491,502). Relapses in infections with Salmonella and other gram-negative bacterial enteric pathogens after appropriate treatment have been well-documented in HIV-infected patients (497,503,504). Salmonella is a particularly common cause of septicemia, which is prone to relapse. Recurrent Salmonella septicemia constitutes an AIDS-defining illness and might require chronic suppressive therapy (488). The development of antimicrobial resistance during therapy, often associated with clinical deterioration or relapse, can also occur among HIV-infected persons with gram-negative enteridities (500,501).

Diagnosis

The diagnosis of gram-negative bacterial enteric infection is established through cultures of stool and blood. Because of the high rate of bacteremia associated with Salmonella gastroenteritis in HIV-infected patients, in particular patients with advanced disease, blood cultures should be obtained from any patient with diarrhea and fever.

HIV-infected persons are notably at risk for infection with non-jejuni non-coli Campylobacter species, including C. fetus, C. upsaliensis, C. lari, and the enterohepatic Helicobacter species, H. cineadi, and H. fennelliae (originally described as Campylobacter species). Although blood culture systems will typically grow these bacteria, routine stool cultures performed by most laboratories will fail to identify these more fastidious organisms, which require special conditions for stool culture. Clinicians might wish to notify their clinical laboratory service of a patient's HIV status and to consider evaluation of stool specimens for non-jejuni non-coli Campylobacter if initial microbiological evaluation is unrevealing. Endoscopy can be diagnostically useful. If lower endoscopy is performed, ulcerations similar to those seen with CMV colitis might be evident and can only be distinguished through histopathologic examination and culture. Clinicians should notify their microbiology laboratories if they suspect infection with diarrheagenic E. coli so that appropriate molecular diagnostic methods can be used or the specimen can be sent to a reference laboratory.

Preventing Exposure

Scrupulous handwashing can reduce risk for diarrhea in HIV-infected persons, including diarrhea caused by enteric bacteria (242). HIV-infected persons should be advised to wash their hands after potential contact with human feces (e.g., defecation, cleaning feces from infants), after handling pets or other animals, after gardening or other contact with soil, before preparing food, before eating, and before and after sex (AIII). HIV-infected persons should avoid unprotected sex practices that might result in oral exposure to feces (e.g., anal sex, oral-anal contact) and in addition to hand-washing they should be advised to use barriers during sex to reduce exposures when possible (e.g., condoms, dental dams) (AIII).

Food

Health-care providers should advise HIV-infected persons, particularly those with a CD4⁺ count <200 cells/µL, not to eat raw or undercooked eggs, including specific foods that might contain raw eggs (e.g., certain preparations of hollandaise sauce, Caesar and other salad dressings, certain mayonnaises (e.g., homemade), uncooked cookie and cake batter, and eggnog); raw or undercooked poultry, meat, and seafood (raw shellfish in particular); unpasteurized dairy products; unpasteurized fruit juices; and raw seed sprouts (e.g., alfalfa sprouts or mung bean sprouts) (BIII). Poultry and meat are safest when adequate cooking is confirmed by thermometer (i.e., internal temperature of 180º F (82º C) for poultry and 165º F (74º C) for red meats). If a thermometer is not used when cooking meats, the risk for illness is decreased by eating poultry and meat that have no trace of pink color. However, color change of the meat (e.g., absence of pink) does not always correlate with internal temperature. Produce should be washed thoroughly before being eaten (BIII).

Health-care providers should advise HIV-infected persons to avoid cross-contamination of foods. Uncooked meats, including hot dogs, and their juices should not come into contact with other foods (BIII). Hands, cutting boards, counters, knives, and other utensils should be washed thoroughly after contact with uncooked foods (BIII).

Health-care providers should advise HIV-infected persons that, although the incidence of listeriosis is low, it is a serious disease that occurs with unusually high frequency among severely immunosuppressed HIV-infected persons. Immunosuppressed, HIV-infected persons who wish to reduce the risk for acquiring listeriosis should adhere to the following precautions (CIII):

• Avoid soft cheeses (e.g., feta, Brie, Camembert, blue-veined, and Mexican-style cheese such as queso fresco); hard cheeses, processed cheeses, cream cheese (including slices and spreads), cottage cheese, or yogurt need not be avoided.
• Cook leftover foods or ready-to-eat foods (e.g., hot dogs) until steaming hot before eating.
• Avoid foods from delicatessen counters (e.g., prepared salads, meats, cheeses) or heat/reheat these foods until steaming before eating.
• Avoid refrigerated pâtés and other meat spreads or heat/reheat these foods until steaming; canned or shelf-stable pâté and meat spreads need not be avoided.
• Avoid raw or unpasteurized milk (including goat's milk) or milk products or foods that contain unpasteurized milk or milk products.

Pets

HIV-infected persons should avoid direct contact with stool from new pets, dogs or cats aged <6 months, or stray pets (BIII). Gloves should always be worn when handling feces or cleaning areas that might have been contaminated by feces from pets (BIII). Persons should avoid or limit contact with reptiles (e.g., snakes, lizards, iguanas, and turtles) and chicks and ducklings because of the risk for salmonellosis (BIII).

Travel

The risk for foodborne and waterborne infections among immunosuppressed, HIV-infected persons is magnified during travel to economically developing countries. Persons who travel to such countries should avoid foods and beverages that might be contaminated, including raw fruits and vegetables, raw or undercooked seafood or meat, tap water, ice made with tap water, unpasteurized milk and dairy products, and items sold by street vendors (AII). Foods and beverages that are usually safe include steaming hot foods, fruits that are peeled by the traveler, bottled (including carbonated) beverages, hot coffee and tea, beer, wine, and water that is brought to a rolling boil for 1 minute. Treating water with iodine or chlorine might not be as effective as boiling and will not prevent infection with Cryptosporidium but can be used when boiling is not practical (BIII).

Preventing Disease

Prophylactic antimicrobial agents are not usually recommended for travelers (DIII). The effectiveness of these agents depends on gastrointestinal pathogens' local antimicrobial resistance patterns, which are seldom known. Moreover, these agents can elicit adverse reactions, promote the emergence of resistant organisms, and increase risk for enteric Clostridium difficile infection. However, for HIV-infected travelers, antimicrobial prophylaxis can be considered, depending on the level of immunosuppression and the region and duration of travel (CIII). Use of fluoroquinolones or rifaximin can be considered when prophylaxis is deemed necessary (CIII). As an alternative (e.g., for pregnant women and persons already taking TMP-SMX for PCP prophylaxis), TMP-SMX might offer limited protection against traveler's diarrhea (BIII). Risk for toxicity should be considered before treatment with TMP-SMX is initiated solely because of travel.

Treatment of Disease

Immunocompetent hosts without HIV infection often do not require treatment for Salmonella gastroenteritis; the condition is self-limited and treatment might prolong the carrier state. However, no treatment trials have examined the strategy of watchful waiting for spontaneous resolution among patients with HIV infection, and the risk for bacteremia is sufficiently high that most specialists recommend treatment of all HIV-associated Salmonella infections (BIII).

The initial treatment of choice for Salmonella infection is a fluoroquinolone (AIII) (505). Ciprofloxacin is the preferred agent (AIII) (505); other fluoroquinolones (levofloxacin and moxifloxacin) also would likely be effective in treatment of salmonellosis among HIV-infected persons, but these agents have not been well-evaluated in clinical studies (BIII). Depending on antibiotic susceptibility, alternatives to the fluoroquinolones might include TMP-SMX or expanded spectrum cephalosporins (e.g., ceftriaxone or cefotaxime) (BIII).

The length of therapy for HIV-related Salmonella infection is poorly defined. For patients with CD4⁺ counts >200 cells/µL and mild gastroenteritis, with or without bacteremia, 7--14 days of treatment for salmonellosis is reasonable (BIII); among patients with advanced HIV disease (CD4⁺ count <200 cells/µL), a longer course of antibiotics (e.g., 2--6 weeks) is often recommended (CIII).

Therapy for shigellosis is indicated both to shorten the duration of illness and to prevent spread of the infection to others (AIII) (505). The recommended treatment is with a fluoroquinolone for 3--7 days (AIII). Depending on antibiotic susceptibilities, alternatives to this treatment may include TMP-SMX for 3--7 days or azithromycin for 5 days (BIII). Cases of shigellosis acquired internationally have high rates of TMP-SMX resistance; in addition, HIV-infected persons have higher rates of adverse effects related to this agent. As a result, fluoroquinolones are preferred as first-line treatment. Treating patients who have Shigella bacteremia is less well defined. Depending on the severity of infection, extending treatment to 14 days is reasonable, using the agents described previously (BIII).

As with non-HIV-infected patients, the optimal treatment of campylobacteriosis among persons with HIV infection is poorly defined. Among patients with mild disease, some clinicians might opt to withhold therapy unless symptoms persist for more than several days. Increasing resistance to fluoroquinolones makes the choice of therapy especially problematic. For mild-to-moderate campylobacteriosis, initiating therapy with a fluoroquinolone (e.g., ciprofloxacin) or a macrolide (e.g., azithromycin), pending susceptibility test results, and treating for 7 days is a reasonable approach (BIII). Patients with bacteremia should be treated for >2 weeks (BIII), and adding a second active agent (e.g., an aminoglycoside) might be prudent (CIII).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Patients should be monitored closely for response to treatment, as defined clinically by improvement in systemic signs and symptoms and resolution of diarrhea. A follow-up stool culture to demonstrate clearance of the organism is not generally required if a complete clinical response has been demonstrated, but should be considered for those patients who fail to respond clinically to appropriate antimicrobial therapy or when public health considerations dictate the need to ensure microbiologic cure (e.g., health-care or food service workers). If after a diagnosis of gram-negative bacterial enteritis and diarrhea persists or recurs after intervention, other enteric infections should be considered, particularly Clostridium difficile.

IRIS has not been described in association with treatment for bacterial enteric diarrhea.

Management of Treatment Failure

Treatment failure is defined by the lack of improvement in clinical signs and symptoms of diarrheal illness and the persistence of organisms in stool, blood, or other relevant body fluids or tissue after completion of appropriate antimicrobial therapy for the recommended duration. Some patients with Salmonella bacteremia might remain febrile for 5--7 days despite effective therapy. Therefore, careful observation is required to determine the adequacy of the response.

Treatment should be guided by drug susceptibility testing of isolates recovered in culture. An evaluation of other factors that might contribute to failure or relapse, such as malabsorption of oral antibiotics, a sequestered focus of infection (e.g., an undrained abscess), adverse drug reactions that interfere with antimicrobial activity, or infection with other agents (e.g., C. difficile) should be undertaken as indicated.

Preventing Recurrence

HIV-infected persons with Salmonella septicemia, which typically occurs in those with advanced HIV disease (e.g., CD4⁺ count <200 cells/µL), should be monitored clinically for recurrence after treatment (BIII). For persons with recurrent Salmonella septicemia, 6 months or more of antibiotics treatment of acute disease should be considered as secondary prophylaxis, although the value of this intervention has not been established and must be weighed against the risks of long-term antibiotic exposure (CIII). In patients who have responded to ART, secondary prophylaxis can probably be stopped. Chronic suppressive or maintenance therapy is not recommended for Campylobacter or Shigella infections among persons with HIV infection (EIII). Household contacts of HIV-infected persons who have salmonellosis or shigellosis should be evaluated for persistent asymptomatic carriage of Salmonella or Shigella so that strict hygienic measures or antimicrobial therapy can be instituted and recurrent transmission to the HIV-infected person prevented (BIII).

Special Considerations During Pregnancy

The diagnosis of bacterial enteric infections among pregnant women is the same as among nonpregnant women. Bacterial enteric infections in the pregnant woman should be managed as in the nonpregnant woman, with several considerations. Arthropathy has been noted in immature animals when quinolones are used during pregnancy. However, approximately 400 cases of quinolone use in pregnancy have been reported to various pregnancy registries, and use has not been associated with arthropathy or birth defects after in utero exposure. Thus, quinolones can be used in pregnancy for bacterial enteric infections in HIV-infected pregnant women as indicated (CIII) (395). Alternate agents for use in pregnancy include expanded spectrum cephalosporins, TMP-SMX, or azithromycin, depending on the organism and the results of susceptibility testing (CIII). Neonatal-care providers should be informed if maternal sulfa therapy is used near delivery because of the theoretical increased risk for hyperbilirubinemia and kernicterus to the newborn.

Bartonellosis

Epidemiology

Bartonella species cause infections that include cat scratch disease, trench fever, relapsing bacteremia, endocarditis, bacillary angiomatosis (BA), and bacillary peliosis hepatis (506). The latter two manifestations occur only in immunocompromised persons. BA is caused by either B. quintana or B. henselae (506,507). Nineteen species of Bartonella have been identified, and five have been isolated from humans. However, only B. henselae and B. quintana infections have been identified in HIV-infected persons (507). BA most often occurs late in HIV infection, in patients with a median CD4⁺ count of <50 cells/µL (507). In HIV-infected patients, bartonellosis is often a chronic illness, lasting for months to years, with BA lesions and intermittent bacteremia.

Development of BA lesions caused by B. henselae is statistically linked to cat exposure in patients with HIV infection (507). In contrast, BA caused by B. quintana is associated with body louse infestation and homelessness (507). The body louse serves as the vector of B. quintana among humans. The cat flea is the vector of B. henselae among cats. However, the cat is the most common vector (via a scratch) that is responsible for transmitting B. henselae to humans, most likely when claws become contaminated with feces from B. henselae-infected fleas. In some areas of the United States, the prevalence of B. henselae bacteremia in pet cats approaches 50% (508). Control of cat flea infestation and avoidance of cat scratches are therefore critical strategies for prevention of B. henselae infections in HIV-infected persons. To avoid exposure to B. quintana, HIV-infected patients should avoid and treat infestation with body lice.

Clinical Manifestations

BA lesions have been associated with nearly every organ system, but cutaneous lesions are the most readily identified. BA lesions can be clinically indistinguishable from KS. BA also can cause subcutaneous nodules. Osteomyelitis is usually caused by B. quintana, and only B. henselae can cause bacillary peliosis hepatis. Although isolated organs can appear to be the principal focus of disease, BA represents a hematogenously disseminated infection, and systemic symptoms of fever, night sweats, and weight loss often accompany BA. Bartonella infection is a major cause of unexplained fever in late-stage AIDS patients and should be considered in the differential diagnosis of patients with fever and a CD4⁺ count of <100 cells/µL (509).

Diagnosis

Diagnosis can be confirmed by histopathologic examination of biopsied tissue (510). BA lesions are characterized by vascular proliferation, and a modified silver stain (e.g., Warthin-Starry stain) usually demonstrates numerous bacilli. Tissue Gram staining and acid-fast staining are negative.

A well-characterized serologic test was developed at CDC (511) and is also available at some state health labs. In addition, several private laboratories offer serological testing, but none of these private laboratory tests has been evaluated for sensitivity or specificity with sera from HIV-infected patients. In immunocompetent patients, anti-Bartonella antibodies might not be detectable for 6 weeks after acute infection; in contrast, by the time Bartonella infection is suspected in patients with late-stage HIV infection, they usually have been infected for months or even >1 year. Note that as many as 25% of Bartonella culture-positive patients might never develop antibodies in the setting of advanced HIV infection (509). In those patients who do develop anti-Bartonella antibodies, monitoring of antibody levels might correlate with resolution and recrudescence of Bartonella infection.

Bartonella species can be isolated (with difficulty) from blood, using EDTA tubes. The organisms have been isolated from tissue in only a few laboratories because of the fastidious nature of Bartonella (507). PCR methods have been developed for identification and speciation of Bartonella, but are not widely available.

Preventing Exposure

HIV-infected persons, specifically those who are severely immunocompromised (CD4⁺ counts <100 cells/µL), are at high risk for severe disease caused by B. quintana and B. henselae. The major risk factors for acquisition of B. henselae are contact with cats infested with fleas and receiving cat scratches. Immunocompromised persons should consider the potential risks of cat ownership (AIII). Persons who acquire a cat should acquire an animal aged >1 year and in good health (BII). Cats should be acquired from a known environment, have a documented health history, and be free of fleas. Stray cats and cats with flea infestation should be avoided. Declawing is not advised, but HIV-infected persons should avoid rough play with cats and situations in which scratches are likely (AII). Patients should avoid contact with flea feces ("flea dirt"), and any cat-associated wound should be washed promptly (BIII). Care of cats should include a comprehensive, ongoing flea-control program under the supervision of a veterinarian (BIII). No evidence indicates any benefits to cats or their owners from routine culture or serologic testing of the pet for Bartonella infection or from antibiotic treatment of healthy, serologically positive cats (DII). The major risk factor for B. quintana infection is body lice infestation. Homeless or marginally housed persons should be informed that body louse infestation can be associated with serious illness and provided with appropriate measures to eradicate body lice, if present (AII).

Preventing Disease

Primary chemoprophylaxis for Bartonella-associated disease is not recommended (DIII). However, note that in a retrospective case-control study, MAC prophylaxis using a macrolide or rifamycin was protective against developing Bartonella infection (507).

Treatment of Disease

Guidelines for treatment of Bartonella infections have been published (512). No randomized, controlled clinical trials have evaluated antimicrobial treatment of bartonellosis in HIV-infected patients. Erythromycin and doxycycline have been used successfully to treat BA, peliosis hepatis, bacteremia, and osteomyelitis and are considered first-line treatment for bartonellosis, on the basis of reported experience in case series (AII) (506,507). Therapy should be administered for >3 months (AII). Doxycycline, with or without RIF, is the treatment of choice for bartonellosis infection involving the central nervous system (CNS) and other severe bartonellosis infections (AIII).

Clarithromycin or azithromycin treatment has been associated with clinical response and either of these can be an alternative for Bartonella treatment (BIII). Azithromycin is recommended for patients who are less likely to comply with the more frequent dosing schedule for doxycycline or erythromycin. Penicillins and first-generation cephalosporins have no in vivo activity and should not be used for treatment of bartonellosis (DII). Quinolones and TMP-SMX have variable in vitro activity and an inconsistent clinical response in case reports and are not recommended (DIII).

IRIS has not been described in association with Bartonella infection, but patients with Bartonella CNS or ophthalmic lesions should probably be treated with doxycycline and RIF for 2--4 weeks before instituting ART.

Monitoring and Adverse Effects, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Patients treated with oral doxycycline should be cautioned about pill-associated ulcerative esophagitis that occurs most often when a dose is taken with only a small amount of liquid or at night just before retiring (AIII) (513).

No immune inflammatory response syndrome has been described in association with Bartonellosis and treatment with ART in HIV-infected persons.

Management of Treatment Failure

Among patients who fail to respond to initial treatment, one or more of the second-line alternative regimens should be considered (AIII).

Preventing Recurrence

Relapse can occur after a course of primary treatment. In this setting, long-term suppression of infection with doxycycline or a macrolide is recommended, as long as the CD4⁺ count remains <200 cells/µL (AIII).

Long-term suppression can be discontinued after the patient has received 3--4 months of therapy and when the CD4⁺ count remains >200 cells/µL for >6 months (CIII). Certain specialists would discontinue therapy only if the Bartonella titers have also decreased by fourfold (CIII).

Special Considerations During Pregnancy

Infection with B. bacilliformis in immunocompetent patients during pregnancy has been associated with increased complications and risk for death (514). No data are available on the effect of B. henselae or B. quintana infections in pregnant women with concomitant HIV infection.

The approach to diagnosis of Bartonella infections in pregnant women is the same as in nonpregnant women. Erythromycin treatment should be used (AIII) rather than tetracyclines (EII) during pregnancy because of the increased risk for hepatotoxicity and the accumulation of tetracycline in fetal teeth and bones, resulting in dark, permanent staining of fetal teeth. Third-generation cephalosporins (e.g., ceftizoxime (515) or ceftriaxone) might have efficacy against Bartonella in the pregnant HIV-infected woman, but should be considered second-line therapy after a macrolide. First- and second-generation cephalosporins are not recommended because of their lack of efficacy against Bartonella (EII).

Syphilis

Epidemiology

Syphilis is associated with increased risk for HIV sexual acquisition and transmission (516,517). Recent reports indicate a resurgence of syphilis among men in several U.S. cities and in Western Europe (518--524). Although coexistent HIV infection, particularly in the advanced stages, can modify the diagnosis, natural history, or management of Treponema pallidum infection, the principles of syphilis management are the same for persons with and without coexistent HIV infection (525--529). Recent syphilis treatment recommendations are available in the 2006 CDC STD Treatment Guidelines (529,530).

Clinical Manifestations

Despite multiple case reports and small case series, limited large studies have documented the effect of coexistent HIV on the protean manifestations of syphilis. The few larger studies suggest that HIV infection might shift the clinical manifestations of syphilis, making clinical lesions more apparent, and might accelerate progression of syphilitic disease (526,527). Early syphilis in HIV-infected persons may also cause a transient decrease in CD4⁺ count and increase in HIV viral load that improves with standard treatment regimens (531--533).

Primary syphilis commonly exhibits a single painless nodule at the site of contact that rapidly ulcerates to form a classic chancre; however, among HIV-infected persons, multiple or atypical chancres occur and primary lesions might be absent or missed (526,534).

Progression to secondary syphilis typically follows 2--8 weeks after primary inoculation. Although more rapid progression or severe disease might occur among HIV-infected persons with advanced immunosuppression, the clinical manifestations are similar to those among HIV-uninfected persons. The manifestations of secondary syphilis involve virtually all organ systems. The most common manifestations, macular, maculopapular, papulosquamous, or pustular skin lesions, usually begin on the trunk and spread peripherally, involving palms and soles and accompanied by generalized lymphadenopathy and fever, malaise, anorexia, arthralgias, and headache (527--529). Condyloma lata, moist, flat, papular lesions in warm intertrigenous regions, might resemble papilloma virus infection. Secondary syphilis, particularly acute syphilitic meningitis, can resemble acute primary HIV infection; constitutional symptoms, along with nonfocal CNS symptoms and CSF abnormalities (e.g., lymphocytic pleocytosis with a mildly elevated CSF protein), are common to both (534--539).

Signs and symptoms of secondary syphilis can persist from a few days to several weeks before resolving and evolving to latent or later stages. Latent syphilis lacks overt clinical signs and symptoms, but relapse of manifestations of secondary syphilis might occur, most commonly during the first 1--4 years following infection.

Manifestations of "late" syphilis generally include neurosyphilis, cardiovascular syphilis, and gummatous syphilis or a slowly progressive disease that can affect any organ system. Neurosyphilis can occur at any stage of syphilis. Asymptomatic neurosyphilis is defined as one or more CSF abnormalities (i.e., elevated protein, lymphocytic pleocytosis, or positive VDRL) in the absence of symptoms or signs. Manifestations of symptomatic neurosyphilis (i.e., meningitis or meningovascular or parenchymatous disease) among HIV-infected persons are similar to those in the HIV-uninfected persons. However, clinical manifestations of neurosyphilis, such as concomitant uveitis and meningitis, might be more common among HIV-infected persons (538).

Diagnosis

The diagnosis of syphilis depends on direct detection of the organism (e.g., by darkfield microscopy, direct fluorescent antibody-Treponema pallidum, biopsy with silver stain), or on presumptive serologic diagnosis based upon nontrepomenal tests (e.g., Venereal Disease Research Laboratory [VDRL] and rapid plasma reagin [RPR]) and treponemal tests (e.g., FTA-ABS and TP-PA). The serologic diagnosis of syphilis traditionally has involved screening for nontreponemal antibodies with confirmation of reactive tests by treponemal-based assays (529,540). Recently, some laboratories have initiated a testing algorithm using treponemal-based enzyme immunoassay (EIA) as a screening test with nontreponemal testing for confirmation. This latter strategy may more often identify those with a previous syphilis infection along with those having untreated infection (541). Clinical experience suggests that concurrent HIV infection probably does not change the performance of standard tests for the diagnosis of syphilis. However, false-positive nontreponemal serologic tests that are not confirmed by treponemal serologic tests might be more common among HIV-infected persons (542,543).

Early-stage disease (i.e., primary, secondary, and early-latent syphilis) among HIV-infected persons is confirmed by the identical procedures used for the HIV-uninfected person (e.g., darkfield microscopy of a mucocutaneous lesion and standard serologic tests). HIV infection does not decrease the sensitivity or specificity of darkfield microscopy. Responses to nontreponemal serologic tests (i.e., VDRL and RPR) might be atypical (i.e., higher, lower, or delayed) among HIV-infected versus HIV-uninfected persons with early-stage syphilis (543,544). No data indicate that treponemal tests perform differently among HIV-infected compared with -uninfected patients (545). Similar to HIV-uninfected persons, false-negative serologic tests for syphilis can occur both among HIV-uninfected and HIV-infected persons with documented T. pallidum infection (546,547). Therefore, if serologic tests do not confirm the diagnosis of suspected syphilis, other diagnostic procedures (e.g., repeat serology in 1--2 weeks, exclusion of prozone phenomenon, biopsy, darkfield examination, or direct fluorescent antibody staining of lesion material) should be pursued. By definition, persons with latent syphilis have serological evidence of syphilis in the absence of clinical or other laboratory abnormalities (i.e., normal CSF profiles). Patients with early-latent syphilis have documented infection of <1 year; persons with late-latent syphilis have documented infection for >1 year or the duration of infection is not known. The diagnostic testing recommended for detection of late-stage syphilis (e.g., cardiovascular and gummatous syphilis) among HIV-infected persons is the same as for the HIV-uninfected person.

All persons with syphilis, regardless of disease stage, should be evaluated for clinical evidence of CNS or ocular involvement. CSF abnormalities (elevated protein and mononuclear pleocytosis) are common in early syphilis and in persons with HIV infection. However, whether the prognostic significance of such CSF abnormalities differs between HIV-infected persons and HIV-uninfected persons with primary, secondary, or early-latent syphilis is unknown.

CSF examination should be performed in persons with neurologic or ocular signs or symptoms, active tertiary syphilis, and treatment failure. CSF examination is also recommended for HIV-infected persons with late-latent syphilis, including those with syphilis of unknown duration. Some specialists recommend CSF examination for all HIV-infected persons with syphilis regardless of stage, particularly if serum RPR is 1:32 or with a CD4⁺ count of <350 cells/µL (537,539). The risk for developing clinical neurosyphilis in this circumstance is unknown. CSF abnormalities consistent with neurosyphilis should be treated using standard neurosyphilis treatment regimens.

Among persons without HIV infection, diagnosis of neurosyphilis is established by CSF examination, which might indicate mild mononuclear pleocytosis (e.g., 10--200 cells/µL), normal or mildly elevated protein concentration, or a reactive CSF-VDRL (529,537,539). The CSF-VDRL is specific but not sensitive, and a reactive test establishes the diagnosis of neurosyphilis, but a nonreactive test does not exclude the diagnosis. In comparison, CSF treponemal tests (e.g., the CSF FTA-ABS) are sensitive but not specific, with a nonreactive test excluding the diagnosis of neurosyphilis. Calculated indices (e.g., TPHA-index) are of limited value in establishing the diagnosis of neurosyphilis. PCR-based diagnostic methods are not currently recommended as a diagnostic test for neurosyphilis. A reactive CSF-VDRL and a CSF WBC >10 cells/µL support the diagnosis of neurosyphilis; the majority of specialists would not base the diagnosis solely on elevated CSF protein concentrations in the absence of these other abnormalities.

Establishing the diagnosis of neurosyphilis can be more difficult among persons with HIV infection, because HIV infection itself might be associated with mild mononuclear CSF pleocytosis (5--15 cells/µL), particularly among persons with peripheral blood CD4⁺ counts >500 cells/µL. If neurosyphilis cannot be excluded by a nonreactive CSF treponemal test, such persons should be treated for neurosyphilis, despite the acknowledged uncertainty of the diagnosis.

Preventing Exposure

The resurgence of syphilis among persons with HIV infection in the United States underscores the importance of primary prevention of syphilis among persons with HIV infection. This should begin with routine discussion of sexual behaviors. Providers should discuss client-centered risk reduction messages and provide specific actions that can reduce the risk for acquiring sexually transmitted infections and for transmitting HIV (529,548--550). Routine serologic screening for syphilis is recommended at least annually for all sexually active HIV-infected persons, with more frequent screening (every 3--6 months) for those with multiple partners, unprotected intercourse, sex in conjunction with illicit drug use, methamphetamine use, or partners who participate in such activities (529,551). The occurrence of syphilis in an HIV-infected person is an indication of high-risk behavior and should prompt intensified counseling messages and strong consideration of referral for behavioral intervention. Persons undergoing screening or treatment for syphilis also should be evaluated for all common sexually transmitted diseases (STDs) (529).

Preventing Disease

The same measures that apply to preventing exposure apply to preventing disease.

Treatment of Disease

Management of syphilis in HIV-infected persons is similar to the management in HIV-uninfected persons (529,530,544). However, closer follow-up is recommended to detect potential treatment failure or disease progression.

Penicillin remains the treatment of choice for syphilis regardless of HIV status. HIV-infected persons with early-stage (i.e., primary, secondary, or early-latent) syphilis should receive a single intramuscular (IM) injection of 2.4 million units of benzathine penicillin G (AII). Although most HIV-infected persons with early syphilis respond appropriately to standard benzathine penicillin, some specialists recommend two additional weekly benzathine penicillin injections. The benefit of this treatment approach remains unproven. Enhanced penicillin therapy (i.e., standard benzathine penicillin with high-dose oral amoxicillin and probenecid) did not improve clinical outcome in early-stage syphilis (544) and is not recommended (DII) .

The efficacy of alternative nonpenicillin regimens in HIV-infected persons with early syphilis, including oral doxycycline, ceftriaxone, and azithromycin, has not been evaluated sufficiently in HIV-infected persons to warrant use as first-line treatment. Regardless of HIV infection status, the use of any alternative penicillin treatment regimen should be undertaken only with close clinical and serologic monitoring (BIII). Similarly, although some evidence suggests that a single 2-gram oral dose of azithromycin might have efficacy for treating early syphilis (552,553), molecular resistance of T. pallidum to macrolides and clinical treatment failures with azithromycin have been reported (554--556); such treatment should be used only with close clinical and serologic monitoring to detect treatment failure (CII).

In HIV-infected persons with late-latent syphilis for whom the CSF examination excludes the diagnosis of neurosyphilis, treatment with three weekly IM injections of 2.4 million units benzathine penicillin G is recommended (AIII). Alternative therapy with doxycycline 100 mg by mouth twice a day for 28 days has not been sufficiently evaluated in HIV-infected persons to warrant use as first-line treatment (BIII). If the clinical situation requires the use of an alternative to penicillin, treatment should be undertaken with close clinical and serologic monitoring.

HIV-infected persons with clinical evidence of late-stage (tertiary) syphilis (cardiovascular or gummatous disease) should have a CSF examination to rule out neurosyphilis before initiating therapy. The complexity of tertiary syphilis management is beyond the scope of these guidelines and providers are advised to consult an infectious disease specialist.

HIV-infected persons with clinical or laboratory evidence of neurosyphilis (i.e., CNS, otic, or ocular disease) should receive IV aqueous crystalline penicillin G, 18--24 million units daily, administered 3--4 million units IV every 4 hours or by continuous infusion for 10--14 days (AII) or procaine penicillin 2.4 million units IM once daily plus probenecid 500 mg orally four times a day for 10--14 days (BII) (529,537,539). HIV-infected persons who are allergic to sulfa-containing medications should not be administered probenecid because of potential allergic reaction (DIII).

Because neurosyphilis treatment regimens are of shorter duration than those used in late-latent syphilis, some specialists recommend 2.4 million units IM once per week for up to 3 weeks after completion of neurosyphilis treatment to provide a comparable duration of therapy (CIII) (529). Among patients who are allergic to penicillin, penicillin desensitization is the preferred approach to treating neurosyphilis (BIII). However, limited data indicate that ceftriaxone (2 g daily IV for 10--14 days) might be an acceptable alternative regimen (CIII) (557). Other alternative regimens for neurosyphilis have not been evaluated adequately.

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Clinical and serologic responses to treatment of early-stage (i.e., primary, secondary, and early-latent) disease should be monitored at 3, 6, 9, 12, and 24 months after therapy. Serologic responses to treatment are similar in persons with and without HIV infection; however, subtle variations might occur, including the temporal pattern of response (529,530,544,558).

After successful treatment for syphilis (HIV-infected and -uninfected persons), 15%--20% of persons might remain "serofast," meaning that serum nontreponemal test titers remain reactive at low and unchanging titers, usually <1:8, for prolonged periods (529,544). This serofast state probably does not represent treatment failure. Serologic detection of potential reinfection should be based on an at least a fourfold increase in titer above the established serofast baseline.

Response to therapy of late-latent syphilis should be monitored using nontreponemal serologic tests at 6, 12, 18, and 24 months to ensure at least a fourfold decline in titer. Some retrospective studies have documented concomitant HIV infection associated with poorer CSF and serologic responses to neurosyphilis therapy (559,560). CSF examination should be repeated at 6 months after completion of therapy. If clinical symptoms develop or nontreponemal titers rise fourfold, a repeat CSF examination should be performed and treatment administered accordingly. The earliest CSF indicator of response to neurosyphilis treatment is a decline in CSF lymphocytosis. The CSF VDRL might respond more slowly. Nontreponemal serum titers should be monitored during the next 12--24 months and if the titers do not decline fourfold, consultation with an infectious disease specialist is recommended (529).

No IRIS has been described in association with syphilis and treatment with ART in HIV-infected persons.

Management of Treatment Failure

Retreatment of persons with early-stage syphilis should be considered for those who 1) have a sustained fourfold increase in serum nontreponemal titers after an initial reduction after treatment, or 2) have persistent or recurring clinical signs or symptoms of disease (BIII). Certain specialists recommend retreating persons with early syphilis who do not experience at least a fourfold decrease in serum nontreponemal titers 6--12 months after therapy (BIII). If CSF examination does not confirm the diagnosis of neurosyphilis, such persons should receive 2.4 million units IM benzathine penicillin G administered at 1-week intervals for 3 weeks (BIII). Certain specialists also recommend a course of aqueous penicillin G administered IV or procaine penicillin administered IM plus probenecid for treatment of neurosyphilis in this setting, although data to support this practice are lacking (CIII). If titers do not respond appropriately after retreatment, the value of repeated CSF examination or additional therapy has not been established. Persons with HIV infection might be at increased risk for treatment failure and neurologic complications; the magnitude of these risks is not precisely defined but is likely low (536,561).

Persons with late-latent syphilis should have a repeat CSF examination and be retreated if they have clinical signs or symptoms of syphilis, have a fourfold increase in serum nontreponemal test titer, or experience an inadequate serologic response (less than four-fold decline in nontreponemal test titer) within 12--24 months of therapy (BIII). If the CSF examination is consistent with CNS involvement, retreatment should follow the neurosyphilis recommendations (AIII). Persons with latent syphilis and a normal CSF examination should be treated with benzathine penicillin, 2.4 million units IM weekly for 3 weeks (BIII); certain specialists also recommend adding a neurosyphilis regimen in this setting (CIII). Retreatment for neurosyphilis should then be considered if the CSF WBC count has not decreased 6 months after completion of treatment or if the CSF-VDRL remains reactive 2 years after treatment (BIII).

Preventing Recurrence

No recommendations indicate the need for secondary prophylaxis or prolonged chronic maintenance antimicrobial therapy for syphilis in HIV-infected persons. Targeted mass treatment of high-risk populations has not been demonstrated to be effective and is not recommended. Azithromycin is not recommended as secondary prevention because of azithromycin treatment failures reported in HIV-infected persons and reports of macrolide-resistant T. pallidum (554--556).

Special Considerations During Pregnancy

Pregnant women should be screened for syphilis at the first prenatal visit. In areas where syphilis prevalence is high or among women at high risk (e.g., uninsured, women living in poverty, commercial sex workers, and IDUs), testing should be repeated at 28--32 weeks of gestation and at delivery. All women delivering a stillborn infant after 20 weeks of gestation also should be tested for syphilis. Syphilis screening should also be offered at sites providing episodic care to pregnant women at high risk, including emergency departments, jails, and prisons. No infant should leave the hospital without documentation of maternal syphilis-serology status during pregnancy (562).

The rate of transmission to the fetus and adverse pregnancy outcomes of untreated syphilis are highest with primary, secondary, and early-latent syphilis during pregnancy and decrease with increasing duration of infection thereafter. Pregnancy does not appear to alter the clinical course, manifestations, or diagnostic test results of syphilis infection among adults. Concurrent syphilis infection has been associated with increased risk for perinatal transmission of HIV to the infant (563--568).

Treatment during pregnancy should consist of the same penicillin regimen as recommended for the given disease stage among nonpregnant, HIV-infected adults. Because of treatment failures reported after single injections of benzathine penicillin G among HIV-uninfected pregnant women (569), certain specialists recommend a second injection 1 week after the initial injection for pregnant women with early syphilis (529,570). Because of additional concerns about the efficacy of standard therapy in HIV-infected persons, a second injection in 1 week for HIV-infected pregnant women should be considered (BIII).

No alternatives to penicillin have been proven effective and safe for treatment of syphilis during pregnancy or for prevention of fetal infection. Pregnant women who have a history of penicillin allergy should be referred for skin testing and desensitization and treatment with penicillin (AIII) (529). Erythromycin does not reliably cure fetal infection; tetracyclines should not be used during pregnancy because of hepatotoxicity and staining of fetal bones and teeth (EIII). However, because of insufficient information regarding the use of azithromycin (571) or ceftriaxone (572) treatment in pregnancy, routine use is not a recommended (DIII).

A Jarisch-Herxheimer reaction that occurs during the second half of pregnancy might precipitate preterm labor or fetal distress (573). Women should be advised to seek obstetric attention after treatment if they notice contractions or a decrease in fetal movement during the first 24 hours after treatment. During the second half of pregnancy, syphilis management may be facilitated by a sonographic fetal evaluation for congenital syphilis, but this evaluation should not delay therapy. Sonographic signs of fetal or placental syphilis indicate a greater risk for fetal treatment failure. Such cases should be managed in consultation with obstetric specialists. Evidence is insufficient to recommend specific regimens for these situations. After >20 weeks of gestation, fetal and contraction monitoring for 24 hours after initiation of treatment for early syphilis should be considered when sonographic findings indicate fetal infection.

Repeat serologic titers should be performed in the third trimester and at delivery for women treated for syphilis during pregnancy. Data related to serologic response to syphilis in HIV-infected women are insufficient. Titers can be conducted monthly for women at high risk for reinfection. Clinical and antibody response should be appropriate for the stage of disease, although the majority of women will deliver before their serologic response can be definitively assessed. Maternal treatment is likely to be inadequate if delivery occurs within 30 days of therapy, if clinical signs of infection are present at delivery or if the maternal antibody titer is fourfold higher than the pretreatment titer.

Mucocutaneous Candidiasis

Epidemiology

Oropharyngeal and esophageal candidiasis are common (574). The majority of infection is caused by Candida albicans. Fluconazole (or azole) resistance is predominantly the consequence of previous exposure to fluconazole (or other azoles), particularly repeated and long-term exposure (575--577). In this setting, C. albicans resistance has been accompanied by a gradual emergence of non-albicans Candida species, particularly C. glabrata, as a cause of refractory mucosal candidiasis, particularly in patients with advanced immunosuppression (575,578).

The occurrence of oropharyngeal or esophageal candidiasis is recognized as an indicator of immune suppression, and these are most often observed in patients with CD4⁺ counts <200 cells/µL (574). In contrast, vulvovaginal candidiasis is common among healthy, adult women and is unrelated to HIV status. Recurrent vulvovaginal candidiasis alone should not be considered a sentinel of HIV infection among women. The introduction of ART has led to a dramatic decline in the prevalence of oropharyngeal and esophageal candidiasis and a marked diminution in cases of refractory disease.

Clinical Manifestations

Oropharyngeal candidiasis is characterized by painless, creamy white, plaque-like lesions of the buccal or oropharyngeal mucosa or tongue surface. Lesions can be easily scraped off with a tongue depressor or other instrument. Less commonly, erythematous patches without white plaques can be seen on the anterior or posterior upper palate or diffusely on the tongue. Angular chelosis is also noted on occasion and might be caused by Candida.

Esophageal candidiasis is occasionally asymptomatic but retrosternal burning pain or discomfort and odynophagia are often present. Endoscopic examination reveals whitish plaques similar to those observed with oropharyngeal disease that might progress to superficial ulceration of the esophageal mucosa, with central or surface whitish exudates.

Candida vulvovaginitis might be mild to moderate and sporadic, similar to that in normal hosts, and be characterized by a white adherent vaginal discharge associated with mucosal burning and itching. In those with advanced immunosuppression, episodes might be more severe and more frequently recurrent. Compared with oropharyngeal candidiasis, vaginal candidiasis is less frequent and rarely refractory to azole therapy.

Diagnosis

Diagnosis of oropharyngeal candidiasis is usually clinical and based on the appearance of lesions. The feature that distinguishes these from oral hairy leukoplakia is the ability to scrape off the superficial whitish plaques. If laboratory confirmation is required, a scraping for microscopic examination for yeast forms using a potassium hydroxide (KOH) preparation provides supportive diagnostic information. Cultures of clinical material identify the species of yeast present.

The diagnosis of esophageal candidiasis requires endoscopic visualization of lesions with histopathologic demonstration of characteristic Candida yeast forms in tissue and culture confirmation of the presence of Candida species. The diagnosis of vulvovaginal candidiasis is based on the clinical presentation coupled with the demonstration of characteristic pseudohyphal yeast forms in vaginal secretions examined microscopically after KOH preparation. Culture confirmation is rarely required but might provide supportive information. Because self-diagnosis of vulvovaginitis is unreliable, microscopic and culture confirmation is required to avoid unnecessary exposure to inappropriate treatments.

Preventing Exposure

Candida organisms are common commensals on mucosal surfaces in healthy persons. No measures are available to reduce exposure to these fungi.

Preventing Disease

Data from prospective controlled trials indicate that fluconazole can reduce the risk for mucosal (e.g., oropharyngeal, esophageal, and vaginal) candidiasis among patients with advanced HIV disease (579--582). However, routine primary prophylaxis is not recommended because mucosal disease is associated with very low attributable mortality, acute therapy is highly effective, prophylaxis can lead to disease caused by drug-resistant species, prophylactic agents can produce drug interactions, and prophylaxis is expensive (DIII). ART does reduce the likelihood of mucosal candidiasis (AI).

Treatment of Disease

Oral fluconazole is as effective and, in certain studies, superior to topical therapy for oropharyngeal candidiasis. In addition, it is more convenient and typically better tolerated. Therefore, oral fluconazole is considered the drug of choice (AI) (583).

Initial episodes of oropharyngeal candidiasis can be adequately treated with topical therapy, including clotrimazole troches, nystatin suspension or pastilles, or once-daily miconazole mucoadhesive tablets (BII) (584).

Itraconazole oral solution for 7--14 days is as effective as oral fluconazole but less well tolerated (AI). Posaconazole oral solution (585) is also as effective as fluconazole and is generally better tolerated than itraconazole (AI). They are alternatives to oral fluconazole, although few situations require that these drugs would be used in preference to fluconazole solely to treat mucosal candidiasis. In a multicenter, randomized study, posaconazole was proven more effective than fluconazole in sustaining clinical success after antifungal therapy was discontinued (585). Ketoconazole and itraconazole capsules are less effective than fluconazole because of their more variable absorption. Using these agents to treat mucosal candidiasis is not reasonable if the other options are available (DIII).

Systemic antifungals are required for effective treatment of esophageal candidiasis (AI). A 14--21-day course of either fluconazole (oral or IV) or oral itraconazole solution is highly effective (AI). As with oropharyngeal candidiasis, oral ketoconazole or itraconazole capsules are less effective than fluconazole because of variable absorption (DII). Although IV caspofungin (BI) or IV voriconazole (BI) are effective in treating esophageal candidiasis among HIV-infected patients, oral or IV fluconazole remain the preferred therapies (AI).

Two additional parenteral echinocandins, micafungin and anidulafungin, also are approved for the treatment of esophageal candidiasis. Although the three echinocandins are as effective as fluconazole in the treatment of esophageal candidiasis, they all appear to have a greater relapse rate when compared with fluconazole (586,587). Although symptoms of esophageal candidiasis might be mimicked by other pathogens, a diagnostic trial of antifungal therapy is usually appropriate before endoscopy is used to identify causes of esophagitis (CII).

Vulvovaginal candidiasis in HIV-infected women is usually uncomplicated (90%) and responds readily to short-course oral or topical treatment with any of several therapies, including the following regimens:

• Oral fluconazole (AII)
• Topical azoles (clotrimazole, butaconazole, miconazole, ticonazole, or terconazole (AII)
• Itraconazole oral solution (BII)

Severe or recurrent episodes of vaginitis require oral fluconazole or topical antifungal therapy for >7 days (AIII).

ART reduces the frequency of mucosal candidiasis. Refractory cases of mucosal candidiasis typically resolve when immunity improves in response to ART.

IRIS has not been reported in association with episodes of mucosal candidiasis in HIV-positive persons.

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

For the majority of patients with mucocutaneous candidiasis, response to therapy is rapid, with improvement in signs and symptoms within 48--72 hours. Short courses of topical therapy rarely result in adverse effects, although patients might experience cutaneous hypersensitivity reactions, characterized rash, and pruritus. Oral azole therapy can be associated with nausea, vomiting, diarrhea, abdominal pain, or transaminase elevations. If prolonged azole therapy is anticipated (>21 days), periodic monitoring of liver chemistry studies should be considered (CIII).

The echinocandins thus far appear to be safe and free of substantial side effects; histamine-related infusion toxicity, elevation of transaminase, and rash have been attributed to these drugs. No dose adjustments are required in renal failure.

IRIS has not been described because of Candida.

Management of Treatment Failure or Refractory Mucosal Candidiasis

Refractory oral or esophageal candidiasis is still reported in approximately 4%--5% of HIV-infected persons, typically in those patients with CD4⁺ counts <50 cells/µL who have received multiple courses of azole antifungals.

Treatment failure is typically defined as signs and symptoms of oropharyngeal or esophageal candidiasis that persist after more than 7--14 days of appropriate therapy. Oral itraconazole solution is effective at least transiently in approximately two thirds of persons with fluconazole-refractory mucosal candidiasis (AII). Posaconazole immediate-release oral suspension (400 mg bid for 28 days) is effective in 75% of patients with azole refractory oropharyngeal and/or esophageal candidiasis (AII) (588).

IV amphotericin B is usually effective and can be used among patients with refractory disease (BII). Both conventional amphotericin B and lipid complex and liposomal amphotericin B have been used (BII).

Amphotericin B oral suspension (1 mL four times daily of the 100 mg/mL suspension) is sometimes effective among patients with oropharyngeal candidiasis who do not respond to itraconazole (CIII). However, this product is not available in the United States.

Azole-refractory esophageal candidiasis also can be treated with posaconazole (AII), anidulafungin (BII), caspofungin (CII), micafungin (CII), or voriconazole (CIII).

Preventing Recurrence

As with primary prophylaxis, the majority of HIV specialists do not recommend secondary prophylaxis (chronic maintenance therapy) for recurrent oropharyngeal or vulvovaginal candidiasis because of the effectiveness of therapy for acute disease, the low mortality associated with mucosal candidiasis, the potential for resistant Candida organisms to develop, the possibility of drug interactions, and the cost of prophylaxis (DIII). However, if recurrences are frequent or severe, oral fluconazole can be used for either oropharyngeal (BI) or vulvovaginal (CI) candidiasis (579--581). A recent randomized clinical trial (582) has documented that the number of episodes of oropharyngeal candidiasis and other invasive fungal infections was statistically significantly lower in HIV patients with CD4⁺ count <150 cells/µL when receiving continuous (three times a week) fluconazole versus episodic treatment of recurrences. This clinical trial also proved that the development of clinically significant resistance was not higher in the group of continuous prophylaxis than in the group with episodic administration of Fluconazole, provided that patients received ART.

The decision to use secondary prophylaxis should take into account the effect of recurrences on the patient's well-being and quality of life; the need for prophylaxis for other fungal infections; cost, toxicities, and most importantly, drug interactions (589).

For recurrent esophageal candidiasis, daily fluconazole can be used (BI). Oral posaconazole bid is also effective (BII). However, potential azole resistance should be considered when long-term azoles are considered.

Secondary prophylaxis should be instituted in those patients with fluconazole-refractory oropharyngeal or esophageal candidiasis who have responded to echinocandins, voriconazole, or posaconazole therapy because of high relapse rate until ART produces immune reconstitution (CI).

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)

In situations where secondary prophylaxis is instituted, no data support a recommendation regarding discontinuation. On the basis of experience with other OIs, discontinuing secondary prophylaxis when the CD4⁺ count has risen to 200 cells/µL because of ART would be reasonable (CIII).

Special Considerations During Pregnancy

Pregnancy increases the risk for vaginal colonization with Candida species. Diagnosis of oropharyngeal, esophageal, and vulvovaginal candidiasis is the same as among nonpregnant women.

Topical therapy is preferred for treatment of oral or vaginal candidiasis in pregnancy when possible (BIII). Single-dose, episodic treatment with fluconazole has not been associated with birth defects in humans. However, with chronic use of doses of fluconazole of 400 mg or higher in pregnancy, five cases of a syndrome of craniosynostosis, characteristic facies, digital synostosis, and limb contractures have been reported ("fluconazole embryopathy") (590). On the basis of these data, substitution of amphotericin B for high-dose fluconazole in the first trimester is recommended for invasive or refractory esophageal candidal infections (AIII). Neonates born to women on chronic amphotericin B at delivery should be evaluated for renal dysfunction and hypokalemia. Itraconazole has been teratogenic in animals at high doses, but the metabolic mechanism accounting for these defects is not present in humans, so data are not applicable. Case series in humans do not suggest an increased risk for birth defects with itraconazole, but experience is limited. Posaconazole was associated with skeletal abnormalities in rats at doses similar to human levels and was embryotoxic in rabbits. No human data are available for posaconazole. Voriconazole is FDA category D because of cleft palate and renal defects seen in rats and embryotoxicity in rabbits. No human data on use of voriconazole are available, so use in the first trimester is not recommended. Multiple anomalies are seen in animals with micafungin; ossification defects have been seen with anidulafungin and caspofungin. No human data are available for these drugs, and their use in human pregnancy is not recommended (DIII).

Chemoprophylaxis, either primary or secondary, against oropharyngeal, esophageal, or vaginal candidiasis using systemically absorbed azoles should not be initiated during pregnancy (DIII), and prophylactic azoles should be discontinued for HIV-infected women who become pregnant (AIII).

Cryptococcosis

Epidemiology

The majority of HIV-associated cryptococcal infections are caused by Cryptococcus neoformans; rarely, infection because of Cryptococcus neoformans var. gattii is recognized in the United States. Before the advent of potent ART, approximately 5%--8% of HIV-infected patients in developed countries acquired disseminated cryptococcosis (591). The incidence has declined substantially since then (592). The majority of cases are observed among patients who have CD4⁺ counts of <50 cells/µL.

Clinical Manifestations

Among patients with HIV infection, cryptococcosis most commonly occurs as a subacute meningitis or meningoencephalitis with fever, malaise, and headache (591). Classic meningeal symptoms and signs, such as neck stiffness and photophobia, occur in only one fourth to one third of patients. Encephalopathic symptoms, including lethargy, altered mentation, personality changes, and memory loss, usually resulting from elevated intracranial pressure, occurs in small groups of patients.

Analysis of CSF usually demonstrates a mildly elevated serum protein; glucose ranging from low to normal; a pleocytosis consisting mostly of lymphocytes, although some patients have no cells; and a positive Gram or India ink stain for numerous yeasts. The opening pressure in the CSF is usually elevated, with pressures >20 cm H₂O occurring in up to 75% of patients. When cryptococcosis occurs in the HIV-infected patient, disseminated disease is common. Virtually any organ can be involved, and skin lesions mimicking molluscum contagiosum are frequently observed. In addition, isolated pulmonary infection is evident; symptoms and signs include cough and dyspnea in association with an abnormal chest radiograph.

Diagnosis

Cryptococcal antigen is almost invariably detected in CSF at high titer in patients with meningitis or meningoencephalitis. The serum cryptococcal antigen is also almost always positive in cases of CNS disease and in other instances of disseminated infection. As such, testing for serum cryptococcal antigen is a useful initial screening tool in diagnosing cryptococcosis in HIV-infected patients (593). Up to 75% of patients with HIV-associated cryptococcal meningitis have routine blood cultures positive for C. neoformans.

Preventing Exposure

HIV-infected persons cannot completely avoid exposure to C. neoformans. Limited epidemiologic evidence suggests that specific activities, including exposure to bird droppings, lead to an increased risk for infection.

Preventing Disease

Because the incidence of cryptococcal disease is low, routine testing of asymptomatic persons for serum cryptococcal antigen is not recommended (DIII).

Prospective, controlled trials indicate that fluconazole and itraconazole can reduce the frequency of primary cryptococcal disease among patients who have CD4⁺ counts <50 cells/µL (579,594). However, the majority of HIV specialists recommend that antifungal prophylaxis not be used routinely to prevent cryptococcosis because of the relative infrequency of cryptococcal disease, lack of survival benefits associated with prophylaxis, possibility of drug interactions, potential antifungal drug resistance, and cost (DIII). The need for primary prophylaxis or suppressive therapy for other fungal infections (e.g., candidiasis, histoplasmosis, or coccidioidomycosis) should be considered when making decisions concerning primary prophylaxis for cryptococcosis.

Treatment of Disease

The recommended initial standard treatment is amphotericin B deoxycholate, at a dose of 0.7 mg/kg daily, combined with flucytosine, at a dose of 100 mg/kg daily in four divided doses, for >2 weeks for those with normal renal function (AI). Renal function should be monitored closely and the flucytosine dose adjusted appropriately for patients with renal impairment. The addition of flucytosine to amphotericin B during acute treatment is associated with more rapid sterilization of CSF (595,596). The combination of amphotericin B deoxycholate with fluconazole, 400 mg daily (BII), is inferior to amphotericin B combined with flucytosine for clearing Cryptococcus from CSF but is more effective than amphotericin B alone (BII) (597).

Lipid formulations of amphotericin B also are effective and should be considered for patients who experience renal dysfunction during therapy or have a likelihood of having renal failure. The optimal dose of lipid formulations of amphotericin B has not been determined. An unpublished study demonstrated that liposomal amphotericin B (AmBisome®) at a dose of 6 mg/kg daily had an improved outcome over 3 mg/kg daily (598). The noncomparative CLEAR study used a mean dose of amphotericin B lipid complex (ABLC) of 4.4 mg/kg daily to treat cryptococcosis (599). In an Australian study, a 3-week course of liposomal amphotericin B (AmBisome®) at 4 mg/kg daily resulted in more rapid sterilization of CSF than amphotericin B deoxycholate at 0.7 mg/kg daily (600). On the basis of these data, a dose of 4--6 mg/kg daily for lipid formulations of amphotercin B is recommended (AII).

Fluconazole (400--800 mg daily) combined with flucytosine is an alternative to amphotericin B plus flucytosine (598), but is inferior to amphotericin B (601) and is recommended only for persons who are unable to tolerate or unresponsive to standard treatment (CII).

After at least a 2-week period of successful induction therapy, defined as substantial clinical improvement and a negative CSF culture after repeat lumbar puncture, amphotericin B and flucytosine may be discontinued and follow-up therapy initiated with fluconazole 400 mg daily (AI). This therapy should continue for 8 weeks (AI) (595,596,602). Itraconazole is an acceptable though less effective alternative (BI) (602). Limited data are available for the newer triazoles, voriconazole and posaconazole, as either primary or follow-up therapy for patients with cryptococcosis. Voriconazole should be used cautiously with HIV PIs and efavirenz.

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Increased ICP can cause clinical deterioration despite a microbiologic response and is more likely if the CSF opening pressure is >20 cm H₂O (596,603). In one large clinical trial, 93% of deaths that occurred within the first 2 weeks of therapy and 40% of deaths that occurred within weeks 3--10 were associated with increased ICP (603).

At time of diagnosis, all patients with cryptococcal meningitis should have their opening pressure measured in the lateral decubitus position with good manometrics assured; normal values are <25 cm H₂0. Patients with confusion, blurred vision, papilledema, lower extremity clonus, or other neurologic signs of increased ICP should be managed using measures to decrease ICP. Daily lumbar punctures are usually recommended for initial management. One approach is to remove a volume (typically 20--30 mL) of CSF that halves the opening pressure (604). CSF shunting should be considered for patients in whom daily lumbar punctures are no longer tolerated or whose signs and symptoms of cerebral edema are not being relieved (BIII). Corticosteroids, mannitol, and acetazolamide are not recommended (DIII).

After the initial 2 weeks of treatment, a repeat lumbar puncture should be performed to ensure the organism has been cleared from the CSF, even among those who have improved after the initial 2 weeks of treatment. Positive CSF cultures after 2 weeks of therapy are predictive of future relapse and typically less favorable clinical outcomes. If new symptoms or clinical findings occur later, a repeat lumbar puncture, with measurement of opening pressure and CSF culture, should be performed.

Patients treated with amphotericin B should be monitored for dose-dependent nephrotoxicity and electrolyte disturbances. Preinfusion administration of 500 mL of normal saline appears to reduce the risk for nephrotoxicity during treatment. Infusion-related adverse reactions may be ameliorated by pretreatment with acetaminophen and diphenhydramine; in rare cases, glucocorticosteroids administered approximately 30 minutes before the infusion might be required (CIII).

Patients receiving flucytosine should have flucytosine blood levels monitored to prevent bone marrow suppression and gastrointestinal toxicity; peak serum levels, which occur 2 hours after an oral dose, should not exceed 75 µg/mL. Persons treated with fluconazole should be monitored for hepatotoxicity.

An estimated 30% of patients with cryptococcal meningitis and HIV infection experience IRIS after initiation or reinitiation of ART (605). Patients who have cryptococcal IRIS are more likely to be antiretroviral naïve and have higher HIV RNA levels. Appropriate management of IRIS is to continue ART and antifungal therapy (AII). In patients with severely symptomatic IRIS, short-course glucocorticosteroids are recommended by certain specialists (BIII). Delaying the initiation of potent ART might be prudent, at least until the completion of induction therapy (the first 2 weeks) for severe cryptococcosis, especially if patients have elevated ICP (CIII).

Management of Treatment Failure

Treatment failure is defined as either the lack of clinical improvement after 2 weeks of appropriate therapy, including management of increased ICP, or relapse after an initial clinical response, defined as either a positive CSF culture and/or a rising CSF cryptococcal antigen titer with an associated compatible clinical picture. Although fluconazole resistance has been reported with C. neoformans, it is rare in the United States (606). At this time, susceptibility testing is not recommended routinely (DII).

The optimal therapy for patients with treatment failure has not been established. For those initially treated with fluconazole, therapy should be changed to amphotericin B, with or without flucytosine, and continued until a clinical response occurs (BIII). Liposomal amphotericin B (4--6 mg/kg/day) might have improved efficacy over the deoxycholate formulation (600,607) and should be considered in treatment failures (AII). Higher doses of fluconazole in combination with flucytosine also might be useful (BIII). Caspofungin and other echinocandins have no in vitro activity against Cryptococcus spp. and no role in the clinical management of these patients. The newer triazoles, posaconazole and voriconazole, have activity against Cryptococcus spp. in vitro and might have a role in therapy.

Preventing Recurrence

Patients who have completed the initial 10 weeks of therapy for acute cryptococcosis should be administered chronic maintenance therapy with fluconazole 200 mg daily, either lifelong or until immune reconstitution occurs as a consequence of ART (AI). Itraconazole is inferior to fluconazole for preventing relapse of cryptococcal disease (BI) (608,609).

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)

The risk for recurrence of cryptococcosis appears low when patients have successfully completed a course of initial therapy, remain asymptomatic with regard to signs and symptoms of cryptococcosis, and have a sustained increase (i.e., >6 months) in their CD4⁺ counts to >200 cells/µL after ART. The numbers of such patients who have been evaluated remain limited. In a European study, none of 39 subjects whose antifungal therapy was discontinued had a recurrence of cryptococcosis. The median CD4⁺ count of this cohort was 239 cells/µL, the median HIV RNA concentration was <500 copies/mL, and the median time on potent ART was 25 months (610). A prospective randomized study of 60 patients in Thailand documented no cases of recurrence after 48 weeks when the CD4⁺ count was >100 cells/µL and HIV RNA was undetectable for 3 months (611). On the basis of two published studies and inference from data regarding safety of discontinuing secondary prophylaxis for other OIs during advanced HIV disease, discontinuing chronic maintenance therapy among such patients who have successfully completed a course of intial therapy when the CD4⁺ count is consistently >200 cells/µL is reasonable (BII) (612). Certain HIV specialists would perform a lumbar puncture to determine if the CSF is culture negative and antigen negative before stopping therapy even if patients are asymptomatic (CIII). Maintenance therapy should be reinitiated if the CD4⁺ count decreases to <200 cells/µL (AIII).

Special Considerations During Pregnancy

The diagnosis and treatment of cryptococcal infections during pregnancy is similar to that in nonpregnant adults with the following considerations regarding the use of antifungal during pregnancy. Because of their risk for teratogenicity, azole antifungals should be avoided during the first trimester of pregnancy (EII). Neonates born to women on chronic amphotericin B at delivery should be evaluated for renal dysfunction and hypokalemia.

Histoplasmosis

Epidemiology

Histoplasmosis is caused by the dimorphic fungus Histoplasma capsulatum. In the United States, infection is common in several regions where the disease is endemic, especially the Ohio and Mississippi River Valleys. It is also endemic in Latin America, including Puerto Rico. Among persons with HIV infection residing in areas in which histoplasmosis is endemic, symptomatic disease occurs at an annual incidence approaching 5%. Environmental exposure, positive Histoplasma serology, and a CD4⁺ count <150 cells/µL are associated with an increased risk for symptomatic illness (613).

Virtually all cases of primary histoplasmosis are acquired by inhalation of microconidia from the mycelial phase of the organism. Asymptomatic dissemination of infection beyond the lungs is common and cellular immunity is critical in controlling infection. Reactivation of a silent focus of infection that was acquired years earlier can occur when cellular immunity wanes and is the presumed mechanism for disease occurrence in nonendemic areas. The incidence of symptomatic histoplasmosis in patients with HIV infection appears to have declined since the use of potent ART.

Clinical Manifestations

Disseminated histoplasmosis usually occurs in patients with CD4⁺ counts <150 cells/µL (614). Common clinical manifestations include fever, fatigue, weight loss, hepatosplenomegaly, and lymphadenopathy (615). Cough, chest pain, and dyspnea occur in approximately 50% of patients (614). CNS, gastrointestinal, and cutaneous manifestations occur in a smaller percentage (670), and <10% of patients experience shock and multi-organ failure. Other anatomic sites are less commonly involved. Patients with CNS histoplasmosis typically experience fever, headache, and, if brain involvement is present, seizures, focal neurological deficits, and changes in mental status (614,616). Gastrointestinal disease usually is manifested by diarrhea, fever, abdominal pain, and weight loss (617). For patients with CD4⁺ counts >300 cells/µL, symptoms and signs of histoplasmosis are often limited to the respiratory tract.

Diagnosis

Detection of Histoplasma antigen in blood or urine is a sensitive method for rapid diagnosis of disseminated histoplasmosis but is insensitive for pulmonary infection. Antigen is detected in the urine of 95% and serum of 85% of AIDS patients with disseminated histoplasmosis (618). In patients with severe disseminated histoplasmosis, peripheral blood smears can show the organisms engulfed by WBCs. Histopathologic examination of biopsy material from involved tissues demonstrates the characteristic 2--4 µm budding yeast and can provide a rapid diagnosis.

H. capsulatum can be cultured from blood, bone marrow, respiratory secretions, or other involved sites in >85% of patients with AIDS, but organisms might require several weeks to grow (614,618). Serologic tests are less useful than antigen assays in AIDS patients with disseminated histoplasmosis, but might be helpful in patients who have intact immune responses.

The diagnosis of meningitis can be difficult. A lymphocytic pleocytosis is usually associated with elevated protein and low glucose. Fungal stains are usually negative, and CSF cultures are positive in a minority of cases (619). Histoplasma antigen or anti-Histoplasma antibodies can be detected in CSF in up to 70% of cases and either is diagnostic. For some patients, none of these tests are positive, and a presumptive diagnosis of Histoplasma meningitis is appropriate if the patient has disseminated histoplasmosis and findings of CNS infection not explained by another cause.

Preventing Exposure

Although HIV-infected persons living in or visiting areas in which histoplasmosis is endemic cannot completely avoid exposure, those whose CD4⁺ counts are <150 cells/µL should avoid activities known to be associated with increased risk (CIII). Such activities include creating dust when working with surface soil; cleaning chicken coops that are contaminated with droppings; disturbing areas contaminated with bird or bat droppings; cleaning, remodeling, or demolishing old buildings; and exploring caves (CIII).

Preventing Disease

Initiating Primary Prophylaxis

Data from a prospective, randomized, controlled trial indicate that itraconazole can reduce the frequency of histoplasmosis among patients who have advanced HIV infection and who live in areas in which histoplasmosis is highly endemic (594). However, no survival benefit was observed among persons receiving itraconazole.

Prophylaxis with itraconazole at a dose of 200 mg daily can be considered for patients with CD4⁺ counts <150 cells/µL who are at high risk because of occupational exposure or who live in a community with a hyperendemic rate of histoplasmosis (>10 cases/100 patient-years) (CI).

Discontinuing Primary Prophylaxis

If used, primary prophylaxis can be discontinued once peripheral blood CD4⁺ counts are >150 cells/µL for 6 months in patients on potent ART (BIII). Prophylaxis should be restarted if the CD4⁺ counts fall to <150 cells/µL (CIII).

Treatment of Disease

Patients with moderately severe to severe disseminated histoplasmosis should be treated with an IV lipid formulation of amphotericin B for >2 weeks (or until they improve clinically) followed by oral itraconazole (200 mg three times daily for 3 days and then 200 mg twice daily for a total of >12 months) (AI) (620,621).

In a randomized clinical trial, liposomal amphotericin B at 3.0 mg/kg daily was more effective than standard amphotericin B deoxycholate at 0.7 mg/kg daily (620), inducing a more rapid and more complete response, lowering mortality, and reducing toxicity. Substitution with ABLC at 5.0 mg/kg daily may be an alternative because of cost or tolerability (CIII).

In patients with less severe disseminated histoplasmosis, oral itraconazole at 200 mg three times daily for 3 days followed by 200 mg twice daily is appropriate initial therapy (AII) (622). The liquid formulation of intraconazole is preferred, owing to better absorption and fewer food interactions.

For persons with confirmed meningitis, liposomal amphotericin B should be administered as initial therapy for 4--6 weeks at a dosage of 5 mg/kg daily. This should be followed by maintenance therapy with itraconazole at a dose of 200 mg two or three times daily for a total of >1 year and until resolution of abnormal CSF findings (AII) (616).

Posaconazole has been reported in some salvage studies to be of some benefit (623). Fluconazole has limited to no activity against histoplasmosis and should not be used. The role of other azoles, including voriconazole, is not clear. Voriconazole should be used cautiously with HIV PIs and efavirenz. No published data exist regarding the use of echinocandins for treating patients with histoplasmosis.

Acute pulmonary histoplasmosis in an HIV-infected patient with intact immunity, as indicated by a CD4⁺ count >300 cells/µL, should be managed in a manner similar to that used for a nonimmunocompromised host (AIII) (621).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Serial monitoring of serum or urine for Histoplasma antigen is useful for determining response to therapy. A rise in level is suggestive of a relapse (AIII). Because absorption of itraconazole can be erratic, serum itraconazole levels should be obtained at least once in all patients to ensure adequate absorption (AIII). The serum concentration should be >1 µg/mL, ideally drawn for reasons of consistency as a trough level after at least 7 days on the current regimen. Itraconazole solution is recommended over the capsule formulation because absorption is improved, but this has not been studied specifically in AIDS patients.

IRIS has been reported uncommonly in patients with histoplasmosis (605,624,625). ART should not be withheld because of concern for the possible development of IRIS (AIII).

Management of Treatment Failure

Posaconazole solution at 800 mg daily was recently reported to be successful in three patients with HIV infection whose other previous therapies had failed (623). Voriconazole has been used in several transplant recipients and in one patient with AIDS who failed or could not tolerate therapy with other agents (626,627). Cross resistance between fluconazole and voriconazole has been noted in vitro (628).

Preventing Recurrence

Long-term suppressive therapy with itraconazole (200 mg daily) should be administered for patients with severe disseminated or CNS infection (AII) and in patients who relapse despite receipt of appropriate therapy (CIII). Fluconazole 800 mg daily is less effective than itraconazole (CII) (629). The role of voriconazole and posaconazole is not clear, but both have been used successfully in patients with histoplasmosis (623,626).

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)

An AIDS Clinical Treatment Group (ACTG)-sponsored study reported that discontinuing itraconazole was safe for patients who have been treated for histoplasmosis and who have a good immunologic response to ART (630). In that trial, patients had received >1 year of itraconazole therapy, had negative blood cultures, Histoplasma serum antigen <2 units, CD4⁺ counts >150 cells/µL, and had been on ART for 6 months. No relapses were evident in 32 subjects who were followed for a median of 24 months (630). Thus, discontinuing suppressive azole therapy appears to be safe for patients who meet the criteria described above (AI). Suppressive therapy should be resumed if the CD4⁺ count decreases to <150 cells/µL (BIII).

Special Considerations During Pregnancy

Because of their risk for teratogenicity, azoles should not be used during the first trimester of pregnancy (EII). Neonates born to women on chronic amphotericin B at delivery should be evaluated for renal dysfunction and hypokalemia.

Coccidioidomycosis

Epidemiology

Coccidioidomycosis is caused by a soil-dwelling fungus that consists of two species, Coccidioides immitis and C. posadasii. Most cases in persons with HIV infection have been from the areas in which the disease is endemic, including the Southwestern United States and parts of Central and South America (631). However, sporadic cases have been diagnosed outside those areas, presumably as a result of reactivation of a previous infection.

Cellular immunity is critical in controlling coccidioidomycosis. Symptomatic coccidioidomycosis can occur in persons with normal CD4⁺ concentrations. In patients with no discernible immunodeficiency, disseminated disease occurs in <1%. Black and Filipino men appear to be at higher risk for disseminated disease, as do pregnant women who acquire coccidioidal infection in the second or third trimester.

In patients with HIV infection, immune response to Coccidioides spp. appears to wane with declining CD4⁺ counts and the risk for developing symptomatic disease in areas in which the disease is endemic increases when this count is <250 cells/µL or with a diagnosis of AIDS (632). Retrospective studies have suggested a decline in the incidence of coccidioidomycosis in the areas in which the disease is endemic since the introduction of ART (633).

Clinical Manifestations

Among persons with HIV infection, six common syndromes have been described (634). These are focal pneumonia, diffuse pneumonia (presenting as apparent PCP), cutaneous involvement, meningitis, liver or lymph node involvement, and positive coccidioidal serology tests without evidence of localized infection. Focal pneumonia is most common in those with CD4⁺ counts >250 cells/µL, whereas the other syndromes usually occur in more immunosuppressed patients. Symptoms of meningitis are headache and progressive lethargy. The CSF profile demonstrates a low glucose with elevated protein and a lymphocytic pleocytosis.

Diagnosis

The diagnosis of coccidioidomycosis is confirmed by culture of the organism from clinical specimens or by demonstration of the typical spherule on histopathologic examination of involved tissue. Blood cultures are positive in a minority of patients, usually in those with diffuse pulmonary disease. Coccidioidal IgM and IgG serology, performed by EIA, immunodiffusion, or classical tube precipitin or complement fixation methodology, is useful in diagnosis although it may be less frequently positive among patients with low CD4⁺ counts than among immunocompetent persons. Complement fixation IgG antibody is frequently detected in the CSF in coccidioidal meningitis and is useful in establishing this diagnosis. Culture of the CSF is positive in fewer than one third of patients with meningitis.

Preventing Exposure

Although HIV-infected persons cannot completely avoid activities involving extensive exposure to infection while living in or visiting areas in which Coccidioides spp. is endemic, they should avoid activities involving extensive exposure to disturbed native soil, such as occurs at building excavation sites or during dust storms (CIII).

Preventing Disease

Initiating Primary Prophylaxis

Within an area where the disease is endemic, a positive IgM or IgG serologic test indicates an increased risk for the development of active infection (635) and specialists would recommend treatment if the CD4⁺ count is <250 cells/µL (BIII). Yearly testing for seronegative HIV-infected persons living in such regions is reasonable (CIII).

Although highly immunosuppressed patients (633) might benefit from primary prophylaxis, such therapy for HIV-infected persons without a positive IgM or IgG serologic test who live in the area where disease is endemic is not recommended (DIII). However, several clinicians would empirically provide chemoprophylaxis with either oral fluconazole 400 mg daily or itraconazole 200 mg bid if there were a positive IgM or IgG serologic test and the CD4 cell count was <250 cells/µL (CIII). Outside the region in which coccidiodomycosis is endemic, routine testing does not appear to be useful and should not be performed (DIII).

Discontinuing Primary Prophylaxis

If used, primary prophylaxis can be discontinued once peripheral blood CD4⁺ counts are >250 cells/µL for 6 months (CIII). Primary prophylaxis should be restarted if the CD4⁺ count is <250 cells/µl (BIII).

Treatment of Disease

For patients with clinically mild infection, such as focal pneumonia, or who have a positive coccidioidal serologic test alone, initial therapy with a triazole antifungal is appropriate (BII). Fluconazole or itraconazole at doses of 400 mg daily is recommended (636,637). Data are limited with regard to the newer triazoles, posaconazole and voriconazole, but these agents might be useful in cases that fail to respond to fluconazole or itraconazole. Voriconazole should be used cautiously with HIV PIs and efavirenz.

For patients with either diffuse pulmonary involvement or severely ill patients with extrathoracic disseminated disease, amphotericin B is the preferred initial therapy (AII) (636). Most experience has been with the deoxycholate formulation using 0.7--1.0 mg/kg daily as an initial dose. Data regarding lipid formulations of amphotericin B are limited, but these formulations are likely as effective.

Therapy with amphotericin B should continue until clinical improvement is observed. Certain specialists would use a triazole antifungal concurrently with amphotericin B and continue the triazole once amphotericin B is stopped (BIII) (636).

Treatment of patients with coccidioidal meningitis requires consultation with a specialist. Therapy should begin with a triazole antifungal. Fluconazole at a dose of 400--800 mg daily is preferred (AII) (638), but itraconazole has also been used successfully (639). Successful therapy with voriconazole (640,641) and posaconazole (642) has been described in case reports. Despite successful antifungal therapy, patients might develop hydrocephalus and require CSF shunting. In some instances, triazole antifungals are not effective. In such cases, intrathecal amphotericin B is recommended (AIII).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Monitoring the titer of the complement-fixing (CF) antibody is useful in assessing clinical response to therapy. This should be obtained every 12 weeks (AIII). A rise suggests recurrence of clinical disease. IRIS has not been observed in coccidioidomycosis.

Management of Treatment Failure

Patients whose therapy with fluconazole or itraconazole fails might be candidates for newer triazoles, but data regarding both posaconazole and voriconazole are limited. In most such instances, IV amphotericin B, in combination with triazole therapy, is recommended.

Preventing Recurrence

Patients who complete initial therapy for coccidioidomycosis should be considered for lifelong suppressive therapy using either fluconazole 400 mg daily or itraconazole 200 mg twice daily (AII).

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)

Patients with focal coccidioidal pneumonia who have clinically responded to antifungal therapy appear to be at low risk for recurrence of coccidioidomycosis if their CD4⁺ counts are >250 cells/µL and they are receiving ART. A reasonable plan for treating such patients is to discontinue secondary prophylaxis after 12 months of therapy (CIII) with continued monitoring for recurrence using serial chest radiographs and coccidioidal serology.

In patients with diffuse pulmonary disease or nonmeningeal disseminated coccidioidomycosis, relapses occur even in patients without HIV infection in 25%--33% of cases (643,644). Even in patients with CD4⁺ counts >250 cells/µL on potent ART, therapy should be continued indefinitely (AIII). For patients with meningitis, relapses have occurred in 80% of patients in whom triazoles have been discontinued (645). On the basis of this evidence, therapy for coccidioidal meningitis should be lifelong (AII).

Special Considerations During Pregnancy

Coccidioidomycosis is more likely to disseminate if acquired during the second or third trimester of pregnancy (646). Because of their risk for teratogenicity, azoles should not be used during the first trimester of pregnancy (EII). Neonates born to women on chronic amphotericin B at delivery should be evaluated for renal dysfunction and hypokalemia. One problematic area is coccidioidal meningitis, in which the only alternative treatment is intrathecal amphotericin B. For such situations, the decision regarding choice of treatment should be made in consultation with the mother, infectious diseases consultant, and obstetrician.

Aspergillosis

Epidemiology

Invasive aspergillosis in the HIV-infected person is rare. It is most frequently caused by Aspergillus fumigatus, although certain cases are caused by A. flavus, A. niger, and A. terreus. Invasive aspergillosis occurs among patients with advanced HIV infection and was more common before the advent of ART (647,648). Specific risk factors include neutropenia, use of corticosteroids, exposure to broad-spectrum antibacterial therapy, and previous pneumonia or other underlying lung disease. Patients who have had HIV-associated aspergillosis typically have CD4⁺ counts <100 cells/µL, a history of other AIDS-defining OIs, and are not receiving ART (649).

Clinical Manifestations

Invasive aspergillosis in the HIV-infected patient is evidenced most commonly as a respiratory illness that can be a necrotizing pneumonia or a tracheobronchitis (650). Symptoms of invasive pneumonia are fever, cough, dyspnea, chest pain, hemoptysis, and hypoxemia; the chest radiograph might demonstrate a diffuse, focal, or cavitary infiltrate. A "halo" of low attentuation surrounding a pulmonary nodule or an "air-crescent" on CT scan of the lung is suggestive of disease. Tracheobronchitis is associated with fever, cough, dyspnea, stridor, and wheezing. Bronchoscopic examination demonstrates multiple ulcerative or plaque-like lesions adherent to the tracheal wall (651). Extrapulmonary forms of invasive aspergillosis include sinusitis, cutaneous disease, osteomyelitis, and CNS infection (652).

Diagnosis

The diagnosis of pulmonary aspergillosis is usually based on either 1) the repeated isolation of Aspergillus spp. from cultures or respiratory secretions or 2) the finding of dichotomously branching septate hyphae consistent with Aspergillus spp. in respiratory or other samples in association with a compatible clinical syndrome. Histological evidence of tissue invasion by hyphae with a positive culture for Aspergillus spp. represents a definite diagnosis.

Newer tests based on circulating fungal antigen have been employed to diagnose aspergillosis. These have not been formally evaluated in patients with HIV infection. A sandwich ELISA test for galactomannan, a major fungal cell wall antigen, can be used on serum and bronchoalveolar lavage fluid (653). Although sensitivity and specificity appear reasonable, the test has yielded both false-positive and -negative results and is currently recommended for screening for invasive aspergillosis primarily in stem-cell transplant recipients.

Preventing Exposure

Aspergillus spp. are ubiquitous in the environment, and exposure is unavoidable. Avoiding particularly dusty environments is prudent, especially in areas such as those created by construction because spore counts might be higher in such settings.

Preventing Disease

No data on the prevention of primary aspergillosis in HIV-infected patients exists, although posaconzaole has been reported to be effective among patients with hematologic malignancy and neutropenia (654).

Treatment of Disease

Treatment of aspergillosis in the HIV-infected population has not been examined systematically. The recommended treatment for invasive aspergillosis in patients without HIV infection is voriconazole (655). Voriconazole is the drug of choice but should be used cautiously with HIV PIs and efavirenz (BIII). Amphotericin B deoxycholate at 1 mg/kg daily or lipid-formulation amphotericin B at 5 mg/kg daily are alternatives (AIII), as is caspofungin at 50 mg daily (BII) and posaconazole (BII). Other echinocandins, such as micafungin and anidulafungin, are reasonable alternatives. Posaconazole also has proven to be useful in patients with invasive aspergillosis without HIV infection (656) but is not approved for treatment of aspergillosis. The length of therapy is not established but should continue at least until the peripheral blood CD4⁺ count is >200 cells/µL and there is evidence of clinical response.

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

IRIS has rarely been reported to occur in patients with invasive aspergillosis (657).

Management of Treatment Failure

The overall prognosis is poor among patients with advanced immunosuppression and in the absence of effective ART. No data are available to guide recommendations for the management of treatment failure. If voriconazole was used initially, substitution with amphotericin B, posaconazole, or echinocandins might be considered; the amphotericin B or echinocandins would be a reasonable choice for those who began therapy with voriconazole or posaconazole (BIII).

Preventing Recurrence

No data are available to base a recommendation for or against chronic maintenance or suppressive therapy among patients who have successfully completed an initial course of treatment (CIII).

Special Considerations During Pregnancy

Because of their risk for teratogenicity, azoles should not be used during the first trimester of pregnancy (EII). (See mucocutaneous candidiasis). Neonates born to women on chronic amphotericin B at delivery should be evaluated for renal dysfunction and hypokalemia.

Cytomegalovirus Disease

Epidemiology

Cytomegalovirus (CMV) is a double-stranded DNA virus in the Herpesvirus family that can cause disseminated or localized end-organ disease among patients with advanced immunosuppression. Most clinical disease occurs in previously infected (seropositive) persons and so represents either reactivation of latent infection or reinfection with a novel strain.

End-organ disease caused by CMV occurs among persons with advanced immunosuppression, typically those with CD4⁺ counts <50 cells/µL, who are either not receiving or have failed to respond to ART (658--660). Other risk factors include previous OIs and high plasma HIV RNA levels (>100,000 copies/mL).

Before potent ART, an estimated 30% of patients with AIDS experienced CMV retinitis some time between the diagnosis of AIDS and death (658--660). The incidence of new cases of CMV end-organ disease has declined by 75%--80% with the advent of ART and now is estimated to be <6 cases per 100 person-years (661). For those with established CMV retinitis, recurrence of active lesions occurs at a rate of 0.58/person-year for those with CD4⁺ cells <50 cells/µL, a rate substantially lower than that seen in the pre-ART era. However, even for those with immune recovery sufficient to discontinue anti-CMV therapy (i.e., >100 cells/µL), relapse of the retinitis occurs at a rate of 0.03/person-year and can occur at CD4⁺ counts as high as 1,250 cells/µL (662). Therefore, whether anti-CMV therapy is continued, regular ophthalmologic follow-up is needed.

Clinical Manifestations

Retinitis is the most common clinical manifestation of CMV end-organ disease. CMV retinitis occurs as unilateral disease in two thirds of patients at presentation, but in the absence of therapy or immune recovery, viremic dissemination results in bilateral disease in the majority of patients (663). For patients with unilateral CMV retinitis and CD4⁺ count <50 cells/µL, rates of contralateral disease approach those of the pre-ART era (663).

Peripheral retinitis might be asymptomatic or present with floaters, scotomata, or peripheral visual field defects. Central retinal lesions or lesions impinging on the macula or optic nerve are associated with decreased visual acuity or central field defects. CMV retinitis is a full-thickness necrotizing retinitis, and the characteristic ophthalmologic appearance is that of fluffy yellow-white retinal lesions, with or without intraretinal hemorrhage, and with little inflammation of the vitreous unless immune recovery with potent ART intervenes (658). Blood vessels near the lesions might appear to be sheathed. Occasionally, CMV retinitis lesions, particularly peripheral lesions, might have a more granular appearance.

In the absence of ART or specific anti-CMV therapy, retinitis invariably progresses, usually within 10--21 days after presentation. Progression of retinitis occurs in "fits and starts" and causes a characteristic brushfire pattern, with a granular, white leading edge advancing before an atrophic gliotic scar (672).

Colitis occurs in 5%--10% of persons with AIDS and CMV end-organ disease (659). The most frequent clinical manifestations are fever, weight loss, anorexia, abdominal pain, debilitating diarrhea, and malaise. Extensive mucosal hemorrhage and perforation can be life-threatening complications.

Esophagitis caused by CMV, which occurs in <5%--10% of persons with AIDS who experience CMV end-organ disease, causes fever, odynophagia, nausea, and occasionally mid-epigastric or retrosternal discomfort. CMV pneumonitis is uncommon. CMV neurologic disease causes dementia, ventriculoencephalitis, or ascending polyradiculomyelopathy (664). Patients with dementia typically have lethargy, confusion, and fever, mimicking that of HIV dementia. CSF typically demonstrates lymphocytic pleocytosis (although a mixture of neutrophils and lymphocytes might be evident), low-to-normal glucose levels, and normal-to-elevated protein levels. Patients with ventriculoencephalitis have a more acute course, with focal neurologic signs, often including cranial nerve palsies or nystagmus, and rapid progression to death. Periventricular enhancement of CT or MRI images is indicative of CMV ventriculoencephalitis rather than HIV-related neurologic disease. CMV polyradiculomyelopathy causes a Guillian-Barre--like syndrome characterized by urinary retention and progressive bilateral leg weakness. The clinical symptoms usually progress during several weeks to include loss of bowel and bladder control and to flaccid paraplegia. A spastic myelopathy has been reported and sacral paresthesia might occur. The CSF usually demonstrates a neutrophilic pleocytosis (usually 100--200 neutrophils/µL and some erythrocytes) accompanied by hypoglycorrhachia and elevated protein levels.

Diagnosis

CMV viremia can be detected by PCR or antigen assays and is usually observed in end-organ disease, but viremia also might be present in the absence of end-organ disease (664-669). The presence of serum antibodies to CMV is not diagnostically useful, although a negative IgG antibody level indicates that CMV is unlikely to be the cause of the disease process.

The diagnosis of CMV retinitis is usually made based on recognition of characteristic retinal changes observed through a dilated pupil during an ophthalmoscopic examination performed by an experienced ophthalmologist. Diagnosis by such clinical examination has a 95% positive predictive value. In rare cases, diagnosis might be difficult and PCR of vitreous for CMV and other pathogens might be valuable in the differential diagnosis.

Demonstration of mucosal ulcerations on endoscopic examination combined with colonoscopic or rectal biopsy with histopathologic demonstration of characteristic intranuclear and intracytoplasmic inclusions is required for the diagnosis of CMV colitis (659). The diagnosis of CMV esophagitis is established by the presence of extensive large, shallow ulcers of the distal esophagus and biopsy evidence of intranuclear inclusion bodies in the endothelial cells with an inflammatory reaction at the edge of the ulcer (659).

Culturing CMV from a biopsy or cells brushed from the colon or the esophagus is not sufficient to establish the diagnosis of CMV colitis or esophagitis in the absence of histopathologic changes because certain persons with low CD4⁺ counts might be viremic and have positive cultures for CMV in the absence of clinical disease (669).

Diagnosis of CMV pneumonitis should take into account pulmonary interstitial infiltrates, identification of multiple CMV inclusion bodies in lung tissue, and the absence of other pathogens that are more commonly associated with pneumonitis evident in this population (667). CMV neurologic disease is diagnosed on the basis of a compatible clinical syndrome and the presence of CMV in CSF or brain tissue (660,668 ). Detection of CMV is enhanced by PCR (665,668).

Preventing Exposure

HIV-infected persons who belong to groups at risk with relatively low seroprevalence rates for CMV and who, therefore, cannot be presumed to be seropositive should be tested for antibody to CMV (BIII). These groups include patients who have not had contact with MSM or used injection drugs. HIV-infected adolescents and adults should be advised that CMV is shed in semen, cervical secretions, and saliva and that latex condoms must always be used during sexual contact to reduce the risk for exposure to CMV and to other sexually transmitted pathogens (AII).

HIV-infected adults and adolescents who provide child care or parents of children in day care facilities should be informed that they are at increased risk for acquiring CMV infection (BI). Similarly, parents and other caretakers of HIV-infected children should be advised of the increased risk to children at these centers (BIII). Risk for acquiring CMV infection can be diminished by optimal hygienic practices (e.g., hand-washing and use of latex gloves) (AII).

HIV-exposed infants and infected children, adolescents, and adults who are seronegative for CMV and who require blood transfusion should be administered only CMV antibody-negative or leukocyte-reduced cellular blood products in nonemergency situations (BIII).

Preventing Disease

CMV end-organ disease is best prevented using ART to maintain the CD4⁺ count >100 cells/µL. Although oral valganciclovir would likely prevent the occurrence of CMV retinititis in patients with CD4⁺ counts <50 cells/µL, such therapy is not usually recommended because of cost, the potential to induce CMV resistance, the utility of treating disease when it occurs, and the lack of demonstrated survival advantage (DI). The primary method for preventing severe CMV disease is recognizing the early manifestations of the disease. Patients should be made aware of the importance of increased floaters in the eye and should be advised to assess their visual acuity regularly by using simple techniques (e.g., reading newsprint) (BIII). Regular funduscopic examinations performed by an ophthalmologist are recommended by certain specialists for patients with low (e.g., <50 cells/µL) CD4⁺ counts (CIII).

Natural history studies in the era of ART indicate that CMV viremia can be detected by PCR on at least one occasion in approximately 30% of those whose CD4⁺ counts remain <100 cells/µL (669). Such detection of CMV infection by PCR correlates with the development of future CMV disease and death (669). Furthermore, evidence from a cohort study indicates that patients with CMV retinitis administered systemic therapy had substantially reduced mortality (671). These observations suggest that pre-emptive anti-CMV treatment administered to patients who have evidence of active infection but who have not yet exhibited end-organ disease could be a therapeutic strategy for preventing CMV end-organ disease. Unless future studies document that clinical benefit can be obtained from pre-emptive therapy, the treatment of patients with CMV viremia in the absence of organ system involvement is not recommended (DII).

Treatment of Disease

Oral valganciclovir, IV ganciclovir, IV ganciclovir followed by oral valganciclovir, IV foscarnet, IV cidofovir, and the ganciclovir intraocular implant coupled with valganciclovir are all effective treatments for CMV retinitis (AI) (672--677). Systemic therapy has been documented to reduce morbidity in the contralateral eye (710). This therapy should be considered when choosing among oral, IV, and local options. The choice of initial therapy for CMV retinitis should be individualized based on the location and severity of the lesion(s), the level of underlying immune suppression, and other factors such as concomitant medications and ability to adhere to treatment (AIII). No one regimen has been proven in a clinical trial to have superior efficacy related to protecting vision, and thus clinical judgment must be used when choosing a regimen (673--677). Forms of ganciclovir most often are the first choice for CMV infection or disease. Certain clinical trials were conducted with oral ganciclovir, a preparation that was poorly bioavailable and is no longer marketed. Instead, the prodrug valganciclovir, which is the valine ester of ganciclovir, is administered orally to deliver ganciclovir. In these guidelines, references to oral ganciclovir have been deleted and the equivalent dose of valganciclovir has been substituted.

The ganciclovir intraocular implant plus oral valganciclovir is superior to once-daily IV ganciclovir (and presumably to once-daily oral valganciclovir) for preventing relapse of retinitis (AI) (673--677). For this reason, certain HIV specialists recommend the intraocular implant plus valganciclovir as the preferred initial therapy for patients with immediate sight- threatening lesions (adjacent to the optic nerve or fovea); for patients with small peripheral lesions oral valganciclovir alone may be adequate (BII). Certain ophthalmologists recommend an initial intravitreous injection of ganciclovir at the time CMV retinitis is diagnosed to deliver a high local concentration of ganciclovir to the eye immediately, until the ganciclovir implant can be placed (CIII).

Because ART can control CMV retinitis without anti-CMV therapy in patients who experience immune recovery, some clinicians might consider not treating small peripheral CMV lesions with anti-CMV therapy in ART-naïve patients. However, complications of CMV retinitis, including immune recovery retinitis and retinal detachment, are more common in patients with larger CMV lesions, and ART might take 3--6 months to fully control HIV replication and stimulate sufficient immune recovery to control the retinitis. Furthermore, consistent with natural history studies that associated CMV viremia with increased mortality in the pre- and current ART era (669,678,679), evidence indicates that anti-CMV therapy decreases mortality among patients with CMV retinitis and immune compromise (671). Therefore, even in ART-naïve patients with small peripheral lesions, treatment with systemic anti-CMV therapy, such as valganciclovir for the initial 3--6 months until ART has induced immune recovery, will likely be beneficial (BII).

For patients who have colitis or esophagitis, a majority of HIV specialists would recommend IV ganciclovir or foscarnet (or with oral valganciclovir if symptoms are not severe enough to interfere with oral absorption) for 21--28 days or until signs and symptoms have resolved (BII). Certain HIV specialists also would withhold therapy unless moderate-to-severe symptoms justify the use of systemic treatment if ART is to be initiated soon or can be optimized (BIII).

Criteria for establishing that CMV is the cause of pneumonitis and pulmonary dysfunction have been difficult to establish. If CMV is considered the cause of pulmonary dysfunction based on histology or cytology, treatment with IV ganciclovir, foscarnet, or cidofovir is logical, although few data establish that such therapy affects outcome (CIII).

For neurological disease, initiating therapy promptly is critical for an optimal clinical response. Although combination treatment with ganciclovir and foscarnet might be preferred as initial therapy to stabilize disease and maximize response (BII), this approach is associated with substantial rates of adverse effects, and optimal treatment for neurologic disease if ART can be optimized has not been established.

No data are available to demonstrate that starting ART among treatment-naïve patients with CMV retinitis would have an adverse effect on retinitis, gastrointestinal disease, or pneumonitis. Therefore, initiation of appropriate ART should be administered to those with acute CMV retinitis, gastrointestinal disease, or pneumonitis (BIII). Although no data indicate that IRIS worsens CMV neurologic disease syndromes, because of the localized morbidity that might occur with such an inflammatory reaction, a delay in initiating ART in this setting until clinical improvement occurs might be prudent (CIII).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Management of CMV retinitis requires close monitoring by an experienced ophthalmologist and the primary clinician. Consideration should be given to both treating the infected eye and preventing infection in the contralateral eye using systemic treatment (663,680).

Indirect ophthalmoscopy through a dilated pupil should be performed at the time of diagnosis of CMV retinitis, after completion of induction therapy, 1 month after the initiation of therapy, and monthly thereafter while the patient is on anti-CMV treatment (AIII). Monthly fundus photographs, using a standardized photographic technique that documents the appearance of the retina, provide the optimum method for following patients and detecting early relapse (AIII). For patients who have experienced immune recovery, the frequency of ophthalmologic follow-up can be decreased to every 3 months (AIII). Because relapse of retinitis might still occur among some patients with immune recovery, ophthalmologic follow-up might be indicated; however, the optimal timing and interval of such follow-up has not been established.

Adverse effects of ganciclovir include neutropenia, thrombocytopenia, nausea, diarrhea, and renal dysfunction. Adverse effects of foscarnet include anemia, nephrotoxicity, and electrolyte abnormalities. For patients receiving ganciclovir or foscarnet, monitoring of complete blood counts and serum electrolytes and renal function should be performed twice weekly during induction therapy and once weekly thereafter (AIII). Cidofovir is associated with dose-related nephrotoxicity and hypotony. For patients receiving IV cidofovir, blood urea nitrogen, creatinine, and urinalysis should be performed before each infusion; administration of the drug is contraindicated if renal dysfunction or proteinuria is detected. Even in the absence of retinitis with other CMV end-organ disease, periodic ophthalmologic examinations are needed to monitor for cidofovir-associated uveitis when this agent is used.

Immune recovery uveitis (IRU) is an ocular form of IRIS caused by an immunologic reaction to CMV, characterized by inflammation in the anterior chamber or vitreous in the setting of immune recovery after initiation of ART and is usually observed among those patients with a substantial rise in CD4⁺ counts in the first 4--12 weeks after initiation of ART (681--685). Ocular complications of uveitis include macular edema and the development of epiretinal membranes, which can cause loss of vision. Treatment usually requires periocular corticosteroids or short courses of systemic corticosteroids. Estimated response rates are 50%. One uncontrolled case series suggested that IRU (or CMV retinitis-associated IRIS) might respond to oral valganciclovir (686).

Management of Treatment Failure

For patients without immune recovery after initiation of ART and who are receiving chronic maintenance therapy with systemic anti-CMV drugs, relapse of retinitis is likely to occur. Although drug resistance might be responsible for some episodes of relapse, early relapse is most often caused by the limited intraocular penetration of systemically administered drugs (687--689). Because it results in greater drug levels in the eye, the placement of a ganciclovir implant in a patient who has relapsed while receiving systemic treatment (IV ganciclovir or oral valganciclovir) is usually recommended and often will control the retinitis for 6--8 months until the implant requires replacement (BIII) (690,691).

When patients relapse while receiving maintenance therapy, reinduction with the same drug followed by reinstitution of maintenance therapy can control retinitis, although for progressively shorter periods (692), and the majority of specialists recommend this approach for initial treatment of patients who experience relapsed disease (AII). Changing to an alternative drug at the time of first relapse typically does not result in superior control of the retinitis but should be considered if drug resistance is suspected or if side effects or toxicities interfere with optimal courses of the initial agent (AIII) (692). The combination of ganciclovir and foscarnet is usually superior to systemic therapy with either agent alone and might be considered for patients with relapsed retinitis (692); however, this combination of drugs is accompanied by greater toxicity (BI).

Drug resistance occurs among patients receiving long-term therapy (693--696). Reported rates in the pre-ART era were approximately 25% per person-year (693,697,698) and reported rates are similar for ganciclovir, foscarnet, and cidofovir (693,694). In the ART era, the rate of resistance appears to be less, approximately 10% per person-year. Low-level resistance to ganciclovir occurs through mutations in the CMV UL97 (phosphotransferase) gene, and high-level resistance to ganciclovir typically occurs because of mutations in both the CMV UL97 and UL54 (DNA polymerase) genes (699--704). Resistance to foscarnet or cidofovir each occurs because of mutations in the CMV UL54 gene. High-level resistance to ganciclovir is frequently associated with cross resistance to cidofovir (701) and occasionally to foscarnet (703).

Although early relapse is typically not a result of resistance, later relapse often is. Because patients with resistant CMV nearly always have mutations in the CMV UL97 gene, and because a limited number of mutations are responsible for most drug resistance, susceptibility testing in peripheral blood using a CMV DNA PCR assay and sequencing for CMV UL97 mutations or using a point mutation assay (705,706) might be reasonable for patients who relapse on therapy (707). Virus in the eye and in the blood are identical in >90% of cases (708), so evaluating the blood for resistance is reasonable, and the detection of resistance in the blood or urine correlates with clinical behavior of the retinitis (709). Sequencing the UL97 gene from PCR-amplified specimens from blood can be accomplished in <48 hours, correlates well with conventional drug susceptibility testing and clinical outcomes (707), and, therefore, has clinical utility (BII) when conventional methods of culture and susceptibility testing and viral sequencing are not available or are too time consuming or costly. Conversely, CMV viral load measurements are of limited utility clinically because of their poor positive predictive value, but do have reasonable negative predictive value and might have utility in excluding resistance when sequencing is not available (BII). UL97 mutants usually respond to foscarnet, as do most UL54 mutants (except those associated with resistance to foscarnet).

Patients with low-level ganciclovir-resistant isolates in the eye might respond to a ganciclovir implant because of the higher local levels of ganciclovir resulting from this form of therapy. However, patients with high-level ganciclovir-resistant isolates typically will not respond and will require a switch to alternative therapy.

Preventing Recurrence

After induction therapy, secondary prophylaxis (i.e., chronic maintenance therapy) is recommended for life (AI) (664,668,673,674,710), unless immune reconstitution occurs as a result of ART. Regimens demonstrated to be effective for chronic suppression in randomized, controlled clinical trials include parenteral ganciclovir or valganciclovir, parenteral foscarnet, combined parenteral ganciclovir and foscarnet, parenteral cidofovir, and (for retinitis only) ganciclovir administration through intraocular implant (AI). Repetitive intravitreous injections of fomivirsen also have been demonstrated to be effective in randomized clinical trials, but this drug is no longer available in the United States.

Repetitive intravitreous injections of ganciclovir, foscarnet, and cidofovir have been effective for secondary prophylaxis of CMV retinitis in uncontrolled case series. Because of the risk for hypotony and uveitis, the intravitreal administration of cidofovir should be reserved for extraordinary cases. Intraocular therapy alone does not provide protection to the contralateral eye or to other organ systems and typically should be combined with oral valganciclovir.

The choice of a chronic maintenance regimen for patients treated for CMV disease should be made in consultation with a specialist. For patients with retinitis, this decision should be made in consultation with an ophthalmologist and should consider the anatomic location of the retinal lesion, vision in the contralateral eye, the immunologic and virologic status of the patient, and the patient's response to ART.

Patients with lesions that immediately threaten vision need prompt anti-CMV therapy because progression of the retinitis can occur during the time in which immune recovery is occurring (674,675). Patients with retinitis that immediately threatens sight still might benefit most from the use of the ganciclovir implant because of its ability to deliver high concentrations of drug locally and its superior ability to control retinitis progression (BI). However, replacement of the ganciclovir implant at 6--8 months might not be necessary for those with sustained immune recovery. If the ganciclovir implant is used, it should be combined with oral valganciclovir until immune recovery occurs (BIII).

Chronic maintenance therapy is not routinely recommended for gastrointestinal disease but should be considered if relapses occur (BII). A role for maintenance therapy for CMV pneumonitis has not been established (CIII).

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)

Multiple case series have reported that maintenance therapy can be discontinued safely among adult and adolescent patients with CMV retinitis whose CD4⁺ counts have indicated a sustained (e.g., 3--6 months) increase to >100 cells/µL in response to ART (711-716). Such patients have remained disease free for >30--95 weeks in clinical trials and case series, whereas during the pre-ART era, retinitis typically reactivated in <6--8 weeks after stopping CMV therapy. Plasma HIV RNA levels were varied among these patients, demonstrating that the CD4⁺ count is the primary determinant of immune recovery to CMV. Discontinuing secondary prophylaxis (chronic maintenance therapy) is reasonable for patients with a sustained (3--6 months) increase in CD4⁺ counts >100 cells/µL in response to ART (BII) (711--715,717,718). Such decisions should be made in consultation with an ophthalmologist and should include magnitude and duration of CD4⁺ count increase, anatomic location of the retinal lesions, vision in the contralateral eye, and the feasibility of regular ophthalmologic monitoring (BII). The relapse rate among patients whose anti-CMV therapy has been discontinued for immune recovery is 0.03 per person-year (i.e., 3% per year) and no level of CD4⁺ count is absolutely safe (relapses have been reported at CD4⁺ counts of 1,250 cells/µL). Therefore, all patients who have had anti-CMV maintenance therapy discontinued should continue to undergo regular ophthalmologic monitoring for early detection of CMV relapse and for IRU, optimally every 3 months (AII). Monitoring CMV viral load has poor positive predictive value for relapse of the retinitis and, therefore, is not recommended (DII).

Relapse of CMV retinitis occurs frequently among patients whose anti-CMV maintenance therapies have been discontinued and whose CD4⁺ counts have decreased to <50 cells/µL (717). Therefore, reinstitution of secondary prophylaxis should occur when the CD4⁺ count has decreased to <100 cells/µL (AIII).

Special Considerations During Pregnancy

The diagnostic considerations among pregnant women are the same as for nonpregnant women. Indications for treatment of CMV infection during pregnancy are the same as for nonpregnant HIV-infected adults (AIII). For retinal disease, use of intraocular implants or intravitreous injections for local therapy should be considered in the first trimester, if possible, to limit fetal exposure to systemically administered antiviral drugs (CIII). Systemic antiviral therapy as discussed should then be started after the first trimester.

Ganciclovir is embryotoxic among rabbits and mice and teratogenic (i.e., cleft palate, anophthalmia, aplastic kidney and pancreas, and hydrocephalus) in rabbits (719--721). Safe use in human pregnancy after organ transplantation has been reported (719,720), and use in late pregnancy to treat fetal CMV infection in HIV-uninfected women has also been reported (722). Foscarnet is associated with an increase in skeletal anomalies or variants in rats and rabbits. No experience with use early in human pregnancy has been reported. A single case report of use in the third trimester described normal infant outcome (723). Cidofovir is embryotoxic and teratogenic (i.e., meningomyelocele and skeletal abnormalities) among rats and rabbits. No experience with use of cidofovir in human pregnancy has been reported; use in pregnancy is not recommended (DIII).

On the basis of limited data, toxicity reports and studies, and ease of use of the various drugs, valganciclovir is recognized as the treatment of choice during pregnancy (BIII). No experience has been reported with the use of valganciclovir in human pregnancy, but concerns are expected to be the same as with ganciclovir. The fetus should be monitored by fetal-movement counting in the third trimester and by periodic ultrasound monitoring after 20 weeks of gestation to look for evidence of hydrops fetalis indicating substantial anemia. Because toxicity of foscarnet is primarily renal, weekly monitoring of amniotic fluid volumes by ultrasound is recommended after 20 weeks of gestation to detect oligohydramnios if foscarnet is used.

Rarely, ultrasound findings in the fetus (e.g., cerebral calcifications, abdominal and liver calcifications, hydrops, microcephaly, ventriculomegaly, ascites, and echogenic fetal bowel) might indicate the possibility of in utero CMV infection among pregnant women with CMV end-organ disease (724). In this case, consideration of invasive testing (i.e., amniocentesis and fetal umbilical blood sampling) must be individualized on the basis of clinical history and serologic findings, gestational age, potential risk for HIV transmission, and maternal preference (725). Referral to a maternal-fetal medicine specialist for evaluation, counseling, and potential further testing is recommended.

On the basis of data in HIV-uninfected women, transmission of CMV from mother to infant might occur in utero. However, symptomatic infection in the newborn is usually related to primary CMV infection in the mother during pregnancy, and because >90% of HIV-infected pregnant women are CMV antibody positive in the majority of studies, the risk for symptomatic infection in the fetus is low (726--730). Therefore, treatment of asymptomatic maternal CMV infection during pregnancy solely to prevent infant infection is not indicated (DIII).

Herpes Simplex Virus Disease

Epidemiology

Infections with human herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are common, with a seroprevalence of HSV-1 among adults of approximately 60% and a seroprevalence of HSV-2 among persons aged >12 years in the United States of 17% (731). Approximately 70% of HIV-infected persons are HSV-2 seropositive and 95% are seropositive for either HSV-1 or HSV-2 (732). In most HSV-infected persons, HSV infections are unrecognized clinically. However, regardless of the clinical severity of infection, reactivation on mucosal surfaces occurs intermittently and can result in transmission. HSV-2 is a risk factor for HIV acquisition, and HSV-2 reactivation results in increases in HIV RNA levels in coinfected patients.

Clinical Manifestations

Orolabial herpes is the most common manifestation of HSV-1 infection. Classic manifestations include a sensory prodrome in the affected area, rapidly followed by the evolution of lesions from papule to vesicle, ulcer, and crust stages on the lips. The course of illness in untreated subjects is 7--10 days. Lesions recur 1--12 times per year and can be triggered by sunlight or physiologic stress.

Genital herpes is the most common manifestation of HSV-2 infection. Genital mucosal or skin lesions are similar to external orolabial lesions in appearance and evolution. Local symptoms might include a sensory prodrome consisting of pain and pruritis. Ulcerative lesions are usually the only stage observed on mucosal surfaces. Mucosal disease is occasionally accompanied by dysuria or vaginal or urethral discharge; inguinal lymphadenopathy, particularly in primary infection, is common with genital herpes (733). These classic manifestations occur in certain patients, but most persons with genital herpes have mild and atypical lesions that are not brought to medical attention and that cannot be diagnosed by physical examination. In profoundly immunocompromised patients, extensive, deep, nonhealing ulcerations might occur. These lesions have been reported most often in those with CD4⁺ counts of <100 cells/µL and also might be more commonly associated with acyclovir-resistant virus (734).

The episodes of genital HSV-1 infection are indistinguishable from genital HSV-2 infection but genital HSV-1 infection recurs less frequently than genital HSV-2 infection.

Nonmucosal HSV infections, such as HSV keratitis, HSV encephalitis, HSV hepatitis, and herpetic whitlow, are similar in presentation to those manifestations observed in HIV-seronegative persons; disseminated HSV infection is rare. HSV retinitis manifests as acute retinal necrosis (ARN) and can lead rapidly to loss of vision.

Diagnosis

Because mucosal HSV infections cannot be diagnosed accurately without laboratory confirmation, especially in HIV-seropositive patients, a laboratory diagnosis should be pursued in all cases (529). Viral culture, HSV DNA PCR, and HSV antigen detection are available methods for diagnosis of mucocutaneous HSV lesions caused by HSV. PCR is the most sensitive method, but is not widely available. The virus detected in genital lesions should be typed, because HSV-1 recurs less frequently than HSV-2 in the genital area. Type-specific serologic assays are commercially available and can be used in asymptomatic persons or those with atypical lesions. Because of the poor sensitivity and specificity of clinical diagnosis, extensive interactions between HIV and HSV-2, and the availability of effective therapy for HSV-2, routine type-specific serologic testing for HSV-2 should be considered in persons who seek HIV care. Diagnosis of HSV-2 should be accompanied by counseling that discusses the risk for transmission of infection to sex partners. Guidelines for counseling are provided in the 2006 CDC STD treatment guidelines (http://www.cdc.gov/std/treatment).

Preventing Exposure

The majority of HIV-infected persons have HSV-1 and -2 infections. However, prevention of acquisition of HSV is important for those who are uninfected. HSV-2-seronegative HIV-infected persons should ask their partners to be tested using type-specific serology before initiating sexual activity, because disclosure of HSV-2 in heterosexual HSV-2-discordant couples was associated with reduced risk for transmission of HSV-2 (BII) (735). Consistent use of latex condoms reduced HSV-2 acquisition from women to men and from men to women, and their use should be encouraged for prevention of transmission of HSV-2 and other sexually transmitted pathogens (AII) (736). HIV-infected persons should specifically avoid sexual contact when their partners have overt (genital or orolabial) herpetic lesions (AII). However, sexual transmission of HSV can occur during asymptomatic shedding. The use of suppressive antiviral therapy (valacyclovir 500 mg once daily) in persons with genital herpes reduced HSV-2 transmission to susceptible heterosexual partners by 50% (737); the effectiveness of this approach in reducing HSV-2 transmission from HIV-seropositive persons or to HIV-seropositive persons has not been evaluated.

Preventing Disease

The dose, duration, and efficacy of antiviral prophylaxis after exposure to HSV have not been evaluated.

Treatment of Disease

Patients with HSV infections can be treated with episodic therapy when lesions occur or with daily therapy to prevent recurrences. The management of genital HSV-2 in HIV-infected persons should include several factors, including frequency and severity of HSV recurrences, the risk for HSV-2 transmission to susceptible partners, and the potential for interactions between HIV and HSV-2 that might result in increased HIV in plasma and genital secretions. Treatment for individual recurrences does not influence the natural history of genital HSV-2 infection and does not reduce the risk for HSV-2 transmission to sex partners, a major concern of persons with genital herpes.

Patients with orolabial lesions can be treated with oral valacyclovir, famciclovir, or acyclovir for 5--10 days (AII). Severe mucocutaneous HSV lesions respond best to initial treatment with IV acyclovir (AII) (734,738). Patients may be switched to oral therapy after the lesions have begun to regress. Therapy should be continued until the lesions have completely healed. Genital HSV infection should be treated with oral valacyclovir, famciclovir, or acyclovir for 5--14 days (AI). Short-course therapy (1, 2, or 3 days) should not be used in patients with HIV infection.

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Acyclovir, valacyclovir, and famciclovir are occasionally associated with nausea or headache. No laboratory monitoring is needed in patients receiving episodic or suppressive therapy unless the patient has substantial renal impairment. For patients receiving high-dose IV acyclovir, monitoring of renal function and dose adjustment as necessary are recommended at initiation of treatment and once or twice weekly for the duration of treatment. Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome has been reported among HIV-infected patients treated with high-dose (8 grams/day) valacyclovir but has not been reported at doses used for therapy of HSV infection (742).

Cutaneous lesions that are atypical and occasionally recalcitrant to therapy have been reported in persons initiating ART and have been attributed to IRIS

Management of Treatment Failure

Treatment failure related to resistance to anti-HSV drugs should be suspected if lesions do not begin to resolve within 7--10 days after initiation of therapy. Among immunocompromised patients with suspected acyclovir-resistant HSV, viral culture of the lesion should be obtained and, if virus is isolated, susceptibility testing performed to confirm drug resistance (AII) (743).

The treatment of choice for acyclovir-resistant HSV is IV foscarnet (AI) (744,745). Topical trifluridine, cidofovir, and imiquimod also have been used successfully for lesions on external surfaces, although prolonged application for 21--28 days or longer might be required (CIII).

Preventing Recurrence

Most recurrences of genital herpes can be prevented using daily anti-HSV therapy, and this is recommended for persons who have frequent or severe recurrences (AI) (739). The option for suppressive therapy should be discussed with every HSV-2-infected patient. Suppressive therapy with oral acyclovir, valacyclovir, or famciclovir is effective in preventing recurrences (AI) (739--741). Suppressive therapy with valacyclovir should be 500 mg twice daily in HIV-infected persons (AI), or twice-daily regimens with acyclovir or famciclovir should be used. Daily anti-HSV suppressive therapy in HIV-infected persons also results in a decrease in HIV concentration in plasma and anal and genital secretions. Whether this regimen results in clinical benefit or decreased infectiousness is not known.

HIV-infected patients receiving ART who have immune reconstitution often experience improvement in the frequency and severity of their clinical episodes of genital herpes. However, immune reconstitution does not reduce the frequency of genital HSV shedding.

Special Considerations During Pregnancy

Diagnosis of mucocutaneous HSV infections is the same for pregnant women as for nonpregnant women. Episodic therapy for first-episode HSV disease and for recurrences can be offered during pregnancy, but suppressive therapy is not used routinely. Visceral disease is more likely to occur during pregnancy and can be fatal. Acyclovir is the antiviral drug with the most reported experience in pregnancy and appears to be safe (746); therefore, acyclovir is the first choice for therapy of HSV infections in pregnancy (AIII).

An additional concern with HSV during pregnancy is the potential for HSV transmission to the fetus and neonate. The rate of HSV transmission to the newborn in HSV-2-seropositive pregnant women is low, unless the pregnant woman has acquired genital HSV in late pregnancy. The predominant risk for HSV transmission is maternal genital shedding of HSV at delivery. Cesarean delivery is recommended for women with a genital herpes prodrome or visible HSV genital lesions at the onset of labor (BII) (724). Maternal genital herpes is a risk factor for perinatal mother-to-child HIV transmission (747). Whether HSV suppression reduces the risk for HIV transmission during pregnancy, birth, or breastfeeding is unknown.

Use of acyclovir in late pregnancy suppresses genital herpes outbreaks and reduces the need for Cesarean delivery for recurrent HSV in HIV-seronegative women (748) and is likely to have similar efficacy in HIV-seropositive women (BII). However, the use of acyclovir in HIV-infected pregnant women to reduce the risk for intrapartum HIV and HSV transmission to the neonate has not been evaluated.

HHV-6 and HHV-7 Disease

Epidemiology

The highest geometric mean titers of HHV-6 antibody occur during the first 3 years of life, indicating a clustering of primary infections in infants and toddlers (749,750). Approximately 90% of healthy children become infected with HHV-6 by 12 months of life (751), and virtually 100% acquire infection by 3 years of age (750). HHV-6 seroprevalence remains high throughout adulthood (750,751). Most children likely acquire infection through contact with the secretions of adult caretakers who shed the virus in saliva; approximately 85% of healthy or HIV-infected adults shed HHV-6 intermittently in their saliva (752).

Primary HHV-7 infection also usually occurs during early childhood. Most adults have serologic evidence of previous HHV-7 infection. (753). Eighty to ninety percent of HHV-7-- infected adults, regardless of HIV status, shed HHV-7 intermittently in their saliva.

Clinical Manifestations

HHV-6B causes exanthem subitum (roseola), a common disease of childhood (754). In addition, HHV-6B is a major cause of emergency room visits and hospitalizations for infants and young children (755). HHV-6 also produces a spectrum of neurologic diseases, including encephalitis and febrile seizure (756). Although HHV-6 has been described as a cause of disease in other immunocompromised patients, it has not been identified as an important opportunistic pathogen in HIV-infected patients.

Both HHV-6 and HIV can simultaneously infect the same CD4⁺ cells under experimental conditions. Studies evaluating the effect of HHV-6 coinfection on active HIV viral replication in vitro have yielded contradictory results, with some investigations documenting enhanced HIV replication (757), whereas others reported inhibition of HIV replication (758). In vivo studies have suggested a possible role for HHV-6 coinfection in the progression of HIV disease (759,760), but this remains unconfirmed.

HHV-7 has not been definitively documented to cause a specific disease, with no apparent correlation between HHV-7 and HIV plasma load, suggesting that HHV-7 infection might not be stimulated by or interact with HIV infection (761).

Diagnosis

A fourfold or greater rise in anti-HHV-6 antibody titer between acute and convalescent serum samples suggests that active viral replication has occurred. Detection of HHV-6 IgM in infants and young children is a reliable marker of primary infection, although extrapolation to adults is problematic because IgM can be detected during HHV-6 reactivation. Detection of HHV-6 DNA in cell-free plasma specimens by PCR suggests active HHV-6 replication (762).

Preventing Exposure

HHV-6 and HHV-7 are ubiquitous universal infections, and prevention of exposure is not feasible.

Preventing Disease

Because of the ubiquity of HHV-6 and -7 during early childhood and the lack of an effective vaccine, prevention of primary HHV-6 and -7 infections or HHV-6 disease is not feasible.

Treatment of Disease

Antiviral susceptibility patterns of HHV-6 resemble those of CMV. HHV-6 replication is readily inhibited by foscarnet, cidofovir, and ganciclovir at levels that are easily achievable in the human plasma. Indications for treatment of HHV-6 infection in HIV-seropositive patients are unclear. However, if disease in an HIV-infected person is determined to be caused by HHV-6, ganciclovir or foscarnet can be considered treatment options using treatment schedules and doses similar to those used for CMV disease (CIII). HHV-7 has not been recognized as a cause of disease in HIV-infected persons, and no recommendation for treatment can be made.

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

See CMV treatment recommendations for monitoring and adverse events. HHV-6 and -7 have not been demonstrated to be associated with IRIS.

Management of Treatment Failure

Mutations conferring resistance of HHV-6 to ganciclovir, cidofovir, and foscarnet have been described (763). Theoretically, treatment failures could be managed by switching classes of antiviral medications (e.g., changing from ganciclovir to foscarnet), but data are completely lacking (CIII).

Preventing Recurrence

No data exist on prevention of HHV-6 or HHV-7 reactivation from latency in HIV-infected patients. Use of antiviral medications for this indication is not recommended (DIII).

Special Considerations During Pregnancy

Given the epidemiology of HHV-6 infection, symptomatic infection and indications for treatment in pregnancy are expected to be rare. See special considerations for CMV for a discussion of concerns regarding use of ganciclovir and foscarnet in pregnancy. Treatment of HHV-7 during pregnancy is not indicated.

Varicella-Zoster Virus Diseases

Epidemiology

Approximately 95% of adults (aged >21 years) born in the United States have had primary varicella-zoster virus (VZV) infection, known as varicella (or chickenpox). Reactivation of latent VZV results in herpes zoster (or shingles). A person's lifetime risk for herpes zoster is 15%--20%, with the highest incidence occurring in the elderly and immunocompromised persons. The incidence of herpes zoster is >15-fold higher for HIV-infected adults than for age-matched controls (764). Herpes zoster can occur in HIV-infected adults at any CD4⁺ count, but frequency of disease is highest with CD4⁺ counts of <200 cells/µL and is not reduced by ART (765--767).

Clinical Manifestations

The varicella rash first appears on the head, then on the trunk, and finally on the extremities, evolving through stages of vesicles, pustules, and crusts. The rash is characterized by rapid evolution of lesions during the initial 8--12 hours and by successive crops of new lesions. New vesicle formation continues for 2--4 days, accompanied by pruritus, fever, headache, malaise, and anorexia. Varicella can cause substantial morbidity in HIV-seropositive adolescents and adults. Visceral dissemination, especially VZV pneumonitis, is well documented (768). Because most HIV-infected adults in the United States are VZV seropositive, varicella is an uncommon occurrence in this population.

Herpes zoster manifests as a painful cutaneous eruption in a dermatomal distribution, often preceded by prodromal pain. The most common sites for herpes zoster are the thoracic dermatomes (40%--50% of cases), followed by cranial nerve (20%--25%), cervical (15%--20%), lumbar (15%), and sacral (5%) dermatomes. Skin changes begin with an erythematous maculopapular rash, followed by the appearance of clear vesicles and accompanied by pain (which might be severe). New vesicle formation typically continues for 3--5 days, followed by lesion pustulation and scabbing. Crusts typically persist for 2--3 weeks and cutaneous dissemination might be as high as 25% to 50%. About 20%--30% of HIV-infected patients have one or more subsequent episodes of herpes zoster, which might involve the same or different dermatomes. The probability of a recurrence of herpes zoster within 1 year of the index episode is approximately 10% (767,769). Approximately 10%--15% of HIV-seropositive patients report post-herpetic neuralgia (PHN) as a complication following herpes zoster (767,770).

Most herpes zoster-related complications, including herpes zoster dissemination, occur in patients with CD4⁺ counts of <200 cells/µL (771). The CNS is the primary target organ for herpes zoster dissemination in patients coinfected with HIV. Various VZV-related neurologic syndromes occur in HIV-infected patients, including CNS vasculitis, multifocal leukoencephalitis, ventriculitis, myelitis and myeloradiculitis, optic neuritis, cranial nerve palsies and focal brain-stem lesions, and aseptic meningitis.

ARN and progressive outer retinal necrosis (PORN) are variants of necrotizing retinopathy caused by VZV. Although ARN can occur in both immunocompetent and immunocompromised patients, PORN occurs almost exclusively in AIDS patients with CD4⁺ count <100 cells/µL (772). In contrast to ARN, PORN is characterized by minimal inflammation in the aqueous and vitreous humor, absence of retinal vasculitis, and multiple discrete peripheral lesions in the outer retinal layer (773). PORN lesions rapidly coalesce, causing full-thickness retinal necrosis and subsequent retinal detachment (774). Both ARN and PORN are associated with high rates of visual loss.

Diagnosis

Varicella and herpes zoster are distinctive in appearance and can usually be diagnosed clinically. Varicella can be diagnosed retrospectively by documenting seroconversion. When lesions are atypical or the diagnosis is uncertain, swabs from a fresh lesion or tissue biopsies can be submitted for viral culture, direct fluorescent antigen testing, or PCR. Histopathology and PCR can aid with diagnosis of VZV infections of visceral organs (e.g., encephalitis, retinitis, and pneumonitis).

Preventing Exposure

HIV-infected persons who are susceptible to VZV (i.e., those who have not been vaccinated, have no history of varicella or herpes zoster, or are seronegative for VZV) should avoid exposure to persons with chickenpox or herpes zoster (AII). VZV-susceptible household contacts of susceptible HIV-infected persons should be vaccinated to prevent acquisition of chickenpox and potential transmission of VZV to their susceptible HIV-infected contacts (BIII).

Preventing Disease

Postexposure Prophylaxis

For prophylaxis against chickenpox, HIV-infected children and adults who are susceptible to VZV should receive varicella-zoster immune globulin (VariZIG™) as soon as possible (but within 96 hours) after close contact with a person who has active varicella or herpes zoster (AIII). As of June 2007, VariZIG can be obtained only under a treatment IND; contact FFF Enterprises, 800-843-7477. The duration of protection should last at least for 3 weeks. Patients receiving monthly high-dose immune globulin intravenous (IGIV) (>400 mg/kg) are likely to be protected and probably do not require VariZIG if the last dose of IGIV was administered <3 weeks before exposure. Risk for VZV transmission is higher from exposure to a patient with chickenpox than from exposure to localized herpes zoster.

Among VZV-susceptible immunocompetent children, post-exposure varicella vaccination has been shown to reduce the risk for chickenpox developing in children and is more effective than pre-emptive therapy with acyclovir. Post-exposure varicella vaccination (for patients with CD4⁺ counts of >200 cells/µL) or short-term post-exposure administration of acyclovir may be considered for preventing chickenpox among susceptible HIV-infected adolescents or adults, but has not been studied in this population (CIII).

Long-term--- -- drug prophylaxis for prevention of primary VZV infection in HIV-infected persons is not recommended (DIII).

Vaccination

The live attenuated varicella vaccine has been documented to be safe and immunogenic in HIV-infected children aged >8 years with CD4⁺ counts >200 cells/µL (CD4⁺ percentage is >15%) (775) and is recommended for those children (776). No studies have evaluated the vaccine in HIV-infected adolescents or adults, but varicella vaccination (two doses, administered 3 months apart) may be considered in HIV-seropositive/VZV-seronegative persons >8 years old with CD4⁺ counts >200 cells/µL (CIII). If vaccination results in disease because of vaccine virus, therapy with acyclovir is recommended (AIII). Administration of varicella vaccine to more severely immunocompromised HIV-infected patients is not recommended (DIII). Because of the high prevalence of VZV seropositivity in adults, use of varicella vaccine in this population will be infrequent. Routine serologic testing to determine the VZV serologic status of HIV-infected adults is not recommended.

Treatment of Disease

No controlled prospective studies of antiviral therapy for chickenpox in HIV-infected adults have been reported. For uncomplicated varicella, recommended treatment options are oral acyclovir (20 mg/kg body weight up to a maximum dose of 800 mg five times daily), valacyclovir (1 g PO tid), or famciclovir (500 mg PO tid) for 5--7 days (AII). IV acyclovir for 7--10 days is the recommended initial treatment for HIV-infected patients with severe chickenpox (AIII) (768,777,778). If no evidence of visceral involvement with VZV is available, switching to oral antiviral therapy after the patient has defervesced may be permissible (AIII) (779).

Prompt antiviral therapy should be instituted in all immunosuppressed herpes zoster patients within 1 week of rash onset or any time before full crusting of lesions. The recommended treatment options for acute localized dermatomal herpes zoster in HIV-infected patients are oral valacyclovir, famciclovir, or acyclovir for 7--10 days (AII), although longer durations of therapy should be considered if lesions resolve slowly. Valacyclovir or famciclovir are preferred because of their improved pharmacokinetic properties and simplified dosing schedule. If cutaneous lesions are extensive or if visceral involvement is suspected, IV acyclovir should be initiated and continued until clinical improvement is evident (AII) (780). A switch from IV acyclovir to oral antiviral therapy (to complete a 10--14 day treatment course) is reasonable when formation of new cutaneous lesions has ceased and the signs and symptoms of visceral VZV infection are improving (AIII). Because of the absence of data to support benefit in this population, adjunctive corticosteroid therapy for herpes zoster is not recommended (DIII).

Optimal antiviral therapy for PORN remains undefined (774,781). Prognosis for visual preservation in involved eyes is poor despite aggressive antiviral therapy. A treatment regimen recommended by certain specialists is a combination of IV ganciclovir and foscarnet, plus intravitreal injections of ganciclovir and/or foscarnet (AIII). Optimization of ART in HIV-infected patients with PORN is also recommended (AIII). Anecdotal reports have described success with IV cidofovir. ARN appears to be more responsive to antiviral therapy; one recommended treatment is high-dose IV acyclovir (10 mg/kg every 8 hours for 10--14 days), followed by prolonged oral valacyclovir (1 gram tid for 6 weeks) (AIII). Involvement of an experienced ophthalmologist in management of patients with VZV retinitis is strongly recommended (AIII).

The incidence of herpes zoster in HIV-infected adults does not appear to be affected by ART therapy. Optimization of ART is recommended in patients with VZV infections (e.g., PORN) (AIII) that are difficult to treat.

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

For monitoring and adverse event recommendations related to anti-herpesvirus drugs, see preceding sections on HSV and CMV. Providers should be aware of the increased incidence of herpes zoster after initiation of ART. Such episodes should be treated as other episodes of herpes zoster.

Immune reconstitution following initiation of ART might be associated with an increased frequenty of VZV reactivation (782,783). Between 4 and 16 weeks after beginning ART, the risk for herpes zoster increases two- to fourfold from baseline. During the 6 months after the start of combination ART, the incidence of herpes zoster exceeds 90 episodes per 1,000 person years. The percentage of CD8⁺ lymphocytes at baseline and the magnitude of their increase at 1 month after initiation of drug therapy are strongly associated with an increased risk for herpes zoster. The clinical presentation and natural history of herpes zoster in the setting of immune reconstitution do not differ from those observed in other HIV-infected patients.

Management of Treatment Failure

Treatment failure caused by resistance of VZV to acyclovir (and related drugs) should be suspected if lesions do not improve within 10 days of initiation of therapy or if they have an atypical (e.g., verrucous) appearance. A viral culture should be obtained, and if VZV is isolated, susceptibility testing performed to establish antiviral drug susceptibility or resistance and to document the need for alternative therapy. Among patients with suspected or proven acyclovir-resistant VZV infections, treatment with IV foscarnet is recommended (AII) (784).

Preventing Recurrence

No intervention has been recognized as preventing the recurrence of herpes zoster among HIV-infected persons. An attenuated virus vaccine for prevention of herpes zoster has been approved for use in immunocompetent persons aged >60 years, but data regarding its use in HIV-infected persons are lacking. Prospective clinical trials to evaluate the safety and immunogenicity of herpes zoster vaccine in HIV-seropositive subjects are planned. Administration of herpes zoster vaccine to HIV-infected persons is not recommended (DIII).

Special Considerations During Pregnancy

HIV-infected pregnant women who are susceptible to VZV and have close contact to a person with active varicella or herpes zoster should receive VariZIG as soon as possible (within 96 hours) after exposure to VZV (AIII). If oral acyclovir is used for post-exposure prophylaxis, VZV serology should be performed so that the drug can be discontinued if the patient is seropositive for VZV (CIII). Pregnant women should not receive varicella vaccine (EIII).

Specific risks among HIV-infected women with varicella during pregnancy have not been reported. For HIV-seronegative women with chickenpox, the risk for transmitting VZV to the infant resulting in congenital varicella syndrome is 0.4% when infection occurs at or before 12 weeks of gestation, 2.2% with infection at 13--20 weeks, and is negligible after 20 weeks (785). Women with varicella during the first half of pregnancy should be counseled about the risks and offered detailed ultrasound surveillance for findings indicative of fetal congenital varicella syndrome (785). Administration of varicella-zoster immune globulin does not alter the risk for congenital varicella syndrome. Infants born to women who have chickenpox from 5 days before until 2 days after delivery should receive VariZIG to reduce the severity and mortality of neonatal varicella acquired during maternal viremia (AIII) (783).

Oral acyclovir or valacyclovir are the preferred treatments for HIV-infected pregnant women who have uncomplicated chickenpox during pregnancy (BIII). Pregnant women who have severe varicella or who exhibit signs or symptoms of VZV pneumonitis should be hospitalized and treated with IV acyclovir (10 mg/kg every 8 hours) (AII).

No controlled studies of antiviral therapy of herpes zoster during pregnancy have been reported. Recommended therapy for uncomplicated shingles in pregnant HIV-infected women is oral acyclovir or valacyclovir (BIII).

Human Herpesvirus-8 Disease

Epidemiology

Human herpesvirus-8 (HHV-8) seroprevalence among the general population in the United States is 1%--5%. The seroprevalence is greater among MSM (20%--77%) (800), regardless of HIV infection, and is also higher in certain Mediterranean countries (10%--20%) and in parts of sub-Saharan Africa (30%--80%). HHV-8 is associated with all forms of KS (i.e., classic, endemic, transplant-related, and AIDS-related) and certain rare neoplastic (e.g., primary effusion lymphoma [PEL]) and lymphoproliferative disorders (multicentric Castleman disease [MCD]). The precise pathogenesis is unclear even though seroconversion to HHV-8 precedes the development of these tumors (786). Patients who are HHV-8 seropositive and have HHV-8 viremia have an increased risk (approximately ninefold) for experiencing KS compared with HHV-8 seropositive men without HHV-8 viremia (787), and HHV-8 viremia almost always accompanies symptomatic episodes of MCD (788).

The overall incidence of KS was as high as 20% among patients with AIDS before the advent of effective ART. However, even before the widespread use of ART, the incidence had declined, perhaps because of ganciclovir, foscarnet, and cidofovir use for treatment of CMV disease. These agents inhibit the replication of HHV-8 in vitro, (789,790, 803) and observational studies indicate that patients receiving ganciclovir or foscarnet (but not acyclovir) develop KS at a reduced rate (710,791--793). The incidence of KS has declined after the introduction of PIs and HAART (794). PEL and MCD remain rare (795).

KS and PEL are described most frequently among HIV-infected persons with more advanced immunosuppression (CD4⁺ counts of <200 cells/µL), although they can occur at any CD4⁺ count. Episodes of MCD might present at any CD4⁺ count.

Clinical Manifestations

Most persons with chronic HHV-8 infection are asymptomatic (796). Acquisition of HHV-8 has been associated with a primary infection syndrome consisting of fever, rash, lymphadenopathy, bone marrow failure, and occasional rapid progression to KS (797,798). MCD manifests with generalized adenopathy and fever and can progress to multi-organ failure (795). KS symptoms vary widely, but most persons have nontender, purplish, indurated skin lesions. Intraoral lesions are common and visceral dissemination can occur, occasionally without the presence of skin lesions. Other manifestations of HHV-8 infection are beyond the scope of this report. Asymptomatic HHV-8 infection is often associated with HHV-8 shedding in the saliva and occasional shedding in genital secretions (796,799,800); viral shedding might result in HHV-8 transmission to uninfected partners.

Diagnosis

Routine screening for HHV-8 by PCR or serologic testing for HHV-8 antibody is not indicated for HIV-infected persons. Use of PCR to quantify HHV-8 in the peripheral blood is helpful in the diagnosis and management of persons with MCD (788).

Preventing Exposure

Recommendations related to preventing exposure to HHV-8 do not exist.

Preventing Disease

Despite observational evidence supporting a role for anti-HHV-8 therapy in preventing the development of KS, the toxicity of current anti-HHV-8 therapy outweighs the potential benefits of administration (DIII).

Treatment of Disease

Although ganciclovir, foscarnet, and cidofovir have in vitro activity against HHV-8, and limited studies indicate these agents might be associated with reduced KS disease progression or lesion regression, larger and more definitive studies are needed to determine whether antiviral therapy has a useful role in managing HHV-8-associated diseases. KS regression has been documented after ganciclovir or foscarnet therapy (801--803), although one study indicated cidofovir was ineffective (804). The use of IV ganciclovir or oral valganciclovir is, however, recommended in the treatment of MCD (BII) (805) and might be useful adjunctive therapy in the treatment of PEL (BII) (806,807). Highly active ART that suppresses HIV replication should be administered to all HIV-infected persons with KS, PEL, or MCD (BII), although insufficient evidence exists to support using one HAART regimen over another. Chemotherapy, in combination with ART, should be considered for patients with PEL or visceral KS (BII) and might be a useful adjunctive therapy in persons with widely disseminated cutaneous KS (CIII). Rituximab also appears to be an effective alternative to antiviral therapy in the treatment of MCD (BII) (808).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Fatal IRIS has been reported in persons initiating ART with pre-existing KS and MCD. The frequency of HHV-8-associated IRIS is not known but suppression of HIV replication and immune reconstitution are key components of therapy and initiation of ART should not be delayed.

Preventing Recurrence

Effective suppression of HIV replication with ART among HIV-infected patients with KS might prevent KS progression or occurrence of new lesions and should be considered for all persons with evidence of active KS (BII). Suppression of HIV replication also is recommended for persons with MCD (BII) and those with malignant lymphoproliferative disorders.

Special Considerations During Pregnancy

The seroprevalence of HHV-8 infection among HIV-infected pregnant women varies by geographic area, ranging from 1.7% among U.S.-born and 3.6% among Haitian-born women in New York City to 11.6% among pregnant women from four other U.S. cities (809). Pregnancy does not appear to affect the prevalence of antibodies to HHV-8 or the antibody levels (84), although levels of HHV-8 DNA in the peripheral blood might increase late in pregnancy (810). HHV-8 seropositivity does not appear to influence pregnancy outcome. Routine screening for HHV-8 by PCR or serology is not indicated for HIV-infected pregnant women (DII). In vitro models suggest that beta-human chorionic gonadotropin induces regression of KS tumors, but clinical reports on the incidence and natural history of KS in pregnancy are conflicting (811--814).

Diagnosis of KS or other HHV-8-associated neoplasms in pregnancy should be the same as in nonpregnant women. Recommendations for the treatment of HHV-8 malignancies are beyond the scope of these guidelines. Treatment should be undertaken in consultation with a specialist.

Perinatal transmission of HHV-8 might occur infrequently. Evidence supporting vertical transmission during pregnancy or the intrapartum period includes cases of KS occurring in the infant shortly after birth (815,816), higher risk for transmission with higher maternal antibody titer (and by inference higher maternal levels of HHV-8) (817), and detection of similar strains of HHV-8 DNA by PCR in specimens drawn at birth from HHV-8-seropositive mothers and their infants (818). Data indicate increased mortality through age 24 months among HIV-infected infants born to HHV-8-seropositive compared with HHV-8-seronegative mothers (815--817,819--824), but these studies could not completely account for other confounding factors affecting HIV-infected infants. The majority of studies document a substantially higher rate of HHV-8 seropositivity among children born to HHV-8 antibody-positive compared with HHV-8 antibody-negative women (819--824).

Human Papillomavirus Disease

Epidemiology

Human papillomavirus (HPV), a common sexually transmitted DNA virus (825--830), is the most frequent cause of cervical cancer (831--833). Most HPV infections, however, resolve or become latent and undetectable (828,834,835), whereas persistent infection with an oncogenic HPV type is required for tumorigenesis. Of more than 100 HPV types, more than 40 can infect the cervix, and at least 13 of these are considered oncogenic types, including HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 66 (836). HPV16 alone accounts for approximately 50% of cervical cancers in the general population and HPV18 for another 10%--15%, whereas the other oncogenic HPV types each individually account for <5% of tumors (832,837). HPV types 6 and 11 cause 90% of genital warts (838).

Cervical cancer is the second most common cause of cancer in women worldwide, with almost twofold higher incidence in developing countries than in industrialized countries (839). In the United States and Western Europe, women with HIV/AIDS have several-fold higher rates of cervical cancer compared with the general population, according to studies linking population-based cancer registries with registries for HIV/AIDS (840--843). In Africa, findings have varied (844), but the only African study with a prospective registry-based design reported substantially increased risk for cervical cancer in women with HIV/AIDS, and cervical cancer represented 10% of all tumors detected (845). Furthermore, HIV seropositivity is associated with a high prevalence of HPV infection, low-grade cervical intraepithelial neoplasia (CIN), and the precursor to cervical cancer, CIN 3 (846--865). Among HIV-infected women, rates of oncogenic HPV and high-grade CIN increase with diminished CD4⁺ count and higher HIV RNA levels (858,860,866--876).

Other cancers caused by oncogenic HPV infection include most anal cancers and a subset of tumors of the vulva, vagina, penis, oral cavity, and oropharynx (836,877). HPV16 is the type present in the majority of these HPV-positive noncervical cancers. As with cervical cancer, the incidence of anal cancer and the other HPV-associated tumors is substantially higher in patients with HIV/AIDS than in the general population (841,842,878). Furthermore, high-grade anal intraepithelial neoplasia (AIN), the likely anal cancer precursor lesion, is more common in HIV-seropositive adults than in HIV-seronegative adults (879--883) as are anal and genital warts and, in women, vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VAIN) (884--886).

Although ART has altered HIV natural history, its effect on HPV and HPV-associated neoplasia is less clear. Certain studies have found reduced persistence/progression of cervical intralepithelial neoplasia (CIN) with use of ART. Conversely, most studies have not reported reduced persistence/progression of high-grade anal intraepithelial neoplasia (AIN) (AIN 2 or AIN 3) among men using ART (882,892--894), and most studies of cancer incidence have failed to document decreases in either cervical or anal cancer incidence since the widespread introduction of ART (882,892,894--899). Similarly, the incidence of high-grade vulvar neoplasia was not reduced with ART use (884), even though rates of low-grade vulvar lesions and anal or genital warts did decrease with ART (884,900). Whether ART has an effect on warts among HIV-infected persons is unclear (884,888,900). With ART having limited or no effect on HPV-associated cancers, and HIV-seropositive persons living longer, HIV-seropositive women and men will increasingly enter middle age, when the incidence of cervical and other HPV-associated cancers typically increases (901--903). Future increases in HPV-associated cancer rates among these patients are possible, particularly for cancers for which no routine screening, such as anal cancer is available. Continued careful monitoring of cancer rates in HIV-positive patients during the highly aggressive antiretroviral therapy (HAART) era is warranted.

Clinical Manifestations

The principal clinical manifestations of mucosal HPV infection are genital, anal, and oral warts; CIN; VIN; VAIN; AIN; squamous cell cancers; and cervical adenocarcinomas. A subset of oropharyngeal cancers are caused by HPV (877). HPV6 and 11 also cause recurrent respiratory papillomatosis, a rare condition in which papillomas grow in the respiratory tract.

Genital, Anal, and Oral Warts

Warts (condyloma acuminata) are usually flat, papular, or pedunculated growths on the mucosa or epithelium. The lesions might be a few millimeters to 1--2 centimeters in diameter; multiple lesions might be present. Certain persons with warts are asymptomatic although some have genital itching or discomfort.

CIN, VIN, and Squamous Cell Cancers

No characteristic symptoms are associated with CIN. These lesions are often asymptomatic but might manifest with bleeding. Cervical cancer also might be asymptomatic or might manifest with bleeding, pain, or a palpable mass.

AIN, VAIN, VIN and Oral HPV-Related Disease

No characteristic symptoms are associated with VAIN, VIN, and AIN. These lesions are often asymptomatic but might manifest with bleeding or itching, and external lesions might be visible or palpable. Similarly, squamous cell cancers at these sites also might be asymptomatic or they might manifest with bleeding, pain, or a visible/palpable mass.

Diagnosis

Genital, Anal, and Oral Warts

Diagnosis of genital and oral warts is made by visual inspection and can be confirmed by biopsy, although biopsy is needed only under certain circumstances (e.g., if the diagnosis is uncertain; the lesions do not respond to standard therapy; the disease worsens during therapy; or warts are pigmented, indurated, fixed, bleeding, or ulcerated). No data support the use of HPV tests in the routine diagnosis or management of visible genital or oral warts (529).

CIN, VIN, and Squamous Cell Cancers

The same cytology (Papanicolaou or Pap test) and colposcopic techniques used to detect CIN among HIV-seronegative women should be used in HIV-seropositive patients (904). Clinicians should be aware of such cytology and histology terms (Table 11). The entire genitalia and anal canal should be inspected carefully for visual signs of warts, intraepithelial neoplasia, or invasive cancer. Cervical cytology, tissue histology, or both should be performed according to the schedule described in the following sections.

After the Pap test, a digital examination of the vaginal, vulvar, and perianal regions and the anal canal should be performed as part of routine evaluation to feel for masses.

After an abnormal Pap test, a colposcopically directed cervical biopsy is the principal means of identifying CIN so that the lesion can be treated to prevent development of cervical cancer and to determine appropriate follow-up. For further details, see the section on prevention of cervical cancer.

AIN, VAIN, VIN and Oral HPV-Related Disease

AIN might first be recognized using a combination of visual inspection and anal cytology (termed anal SIL or ASIL), but as with CIN the diagnosis of AIN is principally made using anoscopically directed biopsy. Similarly, VAIN, VIN, and oral dysplasia are recognized through visual inspection and biopsy as needed. See the section on prevention of anal cancer.

Role of HPV Testing

Although a clinical test is available to detect 13 types of oncogenic HPV infection, no recommendations exist for use of this test in HIV-seropositive women. HIV-seropositive women should be referred for colposcopy if their cervical Pap test is interpreted as ASC US, ASC-H (or atypical glandular cells [ACG]), low-grade squamous intraepithelial lesions (LSIL), or high-grade squamous intraepithelial lesions (HSIL) (368,904,905). HPV testing may be used in the management of HIV-seronegative women with a cytologic diagnosis of ASC-US. "is practice has been recommended for similar use in HIV-seropositive women in American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines (906), but at present, insufficient data are available to support this practice. Unlike for HIV-seronegative women, no recommendations exist for the use of HPV testing for triage of HIV-seropositive women aged >30 years with normal cervical cytology (e.g., to less or more frequent Pap tests based on a hybrid capture test) or in follow-up of CIN after treatment. No recommendations are available for HPV testing of anal specimens or other noncervical specimens.

Preventing Exposure

Consistent and correct use of male latex condoms has been associated with 72% reduction in risk for acquisition of genital HPV infection among sexually active college age women (907). Evidence confirms that condom use might reduce the risk for HPV-associated disease, including warts, cervical cancer, and CIN in women (908,909). Fewer data are available on prevention of HPV infection and HPV-associated conditions among HIV-seropositive patients. Laboratory studies have indicated that latex condoms provide a sufficient barrier to prevent passage of particles the size of HPV (908,910). Although condoms might not prevent transmission of HPV from skin outside the area of condom coverage, they should be used by sexually active HIV-seropositive patients to reduce the risk for transmission or acquisition of sexually transmitted infections (AII).

A vaccine targeted against HPV16 and HPV18 (the two HPV types responsible for 60%--70% of cervical cancers) and HPV6 and HPV11 (which cause most anogenital warts) was licensed and recommended for use in 2006 (911,912). This quadrivalent HPV vaccine was efficacious in preventing HPV infection and high-grade CIN associated with vaccine-related HPV types among young HIV-seronegative women (913--916). A second vaccine targeting HPV16 and 18 has had similar efficacy. No data are available regarding the safety, tolerability, immunogenicity, or efficacy in HIV-infected women, and specific recommendations for HIV-seropositive women await data from ongoing studies. However, given the safety of other noninfectious vaccines in HIV-seropositive patients, the HPV vaccine is not absolutely contraindicated in HIV-seropositive women, and it may be used in circumstances when the clinician believes clinical benefit can be derived. The HPV vaccine has not demonstrated therapeutic benefit to treat existing HPV-related lesions in either HIV-seropositive or HIV-seronegative women, and women who have already acquired one sexually transmitted infection (e.g., HIV infection) are presumably more likely to have acquired others (e.g., infections with various HPV types). No published studies support using the HPV vaccine to prevent HPV infection and associated lesions of the anus, penis, or oral cavity; the vaccine is not currently approved for use in men in the United States. As in HIV-seropositive women, no data on the safety or efficacy of the HPV vaccine in HIV-positive men are available.

Preventing Disease

Preventing Cervical Cancer

See the guidelines for the use of cytology and biopsy to diagnose CIN. Also see section regarding treatment of CIN.

After obtaining a complete medical history, including the history of previous cervical disease, HIV-seropositive women should have a pelvic examination and a Pap test. The Pap test should be obtained twice during the first year after diagnosis of HIV infection and, if the results are normal, annually thereafter (AII). If the results of the Pap test are abnormal, care should be provided according to the Guidelines for Management of Women with Abnormal Cervical Cancer Screening Tests by ASCCP (904).

Regardless of CD4⁺ count, plasma HIV viral load, or antiretroviral treatment status, colposcopy and appropriate directed biopsy are recommended for HIV-seropositive women with cytological reports of "atypical squamous cells, cannot exclude high grade SIL" (ASC-H), (BII), LSIL (AII), HSIL (AII), or squamous cell carcinoma (AII) (529). HPV testing may be used in the management of HIV-seronegative women with a cytologic diagnosis of ASC-US. This has been recommended for similar use in HIV-seropositive women in recent ASCCP guidelines (904). However, published data are limited, conflicting, and insufficient to support the use of HPV DNA testing in triage of ASC-US among HIV-seropositive women (DIII). A prudent plan is to perform routine colposcopy for HIV-seropositive women with ASC-US (CIII).

Among women with ASC-US on a Pap test, if a biopsy-confirmed CIN is absent and the colposcopic exam was adequate, follow-up with cervical cytology in 12 months is recommended (BIII), with referral back to colposcopy if results of ASC-US or greater are obtained. After two repeated results negative for intraepithelial lesion or malignancy, an affected woman can return to routine annual cytological screening (AII). ASCCP guidelines should be followed if the colposcopic exam is not adequate or when CIN is found.

If no CIN 2 or 3 lesion is identified at colposcopy among women with ASC-H, and a review of the results confirms the reading of ASC-H, cytological follow-up is recommended at 6 and 12 months (CIII). Women with ASC-US or greater on repeat cytology should again be referred for repeat colposcopy (BII).

For women referred to colposcopy for LSIL, if the colposcopy is satisfactory (entire squamocolumnar junction can be visualized with the colposcope) and no lesion or CIN is identified, follow-up with repeat cytological testing at 6 and 12 months is recommended (BII). ASCCP guidelines should be followed if the colposcopy is unsatisfactory or CIN is found.

A cytological result of HSIL identifies a woman at high risk for high-grade CIN or invasive cervical cancer. An immediate loop electrosurgical excision or colposcopy with endocervical assessment is an acceptable method for managing women with HSIL (BII). ASCCP guidelines should be followed if the colposcopy is satisfactory and no lesion or only CIN 1 is identified, or the colposcopy is unsatisfactory, or CIN 2 or 3 is found.

AGC on cytology is associated with greater risk for CIN and glandular neoplasia than ASC-US or LSIL. The Bethesda system has classified AGC into three categories: AGC, either endocervical, endometrial, or glandular cells not otherwise specified ("AGC NOS"); AGC, either endocervical or glandular cells favor neoplasia ("AGC favor neoplasia"); and endocervical adenocarcinoma in situ (AIS). Colposcopy with endocervical sampling is recommended for all the subcategories of AGC and AIS (AII). Endometrial sampling is recommended in conjunction with colposcopy and endocervical sampling in women 35 years of age and older (BII). ASCCP guidelines should be followed for women under the age of 35 and for subsequent evaluation of AGC.

For women with "AGC favor neoplasia" or AIS, those with normal colposcopy should undergo a diagnostic excisional procedure (e.g., cold knife excision, loop electrosurgical excision) (BII). If the initial colposcopy is normal in a woman with "AGC NOS," repeat cytology is recommended at 4--6-month intervals until four consecutive tests negative for intraepithelial neoplasia are obtained before returning to routine cytological screening (BIII). If abnormal cytology, including ASC, is obtained on follow-up cytology, repeat colposcopic examination or referral to a specialist is recommended (BIII).

Preventing Vaginal and Vulvar Cancer

In keeping with recommendations for HIV-seronegative women, routine screening of HIV-seropositive women for vaginal cancer following a hysterectomy for benign disease is not recommended, but women with a history of high-grade CIN or invasive cervical cancer are at increased risk and should be followed with a regular vaginal cuff Pap test (AIII) (917,918). For patients with abnormal vaginal cuff Pap tests with no visible vaginal colposcopic abnormalities, vaginal colposcopy and use of Lugol's iodine to stain the vagina are recommended (AIII). Vaginal colposcopy is also indicated in the presence of concomitant cervical and vulvar lesions (919,920). Classification of VAIN parallels that of the cervix (i.e., VAIN 1, VAIN 2, and VAIN 3).

No screening procedure is available for vulvar cancer. However, for HIV-seropositive women with a past history of cervical or VAIN/cancer, an inspection of the vulva with or without colposcopy should be encouraged as part of their regular follow-up (CIII). Diagnosis of VIN/cancer should be confirmed with a biopsy (AII). A wedge biopsy under local anesthesia is usually done.

Preventing Anal Cancer

High-grade AIN (AIN 2 or 3) has the potential to progress to invasive anal cancer (921,922). Evidence from multiple studies demonstrates that HIV-seropositive MSM and HIV-seropositive women are at increased risk for AIN 2 or 3 and are at increased risk for anal cancer compared with the general population. The incidence of anal cancer has not declined since the widespread introduction of ART (899). This evidence and a cost-effectiveness analysis projecting that screening and treatment for anal precancerous lesions detected by Pap tests provide clinical benefits comparable to other OI prevention measures for HIV-seropositive persons (923), anal cytology screening of HIV-seropositive MSM and of women might be useful preventive strategies. However, studies of screening and treatment programs for AIN 2 or 3 should be implemented before definitive recommendations for anal cytology screening can be made. No national recommendations exist for routine screening for anal cancer (529). Until such time, certain specialists recommend an annual digital rectal examination as an important procedure to detect masses on palpation that might be anal cancer (BIII) (924). In addition, certain specialists recommend anal cytologic screening for HIV-seropositive men and women (CIII). If anal cytology is performed and indicates ASC-US or ASC-H, LSIL, or HSIL (BIII), then it should be followed by high-resolution anoscopy (HRA). Visible lesions should be biopsied to determine the level of histologic changes and to rule out invasive cancer (BIII). See section on treatment for details of treatment of AIN.

Preventing Other HPV-Associated Cancers Among HIV-Seropositive Men and Woman

Other cancers that have been associated with HPV infection among HIV-seropositive men and women include oropharyngeal squamous cell and penile cancers (841,897,925). Prevention options for these cancers are unclear. Circumcision might reduce the risk for penile cancer as documented in one study (926); however, the benefits of circumcision to prevent HPV infection and penile cancer have not been studied in a randomized clinical trial or among HIV-seropositive men. No national recommendations exist for screening for oropharyngeal or penile cancer or precancerous lesions among those with HIV infection.

Treatment of HPV-Associated Genital and Anal Lesions

Treatment of Genital and Oral Warts

Treatments are available for genital warts, but none is uniformly effective (529). No single treatment has been demonstrated to be superior to any other, and no single treatment is ideal for all patients or all warts. Recurrences are common regardless of the modality (927). Data are limited on the response of HIV-seropositive patients to the available treatments for genital warts. In the absence of data specific to the HIV-seropositive population, guidelines for the treatment of STDs for HIV-seronegative patients should be followed (529). Data are insufficient to recommend a single treatment modality for all patients, and more than one treatment option might be required for refractory or recurrent lesions among patients with HIV infection.

Patient-applied treatments are generally recommended for uncomplicated external warts that can be easily identified by the patient and consist of the following options:

Podophyllotoxin (e.g., podofilox [0.5% solution or gel]) is an antimitotic agent that should be applied topically to warts twice daily for 3 days, followed by 4 days of no therapy. Treatment can be repeated weekly for up to four cycles (BIII). The efficacy is 40%--60% in immunocompetent subjects (928,929).

Imiquimod (5% cream) is a topical cytokine inducer that recruits an inflammatory response to the site of the wart. Patients should apply the cream once daily at bedtime three times a week for up to 16 weeks. The treatment area should be washed with soap and water 6--10 hours after the application (BII). The efficacy of imiquimod in immunocompetent persons is 30%--70%; the overall response in HIV-seropositive persons might be lower than in immunocompetent persons (930--932).

Provider-applied treatments are typically recommended for complex or multicentric lesions or those lesions inaccessible to patient-applied treatments. These include intra-anal and vaginal warts. Options are summarized as follows:

Cryotherapy (liquid nitrogen or cryoprobe) destroys lesions by thermal-induced cytolysis. Liquid nitrogen should be applied until each lesion is thoroughly frozen and repeated every 1--2 weeks. Certain specialists recommend allowing the lesion to thaw and freezing a second time in each session (BIII). The efficacy of cryotherapy is 60%--80%.

Trichloroacetic acid (TCA) or bichloroacetic acid (BCA) (80%--90%) act as caustic agents to kill wart tissue. Providers should apply a small amount to warts only and allow them to dry, at which time a white "frosting" develops. If an excess amount of acid is applied, the treated area should be powdered with talc, sodium bicarbonate, or liquid soap to remove unreacted acid. The treatment can be repeated weekly for 3--6 weeks (BIII). The expected efficacy is 60%--80%.

Surgical treatments (tangential scissor excision, tangential shave excision, curettage, electrosurgery, electrocautery, infrared coagulation) can be used for external genital and anal warts (BIII). Laser surgery also can be used, but is usually more expensive (CIII). The efficacy of surgical removal can approach 100%, depending on the location of the lesions.

Podophyllin resin is a crude extract that contains podophyllotoxin and other cytotoxins and induces wart necrosis after topical application. It is prepared as a 10%--25% suspension in tincture of benzoin. It is applied to all lesions by the provider (up to 10 cm² of skin area) and then removed by washing a few hours later. Applications can be repeated weekly for 3--6 weeks (CIII). Efficacy is 20%--80%. It is usually only applied to external lesions and use of podophyllotoxin is preferred over podophyllin resin.

Other treatments might be options, but because of limited available data, difficult administration, or possible side effects these treatments should be considered only if the treatments described above are ineffective. In limited, uncontrolled studies, topical application of cidofovir has reported activity against genital warts (CIII) (933,934). No topical formulation is commercially available. Intralesional interferon has been used for the treatment of genital warts but because of cost, difficult administration, and potential for systemic side effects (i.e., fever, fatigue, myalgias, and leukopenia) it is not recommended for first-line treatment (DIII). Among non-HIV--infected persons, the overall efficacy of interferon in treating genital warts is not superior to other therapies and it has not been specifically studied for efficacy among HIV-infected persons.

Oral warts can be located on various surfaces in the mouth. In contrast to other oral manifestations of HIV, an increased prevalence of oral warts in patients on ART has been reported from the United States and the United Kingdom (935,936). No randomized trials of treatment of oral warts exist. Treatments include surgical excision and cryotherapy; some topical modalities have had success (937).

Treatment of CIN and Cervical Cancer

HIV-infected women with CIN should be managed by a specialist. Women having undergone satisfactory colposcopy with biopsy-confirmed CIN 1 preceded by ASC-US, ASC-H, or LSIL cytology can be followed with repeat cytological assessment at 6 and 12 months (BII). Referral to colposcopy is indicated if follow-up shows ASC or greater (AII). After two consecutive negative cytology tests, annual cytologic screening can be resumed (AII). If CIN 1 persists for at least 2 years, either continued follow-up or treatment with excision or ablation is acceptable (AI). ASCCP guidelines should be followed if the colposcopy is unsatisfactory, the endocervical sampling contains CIN, or the patient has been previously treated (AIII) (938). A diagnostic excisional procedure or observation with colposcopy and cytology at 6- month intervals for 1 year is acceptable for CIN 1, preceded by HSIL or AGC-NOS (BIII). Women with satisfactory colposcopy and biopsy-confirmed high-grade CIN can be treated with either ablation (cryotherapy, laser vaporization, electrocautery, diathermy, and cold coagulation) or excisional methods (loop electrosurgical excision procedure [LEEP], laser conization, cold knife conization) (AI). In patients with recurrent high-grade CIN, diagnostic excisional methods are recommended (AII). Hysterectomy is acceptable for treatment of recurrent/persistent biopsy-confirmed high-grade CIN (BII). ASCCP guidelines should be followed if colposcopy is unsatisfactory (938).

After treatment of high-grade CIN, follow-up with cervical cytology or combination of cervical cytology and colposcopy at 6-month intervals with at least two cytologic results of "negative for squamous intraepithelial lesion or malignancy" is acceptable (AI). Annual cytology can be done thereafter. Any ASC or greater requires colposcopy (AII).

Invasive cervical cancer is usually treated by radical hysterectomy with lymph node dissection or by radiation therapy for advanced disease. If cone biopsy or loop excision reveals microinvasive cervical cancer with clear margins, a simple hysterectomy can be done. An alternative for women with microinvasive lesions who want to preserve their fertility is local surgical procedure such as LEEP or cone biopsy with careful follow-up.

Treatment of VIN and Vulvar Cancer and of VAIN and Vaginal Cancer

Various treatment modalities for VIN are available, including local excision, laser vaporization, or ablation. Management of vulvar cancer must be individualized in consultation with a specialist. The cornerstone of the treatment of vulvar cancer is surgery. There is no standard operation and the emphasis is on the most conservative operation consistent with curing the disease. Radical vulvectomy with "en bloc" inguinofemoral lymphadenectomy has led to a favorable prognosis but with substantial morbidity (939,940). Further studies are needed to determine the optimal combined modality treatments. Radiation is also an option for some patients. The optimal treatment recommendations for HIV-seropositive women with advanced vulvar cancer remain unclear.

Similarly, treatment of VAIN is individualized in consultation with a specialist and depends on the patient's medical condition and the location and extent of the disease. Various methods of local tissue ablation to more extensive surgery have been used to treat VAIN. Treatment options include topical 5-fluorouracil, 5% imiquimod cream, laser vaporization with CO₂ laser, and excisional procedures with electrosurgical loops or a scalpel excision. On occasion, total vaginectomy may be necessary. Radiation therapy is the treatment of choice for vaginal cancer.

Treatment of AIN and Anal Cancer

For AIN, no randomized, controlled therapeutic trials have been reported and data are insufficient to recommend a specific treatment approach. Treatment decisions are based on assessment of the size and location of the lesion and the grade of histology. The least aggressive approaches should be tried first whenever possible (CIII): for example, several different treatments, including topical 5-fluorouracil, photodynamic therapy, infrared coagulation, cryotherapy, laser therapy, and surgical excision, have been described in small open-label studies (881,922,941--944). In retrospective analysis, infrared coagulation has been proven to have moderate efficacy to treat AIN 2 or 3 in HIV-seropositive patients (CIII) (943) and was safe and well tolerated in this population in a recent AIDS Malignancy Consortium study. No indications exist for radiation therapy for patients with AIN in the absence of evidence of invasive cancer (EIII).

The results of studies do not indicate that treatment for AIN should be modified for patients receiving ART. Conversely, no evidence indicates that ART should be instituted or modified for the purpose of treating AIN (CIII).

Treatment of anal cancer must be individualized in consultation with a specialist.

Treatment of HPV-Associated Disease at Other Sites, Including the Penis and Mouth

Penile and some oral cancers are associated with HPV infection. Treatment options do not differ between HIV-seropositive and HIV-seronegative men and women. Data suggest a more favorable prognosis among HPV-associated oropharyngeal cancers compared with non-HPV associated oropharyngeal cancers (945).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Monitoring is required during and after treatment of genital warts because each of the treatments has associated toxicity and recurrences are common after treatment. Patients can be monitored by physical examination for evidence of recurrence. The major toxicity of podophylloxotin and topical podophyllin resin is local skin irritation. Also, if podophyllin is applied to a large treatment area, systemic absorption can cause nausea, vomiting, and CNS effects. The major toxicity of imiquimod is inflammation at the application site. The major toxicity of cryotherapy is local pain. The major side effects of surgical treatment for genital warts are local pain, bleeding, and secondary infection. The major adverse events associated with acid cauterization are local pain and irritation or ulceration of adjacent normal skin. Intralesional interferon can be associated with systemic toxicities of interferon, including fever, fatigue, myalgia, malaise, depression, and other influenza-like symptoms. Infrared coagulation might lead to bleeding and abscess formation.

Because risk for recurrence of CIN and cervical cancer after conventional therapy is increased among HIV-seropositive persons, patients should be followed after treatment with frequent cytologic screening and colposcopic examination according to published guidelines (AII) (853,946). Treatment of CIN with ablative and excisional modalities can be associated with several adverse events such as pain and discomfort, intraoperative hemorrhage, postoperative hemorrhage, infection, and cervical stenosis.

Each of the treatment modalities for AIN described above is associated with adverse events, primarily pain, bleeding, ulceration, and, rarely, development of abscesses, fissures, or fistulas. Patients may be monitored for adverse events using the methods described above. Treatment of anal cancer is associated with a high rate of morbidity, even when the treatment is successful. Adverse events associated with anal cancer treatment include short-term side effects commonly associated with chemotherapy, such as neutropenia, and longer-term toxicities associated with radiation therapy, such as radiation proctitis.

IRIS has not been described in association with HPV infections.

Management of Treatment Failure

Treatment failure is defined as the persistence or recurrence of lesions after appropriate therapy. For persistent or recurrent genital warts, retreatment with any of the modalities previously described should be considered, preferably with an alternative modality to the one that previously failed (AIII). Genital warts often require more than one course of treatment. A repeat diagnostic excision or hysterectomy is acceptable for women with histological diagnosis or recurrent or persistent CIN 2 or 3 (BII) (853). Lesion persistence and recurrences after treatment of AIN are common. No data exist to guide the choice of treatment for recurrence of AIN, but either the original therapeutic modality or a different one may be used. Treatment of anal cancer that recurs after standard chemoradiation therapy often consists of abdominoperineal resection of the tumor.

Preventing Recurrence

HIV-seropositive women are at high risk for recurrent CIN after therapy, and HIV-seropositive men and women are at high risk for recurrent AIN. Preventing recurrence requires careful follow-up of patients after treatment. Patients should be monitored with cytologic screening according to published guidelines and, when indicated, colposcopic examination for recurrent lesions (AI) (923,947). In one study of HIV-seropositive women treated for high-grade CIN, low-dose intravaginal 5-fluorouracil (i.e., 2 grams twice weekly for 6 months) reduced the short-term risk for recurrence (948). However, clinical experience with this therapy is too limited to provide a recommendation for use and no follow-up study to confirm these observations has been reported. One study documented that women receiving ART are less likely to have recurrence of CIN compared with women who are not receiving treatment (949), but treatment for CIN should not be considered an indication for ART.

No guidelines exist regarding frequency of monitoring after therapy and the monitoring intervals will vary depending on the treatment approach, extent of disease, and other factors. Patients with AIN can be monitored by anal cytology, standard anoscopy, HRA, and biopsy as indicated. Patients with perianal intraepithelial neoplasia can be monitored by visual inspection and biopsy as indicated. Recommendations for monitoring patients for recurrence of anal cancer after completion of therapy are the same for HIV-seropositive and HIV-seronegative persons.

No indication exists for secondary prophylaxis (chronic maintenance therapy) with any of the conventional modalities to prevent recurrence of genital warts, CIN, or AIN.

Special Considerations During Pregnancy

HIV-infected pregnant women with genital warts or anogenital HPV-related neoplasia are best managed by an interdisciplinary team of specialists (e.g.,OB/GYN, infectious disease physician). Pregnancy might be associated with an increased frequency and rate of growth of genital warts (950--952). Podophyllin and podofilox should not be used during pregnancy (EIII). Use of podophyllin has been associated with an increased risk for fetal death in several animal models and case reports in humans, but not with congenital anomalies. No experience with imiquimod in human pregnancy has been reported; therefore, its use in pregnancy is not recommended (DIII). No anomalies have been observed among animals with use during pregnancy.

Other topical treatments (e.g., bichloroacetic and trichloroacetic acid) and ablative therapies (i.e., laser, cryotherapy, and excision) can be used during pregnancy.

Transmission of genital HPV6 and 11 from vaginal secretions at delivery is the presumed mechanism of early onset recurrent laryngeal papillomatosis in infants. This condition is rare but is more common among women who have genital warts at delivery (953). Cesarean delivery is not known to prevent this condition in infants and children (950--952) (954). No change in obstetrical management is indicated for women with HPV infection unless extensive condylomata are present that might impede vaginal delivery or cause extensive bleeding (955--958).

For evaluation of CIN, all pregnant women should have a Pap test at their initial prenatal visit unless a normal cervical cytology result has been obtained within the past year (80). Cytobrush sampling can be done during pregnancy (959). Pregnant women with abnormal cervical cytology results should undergo colposcopy and cervical biopsy of lesions suspicious for high-grade disease or cancer (BIII). Endocervical curettage is unacceptable in pregnant women (EIII). Increased bleeding might occur with cervical biopsy during pregnancy.

Pregnant women with ASC-US can be managed the same as nonpregnant women, with the exception that it is acceptable to defer colposcopy until at least 6 weeks postpartum (CIII). In the absence of invasive disease, treatment of CIN is not recommended during pregnancy. Re-evaluation with cytology and colposcopy is recommended after 6 weeks postpartum. Women with CIN can deliver vaginally.

Pregnant women with suspected cervical cancer should be referred to a gynecologic oncologist for definitive diagnosis, treatment, and delivery planning. Vaginal delivery is not recommended for women with invasive cervical cancer.

The effects of treatment of AIN on pregnancy are not known. Most experts recommend deferral of diagnosis and treatment of AIN until after delivery unless a strong clinical suspicion of anal cancer exists.

Hepatitis B Virus Infection

Epidemiology

Hepatitis B virus (HBV) is the leading cause of chronic liver disease worldwide (960,961). In countries with a low prevalence of endemic chronic HBV infection, HBV is transmitted primarily through sexual contact and injection-drug use, whereas perinatal and early childhood exposures are responsible for the majority of HBV transmission in high-prevalence countries. Although risk factors are similar, HBV is transmitted more efficiently than HIV (960--962). Up to 90% of HIV-infected persons have at least one serum marker of previous exposure to HBV (963,964), and approximately 10% have evidence of chronic hepatitis B (965--967). Several genotypes of HBV (A--H) have been identified and are geographically distributed. Genotype A is the most common among patients in the United States and Western Europe.

Clinical Manifestations

Most patients with acute or chronic HBV infection are asymptomatic or have nonspecific symptoms, such as fatigue. When present, symptoms of acute infection might include right upper quadrant abdominal pain, nausea, vomiting, fever, and arthralgias with or without jaundice.

Chronic HBV might lead to mild, moderate, or severe hepatitis with eventual development of cirrhosis and portal hypertension. The physical examination might be notable for signs of cirrhosis such as spider angiomata, palmar erythema, and signs of portal hypertension such as splenomegaly. Uncommon extrahepatic manifestations include polyarteritis nodosa, glomerulonephritis, and vasculitis. Without proper laboratory screening, HBV infection might not be clinically apparent until the onset of end-stage liver disease (ESLD), which is manifested as portal hypertension with ascites, variceal bleeding, coagulopathy, jaundice, or hepatic encephalopathy.

Hepatocellular carcinoma (HCC), which might complicate HBV infection before the onset of cirrhosis, is usually asymptomatic in its early stages. Patients with advanced HCC might experience abdominal pain, symptoms of liver failure, or ESLD, as previously described, or paraneoplastic syndromes (e.g., diarrhea, hypoglycemia, fever).

Diagnosis

Diagnosis of Infection and Disease with Serologic Testing

HIV-infected persons should be tested for HBV infection (789). Initial testing for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc total), and hepatitis B surface antibody (anti-HBs) should be performed because these will identify the majority of patients with chronic hepatitis B or who need vaccination to prevent infection. Certain specialists would test for HBsAg and anti-HBs only, excluding anti-HBc, as its presence or absence does not usually affect clinical practice. Chronic HBV infection is defined as a positive HBsAg and anti-HBc or a positive HBsAg, HBV DNA level, or hepatitis B e antigen (HBeAg) on two occasions at least 6 months apart.

Patients with chronic HBV infection should be tested for HBeAg, antibody to HBeAg (anti-HBe), and HBV DNA. Several tests for HBV DNA detection are available; however, the results are not interchangeable. Laboratories report either copies/mL or International Units (IU/mL). The latter is based upon a WHO standard and has greater interlaboratory reproducibility. HBV DNA levels are usually high in chronic infection. Patients with chronic HBeAg-positive infection tend to have higher levels of replicating virus than those with HBeAg-negative infection (10⁸--10¹⁰ copies/mL of blood compared with 10⁵--10⁶copies/mL). Among HIV-uninfected adults with HBV monoinfection, high HBV DNA levels predict progression of liver disease, development of HCC, and lower responses to therapy. Data characterizing the predictive value in those with HIV/HBV coinfection are lacking.

Some patients test positive for anti-HBc alone, which might signify a false-positive result; exposure in the past with subsequent loss of anti-HBs; or "occult" HBV infection, which can be confirmed by detection of HBV DNA (968,969). The clinical significance of isolated anti-HBc is unknown (968--971). HIV-infected patients have a higher frequency of isolated anti-HBc, particularly those patients with underlying hepatitis C virus (HCV) infection (972). The prevalence of HBV DNA in HIV-infected patients with isolated anti-HBc ranges from 1% to ^-45% (973,974), with most having low levels. Certain specialists recommend that HIV-infected persons with anti-HBc alone should be tested for HBV DNA before vaccination for HBV or before initiating ART because of the risk for reactivation of HBV and the occurrence of IRIS.

Diagnosis of Disease Progression and the Role of Liver Biopsy

Impairment of cellular immunity caused by HIV infection is associated with higher levels of hepatitis B viremia and lower viral clearance rates following acute HBV infection. Limited data indicate that HIV patients with chronic HBV infection are more likely to have detectable HBeAg (975,976), lower rates of seroconversion, and an increased risk for liver-related mortality and morbidity (977). Despite these differences, the pattern of disease progression is similar to that in monoinfected persons.

Liver biopsy with histologic examination remains a valuable tool for characterizing the activity and severity of chronic hepatitis B and might provide important information in monitoring disease progression and guiding treatment. However, the decision to perform a liver biopsy should be individualized based on the phase of chronic HBV as described below. Liver biopsies might result in major complications, such as excessive bleeding (<0.5%), bile peritonitis (0.09%), and, rarely, internal organ injury, although the overall mortality rate is fewer than 1 in 10,000 (978,979).

Patients with a diagnosis of chronic HBV infection who are not treated with antiviral agents should have a complete blood count, platelet count, alanine aminotransferase (ALT), albumin, prothrombin time, and bilirubin monitored at baseline and every 6 months to assess severity and progression of liver disease. Persistent low-level serum aminotransferase abnormalities might be associated with significant liver disease, although normal aminotransferases might also be seen in the setting of cirrhosis. Transient or persistent elevations in serum aminotransferase levels might occur before loss of HBeAg, on discontinuation of anti-HBV therapy, and in association with emergence of HBV drug resistance.

Patients who are HBe-Ag seropositive usually have high HBV DNA levels (>20,000 IU/mL) and abnormal levels of ALT. In some instances, increased levels of ALT might precede a decline in HBV DNA that is accompanied by the loss of HBeAg and development of anti-HBe. Seroconversion marks a transition from active disease to an inactive carrier state (980). This transition can be spontaneous or associated with effective HBV treatment. Approximately 8%--12% of monoinfected patients spontaneously convert from a positive to a negative HBeAg and a positive anti-HBe per year (981). Spontaneous conversion rates in HIV-infected patients appear to be lower.

Although seroconversion usually implies transition to an inactive carrier state, the re-emergence of abnormal liver enzyme tests might reflect HBeAg-negative chronic hepatitis B disease. Although levels of HBV DNA are usually lower than in HBeAg-positive patients, HBeAg-negative patients experience an unrelenting but fluctuating course of disease progression, with viral loads usually ranging from 10⁵ to 10⁶ copies/mL (2 x 10⁴--2 x 10⁵ IU/mL), but they can be higher. Thus, in a patient without HBeAg, HBV DNA levels should still be measured. Liver biopsy is recommended in HBeAg-seronegative patients with detectable HBV DNA primarily for persons aged >40 years with "borderline" indications for treatment, such as those with minimally elevated ALT but high HBV DNA level (982,983).

Persons who acquire HBV infection perinatally have a high chance of becoming "immune tolerant," with normal aminotransferase levels despite the presence of high levels of HBV DNA. Such patients tend to have minimal disease and liver biopsy is usually not indicated; however, they tend to have HBeAg-positive chronic hepatitis B with elevated ALT levels later in life and remain at risk for the development of HCC, cirrhosis, and flares of hepatitis B (980).

The inactive HBsAg carrier state is characterized by a negative HBeAg, normal ALT levels, and an HBV DNA level of <2,000--20,000 IU/mL (or 10,000--100,000 copies/mL). Liver biopsy is not recommended in patients who have cleared the virus (undetectable HBV DNA by PCR assay). However, although their prognosis is usually good, patients in the inactive carrier state remain at risk for reactivation of HBV and development of HCC, but the risk is lower than for those with active HBV replication. This is particularly true for those carriers who are older or who have cirrhosis or coinfection with HCV (984--987).

Reactivation of HBV, spontaneous or related to chemotherapy or immunosuppression, can lead to substantial hepatic flares and necroinflammatory liver disease (988--991). Although reactivation of HBV can be associated with flares in serum aminotransferases, other etiologies for increased aminotransferase levels, such as hepatotoxicity from ARVs or other drugs or acquisition of another hepatitis virus infection such as hepatitis A, C, or hepatitis delta virus (HDV), must be ruled out (992--995).

Patients with chronic hepatitis B are at increased risk for HCC. Among HIV-coinfected persons, who might have an even higher risk for HBV-related HCC than HBV monoinfected patients, monitoring alpha fetoprotein (AFP) level and ultrasound of the liver every 6 months (996) might be recommended; however, the effectiveness of this screening strategy has not been studied in this population, and the optimal HCC screening method and interval are not known (997--999).

Preventing Exposure

HIV-infected persons should be counseled about the risk for household, sexual, and needle-sharing transmission of HBV; the avoidance of behaviors associated with such transmission; and the need for any such susceptible contacts to receive hepatitis A and B vaccine as described below. As drug injection via contaminated syringes previously used by infected persons is the primary route of HBV transmission among IDUs, they should be encouraged to stop using injection drugs, preferably by entering a substance abuse treatment program (AII). If IDUs are unwilling or unable to discontinue the use of injection drugs, they should be advised not to share needles or drug preparation equipment to reduce the risk for transmission of HBV infection (BII). Access to sterile injection equipment may be facilitated through enrollment of IDUs in needle exchange programs (NEPs) (1000--1002).

Persons considering tattooing or body-piercing should be informed of potential risks of acquiring HBV, which could be transmitted if equipment is not sterile or if proper infection control procedures are not followed (AIII).

Safe-sex practices should be encouraged for all HIV-infected persons; barrier precautions (e.g., latex condoms) are recommended to reduce the risk for exposure to sexually transmitted pathogens, including HBV (AII).

Preventing Disease

HIV-infected patients who do not have evidence of previous exposure to HBV should be vaccinated with hepatitis B vaccine (AII). Given the decreased response rate to the vaccine in the setting of HIV infection, all HIV-infected patients should have anti-HBs titers obtained 1 month after completion of the vaccine series to document response (BIII). If no response is observed, revaccination should be considered (BIII). HBV vaccination is safe in HIV-infected patients. Transient increases in HIV RNA have been reported after HBV vaccination but do not appear to have clinical relevance (1003--1005).

A patient who is seropositive for anti-HBc and anti-HBs has resolved infection and does not need vaccination. However, reactivation of HBV has been observed in immunosuppressed patients. The presence of anti-HBs alone at levels of >10 IU/mL is consistent with seroprotection, usually from vaccination (1006), and no further vaccinations are required.

Determining whether hepatitis B vaccine should be administered to patients with "isolated" anti-HBc is not clear because, in addition to a false-positive result, this pattern might signify exposure in the distant past with subsequent loss of anti-HBs or more rarely, occult HBV (1007). One approach in this setting is to administer one dose of hepatitis B vaccine followed in 2 weeks by anti-HBs testing to determine if an anamnestic response occurs, although the overall response rate described in previous studies is low (16%) (973,1008,1009). Larger studies in HIV-uninfected persons with isolated anti-HBc demonstrate that most persons mount a slow, or primary, rather than a rapid, or anamnestic, response after vaccination (1007). The majority of HIV-infected patients with isolated anti-HBc are not immune to HBV infection and should be vaccinated with a complete primary series of hepatitis B vaccine (BII) (973,1009). Certain specialists would test for HBV DNA to rule out occult chronic HBV infection before administering a complete primary series of hepatitis B vaccine.

The immunogenicity of hepatitis B vaccination in HIV-infected adults is 18%--72% (974) and is lower than in HIV-seronegative healthy adults, in whom seroconversion rates are >90% (1010). Compared with HIV-seronegative healthy adults, HIV-seropositive patients also have lower mean antibody titers and have faster declines of protective antibody over time (1004,1011,1012). The negative impact of low CD4⁺ counts on hepatitis B vaccine responses has been a consistent finding across several studies (1003--1005,1013--1016). Other factors associated with lower seroconversion rates include the presence of detectable HIV RNA (1005,1016,1017), coinfection with HCV, occult hepatitis B infection, and the general health status of the host (973,1018--1023).

Several novel approaches have been investigated to improve primary vaccine responses and those among vaccine nonresponders. These have included increasing the dosage of vaccine (1003,1005), the number of doses (1004), or use of adjuvant immunostimulatory molecules (1024). One double-blind, randomized controlled trial that compared the use of a standard dose (20 mcg) with a double dose (40 mcg) of recombinant hepatitis B vaccine in 210 previously unvaccinated HIV-infected patients demonstrated a substantially higher seroconversion rate with use of the double dose of vaccine, but only in the subgroup of patients with CD4⁺ counts >350 cells/µL (1003). In one study of 32 HIV-infected patients, administration of 1 additional vaccine dose increased the proportion of responders only marginally; however, a sixfold increase in geometric mean titers was demonstrated among those who did respond (1014). Doubling the number of vaccine doses in nine HIV-infected patients who did not initially respond to a hepatitis B vaccination series led to protective surface antibody levels in seven persons (1004).

On the basis of these data, early vaccination is recommended in HIV-infected patients before the CD4⁺ count declines to <350 cells/µL (AII) (1014,1025). However, vaccination should not be deferred for those with negative or indeterminate serologies while awaiting a rise in CD4⁺ count to >350 cells/µL. Because some HIV-infected patients with CD4⁺ counts <200 cells/µL do respond to vaccination, vaccination should be performed as previously recommended (AII), with testing for anti-HBs 1 month after completion of the series (BIII). If no response occurs, revaccination should be considered (BIII). Certain specialists might delay revaccination until after a sustained increase in CD4⁺ count is achieved on ART.

One study has suggested that HIV-infected persons with a CD4⁺ count >350 cells/µL had improved responses when vaccinated with 40 mcg of HBV vaccine on a 0-, 1-, and 6-month schedule (1003). Thus, certain specialists recommend initial hepatitis B vaccination in any HIV-infected person with 40 mcg doses of either vaccine at the recommended intervals (CIII). Additional studies are needed to determine optimal vaccination strategies in patients with advanced immunosuppression. ART should be optimized to attain complete suppression of HIV replication and increased CD4⁺ count, as these factors have been associated with better antibody responses to HBV vaccination (CIII). Trials of immunomodulatory agents to improve HBV vaccine responses have led to mixed results, and data are currently insufficient to warrant a recommendation favoring their use (CIII).

No vaccination strategy has been consistently effective or adequately studied in vaccine nonresponders. For patients who have not attained an anti-HBs level >10 IU/mL after completion of a primary vaccine series, a second vaccine series is recommended (BIII). Certain specialists recommend that in such cases, revaccination with 40 mcg doses of either of the available vaccines be considered, regardless of which dose was used initially (CIII). Anti-HBs should be obtained approximately 1 month after completion of the vaccine series to assess vaccine response (BIII) (1025). Certain specialists suggest once yearly evaluations for patients who have an ongoing risk for HBV acquisition (CIII), as recommended for dialysis patients (1026). This is particularly important in patients who have a low level of protective antibody, because loss of antibody over time is related to the maximal antibody response after vaccination, and loss of antibody among dialysis patients has translated into loss of protection against HBV infection (1006,1027,1028). Immune-competent hepatitis B vaccine responders, however, remain protected against the development of clinical disease and chronic HBV infection despite subsequent declines in anti-HBs to <10 IU/mL (1027,1029).

Hepatitis A vaccination is recommended in persons with chronic liver disease, MSM, and IDUs (529,1030). HAV-susceptible, HIV-infected persons with risk factors for HAV infection should receive hepatitis A vaccination (AII). As with hepatitis B vaccination, the response to hepatitis A vaccination is reduced in those with CD4⁺ counts <200 cells/µL. Certain specialists might delay hepatitis A vaccination until the CD4⁺ count is >200 cells/µL on ART (CIII). Antibody response should be assessed 1 month after vaccination; nonresponders should be revaccinated (BIII).

Treatment of Disease

Patients with chronic hepatitis B disease should be advised to avoid or limit alcohol consumption because of its effects on the liver (AIII). In addition, they should be counseled about the risk for household, sexual, and needle-sharing transmission and the need for any such susceptible contacts to receive hepatitis A and B vaccine as described above.

The goals of anti-HBV therapy are to prevent disease progression and reduce HBV-related morbidity and mortality. Treated patients rarely become HBsAg negative because HBV reservoirs generally are not sufficiently reduced by available anti-HBV therapy. HBV might persist in the liver, in the absence of circulating virus, as closed circular DNA (ccDNA), which can lead to reactivation after chemotherapy, steroid use, or immunosuppression, including HIV-associated immunosuppression. Nevertheless, studies in HBV-monoinfected patients suggest suppression of HBV DNA to a "nonreplicative" state, HBeAg seroconversion from positive to negative, seroconversion to anti-HBe, loss of HBsAg, and acquisition of anti-HBs are all associated with decreased incidence of HCC and improved survival; thus, these surrogates also are goals of anti-HBV treatment for HIV-infected persons. For HBeAg-negative patients with increased ALT and HBV DNA levels, long-term antiviral suppression might be indicated because treatment discontinuation has been associated with virologic relapse.

In HIV/HBV-coinfected patients, the imperative to treat depends not only on the level of HBV viremia and degree of biochemical and/or histologic disease, but also on whether the patient is initiating ART. HIV/HBV-coinfected patients initiating ART should be treated for HBV, regardless of the level of HBV DNA, either with antiviral agents active against both HIV and HBV or with antiviral agents with independent activity against each virus (CIII). This approach might reduce the risk for IRIS, particularly in those who have advanced immunodeficiency. If ART is not required, then initiation of treatment for HBV is the same as for HBV-monoinfected patients. Anti-HBV therapy is indicated for persons with abnormal ALT levels and HBV DNA levels >20,000 IU/mL (>10⁵ copies per mL) for HBeAg-positive patients, and abnormal ALT levels with HBV DNA levels >2,000 IU/mL (>10⁴ copies per mL) for HBeAg-negative patients (CIII). However, because of the increased rate of liver disease progression in the setting of HIV infection, certain specialists recommend treatment at any level of detectable HBV DNA, especially in the setting of elevated ALT levels (CIII). In addition, anti-HBV treatment should be considered for HIV-infected patients with low but detectable HBV DNA levels who have substantial histologic inflammatory activity or fibrosis on liver biopsy (CIII). Certain specialists recommend treatment of those with advanced fibrosis or cirrhosis on liver biopsy with any detectable HBV DNA level, provided other causes for chronic liver disease have been eliminated (1031).

Treatment options for HBV in the setting of HIV infection must consider the goals of therapy and the effect treatment might have on both HIV and HBV replication. FDA-approved antiviral drugs available for treatment of HBV infection include lamivudine, adefovir, entecavir, tenofovir, standard interferon-alfa, pegylated interferon (pegIFN)-alfa, and telbivudine. FDA-approved HIV antiretroviral medications, such as emtricitabine (and its single-pill combination with tenofovir), also have substantial activity against HBV, although they are not approved for this indication.

IFN-alfa-2a and -2b, administered in subcutaneous doses of 5 MU daily or 10 MU three times per week, are approved for the treatment of chronic hepatitis B disease among HIV-uninfected persons, but not among HIV-infected patients. Approximately one-third of HIV-seronegative patients will clear HBeAg with either of these IFN regimens (996,1032), and the response is sustained among 80%--90% of persons followed for 4--8 years (1033). PegIFN alfa-2a is also approved for treatment of HBV among HIV-seronegative patients and in clinical trials was proven to be superior to standard IFN for both HBeAg-positive and HBeAg-negative patients when used for 48 weeks (1034,1035). No published data exist regarding efficacy of either formulation of pegIFN in the setting of HIV/HBV coinfection. Although HIV replication can be suppressed by pegIFN alfa (1036), no evidence indicates that IFN selects for resistance mutations that will influence future therapeutic options for HIV infection. On the basis of this information, pegIFN alfa-2a might be considered for treatment of HBV infection in HIV-coinfected patients irrespective of the need for ART for treatment of their HIV infection (CIII).

Among HIV-uninfected persons, the response rates to lamivudine-containing regimens are >50% in patients with ALT levels >5 times the ULN and 20%--35% among patients with ALT levels 2--5 times the ULN. Lamivudine is active against hepatitis B and HIV at the 150 mg twice-daily dose used for treatment of HIV infection. HBeAg seroconversion rates appear to be low in HIV-infected patients treated with this agent. Resistance to lamivudine occurs in the majority of patients on chronic therapy; the rates of resistance appear to be even higher in patients with HIV infection (1037). Because lamivudine is active against both HBV and HIV and monotherapy for HBV will select for HIV resistance mutations, lamivudine should not be used for treatment of HBV in HIV-infected patients who are not also being treated with combination ART for their HIV infection (EIII).

Emtricitabine is active against HBV and HIV. Because of its structural similarities to lamivudine, emtricitabine also is associated with a relatively rapid onset of HBV and HIV drug resistance, and cross resistance of HIV and HBVto lamivudine also should be assumed in patients with suspected lamivudine resistance. As with lamivudine, emtricitabine should not be used for treatment of HBV in coinfected patients who are not being treated with combination ART for their HIV infection (EIII).

Adefovir is effective in both HBeAg-positive and HBeAg-negative patients with chronic HBV infection, although viral suppression occurs at a slower rate than with other agents and rates of seroconversion are low. Despite the slower viral load decline, the onset of drug resistance to adefovir is delayed compared with lamivudine or emtricitabine. The addition of adefovir to lamivudine in HIV/HBV-coinfected patients with HBV lamivudine resistance has been associated with an approximately 4-log₁₀ decline in HBV viremia (1038). During 4 years of treatment, 25% of patients in one study attained complete virologic suppression. In those with detectable HBV viremia, no adefovir-associated mutations were observed. In coinfected patients, initial reports suggested that adefovir dipivoxil might be associated with selection of HIV-associated mutations (K65R and K70E) (1039 ). However, additional studies have not demonstrated selection of these mutations after up to 4 years of therapy, although minority variants could have been missed (1040). On the basis of these data, adefovir might be considered for treatment of HBV in HIV-coinfected patients, irrespective of the need for their HIV infection. (CIII).

Tenofovir, 300 mg daily, is more potent in vitro than adefovir, 10 mg daily, against HBV and data from human clinical trials and clinical experience indicate it is also active against lamivudine-resistant and wild-type HBV. A prospective, randomized, double-blind, placebo-controlled, noninferiority trial comparing tenofovir to adefovir in HIV-infected patients demonstrated benefit of tenofovir in the setting of lamivudine-resistant HBV (1041). Two recent randomized, double-blind studies, one with HBeAg-negative and another with HBeAg-positive patients, demonstrated the superiority of tenofovir over adefovir related to HBV DNA suppression in HBV-monoinfected patients (1042,1043). As with lamivudine and emtricitabine, tenofovir should not be used for treatment of HBV in HIV-coinfected patients who are not receiving combination ART for treatment of their HIV infection because of the risk for acquiring HIV-associated resistance mutations (EII).

Entecavir is approved for treatment of HBV and in clinical trials was proven to be more effective than lamivudine with regard to the rate of HBV DNA decline and viral suppression at 48 weeks of treatment. Of the available agents for treatment of HBV other than interferon, entecavir is associated with the slowest onset of resistance, which usually requires a background of mutations at M204V/I and L180M to emerge. Literature in HIV/HBV coinfection is limited, but in a trial of 68 coinfected, lamivudine-experienced patients who were randomly assigned to receive either entecavir or continue on lamivudine monotherapy, a >3-log₁₀ decline in HBV DNA was noted in the entecavir arm versus the lamivudine arm. No change in HIV RNA levels occurred although these patients were on effective HIV therapy. However, a recent report described three patients who experienced an approximately 1-log₁₀ drop in HIV RNA with initiation of entecavir monotherapy (1044). In addition, one patient who had received lamivudine in the past developed an HIV-associated mutation (M184V) during monotherapy with entecavir. A case report of the M184V emerging in a treatment-naïve patient on entecavir monotherapy also has been reported (1045). An FDA warning is available at http://www.fda.gov/medwatch/safety/2007/Baraclude_DHCP_02-2007.pdf. On the basis of this information, entecavir should not be used as monotherapy for treatment of HBV in HIV-coinfected patients who are not also receiving combination ART for treatment of their HIV infection because of the risk for developing HIV-associated resistance mutations (EII).

Telbivudine has demonstrated efficacy in patients with HBeAg-positive and HBeAg-negative infection and is FDA approved for treatment of chronic HBV infection (1046,1047). It is well tolerated, but like lamivudine, emergence of HBV resistance over time is common. Telbivudine is not active against lamivudine-resistant HBV. Therefore, telbivudine monotherapy is not recommended (DII). No clinical data are currently available in HIV/HBV-coinfected patients, but studies are in progress.

Famciclovir is less active than lamivudine against HBV and is not active in lamivudine-resistant HBV; therefore, its use is not recommended (DII) (1048--1050).

Treatment of HBV in HIV-Infected Patients Who Are Receiving ART

Current guidelines recommend ART for HIV-infected patients who require treatment for HBV infection, regardless of CD4⁺ count. In such patients, simplifying the treatment regimen can be achieved by offering at least two agents with dual activity against HIV and HBV, considering that a third agent is also required for effective treatment of HIV. Chronic administration of lamivudine as the only active drug against HBV leads to a high rate of HBV drug resistance because of key mutations in the YMDD (M204V/I) motif. One retrospective study suggested that the combination of tenofovir and lamivudine was associated with improved viral suppression compared with either agent alone (1051). Other studies also suggested that combination therapy reduces development of drug-resistant mutations (1034,1052). For HIV-infected persons, certain specialists recommend combination therapy with two agents active against HBV to reduce the risk for HBV drug resistance, although no results from controlled trials exist to support this strategy (CII). Certain specialists recommend combination therapy with emtricitabine and tenofovir as part of an ART regimen because of ease of administration, tolerability, and dual HBV and HIV activity (CIII). Initiation of combination therapy also avoids the administration of sequential monotherapy, which can lead to multi-drug HBV resistance over time (1053,1054). The combination of lamivudine and pegIFN is not superior to pegIFN alone and is usually not recommended (1055,1056). The strategy of combination therapy versus monotherapy for treatment of HBV is being evaluated in a comparative clinical trial (1045).

Entecavir also can be considered in patients with complete HIV suppression who do not demonstrate YMDD motif (M204V/I) mutations in HBV DNA (CIII). If entecavir is used in the presence of the M204V/I mutation, then careful monitoring of HBV DNA levels is indicated because of the increased risk for entecavir resistance in the presence of these pre-existing mutations.

Dual HBV and HCV infections are seen in 3%--5% of HIV-infected persons (1057). The replication of one virus usually predominates over another; this phenomenon is referred to as "viral interference." A thorough laboratory evaluation to detect dual HBV and HCV coinfection should include HBV DNA and HCV RNA assays. Among patients infected with HBV, HCV, and HIV, consideration of ART should be the first priority. If ART is administered, then anti-HBV therapy must be included as part of the regimen (as above) and anti-HCV therapy can be introduced as needed. If ART is not desired, IFN-based therapy, which suppresses both HCV and HBV, should be considered (CIII). If IFN-based therapy for HCV has failed, treatment of chronic hepatitis B with nucleoside or nucleotide analogs is recommended (CIII).

Treatment of HBV in HIV-Infected Patients Who Are Not Receiving ART

For patients deferring therapy for HIV infection, agents with sole activity against HBV must be selected for treatment of chronic HBV infection (BIII). The lack of data regarding many of these agents in HIV/HBV-coinfected persons impedes firm treatment recommendations in this population. No data exist regarding the efficacy of pegIFN or the safety or efficacy of telbivudine in HIV-infected persons; adefovir has been evaluated in this population only in those with lamivudine-resistant HBV; and the clinical implications of entecavir-associated HIV resistance mutations prevent its use in this situation. Individualized therapy is necessary; however, certain guiding principles should be followed. The criteria for initiation of treatment for chronic HBV are the same for HIV-infected persons as for those with HBV monoinfection (CIII). Factors that might influence the choice of agent include the immune status of the patient, the level of hepatitis B viremia, and the patient's HBeAg status. For patients with CD4⁺ counts >350 cells/µL, adefovir or pegIFN alfa-2a monotherapy for 48 weeks might be considered, with close monitoring of HBV DNA levels and follow-up to evaluate for HBeAg seroconversion (CIII).

Duration of Anti-HBV Therapy

In HIV-seronegative patients, HBeAg seroconversions are sustained among approximately 80% of patients if lamivudine is continued 6--12 months after seroconversion. On the basis of data in HIV-uninfected persons, HIV/HBV-coinfected persons who are HBeAg positive and who become HBeAg negative and anti-HBe positive on lamivudine therapy should be treated for a minimum of 6--12 months beyond HBeAg seroconversion (BIII). All patients receiving ART should continue HBV therapy, even if they have seroconverted to anti-HBe (CIII).

Similar guidance on the duration of therapy can be applied to the use of other HBV active agents, with the exception of peg-IFN-based therapy, which is administered for a standard 48-week course. If HBeAg seroconversion does not occur but viral suppression has been achieved, treatment with anti-HBV agents, if tolerated, should be continued indefinitely (CIII).

Among HIV-seronegative, HBeAg-negative patients with chronic hepatitis B who are treated with lamivudine, ALT and HBV DNA levels might decline, but high rates of relapse have been reported when therapy is stopped (1058). Considering these findings, a majority of specialists would continue therapy indefinitely to achieve long-term HBV viral suppression (CIII).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Treatment response should be monitored by testing for HBV DNA and HBeAg at 3-month intervals and at 6--12-month intervals after stopping treatment. A virologic response is defined as a >2-log10 decrease in HBV DNA after 6 months of therapy. Ideally, the HBV DNA level after 6--12 months is <20--100 IU/mL based on a real-time PCR assay (1059). A maintained virological response is a response that continues while on therapy, and a sustained virological response is one that is still present 6 months after stopping therapy. For patients who are HBeAg positive, loss of HBeAg is also a measure of virological response. Other markers that should be monitored and indicate treatment success include improvement in liver histology based on biopsy; normalization of serum aminotransferases; and, in those with loss of HBeAg, the development of anti-HBe. Sustained loss of HBsAg is considered by some to be a complete response; however, this desirable serologic response is uncommon (1060).

Major toxicities of IFN-alfa (pegylated or standard) include influenza-like symptoms (e.g., fever, myalgia, headache, and fatigue), neuropsychiatric abnormalities (e.g., depression, irritability, and cognitive dysfunction), cytopenias (e.g., thrombocytopenia, neutropenia, and reversible reduction in CD4⁺ count), retinopathy, neuropathy, and exacerbation of autoimmune disease. Depression might be severe enough to trigger suicide. Certain specialists recommend psychiatric evaluation before initiation of IFN-alfa for patients with a prior history of depression and frequent (monthly) monitoring for signs and symptoms of depression during treatment. Hypo- or hyperthyroidism, which is often irreversible, might occur 3--6 months after initiation of therapy with IFN-alfa. As a result, serum thyroid stimulating hormone (TSH) level should be monitored at baseline and periodically (e.g., every 3 months) for the duration of treatment. Depending on the severity of these toxicities and individual patient tolerance, side effects might be dose limiting or interfere with the ability to complete a course of treatment. IFN-alfa is contraindicated in patients with decompensated liver disease.

Adefovir causes renal tubular disease at doses of 30 mg/day or higher, but this toxicity is uncommon at the recommended 10 mg/day dose. Renal toxicity with tenofovir used solely for treatment of HBV has been reported rarely, although isolated cases of increased serum creatinine or renal tubular dysfunction have been observed, and might be more frequent in HIV-infected persons with underlying renal insufficiency or those treated for prolonged periods. Patients on either drug should have baseline urinalysis and creatinine monitoring. Periodic monitoring of serum creatinine and phosphate also should be done in patients receiving adefovir or tenofovir, especially those with underlying diabetes or taking other nephrotoxic agents, because they might be at increased risk for renal toxicity (1061).

When anti-HBV therapy with lamivudine, adefovir, or tenofovir is initiated, discontinuation is associated with a flare of liver disease in approximately 15% of cases, with loss of the benefit accrued from previous anti-HBV treatment (1062) and possible decompensation of liver disease. Even for patients not receiving ART, certain specialists recommend that when anti-HBV therapies are initiated, they should be continued unless contraindicated or unless the patient has been treated for 6--12 months beyond loss of HBeAg positivity (CIII). However, the risks and benefits of this practice are unknown. If anti-HBV therapy is discontinued and a flare occurs, anti-HBV therapy should be reinstituted because it can be potentially life saving (BIII).

Return of immune competence after ART (or after steroid withdrawal or chemotherapy) can lead to reactivation of HBV-associated liver disease. Any immune reconstitution can lead to a rise in serum aminotransferases, so called "hepatitis flare" (1063), which constitutes IRIS in HIV/HBV-coinfected persons. IRIS might be manifested by dramatic increases in serum aminotransferases as CD4⁺ counts rise within the first 6--12 weeks after starting ART, with signs and symptoms characteristic of acute hepatitis. After introduction of ART, serum aminotransferases should be monitored closely; some experts recommend monthly for the first 3--6 months and then every 3 months thereafter (CIII). Any association between abnormal aminotransferases and clinical jaundice or synthetic dysfunction (elevated INR and low serum albumin) should prompt consultation with a hepatologist.

All patients with HBV and HIV must receive concomitant anti-HBV therapy when ART is used because these flares can be life threatening. Flares are worse in patients with more severe liver disease, especially cirrhosis. Distinguishing hepatotoxicity or other causes of hepatitis (acute HAV or acute HCV) from IRIS in this setting is difficult. When changing antiretroviral regimens, continuing agents with anti-HBV activity is important because of the risk for IRIS.

All classes of ARVs have been associated with hepatotoxicity as evidenced by substantial elevations in serum aminotransferases (1064). ARV-associated hepatotoxicity might be dose dependent or idiosyncratic. The risk for hepatotoxicity has been consistently associated with elevated pre-ART aminotransferases and the presence of HBV or HCV coinfection (1065--1073). Despite the increased risk for hepatotoxicity in the setting of HCV or HBV coinfection, the majority of (80%--90%) coinfected patients do not have hepatotoxicity (1067), and clinically significant hepatotoxicity is rare; aminotransferases return to baseline in the majority of cases, even if the offending medication is continued (1066,1074). Therefore, discontinuing ART is probably not necessary in the presence of hepatotoxicity unless the patient has symptoms of hypersensitivity (fever, lymphadenopathy, rash), symptomatic hepatitis (nausea, vomiting, abdominal pain, or jaundice), or elevations of serum aminotransferase levels >10 times the ULN. However, the development of jaundice is associated with severe morbidity and mortality and should trigger discontinuation of the offending drug(s) (1075).

The major problem in managing adverse effects and drug-induced liver injury is determining which medication is the offending culprit and distinguishing drug toxicity from hepatic flares associated with IRIS. Close interaction of HIV clinicians and hepatologists is needed because liver histology might help to differentiate drug toxicity (e.g., eosinophils) from viral hepatitis (e.g., portal inflammation). Spontaneous HBV clearance can be associated with a flare, but occurs rarely in HIV-infected patients. Initiation of ART without anti-HBV therapy might lead to reactivation of HBV. A hepatic flare might also occur when patients must discontinue their ART. Although this should be discouraged, if ART must be discontinued for some reason, patients need to be counseled about the urgent need to continue HBV therapy but without any agents active against HIV to prevent inadvertent mono or dual anti-HIV drug selection pressure favoring development of HIV drug resistance. Elevated aminotransferases might also occur after the onset of drug resistance, which is common and increases over time with medications such as lamivudine (1037). Serum HBV DNA testing will help determine if a flare of HBV has occurred. In this situation, HBV resistance testing should be undertaken in consultation with a specialist. Other causes of abnormal liver tests should be sought, including drugs, alcohol, viral hepatitis, and nonalcoholic fatty liver disease.

Management of Treatment Failure

Treatment failure is defined as the presence of HBV DNA greater than 1 log₁₀ above nadir in a patient who is consistently adherent to therapy. Laboratory findings associated with treatment failure include persistent ALT elevations and persistently positive HBeAg for those who had detectable HBeAg at treatment onset.

In HIV-infected persons with lamivudine-resistant HBV, data from a case series of 35 HIV-HBV coinfected patients indicated that treatment with the combination of adefovir and continuation of lamivudine has substantial antiviral effect against lamivudine --resistant HBV (1076). Addition of either adefovir or tenofovir appears to lead to greater declines in HBV DNA in lamivudine-resistant coinfected patients (1041). Flares of liver disease have been reported with development of resistance to lamivudine. The rate of development of lamivudine resistance is approximately 20% per year among HIV/HBV-coinfected persons treated with lamivudine (1037). If lamivudine resistance is suspected or documented, tenofovir or adefovir should be added to lamivudine therapy (CIII). HBV DNA testing might be useful in this setting because increasing levels are associated with emergence of lamivudine resistance or relapse, and stable levels should suggest an alternative cause of acute deterioration. Patients receiving lamivudine who have no detectable HIV RNA, but do have detectable plasma HBV DNA, can be assumed to be lamivudine resistant. Treatment options for patients on ART who have lamivudine-resistant HBV, but fully suppressed HIV, include the addition of adefovir or pegIFN to lamivudine, or tenofovir can be exchanged for one of the nucleoside agents in the ART regimen (CIII). Persons with lamivudine-resistant HBV will have cross resistance to emtricitabine and telbivudine. In the setting of lamivudine-resistant HBV disease, either lamivudine or emtricitabine should be continued because this might decrease development of mutations to other anti-HBV drugs (CIII).

Treatment for ESLD among HIV/HBV-coinfected patients should be managed as it is in HIV-seronegative patients (BI). IFN-alfa is contraindicated in ESLD, but limited data indicate that lamivudine, adefovir, or tenofovir can be used safely (1037,1077,1078). All patients with ascites should undergo paracentesis for analysis to verify that portal hypertension is the etiology and to exclude spontaneous bacterial peritonitis (SBP) (1079). Assessment of the serum-ascites albumin gradient (SAAG) is advisable; SAAG >1.1 mg/dL strongly suggests ascites secondary to portal hypertension. Management includes sodium restriction (>2 g/day) to alleviate fluid retention and diuretics. The recommended diuretic regimen is spironolactone alone or combined with furosemide (ratio of 40 mg furosemide: 100 mg spironolactone). Consideration should be given to primary prophylaxis against SBP with the administration of oral antibiotics such as norfloxacin (400 mg/day) or TMP-SMX (1 double-strength tablet/day) in those with an ascites total protein <1 g/dL (1080). Secondary antibiotic prophylaxis is recommended for all persons with a history of SBP (AI).

Esophagogastroduodenoscopy (EGD or upper endoscopy) should be performed in all persons who progress to cirrhosis, particularly those with thrombocytopenia, at the time of diagnosis and then every 1--2 years to identify substantial gastroesophageal varices. For persons with varices, nonselective beta blockers (e.g., nadolol or propranolol) are the mainstay of both primary and secondary prevention of variceal hemorrhage; esophageal variceal ligation or banding is another preventive option, particularly for persons who cannot tolerate beta blockers. Hepatic encephalopathy, due to the accumulation of unmetabolized ammonia and other false neurotransmitters absorbed from the gut in the setting of liver dysfunction, might be subtle in early stages (916). Preventive measures include restriction of animal dietary protein consumption and the use of nonabsorbable disaccharides (e.g., lactulose) and/or antibiotics (e.g., neomycin, rifaximin).

Patients with HBV-related cirrhosis are at increased risk for HCC (1081). Whether additional risk occurs in the setting of HIV infection is unclear (998). Although the optimal screening strategy to detect HCC is unknown, screening for HCC is recommended in patients with documented cirrhosis using hepatic ultrasound imaging performed at 6--12-month intervals (BIII) (1082). The utility of serum AFP for HCC screening in persons with HIV is unknown, and, because of poor specificity and sensitivity, results of AFP testing should be confirmed with liver imaging studies. In the absence of contraindications, HIV/HBV-coinfected persons with decompensated liver disease and/or early HCC are candidates for orthotopic liver transplantation because HIV infection is not a contraindication to organ transplantation with the use of effective ART (1083). Persons with cirrhosis should undergo periodic assessment of their liver disease status through the application of validated prognostic models (Child-Pugh-Turcotte [CPT] Score and Model for End-stage Liver Disease [MELD]) that predict mortality risk and are used to determine the medical need for liver transplantation (1084). Where feasible, coinfected persons with well-controlled HIV infection found to have liver decompensation (defined as CPT score >7 and/or MELD score >10) or evidence of early HCC should be referred for orthotopic liver transplantation (BIII). Because transplantation does not cure HBV infection, post-transplant HBV treatment is required (BIII).

Special Considerations During Pregnancy

Pregnant women, including HIV-infected women, should be screened for HBsAg. Those who are HBsAg negative and without antibody to hepatitis B should be offered vaccination against hepatitis B. This vaccination can be administered during pregnancy, preferably after the woman is on a stable ART regimen, to prevent the theoretical risk for HIV RNA rebound with vaccination. Treatment of symptomatic acute HBV infection during pregnancy should be supportive, with special attention given to maintaining blood glucose levels and normal clotting status. Risk for preterm labor and delivery might be increased with acute HBV infection.

Treatment of chronic HBV infection is usually not indicated in pregnancy (DIII), but HBV positivity must be taken into account when considering therapy options for the HIV-infected pregnant woman.

For women having indications for ART for their own health and expected to continue antiretrovirals postpartum, a regimen including two agents with activity against hepatitis B should be used (AIII) (1085). Of the antiretroviral agents with activity against hepatitis B, the one most used in pregnancy is lamivudine. Approximately 1,800 cases of pregnancy outcomes after first-trimester exposure to lamivudine have been reported to the Antiretroviral Pregnancy Registry (APR) with no indication of an increased risk for birth defects after exposure (1086). Lamivudine has been well tolerated by pregnant women. Tenofovir was not teratogenic in animals, but reversible bone changes at high doses were seen in multiple animal species. A total of 266 cases of first-trimester exposure have been reported to the APR with no increase in birth defects noted (1086). Although tenofovir is not usually recommended as a first-line agent in pregnancy, in the setting of maternal chronic HBV infection, it can be included as the second agent with anti-HBV activity, in addition to lamivudine (BIII). Several other antiretroviral agents with activity against HBV, including emtricitabine, adefovir, and telbivudine, have been evaluated and not found to be teratogenic in animals, but experience with these agents in human pregnancy is limited. These agents could be included in a regimen during pregnancy if other options are not appropriate. Entecavir was associated with skeletal anomalies in rats and rabbits but only at high, maternally toxic doses. Data on use of entecavir in human pregnancy are not available. Cases of exposure during pregnancy to any of the antiretrovirals and HBV drugs listed should be reported to the Antiretroviral Pregnancy Registry (800-258-4263; http://www.apregistry.com). Interferons are not recommended for use in pregnancy, and ribavirin (RBV) is contraindicated in pregnancy. Although IFNs are not teratogenic, they are abortifacient at high doses in monkeys and should not be used in pregnant women because of the direct antigrowth and antiproliferative effects of these agents (1087).

The choice of antiretroviral regimen for the pregnant woman with chronic HBV infection who requires antiretrovirals during pregnancy only for prevention of mother-to-child transmission (MTCT) and plans to discontinue therapy after delivery is more complex. Options include starting a triple therapy regimen including two agents with activity against HBV (as discussed above) but stopping therapy after delivery and monitoring closely for a flare of HBV activity, or using a regimen not including drugs active against HBV to avoid a potential flare when discontinued. As an alternative, if only short-term therapy is planned (e.g., starting in the third trimester), consideration should be given to using a combination antiretroviral regimen using lamivudine as the sole agent with activity against HBV (CIII). Certain specialists recommend the first option, using a regimen with dual HBV activity. This recommendation is made even when planning to discontinue postpartum because of the concern about potential IRIS-related flare of HBV activity during pregnancy, even among women with relatively high CD4⁺ counts, if ARV without anti-HBV activity is used. They believe that treating a potential flare in the postpartum period after discontinuing ARV is associated with less risk than treating an immune-mediated flare during pregnancy. In addition, using drugs with anti-HBV activity during pregnancy will lower HBV levels and potentially decrease the risk for failure of hepatitis B immune globulin (HBIG) and hepatitis B vaccine to prevent perinatal transmission of HBV, which is increased among women with high HBV DNA levels. Certain specialists would use an antiretroviral regimen without anti-HBV activity to avoid the possibility of flare when discontinued postpartum and to avoid the use of tenofovir, a drug with limited experience with long-term use in pregnancy. Certain specialists would use a highly active regimen that includes lamivudine as the only antiretroviral agent with activity against HBV, especially if starting the regimen later in pregnancy because of late care or delayed HIV diagnosis, to avoid use of tenofovir while still treating HBV. Decisions regarding choice of ARV regimen should be made taking into account CD4⁺ count, HIV RNA levels, time needed for chronic HIV therapy, HBV levels and indications for HBV therapy, gestational age when starting therapy, and patient preference.

Infants born to HBsAg-positive women should receive HBIG and hepatitis B vaccine within 12 hours of birth (AI). The second and third doses of vaccine should be administered at 1 and 6 months of age, respectively. This regimen is >95% effective in preventing HBV infection in these infants. Postvaccination testing for anti-HBs and HBsAg should be performed at age 9--15 months because of the infant's ongoing exposure to HBV.

Hepatitis C Virus Infection

Epidemiology

Hepatitis C virus (HCV) is a single-stranded RNA virus that is most efficiently spread through direct blood exposure to contaminated blood or blood products. Both HIV and HCV can be transmitted by percutaneous exposure to blood, through sexual intercourse, and from a mother to her infant. However, the relative efficiency of transmission by these routes varies. HCV is approximately 10 times more infectious than HIV through percutaneous blood exposures, but sexual transmission of HCV is inefficient compared with HIV. Transmission of HIV and HCV through contaminated blood products is now rare because of effective screening of blood and blood-derived products in the United States.

Heterosexual transmission of HCV is uncommon but more likely occurs in persons with partners who are coinfected with HIV and HCV. Likewise, existing data suggest that sexual contact is a relatively inefficient mode of HCV transmission between MSM, but sexual HCV transmission has been increasingly reported among sex networks of HIV-infected men, particularly those engaged in high-risk sex practices. Cases of acute HCV infection are increasingly recognized and reported in this patient population (1088).

HCV infection occurs in approximately 2%--5% of infants born to HCV-seropositive mothers. In a majority of studies, the incidence of HCV transmission from mother to infant increases if the mother is coinfected with HIV (1089--1091). Overall, rates of HCV vertical and perinatal transmission are relatively low, although increased in the setting of HIV coinfection (1029,1092).

In the United States, HIV/HCV coinfection is most prevalent in persons who have a history of hemophilia or injection- drug use, in whom HCV infection rates approach 70%--95% compared with 1%--20% in those who acquired HIV through sex (1092,1093). Although studies have suggested that sexual transmission of HCV is inefficient, the exact risk related to different types of sexual activity is unknown. Risk factors for the sexual transmission of HCV include anal-receptive intercourse and concurrent sexually transmitted infection.

Cirrhosis develops in approximately 20% of persons with chronic HCV infection within 20 years after acute infection, although the range and time to development of cirrhosis varies widely. Risk factors for the development of substantial liver disease are older age at the time of infection, male sex, concomitant alcohol use (>20--50 g/day), and advanced immunosupression (CD4⁺ count of <200 cells/µL) (1094--1096). Compared with HCV monoinfection, the natural history of HCV infection is accelerated in the setting of HIV (1097), with more rapid progression to cirrhosis, decompensated liver disease, hepatocellular carcinoma (HCC), and death (1098). Because of its high prevalence and rapid progression, liver disease caused by chronic HCV is a leading cause of death among persons with HIV (997,999). Reports of the effect of immune restoration with ART on liver-related mortality are conflicting, with some studies reporting decreases and others little change in the rate of liver-related mortality (1099,1100). In addition to liver disease, HCV infection might be associated with changes in cognitive and psychiatric function (1101), decreased quality of life (1102), and increased prevalence of diabetes mellitus (1103), all of which potentially affect HIV management.

The effect of HCV infection on HIV disease progression and immune reconstitution is uncertain (1093,1104,1105), although not likely to be clinically relevant based on current observations (1106). Patients with underlying viral hepatitis are at increased risk for progression to ARV-related hepatotoxicity (1068), although most coinfected patients (approximately 90%) do not have severe hepatotoxicity. The risk for ART-associated hepatotoxicity might be related to the underlying degree of liver fibrosis (1107).

Clinical Manifestations

Both acute and chronic HCV infections are typically minimally symptomatic or asymptomatic. Fewer than 20% of patients with acute infection have symptoms characteristic of acute hepatitis, including low-grade fever, mild right upper quadrant pain, nausea, vomiting, anorexia, dark urine, and jaundice. Unexplained elevations of serum ALT or AST levels might be the only laboratory finding during acute infection. Recognition of acute HCV infection is important because antiviral treatment targeting HCV initiated during this period is associated with higher response rates (1108,1109).

Chronic hepatitis C infection is often asymptomatic, although complaints of fatigue are common. Serum cryoglobulins might be present but rarely (<5%) cause symptomatic skin (vasculitis), renal (membranoproliferative glomerulonephritis), or neurologic manifestations. HCV-infected patients might experience cutaneous manifestations, including porphyria cutanea tarda. The rate of these manifestations in the setting of HIV is unknown. With progression of liver disease, patients might experience stigmata of cirrhosis with portal hypertension and ESLD, including spider angiomata, palmar erythema, splenomegaly, caput medusa, ascites, jaundice, pruritus, asterixis, and encephalopathy.

Diagnosis

HIV-infected patients should be tested routinely for evidence of chronic HCV infection. Initial testing for HCV should be performed using the most sensitive immunoassays licensed for detection of antibody to HCV (anti-HCV) in blood (1110).

False-negative anti-HCV immunoassay results might occur among HIV-infected persons with advanced immunosuppression, but this is uncommon with the most sensitive immunoassays (third-generation assays) (1090,1111). If serologic test results are negative or indeterminate and HCV infection is suspected based on elevations of serum aminotransferases or risk factors such as injection-drug use, testing for HCV RNA should be performed (1112). True-negative antibody tests might also occur early in the course of acute HCV, in which elevations in serum aminotransferases and detectable viremia are evident before seroconversion; therefore, HCV RNA testing also should be performed when acute HCV infection is suspected.

To confirm the presence of chronic infection, all HCV-seropositive persons should be tested for plasma HCV RNA using a qualitative or quantitative assay. Quantitative HCV RNA level (i.e., viral load) does not correlate with degree of liver damage and does not serve as a surrogate for measuring disease severity, but it does provide important prognostic information about the response to antiviral therapy. Serial quantitative HCV RNA testing should be limited to persons receiving HCV treatment. Diagnostic assays using reverse transcriptase-polymerase chain reaction (RT-PCR) or transcription-mediated amplification (TMA) have been approved by the FDA for qualitative detection of HCV RNA. A single positive HCV RNA result is sufficient to confirm the diagnosis of active HCV infection, but a single negative result cannot exclude viremia because RNA levels might transiently decline below the limit of detection in persons with active infection, especially during the acute phase of infection. A repeat qualitative assay can be performed to confirm the absence of active infection.

Quantitative tests for HCV RNA include quantitative RT-PCR or branched DNA (bDNA) signal amplification assays. Newer real-time PCR assays have excellent sensitivity with lower limits of detection similar to qualitative assays and a broad dynamic range (e.g., COBAS TaqMan HCV Test; Roche Molecular Systems Inc., Branchburg, NJ). An HCV RNA standard has been established that permits normalization of viral titers in international units (IUs); nonetheless, substantial variability exists among available assays, and if serial values are required to monitor antiviral therapy, continued use of the same quantitative assay for all assessments is strongly recommended.

Six distinct HCV genotypes have been described (1113). Genotype 1 infection accounts for approximately 75% of all HCV infections in the United States and approximately 90% of infections among blacks (1114). In HCV-monoinfected patients, genotype information is used to guide both the duration of treatment and the dosing of RBV. In contrast, in persons with coinfection, only the dosing of RBV is genotype specific. HCV genotyping should be performed in all HIV-infected persons considering HCV treatment to guide RBV dosing and because it is the best predictor of response to IFN-based treatment and might, therefore, influence the decision to treat and/or perform liver biopsy. Repeat HCV genotype testing is not indicated.

Baseline and periodic monitoring of serum ALT and AST levels should be performed. Levels often fluctuate among patients with chronic HCV infection, regardless of HIV infection, and long periods during which these values are normal might be observed. Although higher serum ALT and AST levels are, to some degree, predictive of more rapid disease progression, (1091) substantial liver disease might be present even in the presence of persistently normal ALT levels.

Computed tomography (CT), MRI, and ultrasonography have limited utility in staging liver disease because they are often abnormal only in advanced disease. Ultrasonography is recommended as the initial test for evaluation of persons with liver cirrhosis for the detection of hepatic mass lesions suspicious for HCC. Because of cost, the use of bi- or triphasic CT with contrast or MRI scanning should typically be limited to evaluation of hepatic mass lesions in patients with cirrhosis.

Liver biopsy remains the preferred test for evaluation of HCV-related disease (fibrosis) stage and is useful to assess prognosis and guide treatment decisions. Although ultrasound guidance reduces the risk (1115), liver biopsies might result in major complications, including excessive bleeding (<0.5%), bile peritonitis (0.09%), and, rarely, internal organ injury, although the overall mortality rate is <1 in 10,000 (978,979). Further, disease staging by biopsy is expensive and subject to sampling error because of the heterogeneity of hepatic fibrosis. In some studies, disease progression has been observed during short periods in persons with minimal fibrosis. Therefore, although liver biopsy is helpful in the evaluation of coinfected persons, it is not required before the initiation of therapy for HCV infection, particularly in patients with a high probability of responding to treatment.

Noninvasive testing strategies to evaluate liver fibrosis are an area of active research. Several tests are available that can reliably separate patients with minimal fibrosis from those with cirrhosis, but these tests fail to distinguish intermediate stages of fibrotic disease (1116--1119). Although some tests are proprietary commercial assays (e.g., HCV FibroSURE, Laboratory Corporation of America Holdings), others are based on laboratory tests that are routinely obtained in most HIV-infected persons (FIB-4: age, ALT, AST, and platelet count; APRI: AST-Platelet Ratio Index). Additional studies are evaluating liver stiffness using transient elastography as a surrogate for liver fibrosis (1120). Prospective studies are ongoing to determine the test(s) with the best predictive value for disease progression.

Preventing Exposure

The primary route of HCV transmission among IDUs is drug injection via a syringe previously used by an infected person. An increased frequency of injection, a longer duration of injection-drug use, and cocaine use are additional factors that increase the potential for HCV transmission (1121). Strategies should be pursued to encourage IDUs to stop using injection drugs, preferably by entering a substance abuse treatment program (AII).

In addition to sharing syringes, other factors associated with injection, such as sharing drug solution containers, "cookers," filters, "cottons," and mixing water, also increase the likelihood of HCV transmission (1122). If IDUs are unwilling or unable to discontinue the use of injection drugs, they should be advised not to share needles or drug preparation equipment to reduce the risk for transmission of HCV infection (BII). Access to sterile injection equipment can be facilitated through enrollment of IDUs in NEPs (1000--1002).

Persons considering tattooing or body piercing should be informed of potential risks for acquiring HCV infection, which could be transmitted if equipment is not sterile or if proper infection-control procedures are not followed (AIII).

Although efficiency of sexual transmission of HCV is relatively low, safe-sex practices should be encouraged for all HIV-infected persons; barrier precautions (e.g., latex condoms) are recommended to reduce the risk for exposure to sexually transmitted pathogens, including HCV (AII).

Preventing Disease

All HIV-infected persons should be screened for active HCV infection. HCV-seronegative persons with elevations in serum aminotransferase levels should be screened for acute infection with assays to detect HCV RNA.

Higher rates of viral clearance have been reported in HIV-infected and -uninfected persons treated with IFN-based therapy for acute HCV infection (1108,1109). On the basis of this information and in the absence of contraindications, acutely infected persons (<6 months from the time of HCV exposure) should be routinely offered treatment for HCV infection to prevent the development of chronic HCV infection (BII). The optimal time to initiate therapy for acute HCV is unknown but it might be as soon as 8--12 weeks after acquisition of the infection (1109) (see Treatment Recommendations).

Chronically infected persons should be counseled about methods to prevent liver damage and HCV transmission, evaluated for chronic liver disease, and considered for treatment of HCV infection. All HIV/HCV-coinfected patients should be offered antiviral treatment to prevent development of HCV-related liver disease complications (AI). All HIV-infected patients with HCV coinfection should be advised to avoid or limit alcohol consumption (AII) because alcohol ingestion, particularly in quantities greater than 20--50 grams (approximately 2--5 drinks) per day, might accelerate the progression of liver disease (1123). Enrollment of active substance abusers into drug and/or alcohol treatment programs is strongly recommended. Persons with liver disease should limit ingestion of potentially hepatotoxic medications (e.g., acetaminophen <2 grams/day). Because iron overload might worsen liver disease, patients should avoid iron supplementation in the absence of documented iron deficiency.

Because of its increased morbidity, HIV-infected persons who are coinfected with HCV should be tested for previous or concurrent HBV infection. Despite evidence of decreased response to hepatitis B vaccine in immunosuppressed persons, those without previous HBV infection should be vaccinated. Likewise, because acute HAV infection is more likely to be fulminant in persons with underlying hepatitis, HAV-susceptible HIV-infected persons with risk factors for HAV infection should receive hepatitis A vaccination (AII). As with hepatitis B vaccination, the response to hepatitis A vaccination is reduced in those with CD4⁺ counts <200 cells/µL. Certain specialists recommend delaying hepatitis A vaccination until the CD4⁺ count is >200 cells/µL on ART (BIII). Antibody response should be assessed 1 month after vaccination; nonresponders should be revaccinated (BIII).

Among coinfected persons with cirrhosis, measures to identify and prevent complications of advanced liver disease are identical to those established in persons without HIV and should be performed routinely (BI). All patients with ascites should undergo paracentesis for analysis to verify that portal hypertension is the etiology and to exclude infection (ascites polymorphonuclear cell count >250 cells/mL) (1079). Assessment of the serum-ascites albumin gradient (SAAG) is advisable; SAAG >1.1 mg/dL strongly suggests ascites secondary to portal hypertension. Management includes sodium restriction (>2 g/day) and diuretics to alleviate fluid retention. The recommended diuretic regimen is spironolactone alone or combined with furosemide (ratio of 40 mg furosemide: 100 mg spironolactone). Consideration should be given to primary prophylaxis against spontaneous bacterial peritonitis (SBP) through the administration of oral antibiotics such as norfloxacin (400 mg/day) or TMP-SMX (1 double-strength tablet/day) in those with an ascites total protein <1 grams/dL (1080). Secondary antibiotic prophylaxis is recommended for all persons with a history of SBP (AI). Upper endoscopy should be performed in all persons with cirrhosis, particularly those with thrombocytopenia, at the time of diagnosis and then every 1--2 years to identify substantial varices (1124). For persons with varices, nonselective beta blockers (e.g., nadolol or propranolol) are the mainstay of both primary and secondary prevention of variceal hemorrhage; esophageal variceal ligation or banding is another preventive option, particularly for persons who cannot tolerate beta blockers. Hepatic encephalopathy, caused by the accumulation of unmetabolized ammonia and other false neurotransmitters absorbed from the gut in the setting of liver dysfunction, might be subtle in early stages (916). Preventive measures include restriction of animal dietary protein consumption and the use of nonabsorbable disaccharides (e.g., lactulose) and/or antibiotics (e.g., neomycin, rifaximin).

Patients with HCV-related cirrhosis are at increased risk for HCC (1081). Whether there is additional risk in the setting of HIV infection is unclear (998). Although the optimal screening strategy to detect HCC is unknown, screening is recommended in patients with documented cirrhosis using hepatic ultrasound imaging performed at 6--12-month intervals (BIII) (1082). The utility of serum AFP for HCC screening in persons with HIV is unknown. Because of relatively poor specificity and sensitivity, results of AFP testing should be confirmed with liver imaging studies. In the absence of contraindications, HIV/HCV-coinfected persons with decompensated liver disease and/or early HCC might be candidates for orthotopic liver transplantation because HIV infection is not a contraindication to organ transplantation with the use of effective ART (1083). Persons with cirrhosis should undergo periodic assessment of their liver disease status through the application of validated prognostic models (e.g., Model for End-Stage Liver Disease [MELD] score) that predict mortality risk and are used to determine the medical need for liver transplantation (1084). Where feasible, HIV/HCV-coinfected persons with well-controlled HIV infection found to have liver decompensation (defined as Child-Pugh-Turcotte score >7 and/or MELD score >10) or evidence of early HCC should be referred for orthotopic liver transplantation (BIII).

Treatment of Disease

Antiviral treatment for HCV infection should be considered for all HIV-infected persons with acute or chronic HCV infection (AI). In the absence of contraindications to pegIFN or RBV, treatment for HCV infection should be offered routinely to persons in whom the potential benefits of therapy are judged to outweigh the potential risks, including (but not limited to) persons with the following conditions (BII):

• HCV genotype 2 or 3 infection
• HCV genotype 1 infection with a low HCV RNA level (<800,000 IU/mL) (although certain specialists might not recommend treatment of patients with HCV genotype 1 infection and low or intermittently undetectable HCV RNA, response to pegIFN plus RBV is improved in those with HCV RNA levels <800,000 IU/mL compared with those with levels above this threshold, which might favor treatment in this group)
• Significant hepatic fibrosis (bridging fibrosis or cirrhosis)
• Stable HIV infection not requiring ART
• Acute HCV infection (<6 months' duration)
• Cryoglobulinemic vasculitis
• Cryoglobulinemic membranoproliferative glomerulonephritis
• Strong motivation to treat their HCV infection

The goals of therapy include eradication of HCV infection; prevention of hepatic fibrosis progression; and, among persons with HCV-related cirrhosis, prevention of ESLD, HCC, and death. Although viral eradication is not anticipated in most treated persons, histologic and clinical benefits of therapy have been observed in the absence of virologic response (1125).

On the basis of well-designed, randomized, controlled trials, pegIFN plus RBV is the recommended treatment for hepatitis C in HIV-infected persons (AI). Sustained virologic response (SVR) rates range from 14%--29% for HCV genotype 1 infection and 43%--73% for HCV genotypes 2 and 3 infection (1036,1125--1127). Whereas fixed-dose RBV (800 mg/day) is recommended for HIV-infected persons with genotype 2 or 3 disease, the appropriate RBV dose for persons with genotype 1 disease has not been determined because the pivotal trials studied only fixed-dose RBV. Among HIV seronegative persons with genotype 1, pegIFN plus weight-based RBV (1,000 mg/day for persons weighing <75 kg; 1,200 mg for persons weighing >75 kg) was more effective than fixed-dose RBV (1128). Although the efficacy of weight-based RBV has not yet been established in coinfected persons, several studies indicate that this strategy is not associated with increased risk for adverse effects (e.g., anemia). Accordingly, certain specialists recommend the use of weight-based RBV combined with pegIFN in HIV-infected persons with HCV genotype 1 disease (AII).

For HCV genotypes 1,4,5, or 6, the recommended treatment regimen is either pegIFN alfa-2a (180 mcg) or pegIFN alfa-2b (1.5 mcg/kg) administered by subcutaneous injection weekly plus oral RBV twice daily (<75 kg or 165 lbs body weight, 600 mg each morning and 400 mg each evening; >75 kg or 165 lbs body weight, 600 mg twice daily) for a total duration of 48 weeks (AI). For HCV genotype 2 or 3, the recommended treatment is either pegIFN alfa-2a (180 mcg) or pegIFN alfa-2b (1.5 mg/kg) administered by subcutaneous injection weekly plus oral RBV in a fixed dose of 400 mg twice daily for a total duration of 48 weeks (AI).

The optimal treatment regimen and duration of treatment for acute HCV in coinfected patients has not been determined. Among HIV-seronegative persons, regimens including pegIFN with or without RBV in dosing schedules described above have been administered for 24 weeks