SUGGESTED CITATION: Centers for Disease Control and Prevention. 1993 Sexually transmitted diseases treatment guidelines. MMWR 1993;42(No. RR-14): {inclusive page numbers}.

CIO Responsible for this publication: National Center for Prevention Services,

Division of Sexually Transmitted Diseases and HIV Prevention

Summary

These guidelines for the treatment of patients with sexually transmitted diseases (STDs) were developed by staff members of CDC after consultation with a group of invited experts who met in Atlanta on January 19-21, 1993. Included are new recommendations for single-dose oral therapy for gonococcal infections, chlamydial infections, and chancroid; new regimens for the treatment of bacterial vaginosis (BV) and outpatient management of pelvic inflammatory disease (PID); a new patient-applied medication for treatment of genital warts; and a revised approach to the management of victims of sexual assault. This report includes new sections on subclinical human papillomavirus (HPV) infections and cervical cancer screening for women who attend STD clinics or who have a history of STDs. These recommendations also include expanded sections on the management of patients with asymptomatic human immunodeficiency virus (HIV) infection; vulvovaginal candidiasis (VVC); STDs among patients coinfected with HIV; and STDs among infants, children, and pregnant women.

INTRODUCTION

Physicians and other health-care providers have a critical role in the effort to prevent and treat sexually transmitted diseases (STDs). These recommendations for the treatment of STDs are intended to assist with that effort. They were developed by CDC staff members in consultation with a group of invited experts.

This report was produced through a multi-stage process. Beginning in the spring of 1992, CDC personnel systematically reviewed literature on each of the major STDs, focusing on data and reports that have become available since the 1989 STD Treatment Guidelines were published. Background papers were written and tables of evidence constructed summarizing the type of study (e.g., randomized controlled trial, case series), the study population and setting, the treatments or other interventions, outcome measures assessed, reported findings, and weaknesses and biases in study design and analysis. For these reviews and tables, published abstracts and peer- reviewed journal articles were considered. CDC personnel then developed a draft document based on those reviews.

In January 1993, invited consultants assembled in Atlanta for a 3-day meeting. CDC personnel presented the key questions on STD treatment suggested from their literature reviews and presented the data available to answer those questions. Where relevant, the questions focused on four principal outcomes of STD therapy: a) microbiologic cure, b) alleviation of signs and symptoms, c) prevention of sequelae, and d) prevention of transmission. The consultants then assessed whether the questions identified were the appropriate ones, ranked them in order of priority, and attempted to arrive at answers using the available evidence. In addition, the consultants evaluated the quality of evidence supporting the answers based on the number and types of studies and the quality of those studies.

In several areas, the process diverged from that described above. The section on STD/HIV prevention guidelines was reviewed for comment by experts who had not been present at the January meeting, as well as by additional experts on STD/HIV prevention at CDC. The recommendations for STD screening during pregnancy were developed after CDC staff reviewed the published recommendations of other expert groups that were convened by CDC and other organizations. The sections on HIV infection and early intervention and hepatitis B virus (HBV) also are principally a compilation of recommendations developed by other experts and are provided in this report for the convenience of those who use this document.

Throughout this document the evidence used as the basis for specific recommendations is briefly discussed. More comprehensive, annotated discussions of such evidence will appear in background papers that will be submitted for publication in 1994.

These recommendations were developed in consultation with experts whose experience is primarily with the treatment of patients in public STD clinics. These recommendations also should be applicable to other patient-care settings, including family planning clinics, private doctor's offices, and other primary-care facilities. When using these guidelines, consideration should be given to the disease prevalence and to other characteristics of the practice setting. These recommendations should not be construed as standards or as inflexible rules, but as a source of clinical guidance within the United States.

These recommendations focus on the treatment and counseling of individual patients and do not address other community services and interventions that also play important roles in STD/HIV prevention. Clinical and laboratory diagnoses are described when such information is related to therapy. For a more comprehensive discussion of diagnosis, refer to CDC's STD Clinical Practice Guidelines, 1991 (1).

STD/HIV PREVENTION GUIDELINES

Prevention and control of STDs is based on four major concepts: first, education of those at risk on the means for reducing the risk for transmission; second, detection of asymptomatically infected individuals and of persons who are symptomatic but unlikely to seek diagnostic and treatment services; third, effective diagnosis and treatment of those who are infected; fourth, evaluation, treatment, and counseling of sex partners of persons who have an STD. Although this document deals largely with secondary prevention, namely clinical aspects of STD control, primary prevention of STDs is based on changing the sexual behaviors that place patients at risk.

Physicians and other health-care providers have an important role in the prevention of STDs. In addition to interrupting transmission by treating persons who have bacterial and parasitic STDs, clinicians have the opportunity to provide patient education and counseling and to participate in identifying and treating infected sex partners.

Prevention Methods

Condoms

When used consistently and correctly, condoms are very effective in preventing a variety of STDs, including HIV infection. Multiple cohort studies, including those of serodiscordant couples, have demonstrated a strong protective effect of condom use against HIV infection. Condoms are regulated as medical devices and subject to random sampling and testing by the Food and Drug Administration (FDA). Each latex condom manufactured in the United States is tested electronically for holes before packaging. Condom breakage rates during use are low in the United States ( less than or equal to 2 per 100 condoms tested). Condom failure usually results from inconsistent or incorrect use rather than condom breakage.

Patients should be advised that condoms must be used consistently and correctly to be effective in preventing STDs. Patients should also be instructed in the correct use of condoms. The following recommendations ensure the proper use of condoms:

• Use a new condom with each act of intercourse.

• Carefully handle the condom to avoid damaging it with fingernails, teeth, or other sharp objects.

• Put the condom on after the penis is erect and before any genital contact with the partner.

• Ensure that no air is trapped in the tip of the condom.

• Ensure that there is adequate lubrication during intercourse, possibly requiring the use of exogenous lubricants.

• Use only water-based lubricants (e.g., K-Y JellyTM or glycerine) with latex condoms (oil-based lubricants {e.g., petroleum jelly, shortening, mineral oil, massage oils, body lotions, or cooking oil} that can weaken latex should never be used).

• Hold the condom firmly against the base of the penis during withdrawal, and withdraw while the penis is still erect to prevent slippage.

Condoms and Spermicides

The effectiveness of spermicides in preventing HIV transmission is unknown. No data exist to indicate that condoms lubricated with spermicides are more effective than other lubricated condoms in protecting against the transmission of HIV infection and other STDs. Therefore, latex condoms with or without spermicides are recommended.

Female Condoms

Laboratory studies indicate that the female condom (RealityTM) -- a lubricated polyurethane sheath with a ring on each end that is inserted into the vagina--is an effective mechanical barrier to viruses, including HIV. Aside from a small study of trichomoniasis, no clinical studies have been completed to evaluate protection from HIV infection or other STDs. However, an evaluation of the female condom's effectiveness in pregnancy prevention was conducted during a 6-month period for 147 women in the United States. The estimated 12-month failure rate for pregnancy prevention among the 147 women was 26%.

Vaginal Spermicides, Sponges, Diaphragms

As demonstrated in several cohort studies, vaginal spermicides (i.e., film, gel, suppositories; contraceptive foam has not been studied) used alone without condoms reduce the risk for cervical gonorrhea and chlamydia, but protection against HIV infection has not been established in human studies. The vaginal contraceptive sponge protects against cervical gonorrhea and chlamydia, but increases the risk for candidiasis as evidenced by cohort studies. Diaphragm use has been demonstrated to protect against cervical gonorrhea, chlamydia, and trichomoniasis, but only in case-control and cross-sectional studies; no cohort studies have been performed. Gonorrhea and chlamydia among women usually involve the cervix as a portal of entry, whereas other STD pathogens (including HIV) may infect women through the vagina or vulva, as well as the cervix. Protection of women against HIV infection should not be assumed from the use of vaginal spermicides, vaginal sponges, or diaphragms. The role of spermicides, sponges, and diaphragms for preventing STDs among men has not been studied.

Nonbarrier Contraception, Surgical Sterilization, Hysterectomy

Women who are not at risk for pregnancy may incorrectly perceive themselves to be at no risk for STDs, including HIV infection. Nonbarrier contraceptive methods offer no protection against HIV or other STDs. Women using hormonal contraception (oral contraceptives, NorplantTM, Depo-ProveraTM), who have been surgically sterilized or who have had hysterectomies should be counseled regarding the use of condoms and the risk for STDs, including HIV infection.

Prevention Messages

Preventing the spread of STDs requires that persons at risk for transmitting or acquiring infections change their behaviors. When risks have been identified, the health-care provider has an opportunity to deliver prevention messages. Counseling skills are essential to the effective delivery of prevention messages (i.e., respect, compassion, and a nonjudgmental attitude). Techniques that can be effective in developing rapport with the patient include using open-ended questions, using language that the patient understands, and reassuring the patient that treatment will be provided regardless of considerations such as ability to pay, citizenship or immigration status, language spoken, or lifestyle.

Prevention messages should be tailored to the patient, with consideration given to his or her specific risks. Messages should include a description of measures, such as the following, that the person can take to avoid acquiring or transmitting STDs:

The most effective way to prevent sexual transmission of HIV infection and other STDs is to avoid sexual intercourse with an infected partner.

• If a person chooses to have sexual intercourse with a partner whose infection status is unknown or who is infected with HIV or other STDs, men should use a new latex condom with each act of intercourse.

• When a male condom cannot be used, couples should consider using a female condom.

Injection Drug Users

Prevention messages appropriate for injection drug users are the following:

• Enroll or continue in a drug treatment program.

• Do not, under any circumstances, use injection equipment (needles, syringes) that has been used by another person.

• Persons who continue to use injection equipment that has been used by other persons should first clean the equipment with bleach and water. (Disinfecting with bleach does not sterilize the equipment and does not guarantee that HIV is inactivated. However, thoroughly and consistently cleaning injection equipment with bleach should reduce the rate of HIV transmission when equipment is shared.)

HIV Prevention Counseling

Knowledge of one's HIV status and appropriate counseling are thought to play an important role in initiating behavior change. Counseling associated with HIV testing has two main components: pretest and posttest counseling.

During pretest counseling, the clinician should conduct a personalized risk assessment, explain the meaning of positive and negative test results, ask for informed consent for the HIV test, and help the person to develop a realistic, personalized risk reduction plan.

During posttest counseling, the clinician should inform the patient of the results, review the meaning of the results, and reinforce prevention messages. If the patient is HIV positive, posttest counseling should include referral for follow-up medical services and for social and psychological services, if needed. HIV- seronegative persons at continuing risk for HIV infection also may benefit from referral for additional counseling and prevention services.

HIV counseling is considered to be an important HIV-prevention strategy, although its efficacy in reducing risk behavior is still under evaluation. By ensuring that counseling is empathic and "client-centered," clinicians will be able to develop a realistic appraisal of the person's risk and help him or her to develop a specific and realistic HIV-prevention plan (2).

Partner Notification and Management of Sex Partners

Patients with STDs should ensure that their sex partners, including those without symptoms, are referred for evaluation. Providers should be prepared to assist in that effort. In most circumstances, partners of patients with STDs should be examined. When a diagnosis of a treatable STD is considered likely, appropriate antibiotics should be administered even though there may be no clinical signs of infection and before laboratory test results are available. In most states, the local or state health department can assist in notifying the partners of patients with selected STDs, especially HIV, syphilis, gonorrhea, and chlamydia.

Breaking the chain of transmission is crucial to STD control. For treatable STDs, further transmission and reinfection can be prevented by referral of sex partners for diagnosis, treatment, and counseling. The following two strategies are used for partner notification: a) patient referral (index patients notify their partners), and b) provider referral (partners named by infected patients are notified and counseled by health department staff). When a physician refers an infected person to a local or state health department, trained professionals may interview the patient to obtain names and locating information about all of his or her sex partners. Every health department protects the privacy of patients in partner notification activities. Because of the advantage of confidentiality, many patients prefer that public health officials notify partners.

If a patient with HIV infection refuses to notify partners while continuing to place them at risk, the physician has an ethical and legal responsibility to inform persons that they are at risk of HIV infection. This duty-to-warn may be most applicable to primary care physicians, who often have knowledge about a patient's social and familial relationships. The decision to invoke the duty-to-warn measure should be a last resort -- applicable only in cases in which all efforts to persuade the patient to disclose positive test results to those who need to know have failed.

Although compelling ethical, theoretical, and public health reasons exist to undertake partner notification, the efficacy of partner notification as an STD prevention strategy is under evaluation, and its effectiveness may be disease-specific.

Clinical guidelines for sex partner management and recommendations for partner notification for specific STDs are included for each STD addressed in this report.

Reporting and Confidentiality

The accurate identification and timely reporting of STDs form an integral part of successful disease control. Reporting assists local health authorities in identifying sex partners who may be infected. Reporting also is important for assessing morbidity trends. STD/HIV and acquired immunodeficiency syndrome (AIDS) cases should be reported in accordance with local statutory requirements and in a timely manner.

Syphilis, gonorrhea, and AIDS are reportable diseases in every state. The requirements for reporting other STDs and asymptomatic HIV infection differ from state to state, and clinicians should be familiar with local STD reporting requirements.

Reporting may be provider- and/or laboratory-based. Clinicians who are unsure of local reporting requirements should seek advice from local health departments or state STD programs.

STD and HIV reports are held in strictest confidence and in many jurisdictions are protected by statute from subpoena. Further, before any follow-up of a positive STD test is conducted by program representatives, these persons consult with the patient's health-care provider to verify the diagnosis and treatment.

SPECIAL POPULATIONS

Pregnant Women

Intrauterine or perinatally transmitted STDs can have fatal or severely debilitating effects on a fetus. Pregnant women and their sex partners should be questioned about STDs and should be counseled about the possibility of neonatal infections.

Recommended Screening Tests

The following screening tests are recommended for pregnant women:

• A serologic test for syphilis

All women should be screened serologically for syphilis during the early stages of pregnancy. In populations in which utilization of prenatal care is not optimal, rapid plasma reagin (RPR)-card test screening and treatment, if that test is reactive, should be performed at the time a pregnancy is diagnosed. For patients at high risk, screening should be repeated in the third trimester and again at delivery. (Some states mandate screening all women at delivery.) No infant should be discharged from the hospital without the syphilis serologic status of its mother having been determined at least once during pregnancy and, preferably, again at delivery. Any woman who delivers a stillborn infant after 20 weeks gestation should be tested for syphilis.

• A serologic test for hepatitis B surface antigen (HBsAg)

• A test for Neisseria gonorrhoeae

• A test for Chlamydia trachomatis Pregnant women at increased risk ( less than 25 years of age, or with a new or more than one partner) should be tested and treated, if necessary, during the third trimester to prevent maternal postnatal complications and chlamydial infection among infants. Screening during the first trimester might permit prevention of adverse effects of chlamydia during pregnancy. However, the evidence for adverse effects during pregnancy is minimal. If screening is performed only during the first trimester, a longer period exists for acquiring infection before delivery.

• A test for HIV infection Patients with risk factors for HIV or with a high-risk sex partner should be tested for HIV infection. Some authorities recommend offering HIV tests to all pregnant women, particularly in areas of high HIV seroprevalence. Appropriate counseling should be provided, and informed consent for HIV testing should be obtained.

Other Issues Other STD-related issues to be considered are as follows:

• Pregnant women with primary genital herpes, HBV, primary cytomegalovirus (CMV) infection, group B streptococcal infection, and women who have syphilis and who are allergic to penicillin may need to be referred to an expert for management.

• In the absence of lesions during the third trimester, routine serial cultures for herpes simplex virus (HSV) are not indicated for women with a history of recurrent genital herpes. However, obtaining cultures from such women at the time of delivery may be useful in guiding neonatal management. "Prophylactic" caesarean section is not indicated for women who do not have active genital lesions at the time of delivery.

• The presence of genital warts is not considered an indication for caesarean section.

For a more detailed discussion of these issues, as well as for infections not transmitted sexually, refer to Guidelines for Perinatal Care (3).

NOTE: The sources for these guidelines for screening of pregnant women include Guide to Clinical Preventive Services (4), Guidelines for Perinatal Care (3), and Recommendations for the Prevention and Management of Chlamydia trachomatis Infections, 1993 (5). These sources are not entirely consistent in their recommendations. The Guide to Clinical Preventive Services recommends routine testing for gonorrhea at the first prenatal visit, with repeat testing for those at increased risk, and selective screening for chlamydia at the first prenatal visit. The Guidelines for Perinatal Care does not specifically recommend screening for either gonorrhea or chlamydia, but recommends screening for STDs in the third trimester for women at risk. The Recommendations for the Prevention and Management of Chlamydia trachomatis Infections, 1993 recommend screening for chlamydia during the third trimester for all pregnant women less than 25 years of age or for any woman with a new sex partner or multiple partners. Recommendations to screen pregnant women for STDs are based on disease severity and sequelae, prevalence in the population, costs, medical/legal considerations (including state laws), and other factors. The screening recommendations in this report are more comprehensive (i.e., if followed, more women will be screened for more STDs than would be screened by following other recommendations) and are compatible with other CDC guidelines. Physicians should select a screening strategy compatible with their practice population and setting.

Adolescents

Health-care providers who provide care for patients with sexually transmitted infections should be aware of several issues that relate specifically to adolescents. The rates of many STDs are highest among adolescents; e.g., the rate of gonorrhea is highest among persons 15-19 years of age. Clinic-based studies have demonstrated that the prevalence of chlamydial infections, and possibly of HPV infections, also is highest among adolescents.

All adolescents in the United States can consent to the confidential diagnosis and treatment of STDs. Medical care for these conditions can be provided to adolescents without parental consent or knowledge. Furthermore, in many states adolescents can consent to HIV counseling and testing.

The style and content of counseling and health education should be adapted for adolescents. Discussions should be appropriate for the patient's developmental level and should identify risky behaviors, such as sex and drug use behaviors. Care and counseling should be direct and nonjudgmental.

Children

Management of children with STDs requires close cooperation between the clinician, laboratory, and child-protection authorities. Investigations, when indicated, should be initiated promptly. Some diseases, such as gonorrhea, syphilis, and chlamydia, if acquired after the neonatal period, are almost 100% indicative of sexual contact. For other diseases, such as HPV infection and vaginitis, the association with sexual contact is not as clear (see Sexual Assault and STDs).

Persons with HIV Infection

The management of patients infected with HIV and patients infected with both HIV and other STDs presents complex clinical and behavioral issues. For that reason, these issues are addressed throughout this report (see HIV Infection and Early Intervention and specific disease sections). Because of its effects on the immune system, HIV infection may alter the natural histories of many STDs and the effect of antimicrobial therapy. Such effects are likely to occur as the degree of immunosuppression advances; frequent or severe episodes of some STDs or failure to respond appropriately to therapy should lead the health-care provider to consider HIV infection as a cause. Close clinical follow-up of patients infected with both HIV and STDs is imperative.

STD infection among patients with or without HIV is a sentinel event, often indicating unprotected sexual activity. Further patient counseling is needed in such situations.

HIV INFECTION AND EARLY INTERVENTION

Infection with HIV produces a spectrum that progresses from no apparent illness to AIDS as a late manifestation. The pace of disease progression is variable. The median time between infection with HIV and the development of AIDS among adults is 10 years, with a range from a few months to greater than or equal to 12 years. Most adults and adolescents infected with HIV remain symptom-free for long periods, but viral replication can be detected in asymptomatic persons and increases substantially as the immune system deteriorates. Most people who are infected with HIV will eventually have symptoms related to the infection. In cohort studies of adults infected with HIV, data indicated that symptoms developed in 70%-85% of infected adults, and AIDS developed in 55%- 62% within 12 years after infection. Additional cases are expected to occur among those who have remained AIDS-free for greater than 12 years.

Greater awareness of risky behaviors by both patients and health-care providers has led to increased testing for HIV and earlier diagnosis of early HIV infection, often before symptoms develop (though emotional or psychological problems may occur). Such early identification of HIV infection is important for several reasons. Treatments are available to slow the decline of immune system function. Persons who are infected with HIV and altered immune function also are at increased risk for infections such as tuberculosis (TB), bacterial pneumonia, and Pneumocystis carinii pneumonia (PCP), for which preventive measures are available. Because of its effect on the immune system, HIV affects the diagnosis, evaluation, treatment, and follow-up of many other diseases and may affect the efficacy of antimicrobial therapy for some STDs. Close clinical follow-up after treatment for STDs is imperative.

During early infection, persons with HIV and their families can be educated about the disease and become linked with a support network that addresses their needs and with care systems effective in maintaining good health and delaying the onset of symptoms. Early diagnosis also offers the opportunity for counseling and for assistance in preventing the transmission of HIV infection to others.

For the purpose of these recommendations, early intervention for HIV is defined as care for persons infected with HIV who are without symptoms. However, recently detected HIV infection may not have been recently acquired. Persons newly diagnosed with HIV may be at many different stages of the infection. Therefore, early intervention also involves assuming the responsibility for coordinating care and for arranging access to resources necessary to meet the medical, psychological, and social needs of persons with more advanced HIV infection.

Diagnostic Testing for HIV-1 and HIV-2

HIV infection is most often diagnosed by using HIV-1 antibody tests. Antibody testing begins with a sensitive screening test such as the enzyme-linked immunosorbent assay (ELISA) or a rapid assay. If confirmed by Western blot or other supplemental test, a positive antibody test means that a person is infected with HIV and is capable of transmitting the virus to others. HIV antibody is detectable in greater than or equal to 95% of patients within 6 months of infection. Although a negative antibody test usually means a person is not infected, antibody tests cannot rule out infection that occurred less than 6 months before the test.

Since there is transplacental passage of maternal HIV antibody, antibody tests for HIV are expected to be positive in the serum of both infected and uninfected infants born to a seropositive mother. Passively acquired HIV antibody falls to undetectable levels among most infants by 15 months of age. A definitive determination of HIV infection for an infant less than 15 months of age should be based either on the presence of antibody to HIV in conjunction with a compatible immunologic profile and clinical course or on laboratory evidence of HIV in blood or tissues by culture, nucleic acid, or antigen detection.

Specific recommendations for the diagnostic testing of HIV are listed below:

• Informed consent must be obtained before an HIV test is performed. Some states require written consent. See HIV Prevention Counseling for a discussion of pretest and posttest counseling.

• Positive screening tests for HIV antibody must be confirmed by a more specific confirmatory test (either the Western blot assay or indirect immunofluorescence assay {IFA}) before being considered definitive for confirming HIV infection.

• Persons with positive HIV tests must receive medical and psychosocial evaluation and monitoring services, or be referred for these services.

The prevalence of HIV-2 in the United States is extremely low, and CDC does not recommend routine testing for HIV-2 in settings other than blood centers, unless demographic or behavioral information suggests that HIV-2 infection might be present. Those at risk for HIV-2 infection include persons from a country in which HIV-2 is endemic or the sex partners of such persons. (As of July 1992, HIV-2 was endemic in parts of West Africa and an increased prevalence of HIV-2 had been reported in Angola, France, Mozambique, and Portugal.) Additionally, testing for HIV-2 should be conducted when there is clinical evidence or suspicion of HIV disease in the absence of a positive test for antibodies to HIV-1 (6).

Counseling for Patients with HIV Infection

Behavioral and psychosocial services are an integral part of HIV early intervention. Patients usually experience emotional distress when first being informed of a positive HIV test result, and also later when notified of changes in immunologic markers, when antiviral or prophylactic therapy is initiated, and when symptoms develop. Patients face several major adaptive challenges:

1. accepting the possibility of a curtailed life span, b) coping with others' reactions to a stigmatizing illness, c) developing strategies for maintaining physical and emotional health, and d) initiating changes in behavior to prevent HIV transmission. Many patients also require assistance with making reproductive choices, gaining access to health services and health insurance, and confronting employment discrimination.

Interrupting HIV transmission depends upon changes in behavior by those persons at risk for transmitting or acquiring infection. Though some viral culture studies suggest that antiviral treatment reduces viral burden, clinical data are insufficient to determine whether therapy might reduce the probability of transmission. Infected persons, as potential sources of new infections, must receive extra attention and support to help break chains of transmission and to prevent infection of others. Targeting behavior change programs toward HIV-infected persons and their sex partners, or those with whom they share needles, is an important adjunct to current AIDS prevention efforts.

Specific recommendations for counseling patients with HIV infection are listed below:

• Persons who test positive for HIV antibody should be counseled by a person who is able to discuss the medical, psychological, and social implications of HIV infection.

• Appropriate social support and psychological resources should be available, either on site or through referral, to assist patients in coping with emotional distress.

• Persons who continue to be at risk for transmitting HIV should receive assistance in changing or avoiding behaviors that can transmit infection to others.

Initial Evaluation and Planning for Care

Practice settings for offering early HIV care are variable, depending upon local resources and needs. Primary-care providers and outpatient facilities must ensure that appropriate resources are available for each patient and must avoid fragmentation of care; it is preferable for persons with HIV infection to receive care from a single source that is able to provide comprehensive care for all stages of HIV infection. But the limited availability of such resources often results in the need to coordinate care among outpatient, inpatient, and specialist providers in different locations. Because of the progressive nature of HIV and the increased risk for bacterial infections, including TB -- even before HIV infection becomes advanced -- it is essential to establish specific provisions for handling the medical, psychological, and social problems likely to arise at any stage of infection. An important component of early intervention is effective linkage with referral settings where off-hours care and specialty services are available. Development of an appropriate plan for care involves the following:

• Identification of patients in need of immediate medical care (e.g., patients with symptomatic HIV infection or emotional crisis) and of those in need of antiretroviral therapy or prophylaxis for opportunistic infections (e.g., PCP).

• Evaluation for the presence of diseases associated with HIV, such as TB and STDs.

• Administration of recommended vaccinations.

• Case management or referral for case management.

• Counseling (see Counseling for Patients with HIV Infection). The CD4+ T-lymphocyte count is the best laboratory indicator of clinical progression, and comprehensive management strategies for HIV infection are typically stratified by CD4 count. Either the absolute number or the percentage of CD4+ T cells may be determined. CD4+ percentage is more consistent than absolute CD4+ count with successive measurements for the same person and less variable with delays in specimen processing. However, most clinical trials have used absolute CD4+ count to evaluate the need for and timing of therapeutic interventions. Patients with CD4+ counts greater than 500/uL usually do not demonstrate evidence of clinical immunosuppression. Patients with 200-500 CD4+ cells/uL are more likely to develop HIV-related symptoms and to require medical intervention. Patients with CD4+ counts less than 200 cells/uL, and those with higher CD4+ counts who develop thrush or unexplained fever (temperature greater than 37.8 C for greater than or equal to 2 weeks) are at increased risk for developing complicated HIV disease. Such patients should be managed in a comprehensive treatment setting with access to specialty resources and hospitalization.

Providers unable to offer therapeutic management of HIV may use the initial evaluation to identify the need for prompt referral to appropriate resources. The initial evaluation of HIV-positive patients should include the following essential components:

• A detailed history, including sexual history, substance abuse history, and a review of systems for specific HIV-related symptoms.

• A physical examination; for females, this examination should include a gynecologic examination.

• For females, testing for N. gonorrhoeae, C. trachomatis, a Papanicolaou (Pap) smear, and wet mount examination of vaginal secretions.

• A syphilis serology.

• A CD4+ T-lymphocyte analysis.

• Complete blood and platelet counts.

• A purified protein derivative (PPD) tuberculin skin test by the Mantoux method and anergy testing with two delayed-type hypersensitivity (DTH) antigens (Candida, mumps, or tetanus toxoid) administered by the Mantoux method or a multipuncture device.

• A thorough psychosocial evaluation, including ascertainment of behavioral factors indicating risk for transmitting HIV and elucidation of information about any partners who should be notified about possible exposure to HIV.

Preventive Therapy for TB

Studies conducted among persons with and without HIV infection have suggested that HIV infection can depress tuberculin reactions before signs and symptoms of HIV infection develop. Cutaneous anergy (defined as skin test response of less than or equal to 3 mm to all DTH antigens) may be present among greater than or equal to 10% of asymptomatic persons with CD4+ counts greater than 500 cells/uL, and among greater than 60% of persons with CD4+ counts less than 200.

HIV-positive persons with a PPD reaction greater than or equal to 5 mm induration are considered to be infected with M. tuberculosis and should be evaluated for preventive treatment with isoniazid after active TB has been excluded. Anergic persons whose risk for tuberculous infection is estimated to be greater than or equal to 10%, based on available prevalence data, also should be considered for preventive therapy. For further details regarding evaluation of patients for TB, refer to Purified Protein Derivative (PPD-tuberculin anergy) and HIV Infection: Guidelines for Anergy Testing and Management of Anergic Persons at Risk of Tuberculosis (7).

The preliminary results from a randomized clinical trial suggest that treatment with isoniazid is effective for preventing active TB among HIV-infected persons. The usual regimen is isoniazid 10 mg/kg daily, up to a maximum adult dose of 300 mg daily. Twelve months of isoniazid preventive treatment is recommended for persons with HIV infection. For further details regarding preventive therapy for TB, refer to The Use of Preventive Therapy for Tuberculous Infection in the United States (8) and Management of Persons Exposed to Multidrug-Resistant Tuberculosis (9).

Recommended Immunizations for Adults and Adolescents

Specific recommendations for immunization of persons infected with HIV are listed below:

• Pneumococcal vaccination and an annual influenza vaccination should be administered.

• Persons at increased risk for acquiring HBV and who lack evidence of immunity may receive a three-dose schedule of hepatitis B vaccine, with postvaccination serologic testing between 1 and 6 months after the vaccination series.

Recommendations for vaccinating HIV-infected persons are based on expert opinions and consensus of the Advisory Committee on Immunization Practices (ACIP). No clinical data exist to document the efficacy of inactivated vaccines among HIV-infected persons, and pneumococcal vaccine failures have been reported. However, the use of inactivated vaccines may be beneficial for persons with HIV infection and there is no evidence that they are harmful. Immunogenicity studies have suggested a generally poorer response among HIV-infected persons, with higher response rates among asymptomatic persons than among those with advanced HIV disease.

Current evidence indicates that HIV infection does not increase susceptibility to HBV, nor does it increase the severity of clinical disease. The presence of HIV infection is not an indication for hepatitis B vaccine, but HIV-infected persons are at increased risk for becoming chronic carriers after hepatitis B infection. Because the routes of transmission of HBV parallel those of HIV, efforts to modify risky behaviors must be the primary focus of prevention efforts. However, vaccine should be administered to HIV-infected patients who continue to have a high likelihood for HBV exposure.

Persons with HIV infection also are at increased risk for invasive Haemophilus influenzae type B (Hib) disease and for complications from measles. Immunization against Hib and measles should be considered for asymptomatic HIV-infected persons who may have an increased risk for exposure to these infections. For further details on immunization of HIV-infected patients, refer to Recommendations of the Advisory Committee on Immunization Practices (ACIP): Use of Vaccines and Immune Globulins in Persons with Altered Immunocompetence (10).

Follow-Up Evaluation

There have been no controlled studies to serve as the basis for recommending specific follow-up tests or follow-up intervals. The suggested frequency of monitoring is based on the slow decrease in CD4+ counts observed among patients in cohort studies, but should be modified depending on the patient's psychological status, the presence of symptoms, or both. Repeat evaluation for STDs also is important in the follow-up of HIV-infected persons and should be performed on all persons who continue to be sexually active. Follow-up evaluation should be performed every 6 months and should include the following:

• An interim history and physical examination;

• A complete blood count, platelet count, and lymphocyte subset analysis;

• Re-evaluation of psychosocial status and behavioral factors indicating risk for transmitting HIV.

To follow CD4+ measurements, providers should use the same laboratory and, optimally, obtain each specimen at the same time each day. When unexpected or discrepant results are obtained or when major treatment decisions are to be made, health-care providers should consider repeating the CD4+ measurement after at least 1 week.

More frequent laboratory monitoring, every 3-4 months, is indicated if CD4+ results indicate a patient is close to a point when a clinical intervention may be indicated.

Continuing Management of Patients with Early HIV Infection

Providing comprehensive, continuing management of patients with early HIV infection can include additional diagnostic studies (e.g., chest x-ray, serum chemistry, antibody testing for toxoplasmosis and hepatitis B), antiretroviral therapy and monitoring, and PCP prophylaxis. Treatment of HIV infection and prophylaxis against opportunistic infections continue to evolve rapidly. This treatment should be undertaken in consultation with physicians who are familiar with the care of persons with HIV infection. The complete therapeutic management of HIV infection is beyond the scope of this document.

Antiretroviral Therapy

The optimal time for initiating antiretroviral therapy has not yet been established. Zidovudine (ZDV) at a dose of 500 mg/day (100 mg orally every 4 hours while the patient is awake) has been recommended for symptomatic persons with less than 500 CD4+ T-cells/uL, and for asymptomatic persons with less than 300 CD4+ T-cells/uL. This recommendation is based on results of short-term follow-up in three randomized clinical trials demonstrating that the initiation of ZDV therapy delays progression to advanced disease. Evidence for improved long-term survival after early treatment is less conclusive. The effects of ZDV may be transient, possibly because of the development of viral resistance or other factors. Sequential or combination therapy with other antiretroviral agents could be more efficacious.

Whether other daily dosages, dose schedules, or dosages based on body weight would result in greater therapeutic benefit or few side effects is not known. Providers should work with patients to design a treatment strategy that is both clinically sound and appropriate for each individual patient's needs, priorities, and circumstances. An initial dose of 600 mg in divided doses has been recommended by a panel of experts convened by the National Institute of Allergy and Infectious Diseases (NIAID). Preliminary data suggest ZDV can yield therapeutic results when the dosing interval is increased to 8 hours, and at doses of 200 mg three times daily. Antiretroviral efficacy is diminished at doses less than 300 mg/day, and it has been suggested that higher oral doses may be required to achieve effective levels in the central nervous system.

There are no data to support the use of antiretroviral drugs other than ZDV as initial therapy. Didanosine (DDI) is recommended for persons who are intolerant of ZDV or who experience progression of symptoms despite ZDV. Two 100 mg tablets of DDI are recommended every 12 hours for persons who weigh greater than or equal to 60 kg; the recommended dose for adults less than 60 kg is one 100 mg tablet and one 25 mg tablet every 12 hours. Two tablets are recommended at each dose so that adequate buffering is provided to prevent gastric acid degradation of the drug.

Benefits have been reported from other antiretroviral regimens, including treatment with combinations of ZDV, DDC (dideoxycytidine {zalcitabine}), and DDI, or switching therapy to DDI after long-term therapy with ZDV. Experience with these alternatives is insufficient to serve as a basis for recommendations. Providers managing patients who are taking antiretroviral therapy should be familiar with evidence being developed in several clinical trials. Current information is available from the NIAID AIDS Clinical Trials Information Service, 1-800-TRIALS-A.

Side effects that are serious (e.g., anemia, cytopenia, pancreatitis, and peripheral neuropathy) and uncomfortable (e.g., nausea, vomiting, headaches, and insomnia) are common during antiretroviral therapy. Although hematologic toxicity from ZDV is less common with the lower doses recommended, approximately 2% of patients who receive 500 mg/day manifest severe anemia by the 18th month of treatment -- most within the 3rd through 8th month of treatment. Careful hematologic monitoring of patients receiving ZDV is recommended.

PCP Prophylaxis

Adults and adolescents with less than 200 CD4+ T-cells/uL or with constitutional symptoms, such as thrush or unexplained fever greater than 100 F for greater than or equal to 2 weeks, and any patient with a previous episode of PCP should receive PCP prophylaxis. Prophylaxis should be continued for the lifetime of the patient.

Based upon evidence from randomized controlled clinical trials, the Public Health Service Task Force on Antipneumocystis Prophylaxis has recommended the following regimens for PCP prophylaxis among adults and adolescents:

• Oral trimethoprim-sulfamethoxazole (TMP-SMX) at a dose of one double-strength tablet (800 mg SMX and 160 mg TMP) orally once a day.

• For patients unable to tolerate TMP-SMX: aerosol pentamidine administered by either the Respirgard II nebulizer regimen (300 mg once a month) or the Fisoneb nebulizer (initial loading regimen of five 60 mg doses during a 2-week period, followed by a 60 mg dose every 2 weeks).

The efficacy of alternatives for patients unable to tolerate TMP-SMX, including dapsone 100 mg orally once a day and sulfa desensitization, has not been studied extensively. For further details on PCP prophylaxis, refer to Recommendations for Prophylaxis Against Pneumocystis carinii pneumonia for adults and adolescents infected with human immunodeficiency virus (11).

Management of Sex Partners

The rationale for implementing partner notification is that early diagnosis and treatment of HIV infection may reduce morbidity and offers the opportunity to encourage risk-reducing behaviors. Two complementary notification processes, patient referral and provider referral, can be used to identify partners. With patient referral, patients inform their own partners directly of their exposure to HIV infection. With provider referral, trained health department personnel locate partners on the basis of the names, descriptions, and addresses provided by the patient. During the notification process, the anonymity of patients is protected; their names are not revealed to sex or needle-sharing partners who are notified. Many state health departments provide assistance with provider referral partner notification upon request.

One randomized trial suggested that provider referral is more effective in notifying partners than patient referral. In that trial, 50% of partners in the provider referral group were notified, yet only 7% of partners were notified by subjects in the patient referral group. However, few data demonstrate whether behavioral change takes place as a result of partner notification and many patients are reluctant to disclose the names of partners because of concern about discrimination, disruption of relationships, and loss of confidentiality for the partners.

When referring to those persons infected with HIV, the term "partner" includes not only sex partners but also injecting drug users who share needles or other injecting equipment. Partner notification is a means of identifying and concentrating risk- reduction efforts on persons at high risk for contracting or transmitting HIV infection. Partner notification for HIV infection must be confidential and should depend upon the voluntary cooperation of the patient.

Specific recommendations for implementing partner notification procedures are listed below:

• Persons who are HIV-positive should be encouraged to notify their partners and to refer them for counseling and testing. Providers should assist in this process, if desired by the patient, either directly or through referral to health department partner notification programs.

• If patients are unwilling to notify their partners or if it cannot be assured that their partners will seek counseling, physicians or health department personnel should use confidential procedures to assure that the partners are notified.

Special Considerations

Pregnancy

Women who are HIV-infected should be specifically informed about the risk for perinatal infection. Current evidence indicates that 15%-39% of infants born to HIV- infected mothers are infected with HIV, and the virus also can be transmitted from an infected mother by breastfeeding. Pregnancy among HIV-infected patients does not appear to increase maternal morbidity or mortality.

Women should be counseled about their options regarding pregnancy. The objective of counseling is to provide HIV-infected women with current information for making reproductive decisions, analogous to the model used in genetic counseling. Contraceptive, prenatal, and abortion services should be available on site or by referral.

Minimal information is available on the use of ZDV or other antiretroviral drugs during pregnancy. Trials to evaluate its efficacy in preventing perinatal transmission and its safety during pregnancy are being conducted. A case series of 43 pregnant women has been published; dosages of ZDV ranged from 300 to 1,200 mg/day. ZDV was well tolerated and there were no malformations among the newborns in this series. Although this observation is encouraging, this series of negative case reports cannot be used to infer that ZDV is not teratogenic.

Burroughs Wellcome Co. and Hoffmann-LaRoche, Inc., in cooperation with CDC, maintain a registry to assess the effects of the use of ZDV and DDC during pregnancy. Women who receive either ZDV or DDC during pregnancy should be reported to this registry (1-800-722-9292, ext. 58465).

HIV Infection Among Infants and Children

Infants and young children with HIV infection differ from adults and adolescents with respect to the diagnosis, clinical presentation, and management of HIV disease. For example, total lymphocytes and absolute CD4+ cell counts are much higher in infants and children than in healthy adults and are age dependent. Specific indications and dosages for both antiretroviral and prophylactic therapy have been developed for children (12). Other modifications must be made in health services that are recommended for infants and children, such as avoiding vaccination with live oral polio vaccine when a child (or close household contact) is infected with HIV.

State laws differ regarding consent of minor persons ( less than 18 years of age) for HIV counseling and testing, evaluation, treatment services, and participation in clinical trials. Although most adolescents receive adult doses of antiretroviral and prophylactic therapy, there are no data on modification of these dosages during puberty. Management of infants, children, and adolescents -- who are known or suspected to be infected with HIV

• requires referral to, or close consultation with, physicians familiar with the manifestations and treatment of pediatric HIV infection.

DISEASES CHARACTERIZED BY GENITAL ULCERS

Management of the Patient with Genital Ulcers

In the United States, most patients with genital ulcers have genital herpes, syphilis, or chancroid. The relative frequency of each varies by geographic area and patient population, but in most areas of the United States genital herpes is the most common of these diseases. More than one of these diseases may be present among at least 3%-10% of patients with genital ulcers. Each disease has been associated with an increased risk for HIV infection.

A diagnosis based only on history and physical examination is often inaccurate. Therefore, evaluation of all persons with genital ulcers should include a serologic test for syphilis and possibly other tests. Although ideally all of these tests should be conducted for each patient with a genital ulcer, use of such tests (other than a serologic test for syphilis) may be based on test availability and clinical or epidemiologic suspicion. Specific tests for the evaluation of genital ulcers are listed below:

• Darkfield examination or direct immunofluorescence test for Treponema pallidum,

• Culture or antigen test for HSV, and

• Culture for Haemophilus ducreyi. HIV testing should be considered in the management of patients with genital ulcers, especially for those with syphilis or chancroid.

A health-care provider often must treat a patient before test results are available (even after complete testing, at least one quarter of patients with genital ulcers have no laboratory-confirmed diagnosis). In that circumstance, the clinician should treat for the diagnosis considered most likely. Many experts recommend treatment for both chancroid and syphilis if the diagnosis is unclear or if the patient resides in a community in which chancroid morbidity is notable (especially when diagnostic capabilities for chancroid and syphilis are not ideal).

Chancroid

Chancroid is endemic in many areas of the United States and also occurs in discrete outbreaks. Chancroid has been well established as a co-factor for HIV transmission and a high rate of HIV infection among patients with chancroid has been reported in the United States and in other countries. As many as 10% of patients with chancroid may be coinfected with T. pallidum or HSV.

Definitive diagnosis of chancroid requires identification of H. ducreyi on special culture media that are not commercially available; even using these media, sensitivity is no higher than 80% and is usually lower. A probable diagnosis, for both clinical and surveillance purposes, may be made if the person has one or more painful genital ulcers, and a) no evidence of T. pallidum infection by darkfield examination of ulcer exudate or by a serologic test for syphilis performed at least 7 days after onset of ulcers, and b) either the clinical presentation of the ulcer(s) is not typical of disease caused by HSV or the HSV test results are negative. The combination of a painful ulcer with tender inguinal adenopathy (which occurs among one-third of patients) is suggestive of chancroid, and when accompanied by suppurative inguinal adenopathy is almost pathognomonic.

Treatment

Successful treatment cures infection, resolves clinical symptoms, and prevents transmission to others. In extensive cases, scarring may result despite successful therapy.

Recommended Regimens

Azithromycin 1 g orally in a single dose or Ceftriaxone 250 mg intramuscularly (IM) in a single dose or Erythromycin base 500 mg orally 4 times a day for 7 days.

All three regimens are effective for the treatment of chancroid among patients without HIV infection. Azithromycin and ceftriaxone offer the advantage of single-dose therapy. Antimicrobial resistance to ceftriaxone and azithromycin has not been reported. Although two isolates resistant to erythromycin were reported from Asia a decade ago, similar isolates have not been reported.

Alternative Regimens

Amoxicillin 500 mg plus clavulanic acid 125 mg orally 3 times a day for 7 days,

or Ciprofloxacin 500 mg orally 2 times a day for 3 days.

NOTE: Ciprofloxacin is contraindicated for pregnant and lactating women, children, and adolescents less than or equal to 17 years of age.

These regimens have not been evaluated as extensively as the recommended regimens; neither has been studied in the United States.

Other Management Considerations

Patients should be tested for HIV infection at the time of diagnosis. Patients also should be tested 3 months later for both syphilis and HIV, if initial results are negative.

Follow-Up

Patients should be re-examined 3-7 days after initiation of therapy. If treatment is successful, ulcers improve symptomatically within 3 days and improve objectively within 7 days after therapy. If no clinical improvement is evident, the clinician must consider whether a) the diagnosis is correct, b) coinfection with another STD agent exists, c) the patient is infected with HIV, d) treatment was not taken as instructed, or e) the H. ducreyi strain causing infection is resistant to the prescribed antimicrobial. The time required for complete healing is related to the size of the ulcer; large ulcers may require greater than or equal to 2 weeks. Clinical resolution of fluctuant lymphadenopathy is slower than that of ulcers and may require needle aspiration through adjacent intact skin -- even during successful therapy.

Management of Sex Partners

Persons who had sexual contact with a patient who has chancroid within the 10 days before onset of the patient's symptoms should be examined and treated. The examination and treatment should be administered even in the absence of symptoms.

Special Considerations

Pregnancy

The safety of azithromycin for pregnant and lactating women has not been established. Ciprofloxacin is contraindicated during pregnancy. No adverse effects of chancroid on pregnancy outcome or on the fetus have been reported.

HIV Infection

Patients coinfected with HIV should be closely monitored. These patients may require courses of therapy longer than those recommended in this report. Healing may be slower among HIV-infected persons and treatment failures do occur, especially after shorter-course treatment regimens. Since data on therapeutic efficacy with the recommended ceftriaxone and azithromycin regimens among patients infected with HIV are limited, those regimens should be used among persons known to be infected with HIV only if follow-up can be assured. Some experts suggest using the erythromycin 7-day regimen for treating HIV-infected persons.

Genital Herpes Simplex Virus Infections

Genital herpes is a viral disease that may be recurrent and has no cure. Two serotypes of HSV have been identified: HSV-1 and HSV-2; most cases of genital herpes are caused by HSV-2. On the basis of serologic studies, approximately 30 million persons in the United States may have genital HSV infection.

Most infected persons never recognize signs suggestive of genital herpes; some will have symptoms shortly after infection and then never again. A minority of the total infected U.S. population will have recurrent episodes of genital lesions. Some cases of first clinical episode genital herpes are manifested by extensive disease that requires hospitalization. Many cases of genital herpes are acquired from persons who do not know that they have a genital infection with HSV or who were asymptomatic at the time of the sexual contact.

Randomized trials show that systemic acyclovir provides partial control of the symptoms and signs of herpes episodes when used to treat first clinical episodes, or when used as suppressive therapy. However, acyclovir neither eradicates latent virus nor affects subsequent risk, frequency, or severity of recurrences after administration of the drug is discontinued. Topical therapy with acyclovir is substantially less effective than the oral drug and its use is discouraged. Episodes of HSV infection among HIV-infected patients may require more aggressive therapy. Immunocompromised persons may have prolonged episodes with extensive disease. For these persons, infections caused by acyclovir-resistant strains require selection of alternate antiviral agents.

First Clinical Episode of Genital Herpes

Recommended Regimen

Acyclovir 200 mg orally 5 times a day for 7-10 days or until clinical resolution is attained.

First Clinical Episode of Herpes Proctitis

Recommended Regimen

Acyclovir 400 mg orally 5 times a day for 10 days or until clinical resolution is attained.

Recurrent Episodes

When treatment is instituted during the prodrome or within 2 days of onset of lesions, some patients with recurrent disease experience limited benefit from therapy. However, since early treatment can seldom be administered, most immunocompetent patients with recurrent disease do not benefit from acyclovir treatment, and it is not generally recommended.

Recommended Regimen

Acyclovir 200 mg orally 5 times a day for 5 days, or Acyclovir 400 mg orally 3 times a day for 5 days, or Acyclovir 800 mg orally 2 times a day for 5 days.

Daily Suppressive Therapy

Daily suppressive therapy reduces the frequency of HSV recurrences by at least 75% among patients with frequent recurrences (i.e., six or more recurrences per year). Suppressive treatment with oral acyclovir does not totally eliminate symptomatic or asymptomatic viral shedding or the potential for transmission. Safety and efficacy have been documented among persons receiving daily therapy for as long as 5 years. Acyclovir-resistant strains of HSV have been isolated from some persons receiving suppressive therapy, but these strains have not been associated with treatment failure among immunocompetent patients. After 1 year of continuous suppressive therapy, acyclovir should be discontinued to allow assessment of the patient's rate of recurrent episodes.

Recommended Regimen

Acyclovir 400 mg orally 2 times a day. Alternative Regimen

Acyclovir 200 mg orally 3-5 times a day.

The goal of the alternative regimen is to identify for each patient the lowest dose that provides relief from frequently recurring symptoms.

Severe Disease

Intravenous (IV) therapy should be provided for patients with severe disease or complications necessitating hospitalization (e.g., disseminated infection that includes encephalitis, pneumonitis, or hepatitis).

Recommended Regimen

Acyclovir 5-10 mg/kg body weight IV every 8 hours for 5-7 days or until clinical resolution is attained.

Other Management Considerations

Other considerations for managing patients with genital HSV infection are as follows:

• Patients should be advised to abstain from sexual activity while lesions are present.

• Patients with genital herpes should be told about the natural history of the disease, with emphasis on the potential for recurrent episodes, asymptomatic viral shedding, and sexual transmission. Sexual transmission of HSV has been documented to occur during periods without evidence of lesions. Many cases are transmitted during such asymptomatic periods.

The use of condoms should be encouraged during all sexual exposures. The risk for neonatal infection should be explained to all patients -- male and female -- with genital herpes. Women of childbearing age who have genital herpes should be advised to inform health-care providers who care for them during pregnancy about their HSV infection.

Management of Sex Partners

Sex partners of patients who have genital herpes are likely to benefit from evaluation and counseling. Symptomatic sex partners should be managed in the same manner as any patient with genital lesions. However, the majority of persons with genital HSV infection do not have a history of typical genital lesions. These asymptomatic persons may benefit from evaluation and counseling; thus, even asymptomatic partners should be queried about histories of typical and atypical genital lesions and encouraged to examine themselves for lesions in the future.

Commercially available HSV type-specific antibody tests have not demonstrated adequate performance characteristics; their use is not currently recommended. Sensitive and specific type-specific serum antibody assays now utilized in research settings might contribute to future intervention strategies. Should tests with adequate sensitivity and specificity become commercially available, it might be possible to accurately identify asymptomatic persons infected with HSV-2, to focus counseling on how to detect lesions by self-examination, and to reduce the risk for transmission to sex partners.

Special Considerations

Allergy, Intolerance, or Adverse Reactions

Effective alternatives to therapy with acyclovir are not available.

HIV Infection

Lesions caused by HSV are relatively common among patients infected with HIV. Intermittent or suppressive therapy with oral acyclovir may be needed.

The acyclovir dosage for HIV-infected persons is controversial, but experience strongly suggests that immunocompromised patients benefit from increased dosage. Regimens such as 400 mg orally 3 to 5 times a day, as used for other immunocompromised persons, have been found useful. Therapy should be continued until clinical resolution is attained.

For severe disease, IV acyclovir therapy may be required. If lesions persist among patients undergoing acyclovir treatment, resistance to acyclovir should be suspected. These patients should be managed in consultation with an expert. For severe disease because of proven or suspected acyclovir-resistant strains, hospitalization should be considered. Foscarnet, 40 mg/kg body weight IV every 8 hours until clinical resolution is attained, appears to be the best available treatment.

Pregnancy

The safety of systemic acyclovir therapy among pregnant women has not been established. Burroughs Wellcome Co., in cooperation with CDC, maintains a registry to assess the effects of the use of acyclovir during pregnancy. Women who receive acyclovir during pregnancy should be reported to this registry (1-800-722-9292, ext. 58465).

Current registry findings do not indicate an increase in the number of birth defects identified among the prospective reports when compared with those expected in the general population. Moreover, no consistent pattern of abnormalities emerges among retrospective reports. These findings provide some assurance in counseling women who have had inadvertent prenatal exposure to acyclovir. However, accumulated case histories comprise a sample of insufficient size for reaching reliable and definitive conclusions regarding the risks of acyclovir treatment to pregnant women and to their fetuses.

In the presence of life-threatening maternal HSV infection (e.g., disseminated infection that includes encephalitis, pneumonitis, or hepatitis), acyclovir administered IV is indicated. Among pregnant women without life-threatening disease, systemic acyclovir should not be used to treat recurrences nor should it be used as suppressive therapy near-term (or at other times during pregnancy) to prevent reactivation.

Perinatal Infections

Most mothers of infants who acquire neonatal herpes lack histories of clinically evident genital herpes. The risk for transmission to the neonate from an infected mother appears highest among women with first episode genital herpes near the time of delivery, and is low ( less than or equal to 3%) among women with recurrent herpes. The results of viral cultures during pregnancy do not predict viral shedding at the time of delivery, and such cultures are not routinely indicated.

At the onset of labor, all women should be carefully questioned about symptoms of genital herpes and should be examined. Women without symptoms or signs of genital herpes infection (or prodrome) may deliver their babies vaginally. Among women who have a history of genital herpes, or who have a sex partner with genital herpes, cultures of the birth canal at delivery may aid in decisions relating to neonatal management.

Infants delivered through an infected birth canal (proven by virus isolation or presumed by observation of lesions) should be followed carefully, including virus cultures obtained 24-48 hours after birth. Available data do not support the routine use of acyclovir as anticipatory treatment for asymptomatic infants delivered through an infected birth canal. Treatment should be reserved for infants who develop evidence of clinical disease and for those with positive postpartum cultures.

All infants with evidence of neonatal herpes should be treated with systemic acyclovir or vidarabine; refer to the Report of the Committee on Infectious Diseases, American Academy of Pediatrics (13). For ease of administration and to lower toxicity, acyclovir (30 mg/kg/day for 10-14 days) is the preferred drug. The care of these infants should be managed in consultation with an expert.

Lymphogranuloma Venereum

Lymphogranuloma venereum (LGV), a rare disease in the United States, is caused by serovars L1, L2, or L3 of C. trachomatis. The most common clinical manifestation of LGV among heterosexuals is tender inguinal lymphadenopathy that is most commonly unilateral. Women and homosexually active men may have proctocolitis or inflammatory involvement of perirectal or perianal lymphatic tissues resulting in fistulas and strictures. When patients seek care, most no longer have the self-limited genital ulcer that sometimes occurs at the site of inoculation. The diagnosis is usually made serologically and by exclusion of other causes of inguinal lymphadenopathy or genital ulcers.

Treatment

Treatment cures infection and prevents ongoing tissue damage, although tissue reaction can result in scarring. Buboes may require aspiration or incision and drainage through intact skin. Doxycycline is the preferred treatment.

Recommended Regimen

Doxycycline 100 mg orally 2 times a day for 21 days. Alternative Regimens

Erythromycin 500 mg orally 4 times a day for 21 days or Sulfisoxazole 500 mg orally 4 times a day for 21 days or equivalent sulfonamide course.

Follow-Up

Patients should be followed clinically until signs and symptoms have resolved.

Management of Sex Partners

Persons who have had sexual contact with a patient who has LGV within the 30 days before onset of the patient's symptoms should be examined, tested for urethral or cervical chlamydial infection, and treated.

Special Considerations

Pregnancy

Pregnant and lactating women should be treated with the erythromycin regimen.

HIV infection

Persons with HIV infection and LGV should be treated following the regimens previously cited.

Syphilis

General Principles

Background

Syphilis is a systemic disease caused by T. pallidum. Patients with syphilis may seek treatment for signs or symptoms of primary infection (ulcer or chancre at site of infection), secondary infection (manifestations that include rash, mucocutaneous lesions, and adenopathy), or tertiary infection (cardiac, neurologic, ophthalmic, auditory, or gummatous lesions). Infections also may be detected during the latent stage by serologic testing. Patients with latent syphilis who are known to have been infected within the preceding year are considered to have early latent syphilis; others have late latent syphilis or syphilis of unknown duration. Theoretically, treatment for late latent syphilis (as well as tertiary syphilis) requires therapy of longer duration because organisms are dividing more slowly; however, the validity of this division and its timing are unproven.

Diagnostic Considerations and Use of Serologic Tests

Darkfield examinations and direct fluorescent antibody tests of lesion exudate or tissue are the definitive methods for diagnosing early syphilis. Presumptive diagnosis is possible with the use of two types of serologic tests for syphilis: a) nontreponemal (e.g., Venereal Disease Research Laboratory {VDRL} and RPR, and b) treponemal (e.g., fluorescent treponemal antibody absorbed {FTA-ABS} and microhemagglutination assay for antibody to T. pallidum {MHA-TP}). The use of one type of test alone is not sufficient for diagnosis. Nontreponemal test antibody titers usually correlate with disease activity, and results should be reported quantitatively. A fourfold change in titer, equivalent to a change of two dilutions (e.g., from 1:16 to 1:4, or from 1:8 to 1:32), is necessary to demonstrate a substantial difference between two nontreponemal test results that were obtained using the same serologic test. A patient who has a reactive treponemal test usually will have a reactive test for a lifetime, regardless of treatment or disease activity (15%-25% of patients treated during the primary stage may revert to being serologically nonreactive after 2-3 years). Treponemal test antibody titers correlate poorly with disease activity and should not be used to assess response to treatment.

Sequential serologic tests should be performed using the same testing method (e.g., VDRL or RPR) by the same laboratory. The VDRL and RPR are equally valid, but quantitative results from the two tests cannot be directly compared because RPR titers are often slightly higher than VDRL titers.

Abnormal results of serologic testing (unusually high, unusually low, and fluctuating titers) have been observed among HIV-infected patients. For such patients, use of other tests (e.g., biopsy and direct microscopy) should be considered. However, serologic tests appear to be accurate and reliable for the diagnosis of syphilis and for evaluation of treatment response for the vast majority of HIV-infected patients.

No single test can be used to diagnose neurosyphilis among all patients. The diagnosis of neurosyphilis can be made based on various combinations of reactive serologic test results, abnormalities of cerebrospinal fluid (CSF) cell count or protein, or a reactive VDRL-CSF (RPR is not performed on CSF) with or without clinical manifestations. The CSF leukocyte count is usually elevated ( greater than 5 WBC/mm3) when active neurosyphilis is present, and it is also a sensitive measure of the effectiveness of therapy. The VDRL-CSF is the standard serologic test for CSF; when reactive in the absence of substantial contamination of the CSF with blood, it is considered diagnostic of neurosyphilis. However, the VDRL-CSF may be nonreactive when neurosyphilis is present. Some experts recommend performing an FTA-ABS test on CSF. The CSF FTA-ABS is less specific (i.e., yields more false positives) for neurosyphilis than the VDRL-CSF; however, the test is believed to be highly sensitive.

Treatment

Parenteral penicillin G is the preferred drug for treatment of all stages of syphilis. The preparation(s) used (i.e., benzathine, aqueous procaine, or aqueous crystalline), the dosage, and the length of treatment depend on the stage and clinical manifestations of disease.

The efficacy of penicillin for the treatment of syphilis was well established through clinical experience before the value of randomized controlled clinical trials was recognized. Therefore, nearly all the recommendations for the treatment of syphilis are based on expert opinion reinforced by case series, open clinical trials, and 50 years of clinical experience.

Parenteral penicillin G is the only therapy with documented efficacy for neurosyphilis or for syphilis during pregnancy. Patients with neurosyphilis and pregnant women with syphilis in any stage who report penicillin allergy should almost always be treated with penicillin, after desensitization, if necessary. Skin testing for penicillin allergy may be useful for some patients and in some settings (see Management of the Patient With a History of Penicillin Allergy). However, minor determinants needed for penicillin skin testing are not available commercially.

The Jarisch-Herxheimer reaction is an acute febrile reaction

• accompanied by headache, myalgia, and other symptoms -- that may occur within the first 24 hours after any therapy for syphilis; patients should be advised of this possible adverse reaction. The Jarisch-Herxheimer reaction is common among patients with early syphilis. Antipyretics may be recommended, but there are no proven methods for preventing this reaction. The Jarisch-Herxheimer reaction may induce early labor or cause fetal distress among pregnant women. This concern should not prevent or delay therapy (see Syphilis During Pregnancy).

Management of Sex Partners

Sexual transmission of T. pallidum occurs only when mucocutaneous syphilitic lesions are present; such manifestations are uncommon after the first year of infection. However, persons sexually exposed to a patient with syphilis in any stage should be evaluated clinically and serologically according to the following recommendations:

• Persons who were exposed to a patient with primary, secondary, or latent (duration less than 1 year) syphilis within the preceding 90 days might be infected even if seronegative, and therefore should be treated presumptively.

• Persons who were sexually exposed to a patient with primary, secondary, or latent (duration less than 1 year) syphilis greater than 90 days before examination should be treated presumptively if serologic test results are not available immediately, and the opportunity for follow-up is uncertain.

• For purposes of partner notification and presumptive treatment of exposed sex partners, patients who have syphilis of unknown duration and who have high nontreponemal serologic test titers ( greater than or equal to 1:32) may be considered to be infected with early syphilis.

• Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically for syphilis.

The time periods before treatment used for identifying at-risk sex partners are 3 months plus duration of symptoms for primary syphilis, 6 months plus duration of symptoms for secondary syphilis, and 1 year for early latent syphilis.

Primary and Secondary Syphilis

Treatment

Four decades of experience indicate that parenteral penicillin G is effective in achieving local cure (healing of lesions and prevention of sexual transmission) and in preventing late sequelae. However, no adequately conducted comparative trials have been performed to guide the selection of an optimal penicillin regimen (i.e., dose, duration, and preparation). Substantially fewer data on nonpenicillin regimens are available.

Recommended Regimen for Adults

Nonallergic patients with primary or secondary syphilis should be treated with the following regimen:

Benzathine penicillin G, 2.4 million units IM in a single dose.

NOTE: Recommendations for treating pregnant women and HIV-infected persons for syphilis are discussed in separate sections.

Recommended Regimen for Children

After the newborn period, children diagnosed with syphilis should have a CSF examination to exclude a diagnosis of neurosyphilis, and birth and maternal medical records should be reviewed to assess whether the child has congenital or acquired syphilis (see Congenital Syphilis). Children with acquired primary or secondary syphilis should be evaluated (including consultation with child-protection services) and treated using the following pediatric regimen (see Sexual Assault or Abuse of Children).

Benzathine penicillin G, 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose.

Other Management Considerations

All patients with syphilis should be tested for HIV. In areas with high HIV prevalence, patients with primary syphilis should be retested for HIV after 3 months.

Patients who have syphilis and who also have symptoms or signs suggesting neurologic disease (e.g., meningitis) or ophthalmic disease (e.g., uveitis) should be fully evaluated for neurosyphilis and syphilitic eye disease (including CSF analysis and ocular slit-lamp examination). Such patients should be treated appropriately according to the results of this evaluation.

Invasion of CSF by T. pallidum with accompanying CSF abnormalities is common among adults who have primary or secondary syphilis. However, few patients develop neurosyphilis after treatment with the regimens described in this report. Therefore, unless clinical signs or symptoms of neurologic involvement are present (e.g., auditory, cranial nerve, meningeal, or ophthalmic manifestations), lumbar puncture is not recommended for routine evaluation of patients with primary or secondary syphilis.

Follow-Up

Treatment failures can occur with any regimen. However, assessing response to treatment is often difficult, and no definitive criteria for cure or failure exist. Serologic test titers may decline more slowly among patients with a prior syphilis infection. Patients should be re-examined clinically and serologically at 3 months and again at 6 months.

Patients with signs or symptoms that persist or recur or who have a sustained fourfold increase in nontreponemal test titer compared with either the baseline titer or to a subsequent result, can be considered to have failed treatment or to be reinfected. These patients should be re-treated after evaluation for HIV infection. Unless reinfection is likely, lumbar puncture also should be performed.

Failure of nontreponemal test titers to decline fourfold by 3 months after therapy for primary or secondary syphilis identifies persons at risk for treatment failure. Those persons should be evaluated for HIV infection. Optimal management of such patients is unclear if they are HIV negative. At a minimum, these patients should have additional clinical and serologic follow-up. If further follow-up cannot be assured, re-treatment is recommended. Some experts recommend CSF examination in such situations.

When patients are re-treated, most experts recommend re-treatment with three weekly injections of benzathine penicillin G 2.4 million units IM, unless CSF examination indicates that neurosyphilis is present.

Management of Sex Partners

Refer to General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy

Nonpregnant penicillin-allergic patients who have primary or secondary syphilis should be treated with the following regimen.

Doxycycline 100 mg orally 2 times a day for 2 weeks or Tetracycline 500 mg orally 4 times a day for 2 weeks.

There is less clinical experience with doxycycline than with tetracycline, but compliance is likely to be better with doxycycline. Therapy for a patient who cannot tolerate either doxycycline or tetracycline should be based upon whether the patient's compliance with the therapy regimen and with follow-up examinations can be assured.

For nonpregnant patients whose compliance with therapy and follow-up can be assured, an alternative regimen is erythromycin 500 mg orally 4 times a day for 2 weeks. Various ceftriaxone regimens also may be considered.

Patients whose compliance with therapy or follow-up cannot be assured should be desensitized, if necessary, and treated with penicillin. Skin testing for penicillin allergy may be useful in some situations (see Management of the Patient With a History of Penicillin Allergy).

Erythromycin is less effective than other recommended regimens. Data on ceftriaxone are limited, and experience has been too brief to permit identification of late failures. Optimal dose and duration have not been established for ceftriaxone, but regimens that provide 8-10 days of treponemicidal levels in the blood should be used. Single dose ceftriaxone therapy is not effective for treating syphilis.

Pregnancy

Pregnant patients who are allergic to penicillin should be treated with penicillin, after desensitization, if necessary (see Management of the Patient With a History of Penicillin Allergy and Syphilis During Pregnancy).

HIV Infection

Refer to Syphilis Among HIV-Infected Patients.

Latent Syphilis

Latent syphilis is defined as those periods after infection with T. pallidum when patients are seroreactive, but show no other evidence of disease. Patients who have latent syphilis and who have acquired syphilis within the preceding year are classified as having early latent syphilis. Patients can be demonstrated to have acquired syphilis within the preceding year on the basis of documented seroconversion, a fourfold or greater increase in titer of a nontreponemal serologic test, history of symptoms of primary or secondary syphilis, or if they had a sex partner with primary, secondary, or latent syphilis (documented independently as duration less than 1 year). Nearly all others have latent syphilis of unknown duration and should be managed as if they had late latent syphilis.

Treatment

Treatment of latent syphilis is intended to prevent occurrence or progression of late complications. Although clinical experience supports belief in the effectiveness of penicillin in achieving those goals, limited evidence is available for guidance in choosing specific regimens. There is very little evidence to support the use of nonpenicillin regimens.

Recommended Regimens for Adults

These regimens are for nonallergic patients with normal CSF examination (if performed).

Early Latent Syphilis

Benzathine penicillin G, 2.4 million units IM in a single dose.

Late Latent Syphilis or Latent Syphilis of Unknown Duration

Benzathine penicillin G, 7.2 million units total, administered as 3 doses of 2.4 million units IM each, at 1-week intervals.

Recommended Regimens for Children

After the newborn period, children diagnosed with syphilis should have a CSF examination to exclude neurosyphilis, and birth and maternal medical records should be reviewed to assess whether the child has congenital or acquired syphilis (see Congenital Syphilis). Older children with acquired latent syphilis should be evaluated as described for adults and treated using the following pediatric regimens (see Sexual Assault or Abuse of Children). These regimens are for nonallergic children who have acquired syphilis and who have had a normal CSF examination.

Early Latent Syphilis

Benzathine penicillin G, 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose.

Late Latent Syphilis or Latent Syphilis of Unknown Duration

Benzathine penicillin G, 50,000 units/kg IM, up to the adult dose of 2.4 million units, for three total doses (total 150,000 units/kg up to adult total dose of 7.2 million units).

Other Management Considerations

All patients with latent syphilis should be evaluated clinically for evidence of tertiary disease (e.g., aortitis, neurosyphilis, gumma, and iritis). Recommended therapy for patients with latent syphilis may not be optimal therapy for the persons with asymptomatic neurosyphilis. However, the yield from CSF examination, in terms of newly diagnosed cases of neurosyphilis, is low.

Patients with any one of the criteria listed below should have a CSF examination before treatment:

• Neurologic or ophthalmic signs or symptoms;

• Other evidence of active syphilis (e.g., aortitis, gumma, iritis);

• Treatment failure;

• HIV infection;

• Serum nontreponemal titer greater than or equal to 1:32, unless duration of infection is known to be less than 1 year; or

• Nonpenicillin therapy planned, unless duration of infection is known to be less than 1 year.

If dictated by circumstances and patient preferences, CSF examination may be performed for persons who do not meet the criteria listed above. If a CSF examination is performed and the results show abnormalities consistent with CNS syphilis, the patient should be treated for neurosyphilis (see Neurosyphilis).

• All syphilis patients should be tested for HIV.

Follow-Up

Quantitative nontreponemal serologic tests should be repeated at 6 months and again at 12 months. Limited data are available to guide evaluation of the response to therapy for a patient with latent syphilis. If titers increase fourfold, or if an initially high titer ( greater than or equal to 1:32) fails to decline at least fourfold (two dilutions) within 12-24 months, or if the patient develops signs or symptoms attributable to syphilis, the patient should be evaluated for neurosyphilis and re-treated appropriately.

Management of Sex Partners

Refer to General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy

For patients who have latent syphilis and who are allergic to penicillin, nonpenicillin therapy should be used only after CSF examination has excluded neurosyphilis. Nonpregnant, penicillin-allergic patients should be treated with the following regimens.

Doxycycline 100 mg orally 2 times a day or Tetracycline 500 mg orally 4 times a day.

Both drugs are administered for 2 weeks if duration of infection is known to have been less than 1 year; otherwise, for 4 weeks.

Pregnancy

Pregnant patients who are allergic to penicillin should be treated with penicillin, after desensitization, if necessary (see Management of the Patient With a History of Penicillin Allergy and Syphilis During Pregnancy).

HIV Infection

Refer to Syphilis Among HIV-Infected Patients.

Late Syphilis

Late (tertiary) syphilis refers to patients with gumma and patients with cardiovascular syphilis, but not to neurosyphilis. Nonallergic patients without evidence of neurosyphilis should be treated with the following regimen.

Recommended Regimen

Benzathine penicillin G, 7.2 million units total, administered as 3 doses of 2.4 million units IM, at 1-week intervals.

Other Management Considerations

Patients with symptomatic late syphilis should undergo CSF examination before therapy. Some experts treat all patients who have cardiovascular syphilis with a neurosyphilis regimen. The complete management of patients with cardiovascular or gummatous syphilis is beyond the scope of these guidelines. These patients should be managed in consultation with experts.

Follow-Up

There is minimal evidence regarding follow-up of patients infected with late syphilis. Clinical response depends partly on the nature of the lesions.

Management of Sex Partners

Refer to General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy

Patients allergic to penicillin should be treated according to treatment regimens recommended for late latent syphilis.

Pregnancy

Pregnant patients who are allergic to penicillin should be treated with penicillin, after desensitization, if necessary (see Management of the Patient With a History of Penicillin Allergy and Syphilis During Pregnancy).

HIV Infection

Refer to Syphilis Among HIV-Infected Patients.

Neurosyphilis

Treatment

Central nervous system disease can occur during any stage of syphilis. A patient with clinical evidence of neurologic involvement (e.g., ophthalmic or auditory symptoms, cranial nerve palsies) with syphilis warrants a CSF examination. Although four decades of experience have confirmed the effectiveness of penicillin, the evidence to guide the choice of the best regimen is limited.

Syphilitic eye disease is frequently associated with neurosyphilis, and patients with this disease should be treated according to neurosyphilis treatment recommendations. CSF examination should be performed on all such patients to identify those patients with CSF abnormalities who should have follow-up CSF examinations to assess response to treatment.

Patients who have neurosyphilis or syphilitic eye disease (e.g., uveitis, neuroretinitis, or optic neuritis) and who are not allergic to penicillin should be treated with the following regimen.

Recommended Regimen

12-24 million units aqueous crystalline penicillin G daily, administered as 2-4 million units IV every 4 hours, for 10-14 days.

If compliance with therapy can be assured, patients may be treated with the following alternative regimen.

Alternative Regimen

2.4 million units procaine penicillin IM daily, plus probenecid 500 mg orally 4 times a day, both for 10-14 days.

The durations of these regimens are shorter than that of the regimen used for late syphilis in the absence of neurosyphilis. Therefore, some experts administer benzathine penicillin, 2.4 million units IM after completion of these neurosyphilis treatment regimens to provide a comparable total duration of therapy.

Other Management Considerations

Other considerations in the management of the patient with neurosyphilis are the following:

• All patients with syphilis should be tested for HIV.

• Many experts recommend treating patients with evidence of auditory disease caused by syphilis in the same manner as for neurosyphilis, regardless of the findings on CSF examination.

Follow-Up

If CSF pleocytosis was present initially, CSF examination should be repeated every 6 months until the cell count is normal. Follow-up CSF examinations also may be used to evaluate changes in the VDRL-CSF or CSF protein in response to therapy, though changes in these two parameters are slower and persistent abnormalities are of less certain importance. If the cell count has not decreased at 6 months, or if the CSF is not entirely normal by 2 years, re-treatment should be considered.

Management of Sex Partners

Refer to General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy

No data have been collected systematically for evaluation of therapeutic alternatives to penicillin for treatment of neurosyphilis. Therefore, patients who report being allergic to penicillin should be treated with penicillin, after desensitization if necessary, or should be managed in consultation with an expert. In some situations, skin testing to confirm penicillin allergy may be useful (see Management of the Patient With a History of Penicillin Allergy).

Pregnancy

Pregnant patients who are allergic to penicillin should be treated with penicillin, after desensitization if necessary (see Syphilis During Pregnancy).

HIV Infection

Refer to Syphilis Among HIV-Infected Patients.

Syphilis Among HIV-Infected Patients

Diagnostic Considerations

Unusual serologic responses have been observed among HIV-infected persons who also have syphilis. Most reports involved serologic titers that were higher than expected, but false-negative serologic test results or delayed appearance of seroreactivity have also been reported. Nevertheless, both treponemal and nontreponemal serologic tests for syphilis are accurate for the majority of patients with syphilis and HIV coinfection.

When clinical findings suggest that syphilis is present, but serologic tests are nonreactive or confusing, it may be helpful to perform such alternative tests as biopsy of a lesion, darkfield examination, or direct fluorescent antibody staining of lesion material.

Neurosyphilis should be considered in the differential diagnosis of neurologic disease among HIV-infected persons.

Treatment

Although adequate research-based evidence is not available, published case reports and expert opinion suggest that HIV-infected patients with early syphilis are at increased risk for neurologic complications and have higher rates of treatment failure with currently recommended regimens. The magnitude of these risks, although not precisely defined, is probably small. No treatment regimens have been demonstrated to be more effective in preventing development of neurosyphilis than those recommended for patients without HIV infection. Careful follow-up after therapy is essential.

Primary and Secondary Syphilis Among HIV-Infected Patients

Treatment

Treatment with benzathine penicillin G 2.4 million units IM, as for patients without HIV infection, is recommended. Some experts recommend additional treatments, such as multiple doses of benzathine penicillin G as suggested for late syphilis, or other supplemental antibiotics in addition to benzathine penicillin G 2.4 million units IM.

Other Management Considerations

CSF abnormalities are common among HIV-infected patients who have primary or secondary syphilis, but these abnormalities are of unknown prognostic significance. Most HIV-infected patients respond appropriately to currently recommended penicillin therapy; however, some experts recommend CSF examination before therapy and modification of treatment accordingly.

Follow-Up

Patients should be evaluated clinically and serologically for treatment failure at 1 month and at 2, 3, 6, 9, and 12 months after therapy. Although of unproven benefit, some experts recommend performing CSF examination after therapy (i.e., at 6 months).

HIV-infected patients who meet the criteria for treatment failure should undergo CSF examination and be retreated just as for patients without HIV infection. CSF examination and re-treatment also should be strongly considered for patients in whom the suggested fourfold decrease in nontreponemal test titer does not occur within 3 months for primary or secondary syphilis. Most experts would re-treat patients with benzathine penicillin G 7.2 million units (as 3 weekly doses of 2.4 million units each) if the CSF examination is normal.

Special Considerations

Penicillin Allergy

Penicillin regimens should be used to treat HIV-infected patients in all stages of syphilis. Skin testing to confirm penicillin allergy may be used (see Management of the Patient With a History of Penicillin Allergy), but data on the utility of that approach among immunocompromised patients are inadequate. Patients may be desensitized, then treated with penicillin.

Latent Syphilis Among HIV-Infected Patients

Diagnostic Considerations

Patients who have both latent syphilis (regardless of apparent duration) and HIV infection should undergo CSF examination before treatment.

Treatment

A patient with latent syphilis, HIV infection, and a normal CSF examination can be treated with benzathine penicillin G 7.2 million units (as 3 weekly doses of 2.4 million units each).

Special Considerations

Penicillin Allergy

Penicillin regimens should be used to treat all stages of syphilis among HIV- infected patients. Skin testing to confirm penicillin allergy may be used (see Management of the Patient With a History of Penicillin Allergy), but data on the utility of that approach in immunocompromised patients are inadequate. Patients may be desensitized, then treated with penicillin.

Syphilis During Pregnancy

All women should be screened serologically for syphilis during the early stages of pregnancy. In populations in which utilization of prenatal care is not optimal, RPR-card test screening and treatment, if that test is reactive, should be performed at the time a pregnancy is diagnosed. In communities and populations with high syphilis prevalence or for patients at high risk, serologic testing should be repeated during the third trimester and again at delivery. (Some states mandate screening at delivery for all women.) Any woman who delivers a stillborn infant after 20 weeks gestation should be tested for syphilis. No infant should leave the hospital without the serologic status of the infant's mother having been determined at least once during pregnancy.

Diagnostic Considerations

Seropositive pregnant women should be considered infected unless treatment history is clearly documented in a medical or health department record and sequential serologic antibody titers have appropriately declined.

Treatment

Penicillin is effective for preventing transmission to fetuses and for treating established infection among fetuses. Evidence is insufficient, however, to determine whether the specific, recommended penicillin regimens are optimal.

Recommended Regimens

Treatment during pregnancy should be the penicillin regimen appropriate for the woman's stage of syphilis. Some experts recommend additional therapy (e.g., a second dose of benzathine penicillin 2.4 million units IM) 1 week after the initial dose, particularly for those women in the third trimester of pregnancy and for women who have secondary syphilis during pregnancy.

Other Management Considerations

Women who are treated for syphilis during the second half of pregnancy are at risk for premature labor or fetal distress, or both, if their treatment precipitates the Jarisch-Herxheimer reaction. These women should be advised to seek medical attention following treatment if they notice any change in fetal movements or if they have contractions. Stillbirth is a rare complication of treatment; however, since therapy is necessary to prevent further fetal damage, that concern should not delay treatment. All patients with syphilis should be tested for HIV.

Follow-Up

Serologic titers should be checked monthly until adequacy of treatment has been assured. The antibody response should be appropriate for the stage of disease.

Management of Sex Partners

Refer to General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy

There are no proven alternatives to penicillin. A pregnant woman with a history of penicillin allergy should be treated with penicillin, after desensitization, if necessary. Skin testing may be helpful for some patients and in some settings (see Management of the Patient With a History of Penicillin Allergy). Tetracycline and doxycycline are contraindicated during pregnancy. Erythromycin should not be used because it cannot be relied upon to cure an infected fetus.

Congenital Syphilis

Diagnostic Considerations

Who Should Be Evaluated

Infants should be evaluated for congenital syphilis if they were born to seropositive (nontreponemal test confirmed by treponemal test) women who meet the following criteria:

• Have untreated syphilis;* or

• Were treated for syphilis during pregnancy with erythromycin; or

• Were treated for syphilis less than 1 month before delivery; or

• Were treated for syphilis during pregnancy with the appropriate penicillin regimen, but nontreponemal antibody titers did not decrease sufficiently after therapy to indicate an adequate response ( greater than or equal to fourfold decrease); or

• Do not have a well-documented history of treatment for syphilis; or

• Were treated appropriately before pregnancy but had insufficient serologic follow-up to assure that they had responded appropriately to treatment and are not currently infected ( greater than or equal to fourfold decrease for patients treated for early syphilis; stable or declining titers less than or equal to 1:4 for other patients).

No infant should leave the hospital without the serologic status of the infant's mother having been documented at least once during pregnancy. Serologic testing also should be performed at delivery in communities and populations at risk for congenital syphilis. Serologic tests can be nonreactive among infants infected late during their mother's pregnancy.

Evaluation of the Infant

The clinical and laboratory evaluation of infants born to women described above should include the following:

• A thorough physical examination for evidence of congenital syphilis;

• A quantitative nontreponemal serologic test for syphilis performed on the infant's sera (not on cord blood);

• CSF analysis for cells, protein, and VDRL;

• Long bone x-rays;

• Other tests as clinically indicated (e.g., chest x-ray, complete blood count, differential and platelet count, liver function tests);

• For infants who have no evidence of congenital syphilis on the above evaluation, determination of presence of specific antitreponemal IgM antibody by a testing method recognized by CDC as having either provisional or standard status;

• Pathologic examination of the placenta or amniotic cord using specific fluorescent antitreponemal antibody staining.

Treatment

Therapy Decisions

Infants should be treated for presumed congenital syphilis if they were born to mothers who, at delivery, had untreated syphilis or who had evidence of relapse or reinfection after treatment (see Congenital Syphilis, Diagnostic Considerations). Additional criteria for presumptively treating infants with congenital syphilis are as follows:

• Physical evidence of active disease;

• X-ray evidence of active disease;

• A reactive VDRL-CSF or, for infants born to seroreactive mothers, an abnormal ** CSF white blood cell count or protein, regardless of CSF serology;

• A serum quantitative nontreponemal serologic titer that is at least fourfold greater than the mother's titer ***;

• Specific antitreponemal IgM antibody detected by a testing method that has been given provisional or standard status by CDC;

• If they meet the previously cited criteria for "Who Should Be Evaluated," but have not been fully evaluated (see Congenital Syphilis, Diagnostic Considerations).

NOTE: Infants with clinically evident congenital syphilis should have an ophthalmologic examination.

Recommended Regimens

Aqueous crystalline penicillin G, 100,000-150,000 units/kg/day (administered as 50,000 units/kg IV every 12 hours during the first 7 days of life and every 8 hours thereafter) for 10-14 days,

or Procaine penicillin G, 50,000 units/kg IM daily in a single dose for 10-14 days.

If more than 1 day of therapy is missed, the entire course should be restarted. An infant whose complete evaluation was normal and whose mother was a) treated for syphilis during pregnancy with erythromycin, or b) treated for syphilis less than 1 month before delivery, or c) treated with an appropriate regimen before or during pregnancy but did not yet have an adequate serologic response should be treated with benzathine penicillin G, 50,000 units/kg IM in a single dose. In some cases, infants with a normal complete evaluation for whom follow-up can be assured can be followed closely without treatment.

Treatment of Older Infants and Children with Congenital Syphilis

After the newborn period, children diagnosed with syphilis should have a CSF examination to exclude neurosyphilis and records should be reviewed to assess whether the child has congenital or acquired syphilis (see Primary and Secondary Syphilis and Latent Syphilis). Any child who is thought to have congenital syphilis (or who has neurologic involvement) should be treated with aqueous crystalline penicillin G, 200,000-300,000 units/kg/day IV or IM (administered as 50,000 units/kg every 4-6 hours) for 10-14 days.

Follow-Up

A seroreactive infant (or an infant whose mother was seroreactive at delivery) who is not treated for congenital syphilis during the perinatal period should receive careful follow-up examinations at 1 month and at 2, 3, 6, and 12 months after therapy. Nontreponemal antibody titers should decline by 3 months of age and should be nonreactive by 6 months of age if the infant was not infected and the titers were the result of passive transfer of antibody from the mother. If these titers are found to be stable or increasing, the child should be re-evaluated, including CSF examination, and fully treated. Passively transferred treponemal antibodies may be present for as long as 1 year. If they are present greater than 1 year, the infant should be re-evaluated and treated for congenital syphilis.

Treated infants also should be followed every 2-3 months to assure that nontreponemal antibody titers decline; these infants should have become nonreactive by 6 months of age (response may be slower for infants treated after the neonatal period). Treponemal tests should not be used to evaluate response to treatment because test results can remain positive despite effective therapy if the child was infected. Infants with CSF pleocytosis should undergo CSF examination every 6 months, or until the cell count is normal. If the cell count is still abnormal after 2 years, or if a downward trend is not present at each examination, the child should be re-treated. The VDRL-CSF also should be checked at 6 months; if still reactive, the infant should be re-treated.

Follow-up of children treated for congenital syphilis after the newborn period should be the same as that prescribed for congenital syphilis among neonates.

Special Considerations

Penicillin Allergy

Children who require treatment for syphilis after the newborn period, but who have a history of penicillin allergy, should be treated with penicillin after desensitization, if necessary. Skin testing may be helpful in some patients and settings (see Management of the Patient With a History of Penicillin Allergy).

HIV Infection

Mothers of infants with congenital syphilis should be tested for HIV. Infants born to mothers who have HIV infection should be referred for evaluation and appropriate follow-up.

No data exist to suggest that infants with congenital syphilis whose mothers are coinfected with HIV require different evaluation, therapy, or follow-up for syphilis than is recommended for all infants.

Management of the Patient With a History of Penicillin Allergy

No proven alternatives to penicillin are available for treating neurosyphilis, congenital syphilis, or syphilis among pregnant women. Penicillin also is recommended for use, whenever possible, with HIV-infected patients. Unfortunately, 3%-10% of the adult population in the United States have experienced urticaria, angioedema, or anaphylaxis (upper airway obstruction, bronchospasm, or hypotension) with penicillin therapy. Re-administration of penicillin can cause severe immediate reactions among these patients. Because anaphylactic reactions to penicillin can be fatal, every effort should be made to avoid administering penicillin to penicillin-allergic patients, unless the anaphylactic sensitivity has been removed by acute desensitization.

However, only approximately 10% of persons who report a history of severe allergic reactions to penicillin are still allergic. With the passage of time after an allergic reaction to penicillin, most persons who have experienced a severe reaction stop expressing penicillin-specific IgE. These persons can be treated safely with penicillin. Many studies have found that skin testing with the major and minor determinants can reliably identify persons at high risk for penicillin reactions. Although these reagents are easily generated and have been available in academic centers for greater than 30 years, currently only penicilloyl-poly-L-lysine (Pre-Pen, the major determinant) and penicillin G are available commercially. Experts estimate that testing with only the major determinant and penicillin G detects 90%-97% of the currently allergic patients. However, because skin testing without the minor determinants would still miss 3%-10% of allergic patients, and serious or fatal reactions can occur among these minor determinant positive patients, experts suggest caution when the full battery of skin test reagents listed in the table is not available.

Recommendations

If the full battery of skin-test reagents is available, including the major and minor determinants (see Penicillin Allergy Skin Testing), patients who report a history of penicillin reaction and are skin-test negative can receive conventional penicillin therapy. Skin-test positive patients should be desensitized.

If the full battery of skin-test reagents, including the minor determinants, is not available, the patient should be skin tested using penicilloyl (the major determinant, Pre-Pen) and penicillin G. Those with positive tests should be desensitized. Some experts believe that persons with negative tests, in that situation, should be regarded as probably allergic and should be desensitized. Others suggest that those with negative skin tests can be test-dosed gradually with oral penicillin in a monitored setting in which treatment for anaphylactic reaction is possible.

Penicillin Allergy Skin Testing

Patients at high risk for anaphylaxis (i.e., a history of penicillin-related anaphylaxis, asthma or other diseases that would make anaphylaxis more dangerous, or therapy with beta-adrenergic blocking agents) should be tested with 100-fold dilutions of the full-strength skin-test reagents before testing with full-strength reagents. In these situations, patients should be tested in a monitored setting in which treatment for an anaphylactic reaction is possible. If possible, the patient should not have taken antihistamines (e.g., chlorpheniramine maleate or terfenadine during the past 24 hours, diphenhydramine HCl or hydroxyzine during the past 4 days, or astemizole during the past 3 weeks).

Reagents (Adapted from Beall {14}) #

Major Determinant

• Benzylpenicilloyl poly-L-lysine (Pre-Pen {Taylor Pharmacal Company, Decatur, Illinois}) (6 x 10-5M).

Minor Determinant Precursors ##

• Benzylpenicillin G (10-2M, 3.3 mg/mL, 6000 U/mL),

• Benzylpenicilloate (10-2M, 3.3 mg/mL),

• Benzylpenilloate (or penicilloyl propylamine)(10-2M, 3.3 mg/mL).

Positive Control

• Commercial histamine for epicutaneous skin testing (1 mg/mL).

Negative Control

• Diluent used to dissolve other reagents, usually phenol saline.

Procedures

Dilute the antigens 100-fold for preliminary testing if the patient has had a life-threatening reaction, or 10-fold if the patient has had another type of immediate, generalized reaction within the past year.

Epicutaneous (prick) tests. Duplicate drops of skin-test reagent are placed on the volar surface of the forearm. The underlying epidermis is pierced with a 26-gauge needle without drawing blood.

An epicutaneous test is positive if the average wheal diameter after 15 minutes is 4 mm larger than that of negative controls; otherwise, the test is negative. The histamine controls should be positive to assure that results are not falsely negative because of the effect of antihistaminic drugs.

Intradermal test. If epicutaneous tests are negative, duplicate 0.02 mL intradermal injections of negative control and antigen solutions are made into the volar surface of the forearm using a 26- or 27-gauge needle on a syringe. The crossed diameters of the wheals induced by the injections should be recorded.

An intradermal test is positive if the average wheal diameter 15 minutes after injection is 2 mm or larger than the initial wheal size and also is at least 2 mm larger than the negative controls. Otherw