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Prevention and Treatment of Tuberculosis Among Patients Infected with Human Immunodeficiency Virus: Principles of Therapy and Revised Recommendations

Summary

These guidelines update previous CDC recommendations for the diagnosis, treatment, and prevention of tuberculosis (TB) among adults and children coinfected with human immunodeficiency virus (HIV) in the United States. The most notable changes in these guidelines reflect both the findings of clinical trials that evaluated new drug regimens for treating and preventing TB among HIV-infected persons and recent advances in the use of antiretroviral therapy. In September 1997, when CDC convened a meeting of expert consultants to discuss current information about HIV-related TB, special emphasis was given to issues related to coadministration of TB therapy and antiretroviral therapy and how to translate this information into management guidelines. Thus, these guidelines are based on the following scientific principles:

  • Early diagnosis and effective treatment of TB among HIV-infected patients are critical for curing TB, minimizing the negative effects of TB on the course of HIV, and interrupting the transmission of Mycobacterium tuberculosis to other persons in the community.

  • All HIV-infected persons at risk for infection with M. tuberculosis must be carefully evaluated and, if indicated, administered therapy to prevent the progression of latent infection to active TB disease and avoid the complications associated with HIV-related TB.

  • All HIV-infected patients undergoing treatment for TB should be evaluated for antiretroviral therapy, because most patients with HIV-related TB are candidates for concurrent administration of antituberculosis and antiretroviral drug therapies. However, the use of rifampin with protease inhibitors or non-nucleoside reverse transcriptase inhibitors is contraindicated.

Ideally, the management of TB among HIV-infected patients taking antiretroviral drugs requires a) directly observed therapy, b) availability of experienced and coordinated TB/HIV care givers, and in most situations, c) use of a TB treatment regimen that includes rifabutin instead of rifampin. Because alternatives to the use of rifampin for antituberculosis treatment are now available, the previously recommended practice of stopping protease inhibitor therapy to allow the use of rifampin for TB treatment is no longer recommended for patients with HIV-related TB. The use of rifabutin-containing antituberculosis regimens should always include an assessment of the patient's response to treatment to decide the appropriate duration of therapy (i.e., 6 months or 9 months). Physicians and patients also should be aware that paradoxical reactions might occur during the course of TB treatment when antiretroviral therapy restores immune function. Adding to CDC's current recommendations for administering isoniazid preventive therapy to HIV-infected persons with positive tuberculin skin tests and to HIV-infected persons who were exposed to patients with infectious TB, this report also describes in detail the use of new short-course (i.e., 2 months) multidrug regimens (e.g., a rifamycin, such as rifampin or rifabutin, combined with pyrazinamide) to prevent TB in persons with HIV infection. A continuing education component for U.S. physicians and nurses is included. INTRODUCTION

These guidelines update previous CDC recommendations for treating and preventing active tuberculosis (TB) among adults and children coinfected with human immunodeficiency virus (HIV) (1-3). The most notable changes in these guidelines reflect both the recent advances in the use of antiretroviral therapy and the findings of clinical trials that evaluated new drug regimens for the treatment and prevention of TB among HIV-infected persons. Antiretroviral therapy is discussed in the context of TB treatment only; more detailed information about antiretroviral therapy is published elsewhere (4).

In September 1997, CDC convened a meeting of expert consultants who reviewed and considered background information about HIV-related TB in the United States and the scientific principles of therapy for both diseases (Part I of this report). The consultants then used this review as the basis for updating the recommendations for HIV-infected patients with TB (Part II). During their review of the scientific principles of therapy, the expert consultants focused on epidemiologic and clinical interactions between Mycobacterium tuberculosis infection and HIV infection, considering the frequency of coexisting TB and HIV infection and rates of drug-resistant TB among patients infected with HIV in the United States; the copathogenicity of TB and HIV disease; the potential for a poorer outcome of TB therapy and paradoxical reactions to TB treatment among HIV-infected patients; drug interactions between rifampin used for TB therapy and agents commonly used in antiretroviral therapy; use of TB treatment regimens that do not contain rifampin; and results of clinical trials of therapies to prevent TB among HIV-infected persons. Thus, in addition to CDC's current recommendations, these new guidelines include information about the following topics:

  • directly observed therapy for all patients with HIV-related TB;

  • rifabutin-containing antituberculosis regimens (or a streptomycin-based alternative regimen that does not contain rifamycin) for treating TB among patients taking antiretroviral drugs that have interactions with rifampin;

  • monitoring responses to antituberculosis treatment to decide about the appropriate duration of TB therapy;

  • occurrence and management of paradoxical reactions during TB treatment, when immune function is restored because of antiretroviral therapy;

  • use of 9 months of isoniazid daily or twice weekly for the treatment of M. tuberculosis infection;

  • short-course multidrug therapy for latent M. tuberculosis infection; and

  • special considerations that apply to children and pregnant women with HIV-related TB.

Health-care professionals need to be familiar with these new guidelines to ensure the use of the most effective management strategies for TB patients infected with HIV, while concurrently promoting optimal antiretroviral therapy for these patients. To help clinicians make informed treatment decisions based on the most current research results, the expert consultants have given each recommendation an evidence-based rating similar to the ratings used in previously issued guidelines (4,5). However, these recommendations are not intended to substitute for the judgment of an expert physician. When possible, the treatment of TB in HIV-infected persons should be directed by (or done in consultation with) a physician with extensive experience in the care of patients with TB and HIV disease. The implementation of these recommendations will help prevent cases of drug-resistant TB, reduce TB treatment failures, and diminish the adverse effects that TB has on HIV replication. Moreover, these guidelines will contribute to efforts to control TB and eliminate it from the United States by minimizing the likelihood of M. tuberculosis transmission, which will prevent the occurrence of new cases of TB.

In future years, health-care professionals can expect changes in the recommendations regarding the therapeutic options used to prevent and treat TB among patients infected with HIV. These changes will reflect the availability of new antiretroviral and antituberculosis agents, new information about existing agents, and subsequent changes in CDC's guidelines for the use of antiretroviral therapy for persons infected with HIV. Multiple copies of this report and all updates are available from the Office of Communications, National Center for HIV, STD, and TB Prevention, CDC, 1600 Clifton Road, Mail Stop E-06, Atlanta, GA 30333. The report also is posted on the CDC Division of TB Elimination Internet website at less than http://www.cdc.gov/nchstp/tbgreater than and the MMWR website at . Readers should consult these sources regularly for updates in the guidelines.

PART I. BACKGROUND AND SCIENTIFIC RATIONALE Frequency of Coexisting TB and HIV Infection and Disease in the United States

In the United States, epidemiologic evidence indicates that the HIV epidemic contributed substantially to the increased numbers of TB cases in the late 1980s and early 1990s (6,7). Overlap between the acquired immunodeficiency syndrome (AIDS) and TB epidemics continues to result in increases in TB morbidity. Analysis of national HIV-related TB surveillance data is limited by incomplete reporting of HIV status for persons with TB. As an alternative, state health department personnel have compared TB and AIDS registries to help estimate the proportion of persons reported with TB who are also infected with HIV. In the most recent comparison conducted by the 50 states and Puerto Rico, 14% of persons with TB in 1993-1994 (27% among those aged 25-44 years) also appeared in the AIDS registry (8). This proportion of TB patients with AIDS is believed to be a minimum estimate for the United States and might represent an increase in the proportion of TB patients identified as having TB and AIDS in 1990 (9%) (6). During 1993-1994, most persons with TB and AIDS (80%) were found in eight reporting areas: New York City, California, Florida, Georgia, Illinois, New Jersey, New York, and Texas (8).

In prospective epidemiologic studies, investigators have estimated that the annual rate of TB disease among untreated, tuberculin skin-test (TST)-positive, HIV-infected persons in the United States ranges from 1.7 to 7.9 TB cases per 100 person-years (Table_1) (9-11). The variability observed in these studies mirrors the differences in TB prevalence observed for different U.S. populations (i.e., the highest case rate was found in a study of a New York City population of intravenous drug users at a time when the incidence of TB was high and increasing {9}; and the lowest case rate was evident in a community-based cohort of persons enrolled in a study of the pulmonary complications of HIV infection at a time and in a population in which the incidence of TB was relatively low {11}). However, in all of these studies, the rate of TB disease among HIV-infected, TST-positive persons was approximately 4-26 times higher than the rate among comparable HIV-infected, TST-negative persons, and it was approximately 200-800 times higher than the rate of TB estimated for the U.S. population overall (0.01%) (12). Therefore, activities to control and eliminate TB in the United States must include aggressive efforts to identify HIV-infected persons with latent TB infection and to provide them with therapy to prevent progression to active TB disease.

Rates of Drug-Resistant TB Among HIV-Infected Persons in the United States

Resistance to antituberculosis drugs is an important consideration for some HIV-infected persons with TB. According to the results of a study of TB cases reported to CDC from 1993 through 1996, the risk of drug-resistant TB was higher among persons with known HIV infection compared with others (13). During this 4-year period, among U.S.-born persons aged 25-44 years with TB, HIV test results were reported as positive for 32% of persons, negative for 23%, and unknown for 45%. Using univariate analysis that excluded patients known to have had a previous episode of TB, investigators found that patients known to be HIV seropositive had a significantly higher rate of resistance to all first-line antituberculosis drugs, compared with HIV-seronegative patients and patients with unknown HIV serostatus (Table_2). Moreover, using a multivariate model that included age, history of previous TB, birth country, residence in New York City, and race/ethnicity, the investigators confirmed HIV-positive serostatus as a risk factor for resistance to at least isoniazid, for both isoniazid and rifampin resistance (multidrug-resistant {MDR} TB) and for rifampin monoresistance (TB resistant to rifampin only). In some areas of the United States with a low level of occurrence of MDR TB, however, differences in MDR TB related to HIV status have not been found (8). Reasons for the increased risk for TB drug resistance among HIV-seropositive persons might reflect a higher proportion of TB disease resulting from recently acquired M. tuberculosis infection (14,15) and thus an increased risk of disease caused by drug-resistant strains in areas with high community and institutional transmission of drug-resistant strains of M. tuberculosis (16). Several well-described outbreaks of nosocomially transmitted MDR TB, primarily affecting persons with AIDS, support this association (17-21).

In the past decade, reports have increased of TB caused by strains of M. tuberculosis resistant to rifampin only, and growing evidence has indicated that this rare event is associated with HIV coinfection (22-32). In retrospective studies, nonadherence with TB therapy has been associated with acquired rifampin monoresistance (22-24); and among a small number of patients, the use of rifabutin as prophylaxis for Mycobacterium avium complex was associated with the development of rifamycin resistance (31). However, the occurrence of TB relapse with acquired rifampin monoresistance also has been documented among patients with TB who initially had rifampin-susceptible isolates and who were treated with a rifampin-containing TB regimen by directly observed therapy (DOT) (30,32). The mechanisms involved in the development of acquired rifampin monoresistance are not clearly understood but could involve the persistence of actively multiplying mycobacteria in patients with severe cellular immunodeficiency, selective antituberculosis drug malabsorption, and inadequate tissue penetration of drugs.

Thus, of critical importance for HIV-infected persons is implementation of TB prevention and control strategies such as a) appropriate use of therapy for latent M. tuberculosis infection, b) early diagnosis and effective treatment of active TB (i.e., administering four-drug antituberculosis regimens by DOT to all coinfected patients), and c) prompt compliance with requirements for reporting TB cases and drug-susceptibility test results. Implementing these strategies for persons coinfected with HIV will not only help reduce new cases of TB in general; it also could decrease further transmission of drug-resistant strains and new cases of drug-resistant TB.

Copathogenicity of TB and HIV Disease

Human immunodeficiency virus type 1 (HIV-1) and M. tuberculosis are two intracellular pathogens that interact at the population, clinical, and cellular levels. Initial studies of HIV-1 and TB emphasized the impact of HIV-1 on the natural progression of TB, but mounting immunologic and virologic evidence now indicates that the host immune response to M. tuberculosis enhances HIV replication and might accelerate the natural progression of HIV infection (33). Therefore, the interaction between these two pathogens has important implications for the prevention and treatment of TB among HIV-infected persons. Studies of the immune response in persons with TB disease support the biologic plausibility of copathogenesis in dually infected persons. The initial interaction between the host immune system and M. tuberculosis occurs in the alveolar macrophages that present mycobacterial antigens to antigen-specific CD4+ T cells (34). These T cells release interferon-gamma, a cytokine that acts at the cellular level to activate macrophages and enhance their ability to contain mycobacterial infection. The activated macrophages also release proinflammatory cytokines, such as tumor necrosis factor and interleukin (IL)-1, cytokines that enhance viral replication in monocyte cell lines in vitro (35-38). The mycobacteria and their products also enhance viral replication by inducing nuclear factor kappa-B, the cellular factor that binds to promoter regions of HIV (39,40).

When TB disease develops in an HIV-infected person, the prognosis is often poor, though it depends on the person's degree of immunosuppression and response to appropriate antituberculosis therapy (41-43). The 1-year mortality rate for treated, HIV-related tuberculosis ranges from 20% to 35% and shows little variation between cohorts from industrialized and developing countries (44-49). The observed mortality rate for HIV-infected persons with TB is approximately four times greater than the rate for TB patients not infected with HIV (44,46,49,50). Although the cause of death in the initial period of therapy can be TB (46), death after the induction phase of antituberculosis therapy usually is attributed to complications of HIV other than TB (45,51,52). Epidemiologic data suggest that active TB accelerates the natural progression of HIV infection. In a retrospective cohort study of HIV-infected women from Zaire, investigators estimated the relative risk of death to be 2.7 among women with active TB compared with those without TB (53). In a retrospective cohort study of HIV-infected subjects from the United States, active TB was associated with an increased risk for opportunistic infections and death (54). The risk of death, or hazard rate, for persons with HIV-related TB follows a bimodal distribution, peaking within the first 3 months of antituberculosis therapy and then again after 1 year (48); the reasons for this distribution are not clear but might relate to the impact of TB on HIV disease progression. The observation that active TB increases deaths associated with HIV infection has been corroborated in studies of three independent cohorts in Europe (55-57).

Early in the HIV epidemic, researchers postulated that the immune activation resulting from concurrent infection with parasitic or bacterial pathogens might alter the natural progression of HIV infection (58). Subsequent observations have demonstrated that immune activation from TB enhances both systemic and local HIV replication. In some patients with active TB, the plasma HIV RNA level rises substantially before TB is diagnosed (59). Moreover, TB treatment alone leads to reductions in the viral load in these dually infected patients. TB and HIV also interact in the lungs, the site of primary infection with M. tuberculosis. In a recently published study of HIV-infected patients with TB, researchers found that the viral load was higher in the bronchoalveolar lavage fluid from the affected versus the unaffected lung and was correlated with levels of tumor necrosis factor in bronchoalveolar fluid (60). Researchers used V3 loop viral sequences to construct a phylogenetic tree and observed that the HIV quasispecies from the affected lung differed from those in the plasma within the same patient. These data suggest that pulmonary TB might act as a potent stimulus for the cellular-level replication of HIV. In summary, recent research findings have improved clinicians' understanding of how HIV affects the natural progression of TB and how TB affects the clinical course of HIV disease, and these findings support the recommendation for prevention, early recognition, and effective treatment for both diseases.

TB Therapy Outcomes Among Patients with HIV-Related TB

Among patients treated for TB, early clinical response to therapy and the time in which M. tuberculosis sputum cultures convert from positive to negative appear to be similar for those with HIV infection and those without HIV infection (30,61,62). However, the data are less clear about whether rates of TB relapse (recurrence of TB following successful completion of treatment) differ among patients with or without HIV infection (63). Current CDC and American Thoracic Society guidelines recommend a 6-month treatment regimen for drug-susceptible TB disease for patients coinfected with HIV (2) but suggest prolonged treatment for patients who have a delayed clinical and bacteriologic response to antituberculosis therapy. Some experts have suggested that to ensure an optimal antituberculosis treatment outcome, all patients with HIV-related TB should be treated with a longer course of therapy (i.e., 9 months), regardless of evidence of early response to therapy (64,65).

To make a recommendation on duration of therapy for HIV-related TB, expert consultants at the September 1997 CDC meeting considered the results of prospective studies that ascertained the posttreatment relapse rate following 6-month TB therapy regimens among patients with HIV infection (Table_3) (29,30,49,66,67). Differences in the study designs, including those pertaining to eligibility for enrollment in the study and to the definition of TB relapse, limited the analysis of combined results from the five studies. Despite this limitation, the expert consultants were able to make the following observations: a) the studies had a posttreatment follow-up duration that ranged from 8 to 22 months (median duration: 18 months); b) in three studies (30,49,67), investigators found that 6-month TB regimens were associated with a clinically acceptable (less than or equal to 5.4%) TB relapse rate; and c) in two studies (29,66), researchers found a high (greater than or equal to 9%) TB relapse rate associated with the use of 6-month TB regimens. In the Zaire study (66), TB patients coinfected with HIV had almost twofold higher posttreatment relapse rates than patients not infected with HIV who received the same TB treatment regimen; however, the authors did not investigate whether the relapses were the result of a recurrence of disease with the same strain of M. tuberculosis or reinfection (new disease) with a different strain. In the other study (29), which enrolled HIV-seropositive patients from 21 different sites in the United States, in all three patients who relapsed, the strain of M. tuberculosis isolated during the relapse episode matched, by DNA fingerprint, the strain of M. tuberculosis that was isolated during the initial episode of TB; this finding ruled out the possibility of reinfection.

The expert consultants who reviewed the available data agreed that short-course (i.e., 6-month) regimens should be used for the treatment of HIV-related pansusceptible TB (i.e., susceptible to all first-line antituberculosis drugs) in the United States, where patients are usually treated with DOT and where response to antituberculosis drugs can be monitored. This approach limits the use of lengthier multidrug antituberculosis therapies to the minimum possible number of patients with TB and HIV disease. Some experts believe the risk of TB treatment failure is increased among patients with advanced HIV-related immunosuppression and therefore advocate greater caution (or longer duration of therapy) when treating such patients for TB. The available data do not permit CDC to make a definitive recommendation regarding this issue. However, the experts recommended that clinicians treating TB in patients with HIV infection should consider the factors that increase a person's risk for a poor clinical outcome (e.g., lack of adherence to TB therapy, delayed conversion of M. tuberculosis sputum cultures from positive to negative, and delayed clinical response) when deciding the total duration of TB therapy.

Paradoxical Reactions Associated with Initiation of Antiretroviral Therapy During the Course of TB Therapy

The temporary exacerbation of TB symptoms and lesions after initiation of antituberculosis therapy -- known as a paradoxical reaction -- has been described as a rare occurrence (68-74) attributed to causes such as recovery of the patient's delayed hypersensitivity response and an increase in exposure and reaction to mycobacterial antigens after bactericidal antituberculosis therapy is initiated (75). Recently, a similar phenomenon was reported among patients with HIV-related TB (76). These reactions appear to be related more often to the concurrent administration of antiretroviral and antituberculosis therapy and occur with greater frequency than do paradoxical reactions associated primarily with the administration of antituberculosis therapy. Patients with paradoxical reactions can have hectic fevers, lymphadenopathy (sometimes severe), worsening of chest radiographic manifestations of TB (e.g., miliary infiltrates, pleural effusions), and worsening of original tuberculous lesions (e.g., cutaneous and peritoneal). However, these reactions are not associated with changes in M. tuberculosis bacteriology (i.e., no change from negative to positive culture and smear), and patients generally feel well and have no signs of toxicity.

In a prospective study, paradoxical reactions were more common among 33 patients with HIV-related TB who received TB treatment and combination antiretroviral therapy (36%) than among 55 patients not infected with HIV who received antituberculosis drugs alone (2%) and among 28 HIV-infected patients (historical control patients during pre-zidovudine era) who received antituberculosis drugs alone (7%) (76). Furthermore, among patients treated for both diseases, the paradoxical reactions were more temporally related to the initiation of combination antiretroviral therapy (mean +/- standard deviation {SD}: 15 +/- 11 days afterward) than to the initiation of antituberculosis treatment (mean SD: 109 +/- 72 days afterward). Researchers investigated potential causes for these symptoms and lesions (i.e., TB treatment failure, antituberculosis drug resistance, nonadherence with TB therapy, drug fever, development of conditions not related to TB or HIV) but considered such causes unlikely because these evaluations produced negative results, and TB was cured in patients who remained on unmodified antituberculosis regimens. Among patients in this study who received combination antiretroviral therapy, which usually included a protease inhibitor, the paradoxical reactions corresponded with a concurrent drop in HIV viral loads after antiretroviral therapy began and, in all but one patient, occurred while peripheral blood CD4+ T-cell counts were less than 200 cells/uL (76). In the historical control group (i.e., patients who were treated for TB but not for HIV), two (7%) of the 28 patients had a paradoxical reaction after antituberculosis therapy was initiated. This finding indicates that treatment of TB alone might sometimes decrease HIV viral load substantially and improve immune function (40,59,68,76).

After reviewing information about paradoxical reactions occurring during the course of TB therapy, expert consultants at the September 1997 CDC meeting concluded that exacerbation of TB signs and symptoms in patients with HIV-related TB can occur soon after combination antiretroviral therapy is initiated. Clinicians should always conduct a thorough investigation to eliminate other etiologies before making a diagnosis of paradoxical treatment reaction. For patients with paradoxical reactions, rarely are changes in antituberculosis or antiretroviral therapy needed. If the lymphadenopathy or other lesions are severe, one option is to continue with appropriate antituberculosis therapy and administer short-term steroids that suppress the enhanced immune response.

In the prospective study (76), despite having low CD4+ T-cell counts, six (86%) of seven TB patients who were initially tuberculin skin-test (TST)-negative had positive TST results after combination antiretroviral therapy was started. The reaction sizes of postantiretroviral TSTs ranged from 7 to 67 mm of induration. Clinicians must be aware of the potential public health and clinical implications of restored TST reactivity among persons who have not been diagnosed with active TB but who might be latently infected with M. tuberculosis. Persons previously known to have negative TST results might benefit from repeat tuberculin testing if they have evidence of restored immune function after antiretroviral therapy is initiated, because TB preventive therapy is recommended for TST-positive HIV-infected persons.

Considerations for TB Therapy for HIV-Infected Patients Treated with Antiretroviral Agents Drug Interactions Between Rifamycins Used for TB Therapy and Antiretroviral Drugs Used for HIV Therapy

Widely used antiretroviral drugs available in the United States include protease inhibitors (saquinavir, indinavir, ritonavir, and nelfinavir) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) (nevirapine, delavirdine, and efavirenz). Protease inhibitors and NNRTIs have substantive interactions with the rifamycins (rifampin, rifabutin, and rifapentine) used to treat mycobacterial infections (3,77). These drug interactions principally result from changes in the metabolism of the antiretroviral agents and the rifamycins secondary to induction or inhibition of the hepatic cytochrome CYP450 enzyme system (78,79). Rifamycin-related CYP450 induction decreases the blood levels of drugs metabolized by CYP450. For example, if protease inhibitors are administered with rifampin (a potent CYP450 inducer), blood concentrations of the protease inhibitors (all of which are metabolized by CYP450) decrease markedly, and most likely the antiretroviral activity of these agents declines as well. Conversely, if ritonavir (a potent CYP450 inhibitor) is administered with rifabutin, blood concentrations of rifabutin increase markedly, and most likely rifabutin toxicity increases as well.

Of the available rifamycins, rifampin is the most potent CYP450 inducer; rifabutin has substantially less activity as an inducer; and rifapentine, a newer rifamycin, has intermediate activity as an inducer (80-82). The four currently approved protease inhibitors and amprenavir (141W94, an investigational agent in Phase III clinical trials) are all, in differing degrees, inhibitors of CYP450 (83,84). The rank order of the agents in terms of potency in inhibiting CYP450 is ritonavir (the most potent); amprenavir, indinavir, and nelfinavir (with approximately equal potencies); and saquinavir (the least potent). The magnitude of the effects of coadministering rifamycins and protease inhibitors has been evaluated in limited pharmacokinetic studies (Table_4) (85-91). The three approved NNRTIs have diverse effects on CYP450: nevirapine is an inducer, delavirdine is an inhibitor, and efavirenz is both an inducer and an inhibitor. The magnitude of the effects of coadministering rifamycins and NNRTIs has also been evaluated in pharmacokinetic studies or has been predicted on the basis of what is known about their potential for inducing or inhibiting CYP450 (Table_5) (92-96).

In contrast to the protease inhibitors and the NNRTIs, the other class of antiretroviral agents available, nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine, didanosine, zalcitabine, stavudine, and lamivudine) are not metabolized by CYP450. Rifampin (and to a lesser degree, rifabutin) increases the glucuronidation of zidovudine and thus slightly decreases the serum concentration of zidovudine (97-100). The effect of this interaction probably is not clinically important, and the concurrent use of NRTIs and rifamycins is not contraindicated (77). Also, no contraindication exists for the use of NRTIs, NNRTIs, and protease inhibitors with isoniazid, pyrazinamide, ethambutol, or streptomycin. These first-line antituberculosis medications, in contrast to the rifamycins, are not CYP450 inducers.

Coadministration of Antituberculosis and Antiretroviral Therapies

According to 1998 U.S. Department of Health and Human Services guidelines on the use of antiretroviral agents among HIV-infected adults and adolescents (4), to improve the length and quality of patients' lives, all persons with symptomatic HIV infection should be offered antiretroviral therapy. HIV-infected patients with TB fall in this category. When used appropriately, combinations of potent antiretroviral agents can effect prolonged suppression of HIV replication and reduce the inherent tendency of HIV to generate drug-resistant viral strains. However, as antiretroviral therapeutic regimens have become increasingly effective, they also have become increasingly complex in themselves as well as in the problems they cause for the treatment of other HIV-associated diseases.

At present, regimens that include two NRTIs combined with a potent protease inhibitor (or, as an alternative, combined with an NNRTI) are the preferred choice for combination antiretroviral therapy for the majority of patients. Each of the antiretroviral drug combination regimens must be used according to optimum schedules and doses (4) because the potential for resistant mutations of HIV decreases if serum concentrations of the multiple antiretroviral drugs are maintained steadily. Because rifampin markedly lowers the blood levels of these drugs and is likely to result in suboptimal antiretroviral therapy, the use of rifampin to treat active TB in a patient who is taking a protease inhibitor or an NNRTI is always contraindicated. Rifabutin is a less potent inducer of the CPY450 cytochrome enzymes than is rifampin and, when used in appropriately modified doses, might not be associated with a clinically significant reduction of protease inhibitors or nevirapine (Table_6). Thus, the substitution of rifabutin for rifampin in TB treatment regimens has been proposed as a practical choice for patients who are also undergoing therapy with protease inhibitors (with the exception of ritonavir {86,87,101-103} or hard-gel capsule saquinavir {Invirase (85)}) or with the NNRTIs nevirapine or efavirenz (but not delavirdine {93,94}). Currently, more clinical and pharmacokinetic data are available on the use of indinavir or nelfinavir with rifabutin than on the use of amprenavir or soft-gel saquinavir (Fortovase ) with rifabutin. Rifapentine is not recommended as a substitute for rifampin because its safety and effectiveness have not been established for the treatment of patients with HIV-related TB. As an alternative to the use of rifamycin for the treatment of TB, the use of streptomycin-based regimens that do not contain rifamycin can be considered for the treatment of TB in patients undergoing antiretroviral therapy with protease inhibitors or NNRTIs.

Use of Rifabutin-Based Regimens for the Treatment of HIV-Related TB

At present, TB drug regimens that include rifabutin instead of rifampin appear to offer the best alternative for the treatment of active TB among patients taking antiretroviral therapies that include protease inhibitors or NNRTIs. This recommendation is based on findings from studies of equivalent in vitro antituberculosis activity of rifabutin and rifampin (104,105) and the results of three clinical trials (106-108). These trials demonstrated that 6-month rifabutin-containing regimens (at a daily dose of either 150 mg or 300 mg) were as effective and as safe as similar control regimens containing rifampin for the treatment of TB (Table_7). The smallest (n=49) of these three trials was conducted in Uganda (108) and is the only one to include HIV-coinfected patients (who were not undergoing antiretroviral therapy at the time of the study). This study indicated that 81% of patients taking a TB treatment regimen containing daily rifabutin converted their sputum from M. tuberculosis positive to negative after 2 months of treatment, compared with a 48% sputum conversion rate among patients taking a TB regimen containing daily rifampin (pless than 0.05). However, when the researchers controlled for differences in baseline characteristics (a greater proportion of patients in the rifampin group had cavitary disease), they found no difference in the time to sputum conversion between the two study groups.

Studies are under way to evaluate the use of rifabutin administered daily (at a dose of 150 mg) or twice a week (at a dose of 300 mg) for the treatment of TB in HIV-infected patients who take protease inhibitors. Physicians at a state tuberculosis hospital in Florida have treated or consulted on the treatment of approximately 30 HIV-infected patients who received a protease inhibitor while undergoing treatment for TB with rifabutin. Patients have been treated for TB primarily with administration of rifabutin (150 mg daily) as part of four-drug therapy for 2-4 weeks, followed by rifabutin (300 mg twice weekly) as part of four-drug therapy to complete 8 weeks of induction, and then a continuation phase consisting of twice-weekly isoniazid and rifabutin (300 mg) to complete 6 months of treatment. To date, patients treated with this regimen have not experienced clinically significant increases in rifabutin serum levels, have had a minimal incidence of adverse reactions from rifabutin (one patient developed a case of uveitis), and have had a good clinical response to TB and HIV therapies. Approximately 80% of the patients attained sputum conversion by the second month of treatment, most have attained and maintained suppression of HIV replication, and no TB relapses have occurred with up to 1 year of posttreatment follow-up (David Ashkin, M.D., and Masahiro Narita, M.D., A.G. Holley State Tuberculosis Hospital, Lantana, Florida, personal communication, 1998).

In previous reports, CDC and the American Thoracic Society jointly recommended the use of rifampin-containing short-course regimens for the initial treatment of HIV-related TB (2). The inclusion of rifampin in regimens to treat TB was supported by data collected from approximately 90 controlled clinical trials conducted from 1968 to 1988 (109). Excluding rifampin from the TB treatment regimen was not recommended because regimens not containing rifampin a) had not been proven to have acceptable efficacy (i.e., have been associated with higher rates of TB treatment failure and death and with slower bacteriologic responses to therapy leading to potential increases in the likelihood of M. tuberculosis transmission) and b) require prolonging duration of therapy from 6 months to 12-15 months. Presently, available data suggest that rifabutin in short-course (i.e., 6 months) multidrug regimens to treat TB provides the same benefits as the use of rifampin. Three additional reasons support the use of rifabutin for treating HIV-related TB: a) observations suggest that rifabutin might be more reliably absorbed than rifampin in patients with advanced HIV disease (110,111); b) the use of rifabutin appears to have been better tolerated in patients with rifampin-induced hepatotoxicity (David Ashkin, M.D., and Masahiro Narita, M.D., A.G. Holley State Tuberculosis Hospital, Lantana, Florida, personal communication, 1998); and c) the use of rifabutin might lessen the possibility of interactions with other medications commonly prescribed for patients with HIV infection (e.g., azole antifungal drugs, anticonvulsant agents, and methadone) (77).

Use of Alternative TB Treatment Regimens that Contain Minimal or No Rifamycin

TB treatment regimens that contain no rifamycins have been proposed as an alternative for patients who take protease inhibitors or NNRTIs. Several clinical trials conducted in Hong Kong and Africa by the British Medical Research Council and published from 1974 through 1984 provide information about nonrifamycin and minimal-rifamycin regimens for the treatment of TB in patients who were not likely to be infected with HIV (Table_8) (112-115). Most of these studies demonstrated high relapse rates when regimens not containing streptomycin were used and when the duration of therapy was less than 9 months. However, in a large (n=404) randomized controlled clinical trial in Hong Kong that evaluated the use of six TB treatment regimens consisting of streptomycin, isoniazid, and pyrazinamide either daily, three times a week, or two times a week for 6 or 9 months (112), almost all patients treated with any of the study regimens achieved rapid sputum conversions (86%-94% of patients converted within 3 months of therapy). In this study, the 30-month posttreatment follow-up relapse rates were high (18%-24%) among patients treated with 6-month regimens, but the relapse rates among patients treated with 9-month regimens (5%-6%) were similar to the relapse rates expected following the use of rifampin-based TB treatments. Thus, the expert consultants who developed these guidelines concluded that treatment of TB without rifamycin always requires longer-duration (at least 9 months) regimens that include streptomycin (or an injectable antituberculosis drug such as capreomycin, amikacin, or kanamycin) (63). However, these TB regimens have not been studied among patients with HIV infection.

Streptomycin is highly bactericidal against M. tuberculosis, but it is rarely used in the United States to treat drug-susceptible TB because of problems associated with its administration by injection that can be intensified in patients with low body mass or wasting and because of potential ototoxicity and nephrotoxicity. The associated potential toxicities and increased duration of therapy and the patient's difficulty in adhering to an injectable-drug-based TB regimen can compromise the effectiveness of streptomycin-based TB regimens, and these limitations should be considered by physicians and patients.

Treatment of Latent M. tuberculosis Infection in Patients with HIV Infection Scientific Rationale

Preventive therapy for TB is essential to controlling and eliminating TB in the United States (116,117). Treatment for HIV-infected persons who are latently infected with M. tuberculosis is an important part of this strategy and is also an important personal health intervention because of the serious complications associated with active TB in HIV-infected persons (118-120). Expert consultants attending the September 1997 CDC meeting and additional consultants attending a September 1998 meeting sponsored by the American Thoracic Society and CDC considered findings from multiple studies (121-130) before developing recommendations about the optimal duration of isoniazid preventive therapy regimens; frequency of administration (intermittency) of preventive therapy; new short-course multidrug regimens; and preventive therapy for anergic HIV-infected adults with a high risk of M. tuberculosis infection.

A key difference in most preventive therapy trials conducted before and after the beginning of the HIV epidemic is that the earlier trials focused on 12-month regimens of isoniazid, whereas five of seven trials (122-126) conducted in HIV-infected populations assessed 6-month regimens of isoniazid (Table_9). Four of these 6-month isoniazid regimens (122-125) were chosen for study on the basis of the operational feasibility of providing therapy in countries with limited resources where preventive therapy programs were not available; the fifth study (126), a U.S. trial conducted among anergic patients, used a 6-month regimen because of the absence of previous data about optimal duration of therapy for TST-negative, HIV-infected patients. Despite these variations, the expert consultants concluded that the findings from these different preventive therapy studies should apply to most persons with latent M. tuberculosis infection, regardless of their HIV serostatus, because similar levels of protection have been observed when identical preventive therapy regimens have been administered to persons infected with HIV and those not infected.

Optimal Duration of Isoniazid Regimens for Treatment of Latent M. tuberculosis Infection

The American Thoracic Society and CDC have previously recommended a regimen of 12 months of isoniazid alone for treatment of latent M. tuberculosis infection in HIV-infected adults (2). The recommended duration of TB preventive therapy for persons not infected with HIV was a minimum of 6 months. When considering the optimal duration of isoniazid preventive therapy, the consultants reviewed findings from two studies conducted in populations not known to be infected with HIV (128,129). One of these studies, a controlled trial conducted in seven European countries, compared the efficacy of three durations (3, 6, and 12 months) of isoniazid preventive treatment for TST-positive persons with stable, fibrotic lesions on chest radiographs (128). In this study, compliant patients who received medication for 12 months had better protection against TB (93%) than those who received medication for 6 months (69%). The other study was conducted among the Inuits in the Bethel area of Alaska, where participants received 0-24 months of isoniazid preventive therapy (129). In an assessment of observed posttherapy case rates of TB relative to the amount of isoniazid ingested (expressed as a percentage of a 12-month regimen), researchers found that higher amounts of therapy corresponded with lower TB rates among participants who had received 0-9 months of isoniazid therapy; after 9 months of therapy, participants had no additional benefits in terms of decreased TB case rates.

Four studies of HIV-infected persons have evaluated 6-month and 12-month regimens of daily isoniazid (121,123,125,127). Both of the studies that evaluated a 6-month regimen included a placebo comparison group and demonstrated reductions in the incidence of TB among persons in the treatment group -- 70% in Uganda (123) and 75% in Kenya (125). A study of the 12-month regimen (121), which was conducted in Haiti and also included a placebo comparison group, demonstrated an 83% reduction in the incidence of TB among persons in the treatment group. A multicenter trial conducted in the United States, Mexico, Brazil, and Haiti (127) demonstrated that the magnitude of protection obtained from a regimen of isoniazid administered daily for 12 months was similar to that obtained from a regimen of rifampin and pyrazinamide administered daily for 2 months. Isoniazid preventive therapy regimens of 6 and 12 months' duration have not been compared with each other in the same study conducted among HIV-infected persons. In summary, these data indicate that a) the optimal duration of isoniazid preventive therapy should be greater than 6 months to provide the maximum degree of protection against TB; b) therapy for 9 months appears to be sufficient; c) therapy for greater than 12 months does not appear to provide additional protection.

Frequency of Administering Isoniazid Preventive Therapy

Two clinical trials (122,124) have evaluated 6-month twice-weekly isoniazid regimens for the prevention of active TB in HIV-infected persons (Table_9). Participants enrolled in the twice-weekly 6-month isoniazid arm of a study conducted in Zambia had a 40% reduction in the rate of TB compared with persons who took a placebo for 6 months (124). The findings of a trial conducted in Haiti (122) suggest that the magnitude of protection obtained from isoniazid administered twice a week for 6 months is equivalent to that obtained from rifampin and pyrazinamide regimens administered twice a week for 2 months. Preventive therapy trials that include twice-weekly isoniazid regimens for greater than 6 months or comparisons of the same drugs administered daily versus intermittently have not been conducted. However, in a Baltimore demonstration project in which isoniazid was administered twice a week (10-15 mg/kg, with a maximum dose of 900 mg) to a cohort of injecting-drug users under directly observed preventive therapy (DOPT), the findings support the efficacy of twice-weekly isoniazid preventive therapy (130). Twice-weekly regimens with DOPT were used in Baltimore because the project staff expected that supervised delivery of therapy would enhance adherence with and completion of the preventive therapy regimen. Thus, the available data suggest that the protection obtained from isoniazid preventive therapy regimens should be the same whether the drug is administered daily or twice a week.

Short-Course Multidrug Regimens for TB Preventive Therapy

Four clinical trials (122-124,127) conducted among HIV-infected populations have evaluated courses of preventive therapy that are shorter than 6 months and that include rifampin in combination with isoniazid or pyrazinamide (Table_9). The largest and most recent of these trials was a multicenter, randomized TB prevention study conducted from 1992 through 1998 (127). Researchers found identical rates of TB (1.2 per 100 person-years) in two groups of TST-positive, HIV-infected persons: those who primarily self-administered isoniazid daily for 12 months and those who primarily self-administered rifampin and pyrazinamide daily for 2 months. Both study groups had similar adverse events and mortality rates; persons taking rifampin and pyrazinamide for 2 months were significantly more likely (80%) to complete therapy than were persons taking isoniazid for 12 months (68%) (pless than 0.001). Two other trials conducted in Haiti and Zambia (122,124) have also evaluated regimens of rifampin and pyrazinamide for the prevention of TB but have not included comparison arms of 12-month isoniazid regimens. The study in Haiti (122) compared patients receiving rifampin and pyrazinamide administered twice a week for 2 months with patients receiving isoniazid twice a week for 6 months; in both arms of the study, one of the twice-weekly doses was administered by DOPT. Investigators observed no difference in TB risk or mortality among participants enrolled in the two treatment arms (122). The placebo-controlled trial in Zambia demonstrated comparable protection from 3 months of rifampin and pyrazinamide versus 6 months of isoniazid; both regimens were self-administered twice a week (124). In the multicenter trial (127) and in the Haiti and Zambia studies (122,124), regimens that included rifampin and pyrazinamide were well tolerated. In a study conducted in Uganda (123), investigators observed no statistically significant reduction in TB rates but a high rate of toxicity and drug intolerance among persons who took three drugs (isoniazid, rifampin, and pyrazinamide) daily for 3 months compared with persons who took a placebo (Table_9); 3 months of daily self-administered rifampin and isoniazid provided protection similar to that of 6 months of daily self-administered isoniazid. Thus, short-course multidrug regimens (i.e., two drugs for 2-3 months) have been shown to be effective for the prevention of active TB in HIV-infected persons. The use of three drugs for preventive therapy, however, can be associated with unacceptably high rates of toxicity, and the use of a 3-month regimen of rifampin and isoniazid is not being considered for use in the United States. Available data indicate that in the United States, a regimen of rifampin and pyrazinamide administered daily for 2 months is a reasonable treatment option for HIV-infected adults with latent M. tuberculosis infection. The available data do not permit CDC to make a definitive statement regarding the intermittent (i.e., twice a week) administration of a 2-month regimen of rifampin and pyrazinamide.

Preventive Therapy for Anergic HIV-Infected Adults with a High Risk of Latent M. tuberculosis Infection

Isoniazid preventive therapy has not been found to be useful or cost-effective in preventing TB when administered to anergic, HIV-infected persons (123,126) (Table_9). The anergic subjects who received isoniazid in the Uganda trial had a statistically insignificant (17%) reduction in the rate of TB (2.5 cases per 100 person-years) compared with patients in the placebo group (3.1 cases per 100 person-years) (123). Similarly, anergic HIV-infected persons with a high risk for tuberculous infection who were enrolled in a U.S. multicenter trial and treated with isoniazid daily for 6 months had a rate of TB (0.4 cases per 100 person-years) that was 50% less than, but not statistically different from, the rate observed among patients treated with placebo (0.9 cases per 100 person-years) (126). In both of these studies, HIV-infected persons with anergy tolerated isoniazid well, as suggested by the low rates of adverse reactions and high rates of therapy completion. These study findings do not support the routine use of preventive therapy in anergic, HIV-infected persons. Preventive therapy for TST-negative, HIV-infected persons also has not been proven effective (121,124, 125) (Table_9); however, some experts recommend primary preventive therapy (to prevent M. tuberculosis infection) for TST-negative or anergic HIV-infected residents of institutions that pose an ongoing high risk for exposure to M. tuberculosis (e.g., prisons, jails, homeless shelters).

Implications of Results of TB Preventive Therapy Trials

The effects of TB preventive therapy on mortality and progression of HIV infection appear to be limited, with the exception that such therapy can protect against the development of TB disease and its associated consequences. Moreover, the duration of this protective effect has not been clearly established for HIV-infected persons. Despite these limitations and uncertainties, preventive therapy is recommended because its benefits in preventing TB disease are thought to be greater than the risks of serious treatment-related adverse events, and such therapy benefits society by helping to prevent the spread of infection to other persons in the community.

The implementation of TB preventive therapy programs should be facilitated by the use of newly recommended short-course multidrug regimens and twice-weekly isoniazid regimens, especially among patients for whom DOPT is feasible. Because of the drug interactions between rifampin and protease inhibitors or NNRTIs, the use of shorter regimens containing rifampin is contraindicated for patients taking these antiretroviral drugs. Although preventive therapy trials evaluating rifabutin use among TST-positive, HIV-infected persons have not been conducted, the expert consultants reviewed available data and agreed that the use of rifabutin instead of rifampin is valid on the basis of the same scientific principles that support the use of rifabutin for the treatment of active TB.

PART II. RECOMMENDATIONS

This section of the report provides clinicians with recommendations for diagnosing, treating, and preventing TB among persons coinfected with HIV while concurrently promoting optimal antiretroviral care for these patients. The recommendations reflect the current state of knowledge regarding the use of antiretroviral agents, but this field of science is rapidly evolving. As new antiretroviral agents and new data regarding existing agents alter therapeutic options and preferences for antiretroviral therapy, these changes might affect future recommendations for the treatment of TB infection and disease among patients coinfected with HIV and the treatment of HIV infection among persons with TB. Expert consultants updated these recommendations after a September 1997 CDC meeting, where they reviewed and considered available information about the scientific principles of therapy for TB and HIV.

To help clinicians make informed treatment decisions based on the most current research results, the expert consultants have given the recommendations evidence-based ratings (general recommendations have no rating). The ratings include a letter and a Roman numeral (Table_10), similar to the ratings used in previously issued guidelines (4,5). The letter indicates the strength of the recommendation, and the Roman numeral indicates the nature of the evidence supporting the recommendation. Thus, clinicians can use the ratings to differentiate between recommendations based on data from clinical trials versus those based on the opinions of experts familiar with the relevant clinical practice and scientific rationale for such practice (when clinical trial data are not available). However, these recommendations are not intended to substitute for the judgment of an expert physician. Management of HIV-related TB disease is complex, and clinical and public health consequences associated with treatment failure are serious. When possible, treatment of TB among HIV-infected persons should be directed by, or conducted in consultation with, a physician with extensive experience in the care of patients with these two diseases.

The objectives of implementing these recommendations are to reduce TB treatment failures, prevent drug-resistant TB, and diminish the adverse effects that TB has on HIV replication. Moreover, these guidelines contribute to efforts to control and eliminate TB from the United States by minimizing the likelihood of M. tuberculosis transmission, which will prevent the occurrence of new cases of TB. Multiple copies of this report and all updates are available from the Office of Communications, National Center for HIV, STD, and TB Prevention, CDC, 1600 Clifton Road, Mail Stop E-06, Atlanta, GA 30333. The report also is posted on the CDC Division of TB Elimination Internet website at and the MMWR website at . Readers should consult these sources regularly for updates in the guidelines.

Active Tuberculosis Clinical and Public Health Principles

Prompt initiation of effective antituberculosis treatment increases the probability that a patient with HIV infection who develops TB will be cured of this disease (45,131). TB treatment also quickly renders patients noninfectious (30), with the resulting reduction in the amount of M. tuberculosis transmitted to others, and it minimizes the patient's risk of death resulting from TB (41-43,132). Therefore, clinicians must immediately and thoroughly investigate the possibility of TB when a patient infected with HIV has symptoms consistent with TB. Persons suspected of having current TB disease should immediately be started on appropriate treatment, ideally with directly observed therapy (DOT) (133-135), and placed in TB isolation as necessary (136,137). Patients with TB and unknown HIV-infection status should be counseled and offered HIV testing. HIV-infected patients undergoing treatment for TB should be evaluated for antiretroviral therapy. Most patients with HIV-related TB are candidates for concurrent administration of antituberculosis and antiretroviral drug therapies (4).

Health-care providers, administrators, and TB controllers must strive to promote coordinated care for patients with TB and HIV and remove existing barriers to information-sharing between TB control programs and HIV/AIDS programs. TB control programs are responsible for setting TB treatment standards for physicians in the community, promoting the awareness and use of recommended TB infection-control practices, and enforcing state and local health department requirements concerning TB case notification and early reporting of drug-susceptibility test results. Because of the complexity of managing HIV-related TB disease and the serious public health consequences of mismanagement, care for persons with HIV-related TB should be provided by, or in consultation with, experts in the management of both TB and HIV disease.

Diagnosis of HIV-Related Tuberculosis

The typical signs and symptoms of pulmonary TB are cough with or without fever, night sweats, weight loss, and upper-lobe infiltrates with or without cavitation on chest x-rays. The diagnosis of TB for some HIV-infected patients might be difficult because TB in an immunocompromised host can be associated with atypical symptoms, a lack of typical symptoms, and a paucity of findings in chest x-rays (138-140). Among persons with AIDS, the diagnosis of TB also can be complicated by the presence of other pulmonary infections such as Pneumocystis carinii pneumonia and Mycobacterium avium complex disease and by the occurrence of TB in extrapulmonary sites. For patients with unusual clinical and radiographic findings, the starting point for diagnosing active TB often is a positive tuberculin skin test (TST). All patients with positive TSTs should be evaluated to rule out active TB (see Diagnosis of M. tuberculosis Infection Among HIV-Infected Persons).

Medical Evaluation of Patients Suspected of Having Active TB Rating Recommendation A.II Every person suspected of having TB should undergo a

thorough medical evaluation (see Box 1(Table_B1)).

A.II The evaluation should include HIV counseling and testing

unless the person has documentation of a) a positive HIV antibody test or b) a negative result to an HIV antibody test conducted within the past 6 months.

Management of HIV-Infected Patients with Active TB Coadministration of TB Treatment and Antiretroviral Therapy

The following management strategies are for patients with HIV-related pulmonary TB a) who are not known to have or who do not have risk factors for multidrug-resistant TB and b) for whom antiretroviral therapy is appropriate. When they first receive care for active TB disease, some patients might already be receiving antiretroviral therapy, whereas other patients might be newly diagnosed with HIV infection (Figure_1). For these newly diagnosed patients, in addition to the currently established recommendations for the immediate initiation of antituberculosis therapy, recently published guidelines (4) recommend the use of antiretroviral therapy. When treatments for HIV and TB disease are begun simultaneously, the optimal setting is one with experienced and coordinated care givers as well as accessible resources to provide a continuum of medical services (e.g., a reliable source of medications and social, psychosocial, and nutritional services).

Because of drug interactions, the use of rifampin to treat TB is not recommended for patients who a) will start treatment with an antiretroviral regimen that includes a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor (NNRTI) at the same time they begin treatment for TB (4) or b) have established HIV infection that is being maintained on such an antiretroviral regimen when TB is newly diagnosed and needs to be treated. Thus, two TB treatment options are currently recommended for these patients: a) a rifabutin-based regimen or b) an alternative nonrifamycin regimen that includes streptomycin (see Treatment Options for Patients with HIV Infection and Drug-Susceptible Pulmonary TB and Figure 1). Using a rifampin-based TB treatment regimen continues to be recommended for patients with HIV infection

  1. who have not started antiretroviral therapy, when both the patient and the clinician agree that waiting to start such therapy would be prudent or b) for whom antiretroviral management does not include a protease inhibitor or an NNRTI (4) (Figure_1).

When determining the time to begin antiretroviral therapy for patients who are acutely ill with TB, clinicians and patients need to consider the existing clinical issues (e.g., drug interactions and toxicities, ability to adhere to two complex treatment regimens, and laboratory abnormalities). A staggered initiation of antituberculosis and antiretroviral treatments for patients not currently on antiretroviral therapy might promote greater adherence to the TB and HIV treatment regimens and reduce the associated drug toxicity of both regimens. This strategy might include starting antiretroviral therapy either at the end of the 2-month induction phase of TB therapy or after TB therapy is completed. When a decision is made to delay initiation of antiretroviral therapy, clinicians should monitor the patient's condition by measuring plasma HIV RNA levels (viral load) and CD4+ T-cell counts and assessing the HIV-associated clinical condition at least every 3 months (4), because such information will assist in decisions regarding the timing for initiating such therapy. For some patients, switching from a rifampin-based TB regimen to either a rifabutin-based or a nonrifamycin-based TB regimen will be necessary if the decision is made to start antiretroviral therapy before completion of antituberculosis therapy. Clinicians and patients should be aware that the potent effect of rifampin as a CYP450 inducer (77,80), which lowers the serum concentration of protease inhibitors and NNRTIs, continues up to at least 2 weeks following the discontinuation of rifampin. Thus, they should consider planning for a 2-week period between the last dose of rifampin and the first dose of protease inhibitors or NNRTIs (see TB Drug Interaction and Absorption and Table 1A of Appendix).

Treatment Options for Patients with HIV Infection and Drug-Susceptible Pulmonary TB A.II DOT and other strategies that promote adherence to therapy

should be used for all patients with HIV-related TB. A.II For patients who are receiving therapy with protease

inhibitors or NNRTIs, the initial phase of a 6-month TB regimen consists of isoniazid, rifabutin, pyrazinamide, and ethambutol. These drugs are administered a) daily for 8 weeks or b) daily for at least the first 2 weeks, followed by twice-a-week dosing for 6 weeks, to complete the 2-month induction phase. The second phase of treatment consists of isoniazid and rifabutin administered daily or twice a week for 4 months (see Six-month RFB-based therapy in Table 1A of Appendix). B.II For patients for whom the use of rifamycins is limited or

contraindicated for any reason (e.g., intolerance to rifamycins, patient/clinician decision not to combine antiretroviral therapy with rifabutin), the initial phase of a 9-month TB regimen consists of isoniazid, streptomycin,* pyrazinamide, and ethambutol administered a) daily for 8 weeks or b) daily for at least the first 2 weeks, followed by twice-a-week dosing for 6 weeks, to complete the 2-month induction phase. The second phase of treatment consists of isoniazid, streptomycin,* and pyrazinamide administered 2-3 times a week for 7 months (see Nine-month SM-based therapy in Table 1A of Appendix). A.I For patients who are not candidates for antiretroviral therapy,

or for those patients for whom a decision is made not to combine the initiation of antiretroviral therapy with TB therapy, the preferred option continues to be a 6-month regimen that consists of isoniazid, rifampin, pyrazinamide, and ethambutol (or streptomycin). These drugs are administered a) daily for 8 weeks or b) daily for at least the first 2 weeks, followed by 2-3-times-per-week dosing for 6 weeks, to complete the 2-month induction phase. The second phase of treatment consists of a) isoniazid and rifampin administered daily or 2-3 times a week for 4 months. Isoniazid, rifampin, pyrazinamide, and ethambutol (or streptomycin) also can be administered three times a week for 6 months (see Six-month RIF-based therapy in Table 1A of Appendix). D.II TB regimens consisting of isoniazid, ethambutol, and

pyrazinamide (i.e., three-drug regimens that do not contain a rifamycin, an aminoglycoside {e.g., streptomycin, amikacin, kanamycin}, or capreomycin) should generally not be used for the treatment of patients with HIV-related TB; if these regimens are used for the treatment of TB, the minimum duration of therapy should be 18 months (or 12 months after documented culture conversion). A.II Pyridoxine (vitamin B6) (25-50 mg daily or 50-100 mg twice

weekly) should be administered to all HIV-infected patients who are undergoing TB treatment with isoniazid, to reduce the occurrence of isoniazid-induced side effects in the central and peripheral nervous system. E.II Because CDC's most recent recommendations for the use of

antiretroviral therapy strongly advise against interruptions of therapy,* and because alternative TB treatments that do not contain rifampin are available, previous antituberculosis therapy options that involved stopping protease inhibitor therapy to allow the use of rifampin (Option I and Option II {3}) are no longer recommended.

Medications and Doses for Treatment of TB No rating When rifabutin is used concurrently with indinavir,

nelfinavir, or amprenavir, the recommended daily dose of rifabutin should be decreased from 300 mg to 150 mg (Table 2A of Appendix). No rating The dose of rifabutin recommended for twice-weekly

administration is 300 mg, and this dose recommendation does not change if rifabutin is used concurrently with indinavir, nelfinavir, or amprenavir (Table 2A of Appendix). No rating Preliminary drug interaction studies suggest that when

rifabutin is used concurrently with efavirenz, the dose of rifabutin for both daily and twice-weekly administration should be increased from 300 mg to 450 mg. No rating Three-times-per-week administration of rifabutin used in

combination with antiretroviral therapy has not been studied, and thus a recommendation for adjustment of dosages cannot currently be made. No rating Experts do not know whether the daily dose of rifabutin

should be reduced when this drug is used concurrently with either soft-gel saquinavir (Fortovase ) or nevirapine. No rating No modifications in the usually recommended doses of

isoniazid, ethambutol, pyrazinamide, or streptomycin (Table 2A of Appendix) are necessary if these drugs are used concurrently with protease inhibitors, NNRTIs, or nucleoside reverse transcriptase inhibitors (NRTIs). No rating The safety and effectiveness of rifapentine

(Priftin{Registered}), a rifamycin newly approved by the U.S. Food and Drug Administration for the treatment of pulmonary tuberculosis, have not been established for patients infected with HIV. Administration of rifapentine to patients with HIV-related TB is not currently recommended.

Duration of TB Treatment A.II The minimum duration of short-course rifabutin-containing TB

treatment regimens is 6 months, to complete a) at least 180 doses (one dose per day for 6 months) or b) 14 induction doses (one dose per day for 2 weeks) followed by 12 induction doses (two doses per week for 6 weeks) plus 36 continuation doses (two doses per week for 18 weeks) (see Six-month RFB-based therapy in Table 1A of Appendix). A.II The minimum duration of short-course rifampin-containing TB

treatment regimens is 6 months, to complete a) at least 180 doses (one dose per day for 6 months) or b) 14 induction doses (one dose per day for 2 weeks) followed by 12-18 induction doses (two to three doses per week for 6 weeks) plus 36-54 continuation doses (two to three doses per week for 18 weeks) (see Six-month RIF-based therapy in Table 1A of Appendix). A.II Three-times-per-week rifampin regimens should consist of at

least 78 doses administered over 26 weeks.* A.II The final decision on the duration of therapy should consider

the patient's response to treatment. For patients with delayed response to treatment (see Box 2(Table_B2)), the duration of rifamycin-based regimens should be prolonged from 6 months to 9 months (or to 4 months after culture conversion is documented). A.II The minimum duration of nonrifamycin, streptomycin-based TB

treatment regimens is 9 months, to complete a) at least 60 induction doses (one dose per day for 2 months) or b) 14 induction doses (one dose per day for 2 weeks) followed by 12-18 induction doses (two to three doses per week for 6 weeks) plus either 60 continuation doses (two doses per week for 30 weeks) or 90 continuation doses (three doses per week for 30 weeks). A.II When making the final decision on the duration of therapy,

clinicians should consider the patient's response to treatment. For patients with delayed response to treatment (see Box 2(Table_B2)), the duration of streptomycin-based regimens should be prolonged from 9 months to 12 months (or to 6 months after culture conversion is documented). A.III Interruptions in therapy because of drug toxicity or other

reasons should be taken into consideration when calculating the end-of-therapy date for individual patients. Completion of therapy is based on total number of medication doses administered and not on duration of therapy alone. A.III Reinstitution of therapy for patients with interrupted TB

therapy might require a continuation of the regimen originally prescribed (as long as needed to complete the recommended duration of the particular regimen) or a complete renewal of the regimen. In either situation, when therapy is resumed after an interruption of greater than or equal to 2 months, sputum samples (or other clinical samples as appropriate) should be taken for smear, culture, and drug-susceptibility testing.

Management of the Coadministration of TB and HIV Therapies, Including the Potential for Paradoxical Reactions

When antituberculosis treatment has been started, all patients should be monitored for response to antituberculosis therapy, drug-related toxicity, and drug interactions. Detailed recommendations for managing antiretroviral therapy are published elsewhere (4), and consultation with experts in this area is highly recommended.

The frequency and type of most TB medication side effects are similar among TB patients with and without HIV infection (30,65,67). When caring for HIV-infected persons, clinicians must be aware of the following problems that can result from the administration of TB medications: a) patients might have a higher predisposition toward isoniazid-related peripheral neuropathy; b) evaluation of dermatologic reactions related to TB medications might be complicated because HIV-infected patients are subject to several dermatologic diseases related to HIV disease or to medications used for other treatment or prophylaxis reasons; and c) patients undergoing concurrent therapy with rifabutin and protease inhibitors or NNRTIs are at risk for rifabutin toxicity associated with increased serum concentrations of this drug. The reported adverse events associated with rifabutin toxicity include arthralgias, uveitis, and leukopenia (86,101-103). Detailed recommendations for managing these adverse reactions are published elsewhere and should be consulted (2,64).

Paradoxical reactions -- temporary exacerbation of symptoms, signs, or radiographic manifestations of TB (e.g., recurrence of fever, enlarged lymph nodes, appearance of cavitation in previously normal chest x-ray) among patients who have experienced a good clinical and bacteriologic response to antituberculosis therapy -- have been reported among patients coinfected with HIV who have restored immune function because of antiretroviral therapy (76). The synchronization and severity of paradoxical reactions associated with antiretroviral therapy are not well understood; therefore, experts do not know whether the occurrence of these reactions should affect the timing of initiating or changing antiretroviral therapy when such therapy is indicated for a patient with HIV infection. However, because an association between paradoxical reactions and initiation of antiretroviral therapy has been noted, clinicians should be aware of this possibility and discuss the risks with patients undergoing therapy for active TB.

Monthly Medical Evaluation and the Diagnosis and Management of Paradoxical Reactions A.II All patients should receive a monthly clinical evaluation (see

Box 2(Table_B2)) to monitor their response to treatment, adherence to treatment, and medication side effects (Table 2A of Appendix). During the early days of therapy, the interval between these evaluations might be shorter (e.g., every 2 weeks). A.II Patients suspected of having paradoxical reactions should be

evaluated to rule out other causes for their clinical presentation (e.g., TB treatment failure) before attributing their signs and symptoms to a paradoxical reaction. C.III Some experts recommend that to avoid paradoxical reactions,

clinicians should delay the initiation of or changes in antiretroviral therapy until the signs and symptoms of TB are well controlled (possibly 4-8 weeks from the initiation of TB therapy).

No rating

For patients with a paradoxical reaction in whom the symptoms are not severe or life-threatening, the management of these reactions might consist of symptomatic therapy and no change in antituberculosis or antiretroviral therapy. For patients with a paradoxical reaction associated with severe or life-threatening clinical manifestations (e.g., uncontrollable fever, airway compromise from enlarging lymph nodes, enlarging serosal fluid collections {pleuritis, pericarditis, peritonitis}, sepsis-like syndrome), the management might include hospitalization and possibly a time-limited use of corticosteroids (e.g., prednisone started daily at a dose of 60-80 mg and reduced after 1 or 2 weeks, with the resolution of symptoms as a guide; in most cases, corticosteroid therapy should last no more than 4-6 weeks).

TB Drug Interaction and Absorption E.II Given the expected drug interactions that would result in

markedly decreased serum levels of antiretroviral agents, and given the overlapping toxicities, the coadministration of rifampin with any of the protease inhibitors or with NNRTIs, as well as the coadministration of rifabutin with ritonavir, hard-gel saquinavir (Invirase ), or delavirdine, is contraindicated. A.II The potent effect of rifampin as a CYP450 inducer, which

lowers the serum concentration of protease inhibitors and NNRTIs, is expected to continue up to at least 2 weeks following the discontinuation of rifampin. Therefore, to diminish the likelihood of adverse effects on drug metabolism, clinicians should plan the start of therapy with protease inhibitors or NNRTIs at least 2 weeks after the date of the last dose of rifampin. A.II Rifabutin is a less potent CYP450 inducer than rifampin

and thus can be used (with adjustments in dosages) concurrently with the NNRTIs nevirapine or efavirenz or with certain protease inhibitors (e.g., indinavir, nelfinavir, and possibly soft-gel saquinavir {Fortovase } and amprenavir). No rating Indinavir serum concentrations are decreased by

rifabutin-related induction of the hepatic cytochrome P450; therefore, when indinavir is used in combination with rifabutin, the dose of indinavir usually is increased from 800 mg every 8 hours to 1,200 mg every 8 hours. No rating Nelfinavir serum concentrations are also decreased when

nelfinavir is used in combination with rifabutin (Table 1A of Appendix); however, the resultant metabolite of nelfinavir is known to be active against HIV. Nevertheless, some experts suggest increasing the dose of nelfinavir from 750 mg three times per day to 1,000 mg three times per day when used in combination with rifabutin. No rating Experts do not know whether dose-modifications are needed

for soft-gel saquinavir (Fortovase ), amprenavir, nevirapine, or efavirenz if these agents are used in combination with rifabutin. No rating Many other medications commonly used by patients with HIV

infection have drug interactions with the rifamycins (rifampin or rifabutin) of sufficient magnitude to require interventions such as dose adjustments or use of alternative therapies. Some examples of these drugs are hormonal contraceptives, dapsone, ketoconazole, fluconazole, itraconazole, narcotics (including methadone), anticoagulants, corticosteroids, cardiac glycosides, hypoglycemics (sulfonylureas), diazepam, beta-blockers, anticonvulsants, and theophylline. No rating Malabsorption of antituberculosis drugs has been

demonstrated in some patients with HIV infection, and in some cases, it has been associated with TB treatment failures and the selection of drug-resistant M. tuberculosis bacilli (141-145). Therapeutic drug monitoring has been advocated by some experts as an adjunct in the management of HIV-related TB (146). This approach might be useful when evaluating patients with TB treatment failure or relapse and in the treatment of multidrug-resistant (MDR) TB. However, the role of therapeutic drug monitoring in the routine management of TB among HIV-infected patients has not been established and is not presently recommended.

Treatment of TB in Special Situations

The following general treatment recommendations address special situations such as drug-resistant forms of HIV-related TB, TB among HIV-infected pregnant women, TB among HIV-infected children, and extrapulmonary HIV-related TB. Detailed recommendations for managing these patients are published elsewhere (2,64,147-150), and consultation with experts in these areas is highly recommended.

Treatment of Drug-Resistant TB A.II TB disease resistant to isoniazid only. The treatment regimen

should generally consist of a rifamycin (rifampin or rifabutin), pyrazinamide, and ethambutol for the duration of treatment. Intermittent therapy administered twice weekly can be used following at least 2 weeks (14 doses) of daily induction therapy (see Duration of TB Treatment). The recommended duration of treatment is 6-9 months or 4 months after culture conversion. Isoniazid is generally stopped when resistance (greater than 1% of bacilli resistant to 1.0 ug/mL of isoniazid) to this drug is discovered; however, when low-level resistance is discovered (greater than 1% of bacilli resistant to 0.2 ug/mL of isoniazid, but no resistance to 1.0 ug/mL of isoniazid), some experts suggest continuing to use isoniazid as part of the treatment regimen. Because the development of acquired rifamycin resistance would result in MDR TB, clinicians should carefully supervise and manage TB treatment for these patients. A.II TB disease resistant to rifampin only. The 9-month treatment

regimen should generally consist of an initial 2-month phase of isoniazid, streptomycin, pyrazinamide, and ethambutol (see Nine-month SM-based therapy in Table 1A of Appendix). The second phase of treatment should consist of isoniazid, streptomycin, and pyrazinamide administered for 7 months. Because the development of acquired isoniazid resistance would result in MDR TB, clinicians should carefully supervise and manage TB treatment for these patients. A.III Multidrug-resistant TB (resistant to both isoniazid and

rifampin). These patients should be managed by or in consultation with physicians experienced in the management of MDR TB. Findings from a retrospective study of patients with MDR TB strongly indicate that early aggressive treatment with appropriate regimens (based on the known or suspected drug-resistance pattern of the M. tuberculosis isolate) markedly decreases deaths associated with MDR TB (63,151-153). Most drug regimens currently used to treat MDR TB include an aminoglycoside (e.g., streptomycin, kanamycin, amikacin) or capreomycin, and a fluoroquinolone. The recommended duration of treatment for MDR TB in HIV-seropositive patients is 24 months after culture conversion, and posttreatment follow-up visits to monitor for TB relapse should be conducted every 4 months for 24 months. Because of the serious personal and public health concerns associated with MDR TB, health departments should always use DOT for these patients and take whatever steps are needed to ensure their adherence to therapy.

A.III TB Treatment for HIV-Infected Pregnant Women

HIV-infected pregnant women who have a positive M. tuberculosis culture or who are suspected of having TB disease should be treated without delay. Choices of T B treatment regimens for HIV-infected pregnant women are those that include a rifamycin (Table 1A of Appendix). Routine use of pyrazinamide during pregnancy is recommended by international organizations but has not been recommended in the United States because of inadequate teratogenicity data (2). However, for HIV-infected pregnant women, the benefits of a TB treatment regimen that includes pyrazinamide outweigh potential pyrazinamide-related risks to the fetus. Aminoglycosides (e.g, streptomycin, kanamycin, amikacin) and capreomycin are contraindicated for all pregnant women because of potential adverse effects on the fetus. Considerations for antiretroviral therapy for pregnant HIV-infected women have been published elsewhere (4). A.II TB Treatment for HIV-Infected Children

HIV-infected children who are suspected of having TB disease should be treated without delay. For HIV-infected children, even those who are too young to be evaluated for visual acuity and red-green perception, ethambutol at a dosage of 15 mg/kg body weight (Table 2A of Appendix) should generally be included as part of the initial regimen, unless the infecting strain of M. tuberculosis is known or suspected of being susceptible to isoniazid and rifampin. If drug-susceptibility results are not available, a four-drug regimen (e.g., isoniazid, rifamycin, pyrazinamide, and ethambutol) for 2 months, followed by intermittent administration of isoniazid and a rifamycin for 4 months, is recommended. Considerations for antiretroviral therapy for children and adolescents have been published elsewhere (154). A.II TB Treatment for HIV-Infected Patients with Extrapulmonary

TB The basic principles that support the treatment of pulmonary TB in HIV-infected patients also apply to extrapulmonary forms of the disease. Most extrapulmonary forms of TB (including TB meningitis, tuberculous lymphadenitis, pericardial TB, pleural TB, and disseminated or miliary TB) are more common among persons with advanced-stage HIV disease (155,156) than among patients with asymptomatic HIV infection. The drug regimens and treatment durations that are recommended for treating pulmonary TB in HIV-infected adults and children (Table 1A of Appendix) are also recommended for treating most patients with extrapulmonary disease. However, for certain forms of extrapulmonary disease, such as meningioma, bone, and joint TB, using a rifamycin-based regimen for at least 9 months is generally recommended.

Latent M. tuberculosis Infection Clinical and Public Health Principles

When caring for persons with HIV infection, clinicians should make aggressive efforts to identify those who also are infected with M. tuberculosis. Because the reliability of the tuberculin skin test (TST) can diminish as the CD4+ T-cell count declines, TB screening with TST should be performed as soon as possible after HIV infection is diagnosed. Because the risk of infection and disease with M. tuberculosis is particularly high among HIV-infected contacts of persons with infectious pulmonary or laryngeal TB, these persons must be evaluated for TB as soon as possible after learning of exposure to a patient with infectious TB.

Health-care providers, administrators, and TB controllers must coordinate their work and establish TB screening initiatives in settings where a) the prevalence of infection with M. tuberculosis among persons with HIV-infection is expected to be high and b) referral for medical evaluation and TB preventive therapy can be accomplished. Such settings include prisons, jails, prenatal-care programs, drug treatment programs, syringe exchange programs, HIV specialty clinics, acute-care hospitals serving populations at high risk of TB, AIDS patient group residences, some community-health centers, psychiatric institutions, mental health residences, and homeless shelters. All HIV counseling and testing sites must have mechanisms in place to ensure that persons identified with HIV infection receive tuberculin skin testing. TB control programs in jurisdictions that have HIV reporting requirements should make efforts to ensure that all persons with HIV infection have TSTs.

Because of the complexity of problems associated with active TB disease in HIV-infected persons, and as part of the efforts to control and eliminate TB in the United States, all HIV-infected persons identified as latently infected with M. tuberculosis should complete a full recommended course of preventive therapy unless such therapy is contraindicated. Public health programs should take an active role in ensuring that patients treated in outpatient settings complete TB preventive therapy. In certain outpatient and institutional settings, directly observed preventive therapy (DOPT) should be used whenever operationally feasible and when resources permit.

Diagnosis of M. tuberculosis Infection Among HIV-Infected Persons

The Mantoux-method TST, with 5 TU of purified protein derivative, is used to diagnose M. tuberculosis infection. A TST reaction size of greater than or equal to 5 mm of induration is considered positive (i.e., indicative of M. tuberculosis infection) in persons who are infected with HIV. Persons with a TST reaction size of less than 5 mm but with a history of exposure to TB also could be infected with M. tuberculosis; this possibility should be investigated (157). Whenever M. tuberculosis infection is suspected in a patient, an evaluation to rule out active TB and assess the need for preventive therapy should be conducted (see Box 3(Table_B3)). This evaluation should include HIV counseling and testing for persons whose HIV status is unknown but who are at risk for HIV infection.

Tuberculin Skin Testing Among HIV-Infected Persons A.I As soon as possible after HIV infection is diagnosed, all

persons should receive a TST unless previously tested and found to be TST-positive. A.II As soon as possible (ideally within 7 days) after learning

of an exposure to a patient with infectious TB, all HIV-infected persons should be evaluated for TB and receive a TST, regardless of any previous TST results. B.III TSTs should be conducted periodically for HIV-infected

persons who are TST-negative on initial evaluation and who belong to populations with a substantial risk of exposure to M. tuberculosis (e.g., residents of prisons, jails, or homeless shelters). C.III Some experts recommend repeat TSTs for HIV-infected persons

who are TST-negative on initial evaluation and whose immune function is restored because of effective antiretroviral therapy. C.I Because results of anergy testing in HIV-infected

populations in the United States do not seem useful to clinicians making decisions about preventive therapy, anergy testing is no longer recommended as a routine component of TB screening among HIV-infected persons (157). However, some experts support the use of anergy testing to help guide individual decisions regarding preventive therapy, and some recommend that a TST be performed on patients previously classified as anergic if evidence indicates that these patients' immune systems have responded to therapy with antiretroviral drugs.

Candidates for TB Preventive Therapy Among HIV-Infected Persons A.I Persons with a TST reaction size of greater than or equal

to 5 mm who have not previously received treatment for M. tuberculosis infection should receive TB preventive treatment, regardless of their age. A.II Persons who have had recent contact with an infectious TB

patient should receive TB preventive treatment, regardless of their age, results of TSTs, or history of previous TB preventive treatment. A.II Persons with a history of prior untreated or inadequately

treated past TB that healed and no history of adequate treatment for TB should receive TB preventive treatment, regardless of their age or results of TSTs. C.III Primary prophylaxis for TST-negative, HIV-infected persons

with an on-going and unavoidable high risk of exposure to M. tuberculosis for the duration of the exposure time (e.g., residents of prisons, jails, or homeless shelters in which the current prevalence of TB is high) should be considered in some situations.

TB Preventive Therapy Regimens, Including Dosage Recommendations

The following recommendations are appropriate for adults with HIV infection who are likely to have latent M. tuberculosis infection with organisms susceptible to isoniazid and rifamycins. Updated recommendations for children are not yet available. Several TB preventive therapy regimens are currently recommended (Table 3A of Appendix). The TB medications used in these regimens have varying doses, toxicities, and monitoring requirements (Table 2A of Appendix). All patients on twice-a-week dosing regimens should receive DOPT; some experts also recommend DOPT for patients on 2-month preventive therapy regimens. The administration of TB preventive therapy regimens that contain rifampin is contraindicated for patients who take protease inhibitors or NNRTIs. For these patients, the substitution of rifabutin for rifampin in preventive therapy regimens is recommended; however, the substitution of rifapentine for rifampin is not currently recommended because rifapentine's safety and effectiveness have not been established for patients infected with HIV.

Recommended Preventive Therapy Regimens for Patients Receiving Protease Inhibitors or NNRTIs A.II For HIV-infected adults, a 9-month regimen of isoniazid

can be administered daily. B.I For HIV-infected adults, a 9-month regimen of isoniazid

can be administered twice a week (DOPT should be used with intermittant dosing regimens). B.III For HIV-infected adults, a 2-month regimen of rifabutin and

pyrazinamide can be administered daily. No rating The concurrent administration of rifabutin is

contraindicated with ritonavir, hard-gel saquinavir (Invirase ), and delavirdine.

Recommended Preventive Therapy Regimens for Patients Not Receiving Protease Inhibitors or NNRTIs A.II For HIV-infected adults, a 9-month regimen of isoniazid can

be administered daily. B.I For HIV-infected adults, a 9-month regimen of isoniazid

can be administered twice a week. A.I For HIV-infected adults, a 2-month regimen of rifampin and

pyrazinamide can be administered daily.

Duration of TB Preventive Therapy A.II Daily isoniazid regimens should consist of at least 270

doses to be administered for 9 months or up to 12 months if interruptions in therapy occur. A.III Twice-a-week isoniazid regimens should consist of at least

76 doses to be administered for 9 months or up to 12 months if interruptions in therapy occur. A.II Daily regimens of rifamycin (rifampin or rifabutin) and

pyrazinamide should consist of at least 60 doses to be administered for 2 months or up to 3 months if interruptions in therapy occur. A.III When calculating the end-of-preventive-therapy date for

individual patients, consider interruptions in therapy because of drug toxicity or other reasons. Completion of therapy is based on total number of medication doses administered and not on duration of therapy alone. A.III When reinstituting therapy for patients with interrupted TB

preventive therapy, clinicians might need to continue the regimen originally prescribed (as long as needed to complete the recommended duration of the particular regimen) or completely renew the entire regimen. In either situation, when therapy is restored after an interruption of greater than or equal to 2 months, a medical examination to rule out TB disease is indicated.

Monthly Monitoring of Patients During TB Preventive Treatment A.II All persons undergoing preventive treatment for TB should

receive a monthly clinical evaluation of their adherence to treatment and medication side effects (see Box 4(Table_B4)).

Treatment of Latent M. tuberculosis Infection in Special Situations A.I DOPT should always be used with intermittent dosing

regimens. B.III DOPT also should be used when operationally feasible,

especially with 2-month preventive therapy regimens and in some special settings (e.g., in some institutional settings, in some community outreach programs, and for some persons who are candidates for preventive therapy because they are household contacts of patients with TB disease who are receiving home-based DOT). A.III For persons who are known to be contacts of patients with

isoniazid-resistant, rifamycin-susceptible TB, a 2-month preventive therapy regimen of a rifamycin (rifampin or rifabutin) and pyrazinamide is recommended. For patients with intolerance to pyrazinamide, a 4-6-month regimen of a rifamycin (rifampin or rifabutin) alone is recommended (158-160) (Table 3A of Appendix). C.III The choices for preventive treatment for persons who are

likely to be infected with a strain of M. tuberculosis resistant to both isoniazid and rifamycins are published elsewhere (161). In general, the recommended preventive therapy regimens for these persons include the use of a combination of at least two antituberculosis drugs that the infecting strain is believed to be susceptible to (e.g., ethambutol and pyrazinamide, levofloxacin and ethambutol). The clinician should review the drug-susceptibility pattern of the M. tuberculosis strain isolated from the infecting source-patient before choosing a preventive therapy regimen. A.III For HIV-infected women who are candidates for TB preventive

therapy, the initiation or discontinuation of preventive therapy should not be delayed on the basis of pregnancy alone, even during the first trimester. A 9-month regimen of isoniazid administered daily or twice a week is the only recommended option (Table 3A of Appendix). No rating For HIV-infected children who are candidates for TB

preventive therapy, a 12-month regimen of isoniazid administered daily is recommended by the American Academy of Pediatrics (162).

Follow-up of HIV-Infected Persons Who Have Completed Preventive Therapy A.II Follow-up care -- including chest x-rays and medical

evaluations -- is not necessary for patients who complete a course of TB preventive treatment, unless they develop symptoms of active TB disease or are subsequently reexposed to a person with infectious TB disease.

Follow-up of HIV-Infected Persons Who Are Candidates for, but Who Do Not Receive, TB Preventive Therapy A.III These persons should be assessed periodically (in intervals

of less than 6 months) for symptoms of active TB as part of their ongoing HIV infection management. Clinicians should educate these persons about the symptoms of TB disease (e.g., cough with or without fever, night sweats, weight loss) and advise them to seek immediate medical attention if they develop such symptoms. If persons present with these symptoms, clinicians should always include TB disease in the differential diagnosis.

CONCLUSIONS

Implementing TB prevention and control strategies for persons infected with HIV has always been important and is even more critical now that a larger selection of new, more potent antiretroviral drugs has enabled clinicians to implement therapies that improve the health and prolong the lives of HIV-infected persons. These antiretroviral therapeutic strategies often include the use of drugs such as the protease inhibitors or the nonnucleoside reverse transcriptase inhibitors (NNRTIs), which because of drug interactions cannot be used concurrently with certain other drugs (e.g., rifampin). Thus, to improve the diagnosis and management of TB and HIV coinfection, TB control programs need to be prepared for the following challenges:

  • Ensure that all patients with TB receive HIV counseling and testing either on site or elsewhere. Patients with latent M. tuberculosis infection who are at risk for HIV infection also should receive HIV counseling and testing.

  • Initiate prompt and effective antituberculosis treatment (ideally with directly observed therapy) for all patients diagnosed with HIV-related TB.

  • Promote optimal antiretroviral therapy for patients with M. tuberculosis and HIV infection.

  • Become knowledgeable about the indications, potential dosing adjustments, and monitoring requirements of a rifabutin-containing regimen (or an alternative regimen that does not contain rifamycin) for the treatment of TB in patients who are undergoing antiretroviral therapy with protease inhibitors or NNRTIs.

  • Identify potential risk factors for TB treatment failure or relapse as well as the potential for paradoxical treatment reactions, and learn how to recognize and manage these outcomes.

  • Follow procedures to ensure early recognition and implementation of effective treatment for drug-resistant TB.

  • Recognize that previous options that involved stopping protease inhibitor therapy to allow the use of rifampin for TB treatment are no longer recommended for two reasons: a) the most recent guidelines for the use of antiretroviral therapy advise against interrupting HIV therapy, and b) alternatives for TB therapy that do not contain rifampin are available.

  • Coordinate efforts and establish TB screening initiatives in settings where a) the prevalence of infection with M. tuberculosis among persons with HIV-infection is expected to be high and b) referral for medical evaluation and therapy for active or latent TB is possible.

  • Be aware of changes in options for TB preventive therapy. In addition to recommendations for using 9 months of isoniazid daily or twice a week, new short-course multidrug regimens (e.g., a 2-month course of a rifamycin such as rifabutin or rifampin with pyrazinamide) can be prescribed for HIV-infected patients with latent M. tuberculosis infection.

When faced with treatment choices, TB controllers and clinicians can use these recommendations to make informed decisions based on the most current research results available, keeping in mind that as new antiretroviral and antituberculosis agents become available, these guidelines will likely change. The aim of these recommendations is to help reduce TB treatment failures, prevent cases of drug-resistant TB, diminish the adverse effects that TB has on HIV replication, and support efforts to not only control TB, but to eliminate it from the United States. Future research should include a) the development of methods for early and accurate diagnosis of M. tuberculosis infection in persons coinfected with HIV, b) strategies to help simplify treatment for active and latent TB and increase adherence to and completion of therapy, and c) basic research to define what host factors protect persons from infection with M. tuberculosis and HIV and from the development of TB and HIV disease.

Acknowledgments

Staff with the Division of Tuberculosis Elimination (DTBE) at CDC's National Center for HIV, STD, and TB Prevention (NCHSTP) and the panel of expert consultants who prepared this report thank the following persons who attended a September 1998 meeting sponsored by the American Thoracic Society and CDC and provided advice about revising the recommendations on TB preventive therapy: George W. Comstock, M.D., Dr.P.H., Johns Hopkins University, School of Public Health, Hagerstown, Maryland; Mark S. Dworkin, M.D., Division of HIV/AIDS Prevention--Surveillance and Epidemiology, NCHSTP, CDC, Atlanta, Georgia; Lawrence J. Geiter, Ph.D., Sequella Global Tuberculosis Foundation, Arlington, Virginia; Peter Godfrey-Faussett, M.D., M.R.C.P., Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland; Richard F. Jacobs, M.D., Department of Pediatrics, Division of Infectious Disease, Arkansas Children's Hospital, Little Rock, Arkansas; Alwyn G. Mwinga, M.D., M.B., Ch.B., M.Sc., M.Med., Department of Medicine, University Teaching Hospital, Lusaka, Zambia; and James D. Neaton, Ph.D., Coordinating Center for Biometric Research, Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota.

The authors also acknowledge the following persons for assisting in the preparation of this report: Ann H. Lanner, Sylvia R. Ivill, Maria V. Fraire, M.P.H., Nickolas M. DeLuca, M.A., Dianne H. Meeks, and Sherry M. Hussain, DTBE, NCHSTP, CDC, Atlanta, Georgia; Amanda Crowell, Judith E. Luchtan, C. Kay Smith-Akin, M.Ed., and Rachel J. Wilson, Epidemiology Program Office, CDC, Atlanta, Georgia; and Paula I. Fujiwara, M.D., M.P.H., Bureau of Tuberculosis Control, New York, New York, and DTBE, NCHSTP, CDC.

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* Every effort should be made to continue administering streptomycin for the total duration of treatment or for at least 4 months after culture conversion (approximately 6-7 months from the start of treatment). Some experts suggest that in situations in which streptomycin is not included in the regimen for all of the recommended 9 months, ethambutol should be added to the regimen to replace streptomycin, and the duration of treatment should be prolonged from 9 months to 12 months. Alternatives to streptomycin are the injectable drugs amikacin, kanamycin, and capreomycin.

* To minimize the emergence of drug-resistant HIV strains, if any antiretroviral medication must be temporarily discontinued for any reason, clinicians and patients should be aware of the theoretical advantage of stopping all antiretroviral agents simultaneously, rather than continuing the administration of one or two of these agents alone (4).

* Three-times-per-week rifabutin regimens, used in combination with antiretroviral therapy, have not been studied.






Table_1
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TABLE 1. Annual rates* of tuberculosis among persons with human imunodeficiency virus infection, by
tuberculin skin-test (TST) status -- selected years and U.S. areas
========================================================================================================
Location and source                     Rate among persons     Rate among persons     Rate ratio
                                        with positive TSTs     with negative TSTs
--------------------------------------------------------------------------------------------------------
New York City Selwyn et al. 1989 (9 )          7.9                     0.3               26.3

San Francisco Daley et al. 1998 (10 )          5.0                     1.0                5.0

Multiple sites
Markowitz et al. 1997 (11 )
  East Coast                                   4.6                     1.3                3.5
  West/Midwest                                 1.7                     0.2                8.5
  All sites                                    4.5                     0.4               11.3
--------------------------------------------------------------------------------------------------------
* Cases per 100 person-years.
========================================================================================================

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Table_2
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TABLE 2. Percentage of tuberculosis (TB) patients* with drug-resistant isolates,+ by drug and human
immunodeficiency virus (HIV) serostatus -- United States, 1993-1996
============================================================================================================
                                                  HIV serostatus (%)
                       --------------------------------------------------------------------------------------
Drug&                   HIV positive (n=5,112)   HIV negative (n=3,754)   HIV status unknown (n=7,186)
-------------------------------------------------------------------------------------------------------------
Isoniazid                        11.3                      5.5                         6.8
Rifampin                          8.9                      1.6                         2.5
Pyrazinamide                      5.1                      1.8                         2.2
Streptomycin                      6.7                      4.1                         5.0
Ethambutol                        3.9                      1.5                         2.0
Isoniazid and rifampin            6.2                      1.3                         1.5
Rifampin only@                    2.4                      0.2                         0.8
-------------------------------------------------------------------------------------------------------------
* Patients were born in the United States, were aged 22-44 years, and were not known to have had a
  previous episode of TB. All TB cases reported from California are included in the HIV-unknown
  category.
+ The patient's Mycobacterium tuberculosis isolate had resistance to at least the specified drug but
  may have had resistance to other drugs as well.
& The differences in drug-resistance rates among patients with TB known to be HIV-seropositive,
  compared with those known to be HIV-seronegative or of unknown status, are statistically significant
  (Chi-square test statistic, p<0.05).
@ These figures were calculated for patients with M. tuberculosis isolates tested for isoniazid and
  rifampin always and streptomycin sometimes. Monoresistant isolates were resistant to rifampin but
  susceptible to the other first-line drugs tested.

Source: CDC, National Tuberculosis Surveillance System.
=============================================================================================================

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Table_3
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TABLE 3. Posttreatment relapse rates and CD4+ T-cell counts among patients enrolled in prospective studies of 6-month* tuberculosis (TB) treatment
regimens, by human immunodeficiency virus (HIV) serostatus
=================================================================================================================================================================================
                                                         Posttreatment     CD4+ T-cell counts
Location and source                 HIV status           relapses (%)           (median)        Comments
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Zaire Perriens et al. 1995     HIV positive (n=124)           9.0            338 cells/uL3      All cases of TB confirmed by culture at baseline.
(66 )
                               HIV negative (n=183)           5.3                               DOT except for 1/2 doses in continuation phase.
                                                                                                Posttreatment follow-up = 12 months.
                                                                                                Culture-based relapse definition; however,relapse vs. reinfection not
                                                                                                assessed by DNA fingerprinting.

Cote d'Ivoire Kassim et al.   HIV-1 positive  (n=106)         3.0          Data not available   Includes culture-positive and clinically diagnosed cases of TB.
1995 (49 )
                               HIV negative (n=194)           3.0                               Self-administered therapy.
                                                                                                Posttreatment follow-up = 18 months.
                                                                                                Relapse definition includes both culture-confirmed and clinically diagnosed
                                                                                                TB.
                                                                                                Relapse vs. reinfection not assessed by DNA fingerprinting.

Haiti Chaisson et al. 1996     HIV positive (n=177)           5.4           475 cells/

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Table_4
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TABLE 4. Effects of coadministering rifamycins and protease inhibitors (PIs) on the systemic exposure
(area-under-the-concentration-time curve {AUC}) of each drug*
====================================================================================================================================
                                                             Rifampin (RIF)                      Rifabutin (RFB)
                                                   -------------------------------     ---------------------------------------------
                                                    RIF's effect   PI's effect on      RFB's effect on PI   PI's effect on RFB
PI and source                                          on PI       RIF
------------------------------------------------------------------------------------------------------------------------------------
Saquinavir +                                        80% decrease   Data not            45% decrease         Data not reported
Sahai et al. 1996 (85

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Table_5
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TABLE 5. Known and predicted effects of coadministering rifamycins and nonnucleoside reverse transcriptase inhibitors (NNRTIs) on the systemic
exposure (area-under-the-concentration-time curve {AUC}) of each drug *
===================================================================================================================================================
                                       Rifampin (RIF)                                   Rifabutin (RFB)
NNRTI and source                       RIF's effect on NNRTI    NNRTI's effect on RIF   RFB's effect NNRTI       NNRTI's effect on RFB
---------------------------------------------------------------------------------------------------------------------------------------------------
Nevirapine                             37% decrease             Unchanged+              16% decrease             Decrease+
Roxane Laboratories, 1997

Delavirdine                            96% decrease             Unchanged+              80% decrease             342% Increase+
Borin et al. 1997 (93 )
Borin et al. 1997 (94 )
Cox et al. 1998 (95 )

Efavirenz                              13% decrease             Unchanged+              Decrease+                Decrease+
Benedek et al. 1998 (96 )
---------------------------------------------------------------------------------------------------------------------------------------------------
* Effects are expressed as a percentage change in AUC of the concomitant treatment relative to that of the drug-alone treatment. No data are
  available regarding the magnitude of these bidirectional interactions when rifamycins are administered two or three times a week instead of
  daily.
+ Predicted effect based on knowledge of metabolic pathways for the two drugs.
===================================================================================================================================================

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Table_6
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TABLE 6. Feasibility of using different antiretroviral drugs and rifabutin
=====================================================================================
                        Can be used in
Antiretroviral         combination with
agent                     rifabutin?       Comments
-------------------------------------------------------------------------------------
Saquinavir (soft-          Probably        Use of the soft-gel formulation
gel formulation)                           (Fortovase(tm)) in higher-than-
                                           usual doses might allow adequate
                                           serum concentrations of this
                                           drug despite concurrent use of
                                           rifabutin.* However, the
                                           pharmacokinetic data for this
                                           combination are limited in
                                           comparison with other protease
                                           inhibitors. Because of the
                                           expected low bioavailability of
                                           the hard-gel formulation
                                           (Invirase(tm)) the concurrent
                                           use of this agent with rifabutin
                                           is not recommended.

Ritonavir                     No           Ritonavir increases
                                           concentrations of rifabutin by
                                           35-fold and results in increased
                                           rates of toxicity (arthralgia,
                                           uveitis, skin discoloration, and
                                           leukopenia). These adverse
                                           events have been noted in
                                           studies of high-dose rifabutin
                                           therapy,
                                           when rifabutin is administered
                                           with clarithromycin (another
                                           CYP450 inhibitor) -- an
                                           indication that these events
                                           might result from high serum
                                           concentrations of rifabutin.

Indinavir                    Yes           Data from drug interaction
                                           studies (unpublished report,
                                           Merck Research Laboratories,
                                           West Point, PA, 1998) suggest
                                           that the dose of indinavir
                                           should be increased from 800 mg
                                           every 8 hours to 1,200 mg every
                                           8 hours if used in combination
                                           with rifabutin.*


Nelfinavir                   Yes           Some clinical experts suggest
                                           that the dose of nelfinavir
                                           should be increased from 750 mg
                                           three times a day to 1,000 mg
                                           three times a day if used in
                                           combination with rifabutin.*

Amprenavir                 Probably        The drug interactions between
                                           amprenavir and rifabutin (and
                                           thus potential for rifabutin
                                           toxicity) are reported to be
                                           similar to those of ritonavir
                                           with rifabutin. However,
                                           potential advantages of using
                                           this combination are that a)
                                           rifabutin has a minimal effect
                                           on reducing the levels of
                                           amprenavir and b) even though it
                                           has not been studied, rifabutin
                                           toxicity is not expected if the
                                           daily dose of rifabutin is
                                           reduced when used in combination
                                           with amprenavir.


NRTIs+                       Yes           Not expected to have clinically
                                           significant interaction.

Nevirapine                   Yes           Not known whether nevirapine or
                                           rifabutin dose adjustments are
                                           necessary when these drugs are
                                           used together.*

Delavirdine                   No           Not recommended on the basis of
                                           marked decreases in
                                           concentrations of delavirdine
                                           when administered with
                                           rifamycins.

Efavirenz                  Probably         Newly approved agent.
                                           Preliminary drug interaction
                                           studies suggest that when
                                           rifabutin is used concurrently
                                           with efavirenz,
                                           the dose of rifabutin for both
                                           daily and twice weekly
                                           administration should be
                                           increased from 300 mg to 450 mg.
-------------------------------------------------------------------------------------
* Daily dose of rifabutin should be reduced from 300 mg to 150 mg if used in
  combination with amprenavir, nelfinavir, or indinavir. It is unknown whether the
  dose of rifabutin should be reduced if used in combination with saquinavir
  (Fortovase(tm)) or nevirapine.
+ Nucleoside reverse transcriptase inhibitiors, including zidovudine, didanosine,
  zalcitabine, sta-vudine, and lamivudine.
=====================================================================================

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Table_7
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TABLE 7. Results from clinical trials* that compared rifabutin (RFB) with rifampin (RIF) in treatment for pulmonary tuberculosis (TB)
==========================================================================================================================================================================
                    No. of patients with
                    clinically significant
Location and source         No. of patients              Treatment* regimen          Bacteriologic conversion     Posttreatment relapses      adverse events
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Brazil                      RFB150 (n=174)               2 months of NH,RFB150,      At 3 months:                 At 2 years:                 RFB150 = 1
Argentina                   RFB300 (n=171)               PZA,EMB; daily/ 4 months    RFB150 = 86%                 RFB150 = 3.4%               RFB300 = 4
Thailand                    RIF (n=175)

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Table_8
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TABLE 8. Posttreatment relapse rates associated with tuberculosis treatment regimens containing
minimal or no rifampin among patients not known to be coinfected with human immunodeficiency virus
======================================================================================================
                                                                            Posttreatment
Location and source                             Treatment regimens          relapses (%)
------------------------------------------------------------------------------------------------------
Hong Kong                                       6 months of SM,INH,PZA;     18
                                                daily
Hong Kong Chest Service/British                 6 months of SM,INH,PZA;     24
Medical Research Council 1977 (112 )            three times a week

                                                6 months of SM,INH,PZA;     21
                                                two times a week

                                                9 months of SM,INH,PZA;      5
                                                daily

                                                9 months of SM,INH,PZA;      6
                                                three times a week

                                                9 months of SM,INH,PZA;      6
                                                two times a week

Algeria                                         2 months of                  3
Algerian Working Group/British Medical          INH,RIF,PZA,EMB; daily/ 4
Research Council 1984 (113 )                    months of INH,RIF; daily
                                                                            17


East Africa                                     6 months of SM,INH,RIF;      2
                                                daily
East African/British Medical                    6 months of SM,INH,PZA;     29
Research Council 1974 (114 )                    daily

East Africa East African/British Medical        1 month of SM,INH,RIF,PZA;   9
Research Council 1980 (115)                     daily/ 5 months of
                                                SM,INH,PZA; two times a
                                                week

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Table_9
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TABLE 9. Results from studies of tuberculosis (TB) preventive therapy among persons coinfected with human immunodeficiency virus
==========================================================================================================================================================
Location and source            TST status of study subjects   Preventive therapy regimen              Rate of TB per    Relative risk of TB  (95% CI)
                                                                                                      100 person-years
----------------------------------------------------------------------------------------------------------------------------------------------------------
Haiti
Pape et al.,1993 (121 )        TST positive (n=25)            12 months of placebo; daily                  10.0         5.8 (1.2-28.7)
                               TST positive (n=38)            12 months of INH; daily                       1.7         1

                               TST negative (n=35)            12 months of placebo; daily                   5.7         1.8 (0.4-9.2)
                               TST negative (n=20)            12 months of INH; daily                       3.2         1
Haiti
Halsey et al.,1994 (122 )      TST positive (n=370)           6 months of INH; two times a week             1.7         1

                               TST positive (n=380)           2 months of RIF,PZA; two times a week         1.8         1.1  (CI not available)
Uganda
Whalen et al.,1997 (123 )      TST positive (n=464)           6 months of placebo; daily                    3.4         1
                               TST positive (n=536)           6 months of INH; daily                        1.1         0.3 (0.1-0.8)
                               TST positive (n=556)           3 months of INH,RIF; daily                    1.3         0.4 (0.2-0.9)
                               TST positive (n=462)           3 months of INH,RIF,PZA; daily                1.7         0.4 (0.2-0.9)

                               Anergic (n=323)                6 months of placebo; daily                    3.1         1
                               Anergic (n=395)                6 months of INH; daily                        2.5         0.7 (0.3-1.9)
Zambia
Mwinga et al.,in press (124 )  TST positive (n=60)            6 months of placebo; two times a week         9.8         1
                               TST positive (n=52)            6 months of INH; two times a week             2.3         0.3 (0.05-1.4)
                               TST positive (n=49)            3 months of RIF,PZA; two times a week         2.7         0.3 (0.05-1.4)

                               TST negative (n=166)           6 months of placebo; two times a week         3.1         1
                               TST negative (n=178)           6 months of INH; two times a week             2.5          0.9 (0.31-2.4)
                               TST negative (n=173)           3 months of RIF,PZA; two times a week         3.8          1.3 (0.50-3.2)
Kenya
Hawken et al.,1997 (125 )      TST positive (n=67)            6 months of placebo; daily                    8.0         1
                               TST positive (n=69)            6 months of INH; daily                        5.6         0.6 (0.2-1.6)

                               TST negative (n=235)           6 months of placebo; daily                    2.7         1
                               TST negative (n=224)           6 months of INH; daily                        3.3         1.2 (0.6-2.7)
United States
Gordin et al.,1997 (126 )      Anergic (n=257)                6 months of placebo; daily                    0.9         1
                               Anergic (n=260)                6 months of INH; daily                        0.4         0.5 (0.1-1.9)
United States, Haiti, Mexico,
and Brazil
Gordin et al.,1998 (127 )      TST positive (n=792)           12 months of INH; daily                       1.2         1
                               TST positive (n=791)           2 months of RIF,PZA; daily                    1.2         1.0 (0.6-1.7)
----------------------------------------------------------------------------------------------------------------------------------------------------------
CI=confidence interval; INH=isoniazid; PZA=pyrazinamide; RIF=rifampin. TST=tuberculin skin test.
==========================================================================================================================================================

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Table_10
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TABLE 10. System used to rate the strength of recommendations and the quality of supporting evidence
=======================================================================================================
Rating
-------------------------------------------------------------------------------------------------------
         Strength of the recommendation
 A       Strong; should always be offered
 B       Moderate; should usually be offered
 C       Optional
 D       Should generally not be offered
 E       Should never be offered

         Quality of evidence supporting the recommendation
 I       At least one randomized trial with clinical endpoints
 II      Clinical trials with laboratory endpoints only or conducted only in populations
         not infected with human immunodeficiency virus
 III     Expert opinion
=======================================================================================================

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Figure_1

Figure_1
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Table_B1
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BOX 1. Components of the medical evaluation for human
immunodeficiency virus-infected patients suspected of having
tuberculosis
=========================================================================
     The medical evaluation should include the following questions
and assessments:
Medical History
-- Ask all patients about their history of tuberculosis (TB)
   treatment. If the patient has previously received treatment, care
   providers must determine the antituberculosis drugs used, duration
   of treatment, history of adverse reactions, reasons for
   discontinuation of treatment, history of adherence with treatment,
   and previous antituberculosis drug-susceptibility test results.

-- Question all patients about the following risk factors for
   drug-resistant TB: a) previous treatment for TB, especially if it
   was incomplete; b) previous residence in a country outside the
   United States where drug-resistant TB is common; c) close contact
   with a person who has drug-resistant TB or multidrug-resistant TB;
   and d) previous residence in an institution (i.e., hospital,
   prison, homeless shelter) with documented transmission of a
   drug-resistant strain of TB.

-- Ask all patients about their history of antiretroviral therapy
   and their history of therapies to prevent opportunistic infections.
   If the patient has previously or is currently receiving these
   treatments, care providers should determine the drugs used,
   duration of treatment, history of adverse reactions, and reasons
   for discontinuation of treatment if treatment ended.

-- Ask female patients whether they might be pregnant. Women of
   childbearing potential with menses more than 2 weeks late should
   receive a pregnancy test. (See TB Treatment for HIV-Infected
   Pregnant Women.)

-- When clinical specimens for culture and susceptibility testing
   cannot be obtained from patients (e.g., young children, patients
   with skeletal or meningeal TB), the culture and drug-susceptibility
   results of the Mycobacterium tuberculosis strain isolated from the
   infecting source-patient should be investigated and reviewed if
   available so that TB treatment for the current patient can be
   tailored appropriately. (See TB Treatment for HIV-Infected
   Children.)

-- If necessary, perform a Mantoux-method tuberculin skin test (TST)
   to help diagnose culture-negative TB.

Chest X-Ray Examination
-- Perform a chest x-ray examination. HIV-related immunosuppression
   reduces the inflammatory reaction and cavitation of pulmonary
   lesions, and therefore HIV-infected patients with pulmonary TB can
   have atypical findings or normal chest x-rays. Children younger
   than age 5 years should undergo both a posterior-anterior and a
   lateral chest x-ray. All other persons should receive a
   posterior-anterior chest x-ray; additional chest x-ray examinations
   should be performed at the physician's discretion. Pregnant women
   who are being evaluated for active TB disease should undergo a
   chest x-ray (with the appropriate shielding) without delay, even
   during the first trimester of pregnancy. Patients suspected of
   having extrapulmonary TB should undergo a chest x-ray to rule out
   pulmonary TB.

Laboratory Tests
-- Collect smears for acid-fast bacilli, cultures, and drug
   susceptibilities from expectorated or induced sputum samples on 3
   consecutive days, preferably in the mornings. Children who are
   unable to produce sputum spontaneously or who cannot use the sputum
   induction machine should be admitted to the hospital for early
   morning gastric aspirates on 3 consecutive, separate days.

-- Obtain a complete blood cell count, including platelets.

-- Conduct chemistry panel tests, especially for liver enzyme levels
   (serum glutamic oxalacetic transaminase or aspartate
   aminotransferase {SGOT/AST} and serum glutamic pyruvic transaminase
   or alanine aminotransferase {SGPT/ALT}); total bilirubin; uric
   acid; blood urea nitrogen; and creatinine.

Other Procedures
-- Perform a baseline visual acuity exam and test for red-green
   color perception for all patients who will be receiving ethambutol.

-- Perform baseline audiometry tests if an aminoglycoside (e.g,
   streptomycin, amikacin, kanamycin) or capreomycin will be
   administered.

-- Perform as necessary procedures such as bronchoscopies and
   bronchoalveolar lavage; biopsies and aspirates (e.g, of peripheral
   lymph nodes, visceral lymph nodes, liver, and bone marrow);
   mycobacterial culturing of nonrespiratory clinical specimens (e.g.,
   blood, urine, pleural fluid); and radiologic evaluations other than
   chest x-rays (e.g., computerized tomographies, magnetic resonance
   imaging).
=========================================================================

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Table_B2
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BOX 2. Components of the monthly medical evaluation for human
immunodeficiency virus-infected patients undergoing treatment for
active tuberculosis
======================================================================
     For patients infected with human immunodeficiency virus (HIV)
who are undergoing treatment for active tuberculosis (TB),
clinicians should include the following components in the monthly
evaluation:

-- Once a month, evaluate symptoms and signs of TB (response to
   treatment) by conducting a) a physical examination (the nature and
   extent of this evaluation will depend on the patient's symptoms and
   the site of disease) and b) for patients with pulmonary TB, an
   examination by smear and culture of an expectorated or induced
   sputum specimen until cultures are no longer positive for
   Mycobacterium tuberculosis.

-- Perform as necessary for individual patients laboratory tests
   such as: complete blood cell count, platelet count, and tests for
   serum glutamic oxalacetic transaminase or aspartate
   aminotransferase (SGOT/AST) and serum glutamic pyruvic transaminase
   or alanine aminotransferase (SGPT/ALT), alkaline phosphatase, total
   bilirubin, uric acid, blood urea nitrogen, and creatinine.

-- To assist in the decision about the duration of TB treatment,
   investigate the possibility of a delayed response to treatment
   (Table 1A of Appendix). Delayed response to treatment should be
   suspected (and in most cases treatment duration should be
   prolonged) if by the end of the 2-month induction phase of therapy,
   patients a) continue to be culture-positive for M. tuberculosis or
   b) do not experience resolution of signs or symptoms of TB or do
   experience progression of signs or symptoms of TB (e.g., persistent
   fever, progressive weight loss, or increase in size of lymph nodes,
   abscesses, or other tuberculous lesions, none of which can be
   accounted for by a disease other than TB). (See Duration of TB
   Treatment.)

-- Some factors potentially associated with TB treatment failure are
   a large mycobacterial load and extensive lung cavitation at
   baseline, nonadherence with the drug regimen (even among patients
   assumed to be on DOT), inappropriately low medication doses, and
   impaired absorption of drugs. Immediately institute corrective
   measures for those factors amenable to intervention.

-- Because patients with HIV-infection often are treated with
   multiple drugs in addition to antituberculosis drugs, at each
   visit, review all medications that the patient is taking and assess
   any change in medications for potential drug interactions with TB
   medications. Efforts to manage these potential problems related to
   drug interactions require the coordinated efforts of care givers
   for HIV and TB disease. (See TB Drug Interaction and Absorption.)

-- Because several antituberculosis drugs have hepatotoxicity as a
   potential side effect (Table 2A of Appendix), advise all persons
   taking TB medications about the symptoms consistent with hepatitis
   (e.g., anorexia, nausea, vomiting, abdominal pain, jaundice) and
   instruct them to discontinue all TB medications immediately and
   seek medical attention promptly if they exhibit such symptoms.
   These patients usually will need an examination by a physician,
   liver function tests, and a planned strategy for restarting TB
   treatment.

-- If ethambutol is administered, perform a monthly visual acuity
   exam and test for red-green color perception.

-- If streptomycin is administered, perform audiometry and renal
   function tests as needed.
======================================================================

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Table_B3
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BOX 3. Components of the baseline medical evaluation for
tuberculosis preventive treatment for patients infected with human
immunodeficiency virus
======================================================================
     When conducting a medical evaluation to rule out active
tuberculosis (TB) and administer preventive treatment for patients
infected with human immunodeficiency virus (HIV), clinicians should
include the following questions and assessments:

Medical History
-- Ask patients about their history of recent close contact with a
   person who has TB disease. If the infecting source-patient is
   known, his or her culture and drug-susceptibility results should be
   investigated and reviewed so that the preventive therapy regimen
   can be tailored appropriately (see Treatment of Latent M.
   Tuberculosis in Special Situations).

-- Assess patients for their risk of increased toxicity associated
   with the medications used for TB preventive therapy (e.g., history
   of excessive alcohol ingestion, liver disease, hepatitis, chronic
   use of other medications).

-- Assess patients for contraindications to TB preventive therapy
   (Table 3A of Appendix).

-- When persons have previously received TB preventive treatment,
   determine what drugs were used, duration of treatment, and any
   history of adverse reactions (Table 2A of Appendix) and adherence
   to preventive therapy.

-- Ask patients about their history of antiretroviral therapy and
   their history of therapies to prevent opportunistic infections. If
   a patient has ever received or is receiving any of these
   treatments, the care provider must determine the drugs used,
   duration of treatment, history of adverse reactions, potential for
   drug interactions with TB medications, and any reasons for
   discontinuation of treatment if treatment ended.

Chest X-Ray Examination
-- A chest x-ray is indicated for all persons being considered for
   preventive therapy, to rule out active pulmonary TB disease.
   Children younger than 5 years old should undergo both a
   posterior-anterior and a lateral chest x-ray. All other individuals
   should receive a posterior-anterior chest x-ray only; additional
   x-rays should be performed at the physician's discretion. Pregnant
   women who have a positive TST or who have negative TST results but
   are recent contacts of a person who has infectious TB disease
   should undergo a chest x-ray (with appropriate shielding) without
   delay, even during the first trimester of pregnancy.

Laboratory Tests
-- Obtain a complete blood cell count, and also obtain a platelet
   count if the patient will be treated with a rifamycin (rifampin or
   rifabutin).

-- Conduct chemistry panel tests, especially for liver enzyme levels
   (serum glutamic oxalacetic transaminase or aspartate
   aminotransferase {SGOT/AST} and serum glutamic pyruvic transaminase
   or alanine aminotransferase {SGPT/ALT}) and total bilirubin. In
   addition, check uric acid levels if the patient will be treated
   with pyrazinamide.

-- Obtain three consecutive sputum samples for smear, culture, and
   drug-susceptibility testing to rule out active TB disease in a)
   persons who have symptoms that indicate TB disease (e.g., cough,
   fever, night sweats, weight loss) and b) persons who have chest
   x-ray findings that indicate past, healed TB (e.g., noncalcified
   fibrotic lesions) and who have a history of no TB treatment or
   inadequate TB treatment.
======================================================================

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Table_B4
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BOX 4. Components of the monthly medical evaluation for human
immunodeficiency virus-infected patients undergoing preventive
treatment for latent Mycobacterium tuberculosisinfection
======================================================================
     For patients infected with human immunodeficiency virus (HIV)
who are undergoing preventive treatment for latent Mycobacterium
tuberculosis infection, clinicians should include the following
components in the monthly evaluation:

-- At every monthly evaluation, review signs and symptoms
   potentially related to active tuberculosis (TB) disease as well as
   signs and symptoms of drug reactions potentially related to
   antituberculosis drugs (Table 2A of Appendix).

-- At the start of preventive therapy and at each subsequent monthly
   visit, remind patients of the need to immediately discontinue
   preventive therapy and seek prompt medical attention if signs and
   symptoms of hepatotoxicity appear (e.g., anorexia, abdominal pain,
   nausea, vomiting, change in color of urine and feces, jaundice).

-- Monthly liver function tests are advised only for a) persons
   whose pretreatment tests were abnormal (greater than 3 times the
   upper level of normal); b) persons who are 35 years or older; and
   c) patients who are pregnant.

-- Patients with HIV infection often are treated with multiple drugs
   in addition to antituberculosis drugs. At each visit, all
   medications that a patient is taking should be reviewed and
   assessed for potential drug interactions with TB medications. Some
   examples of these drugs are hormonal contraceptives, ketoconazole,
   fluconazole, itraconazole, narcotics (including methadone),
   anticoagulants, corticosteroids, cardiac glycosides, hypoglycemics
   (sulfonylureas), diazepam, beta-blockers, anticonvulsants, and
   theophylline. Efforts to manage these potential problems related to
   drug interactions require the coordinated efforts of HIV and TB
   patients' care givers.


======================================================================

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