Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents Disease Specific Recommendations Mycobacterium tuberculosis Disease Epidemiology   In the United States , overall case rates of TB disease are declining with approximately 15,000 new cases reported in 2002 . HIV testing is recommended for suspected or confirmed cases of TB, but this is not uniformly practiced. Therefore, the percentage of TB patients with HIV-1 infection in the United States can only be estimated. In 1999, approximately 10% of all TB cases in the United States were known to be HIV-1 infected. The World Health Organization (WHO) estimates that TB is the cause of death for 11% of all AIDS patients . The percentage and absolute number of patients with TB disease who are HIV-1 infected is declining in the United States because of improved infection-control practices and better diagnosis and treatment of both HIV-1 infection and TB. With increased voluntary counseling and testing and the increasing use of treatment for latent TB infection, TB disease will probably continue to decrease among HIV-1--infected persons in the United States and Western Europe . Persons at high risk for TB in the United States include injection-drug users, persons from high prevalence countries, and those who live or work in congregate settings. TB disease occurs among HIV-1--infected persons at all CD4+ T lymphocyte counts. The clinical manifestations might be altered depending on the degree of immunosuppression. Those with more advanced immunosuppression (CD4+ T lymphocyte count <200 cells/µL) are more likely to have extrapulmonary or disseminated disease. In areas where TB is endemic, certain patients have higher CD4+ T lymphocyte counts at the time HIV-1--related TB disease develops; in countries with low rates of TB disease (e.g., United States and countries in Western Europe), more patients have advanced HIV-1 disease at the time TB develops. TB disease in persons with HIV-1 infection can develop immediately after exposure (i.e., primary disease) or as a result of progression after establishment of latent TB infection (i.e., reactivation disease). Primary TB has been reported in certain group outbreaks, particularly in persons with advanced immune suppression, and might account for one third or more of cases of TB disease in the HIV-infected population Progression to disease among those with latent TB infection is more likely among HIV-1--infected than in HIV-uninfected persons. HIV-uninfected persons with a positive tuberculin skin test (TST) result have a 5%--10% lifetime risk for developing TB, compared with a 7%--10% annual risk in the HIV-1--infected person with a positive TST result. Patients with TB disease have higher HIV-1 viral loads and a more rapid progression of their HIV-1 illness than comparable HIV-1--infected patients without TB . Clinical Manifestations The clinical, radiographic, and histopathologic presentation of HIV-1--related TB disease is heavily influenced by the degree of immunodeficiency). With CD4+ T lymphocyte counts >350 cells/µL, HIV-1--related TB appears like TB among HIV-uninfected persons. The majority of patients have disease limited to the lungs, and common chest radiographic manifestations include upper lobe fibronodular infiltrates with or without cavitation). However, extrapulmonary disease is more common in HIV-1--infected persons than in non-HIV--infected persons. When extrapulmonary disease occurs in HIV-1--infected persons, clinical manifestations are not substantially different from those described in HIV-uninfected patients. With increasing degrees of immunodeficiency, extrapulmonary TB, with or without pulmonary involvement, becomes more common. At CD4+ T lymphocyte counts <50 cells/µL, extrapulmonary TB (pleuritis, pericarditis, and meningitis) is common. Among severely immunocompromised patients, TB can be a severe systemic disease with high fevers, rapid progression, and sepsis syndrome. The chest radiographic findings of TB disease in advanced AIDS are markedly different compared with those among patients with less severe HIV-1 infection; lower lobe, middle lobe, and miliary infiltrates are common and cavitation is less common. Patients with HIV-1 infection and pulmonary TB can have sputum smears and culture results positive for acid-fast bacilli (AFB) or M. tuberculosis, respectively, even with a normal chest radiograph. Histopathological findings are also affected by the degree of immunodeficiency. Patients with relatively intact immune function have typical granulomatous inflammation associated with TB disease. With progressive immunodeficiency, granulomas become poorly formed or can be completely absent (189). Diagnosis Suspicion of TB, and assiduous efforts to obtain appropriate diagnostic specimens are important in diagnosing HIV-1--related TB disease. The evaluation of suspected HIV-1-related TB should always include a chest radiograph. Sputum samples for AFB smear and culture should be obtained from patients with pulmonary symptoms, cervical adenopathy, or chest radiographic abnormalities. Sputum samples from a substantial fraction of cases of pulmonary TB are negative by direct smear microscopy. Nucleic-acid amplification (NAA) tests are useful in providing rapid identification of M. tuberculosis from sputum smear-positive specimens, but false-negative results can occur among patients with TB disease. The positive predictive value of NAA tests are decreased in persons who have sputum smear-negative results. Among patients with signs of extrapulmonary TB, needle aspiration of skin lesions, nodes, pleural, or pericardial fluid might allow for rapid diagnosis, culture, and susceptibility testing. Tissue biopsy is helpful among patients with negative fine-needle aspirates. Among patients with signs of disseminated disease, mycobacterial blood culture might allow a definitive diagnosis. Mycobacterial blood culture is more sensitive for diagnosis of TB among severely immunodeficient patients. Among patients with relatively intact immune function, the yield of sputum smear and culture examinations is similar to that of HIV-uninfected adults, with positive smear results being more common among patients with cavitary pulmonary involvement (191). TST is positive in the majority of patients with pulmonary disease and CD4+ T lymphocyte counts >200 cells/µL. Among patients with more severe immunodeficiency, sputum smear and culture examinations become somewhat less sensitive, and TST has limited diagnostic value because it is often negative (192). However, the yield of mycobacterial stain and culture of specimens from extrapulmonary sites (node aspirates and pleural and pericardial fluid) is higher among patients with advanced immunodeficiency compared with HIV-uninfected adults (193--195). Smear-positive specimens from these sites probably represent a high burden of organisms resulting from lack of effective immune response to mycobacteria and inability to limit mycobacterial replication and kill the organisms. A positive smear result in any of these specimens (sputum, needle aspirate, tissue biopsy) represents some form of mycobacterial disease but does not always represent TB. However, because TB is the most virulent mycobacterial pathogen and can be spread from person to person if pulmonary involvement is present, patients with smear-positive results should be treated for TB disease until definitive mycobacterial species identification is made. Drug susceptibility testing and adjustment of the treatment regimen based on the results are critical to the successful treatment of TB and to prevention of transmission of drug-resistant M. tuberculosis in the community. Therefore, for all patients with TB disease, testing for susceptibility to first line agents (isoniazid [INH], rifampin [ RIF], and ethambutol [EMB]) should be performed, regardless of the source of the specimen. Pyrazinamide (PZA) susceptibility testing should be performed on an initial isolate if there is a sufficiently high prevalence of PZA resistance in the community. Second-line drug susceptibility testing should be performed only in reference laboratories and should be limited to specimens from patients who have had previous therapy, who are contacts of patients with drug-resistant TB disease, who have demonstrated resistance to rifampin or to other first-line drugs, or who have positive cultures after >3 months of treatment. Treatment Recommendations Treatment of HIV--1-related TB disease should follow the general principles developed for TB treatment among non-HIV--infected persons (AI). Early diagnosis and treatment are critical. Because of the severity of TB disease among immunocompromised patients, directly observed therapy (DOT) is strongly recommended for patients with HIV-1--related TB (AI). Multiple drugs and DOT are used to provide effective therapy, to prevent acquired drug resistance during treatment, and to allow cure with a relatively short course of treatment (6--9 months). HIV-1--infected patients have other social and medical needs and treatment success is enhanced by a case-management approach, which incorporates assistance with all of these needs (enhanced DOT) in addition to providing DOT. Multiple concerns should be considered in the treatment of HIV-1--associated TB disease. First, treatment is effective, but the optimal duration of treatment is uncertain. Second, acquired drug resistance is unusual with the use of DOT, but does occur among HIV-1--infected persons. Third, the risk for acquired rifamycin resistance has led to specific recommendations about dosing frequency. Finally, the use of potent ART among patients being treated for TB is complicated by overlapping drug toxicity profiles, drug-drug interactions, and an increase in TB manifestations during immune reconstitution (paradoxical reactions). Recent studies indicate that, with careful attention to these complicating factors, the prognosis of HIV-1--associated TB disease can be substantially improved with the provision of potent ART (AII), although the optimal relative timing between anti-TB and HIV therapy is uncertain. Treatment of drug susceptible TB disease in HIV-1--infected adults should include the use of a 6-month regimen consisting of an initial phase of INH, RIF or rifabutin, PZA, and EMB given for 2 months followed by INH and RIF (or rifabutin) for 4 months when the disease is caused by organisms known or presumed to be susceptible to first-line anti-TB drugs ) (AI). When the organism is susceptible to INH, RIF, and PZA, EMB should be discontinued (AI).   The optimal duration of therapy for HIV-1--related TB disease remains controversial. Studies in developing countries have shown that patients with HIV-1--related TB respond well to standard 6-month treatment regimens, with rates of treatment failure and relapse similar to those of HIV-uninfected patients). However, it is unclear whether these results are applicable to patients with advanced HIV-1 disease and TB. While awaiting definitive randomized comparisons in HIV-1--infected patients with TB disease, 6 months of therapy is probably adequate for the majority of cases, but prolonged therapy (up to 9 months) is recommended (as in HIV-negative patients) for patients with a delayed clinical or bacteriological response to therapy (symptomatic or positive culture results at or after 2 months of therapy, respectively) or perhaps with cavitary disease on chest radiograph (BII).   Intermittent dosing (twice- or thrice- weekly) facilitates DOT by decreasing the total number of encounters required between the patient and the provider, making observed therapy more practical to deliver. However, once- or twice-weekly dosing has been associated with an increased rate of acquired rifamycin resistance among patients with advanced HIV-1 disease (CD4+ T lymphocyte count <100 cells/µL). Acquired rifamycin resistance was relatively common with once-weekly rifapentine plus INH and also occurred in trials of twice-weekly rifabutin plus INH and twice-weekly RIF plus INH  Therefore, once-weekly rifapentine is contraindicated among HIV-1--infected patients (EI), and it is recommended that RIF- and rifabutin-based regimens be given at least three times a week for patients with TB and advanced HIV-1 disease (CD4+ T lymphocyte count <100 cells/µL) (AII). Although treatment approaches to this population need to be further evaluated in prospective trials, a prudent management strategy consists of daily DOT during the first 2 months of therapy and thrice-weekly DOT during the continuation phase of anti-TB therapy (BII).   Monitoring and Adverse Events Close follow-up, consisting of clinical, bacteriologic, and occasionally, laboratory and radiographic evaluations, is essential to ensure treatment success. In patients with pulmonary TB, at least one sputum specimen for microscopic examination and culture should be obtained at monthly intervals until two consecutive specimens are negative on culture (AII). Drug susceptibility tests should be repeated on isolates from patients who have positive cultures after 3 months of treatment. Patients who have positive cultures after 4 months of treatment should be considered as having failed therapy and managed accordingly. For patients with extrapulmonary TB, the frequency and types of evaluations will depend on the sites involved and the ease with which specimens can be obtained. A detailed clinical assessment should be performed at least monthly to identify possible medication intolerance and to assess adherence. As a routine, monitoring blood tests for patients being treated with first-line drugs unless baseline abnormalities were identified is unnecessary (AII). More frequent clinical and laboratory monitoring is indicated for patients with underlying liver disease, including hepatitis C co-infection.   INH, RIF, and PZA all can cause drug-induced hepatitis, and the risk might be increased in patients taking other potentially hepatotoxic agents or in persons with underlying liver dysfunction. However, because of the effectiveness of these drugs (particularly INH and RIF), they should be used, if at all possible, even in the presence of preexisting liver disease (AIII). Frequent clinical and laboratory monitoring should be performed to detect any exacerbation. Independent of HIV status for all patients with TB disease, multiple treatment options exist if serum aminotransaminases are >3 times the upper limit of normal before the initiation of treatment, and the abnormalities are not thought to be caused by TB disease. One option is to use standard therapy with frequent monitoring. A second option is to treat with RIF, EMB, and PZA for 6 months, avoiding INH (BII). A third option is to treat with INH and RIF for 9 months, supplemented by EMB for the first 2 months, thereby avoiding PZA (BII). Among patients with severe liver disease, a regimen with only one hepatotoxic agent, generally RIF plus EMB, can be given for 12 months, preferably with another agent, such as a fluoroquinolone, for the first 2 months (CIII). As previously indicated, treatment might need to be lengthened for patients who are HIV-1-infected. For patients who develop worsening hepatic function on treatment, a specialist should be consulted.   Tests to monitor hepatotoxicity (aminotransferases, bilirubin, and alkaline phosphatase), renal function (serum creatinine), and platelet count should be obtained for all patients started on treatment for TB. At each monthly visit, patients taking EMB should be asked about possible visual disturbances including blurred vision or scotomata. Monthly testing of visual acuity and color discrimination is recommended for patients taking doses that, on a milligram per kilogram basis, are greater than those listed in recommended doses and for patients receiving the drug for >2 months.   Patients with TB disease caused by strains of M. tuberculosis resistant to at least INH and RIF (multidrug-resistant [MDR]) are at high risk for treatment failure and further acquired drug resistance. Such patients should be referred to or have consultation obtained from specialized treatment centers as identified by the local or state health departments or CDC. Although patients with strains resistant to RIF alone have a better prognosis than patients with MDR strains, they are also at increased risk for treatment failure and additional resistance and should be managed in consultation with an expert.