Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents Disease Specific Recommendations Antiretroviral Therapy in the Management of TB Disease and Paradoxical Reactions      Rifamycin drugs are essential components of short-course regimens for treatment of TB disease. However, substantial adverse pharmacologic interactions occur between rifamycins and commonly used antiretroviral drugs (e.g., PIs and NNRTIs) as a result of changes in drug metabolism resulting from induction of the hepatic cytochrome P-450 (CYP450) enzyme system .  Of the available rifamycins, RIF is the most potent CYP450 inducer and rifabutin has substantially less inducing activity. Despite such interactions, a rifamycin should generally not be excluded from the TB treatment regimen among patients receiving potent ART, except in unusual circumstances (AII). Either RIF or rifabutin can be used with NRTIs. Rifabutin can be used with certain PIs or NNRTIs (other than delavirdine) and has fewer problematic drug interactions than does rifampin). Adjustments in rifabutin or elements of the ART regimen might be necessary with certain combinations. Two antiretroviral drug regimens have been associated with a favorable outcome when administered with RIF: efavirenz (potentially using an increased dose of 800 mg/day) plus 2 NRTIs and ritonavir (600 mg twice daily) plus 2 NRTIs. Serum concentrations of nevirapine might be adequate even in the presence of concentrations of RIF associated with enzyme induction, but clinical data are lacking. RIF should not be used with nelfinavir, saquinavir, indinavir, amprenavir, atazanavir, or dual PI combinations using low dose ritonavir (<200 mg twice daily) for which dosing guidelines are not available (EII). The optimal time for initiating ART during TB treatment is unknown. Because of the risk for prolonged airborne transmission of M. tuberculosis, initiation of treatment for TB disease should never be delayed (AI). Early initiation of ART (within the first 2--4 weeks after the start of TB therapy) might decrease HIV-1 disease progression but might be associated with a relatively high incidence of side effects and paradoxical reactions (some severe enough to warrant discontinuation of both antiretroviral and anti-TB drugs). Delaying the initiation of ART for 4--8 weeks after starting antituberculous therapy has the potential advantages of being better able to ascribe a specific cause for a drug side effect, decreasing the severity of paradoxical reactions, and decreasing the adherence challenge for the patient. Until controlled studies are conducted to evaluate the optimal time for starting ART in patients with HIV-1--associated TB disease, this decision should be individualized on the basis of the patient's initial response to TB therapy, occurrence of side effects, and acceptance of multidrug ART. For these considerations, health-care providers should avoid beginning the simultaneous administration of both potent ART and combination chemotherapy for TB; most health-care providers would wait at least 4--8 weeks (BIII).  Patients already receiving ART at the time treatment for TB is started require a careful assessment of the ART regimen and, if necessary, changes to ensure optimum treatment of the HIV-1 infection in the setting of TB therapy. Because of the difficulties associated with the accurate diagnosis of an adverse drug reaction and in determining the responsible agent, the first-line anti-TB drugs should not be stopped permanently without strong evidence that the anti-TB drug was the cause of the reaction. In such situations, consultation with an expert in treating TB in persons with HIV-1 infection is recommended. Patients might experience temporary exacerbation of symptoms, signs, or radiographic manifestations of TB disease after beginning anti-TB treatment. This phenomenon is termed a paradoxical (or immune reconstitution) reaction. This reaction occurs among non-HIV-1--infected persons, but it is more common among those with HIV-1 infection, particularly those treated with ART. These reactions presumably develop as a consequence of reconstitution of immune responsiveness brought about by ART or perhaps by treatment of TB itself . Signs of a paradoxical reaction can include high fevers, increase in size and inflammation of involved lymph nodes, new lymphadenopathy, expanding central nervous system lesions, worsening of pulmonary parenchymal infiltrations, and increasing pleural effusions. Such findings should be attributed to a paradoxical reaction only after a thorough evaluation has excluded other possible causes, especially TB therapy failure. A paradoxical reaction that is not severe should be treated symptomatically with nonsteroidal anti-inflammatory agents without a change in anti-TB or antiretroviral therapy (BIII). Approaches to the management of severe reactions (e.g., high fever, airway compromise from enlarging lymph nodes, enlarging serosal fluid collections, and sepsis syndrome) have not been studied. However, case reports have documented improvements with the use of prednisone or methylprednisolone used at a dose of approximately 1mg/kg body weight and gradually reduced after 1--2 weeks (CIII). Management of Drug Resistance and Treatment Failure If resistance to INH (with or without resistance to streptomycin) is detected, INH and streptomycin, if used, should be discontinued and the patient treated with a 6-month regimen of RIF, PZA, and EMB, which is nearly as effective as the conventional INH-containing regimen (BII). Alternatively, treatment with RIF and EMB for 12 months can be used, preferably with PZA during at least the initial 2 months (BII). Treatment regimens for TB disease caused by RIF monoresistant strains are less effective, and patients infected with these strains are at increased risk for relapse and treatment failure. A minimum of 12--18 months of treatment with INH, EMB, and a fluoroquinolone (e.g., levofloxacin) with PZA administered during the first 2 months is recommended (BIII). An injectable agent (e.g., amikacin or capreomycin) might be included in the first 2--3 months for patients with severe disease. Patients with MDR-TB are at high risk for treatment failure and relapse and require especially close follow-up during (and often after) treatment. Treatment regimens for MDR-TB should be individualized, taking into account the resistance pattern, relative activities of available anti-TB agents, the extent of disease, and presence of co-morbid conditions. The management of MDR-TB is complex and should be undertaken only by an experienced specialist or in close consultation with specialized treatment centers (AIII). Prevention of Recurrence Secondary prophylaxis (chronic maintenance therapy) for patients who have successfully completed a recommended regimen of treatment for TB disease is unnecessary (DII). However, reinfection can occur. Special Considerations During Pregnancy HIV-1--infected pregnant women who do not have documentation of a negative TST result during the preceding year should be tested during pregnancy. The frequency of anergy is not increased during pregnancy, and routine anergy testing for HIV-1--infected pregnant women is not recommended. The diagnostic evaluation for TB disease in pregnant women is the same as for nonpregnant adults. Chest radiographs with abdominal shielding result in minimal fetal radiation exposure. An increase in pregnancy complications, including preterm birth, low birthweight, and intrauterine growth retardation, might be observed among pregnant women with either pulmonary or extrapulmonary TB not confined to the lymph nodes, especially when treatment is not begun until late in pregnancy Therapy of TB disease during pregnancy should be the same as for the nonpregnant adult, but with attention given to the following considerations (BIII): INH is not teratogenic in animals or humans. Hepatotoxicity might occur more frequently in pregnancy and the postpartum period. Certain health-care providers recommend monthly monitoring of transaminases during pregnancy and the postpartum period (CIII). RIF is not teratogenic in humans. Because of a potential increased risk for RIF-related hemorrhagic disease among neonates born to women receiving anti-TB therapy during pregnancy, prophylactic vitamin K, 10 mg, should be administered to the neonate (BIII). PZA is not teratogenic among animals. Experience is limited with use in human pregnancy. Although WHO and the International Union Against Tuberculosis and Lung Diseases have made recommendations for the routine use of PZA in pregnant women, it has not been recommended for general use during pregnancy in the United States because data characterizing its effects in this setting are limited . If PZA is not included in the initial treatment regimen, the minimum duration of therapy should be 9 months. EMB is teratogenic among rodents and rabbits at doses that are much higher than those used among humans. No evidence of teratogenicity has been observed among humans. Ocular toxicity has been reported among adults taking EMB, but changes in visual acuity have not been detected in infants born after exposure in utero. Experience during pregnancy with the majority of the second line drugs for TB is limited. MDR-TB in pregnancy should be managed in consultation with an expert. Therapy should not be withheld because of pregnancy (AIII). The following concerns should be considered when selecting second-line anti-TB drugs for use among pregnant women: Although no longer a first line agent, streptomycin use has been associated with a 10% rate of VIII nerve toxicity in infants exposed in utero; its use during pregnancy should be avoided if possible (DIII). Hearing loss has been detected in approximately 2% of children exposed to long-term kanamycin therapy in utero; like streptomycin, this agent should generally be avoided if possible (DIII). There is a theoretical risk of ototoxicity in the fetus with in utero exposure to amikacin and capreomycin, but this risk has not been documented, and these drugs might be alternatives when an aminoglycoside is required for treatment of MDR-TB (CIII). Because arthropathy has been noted in immature animals with the use of quinolones during pregnancy, quinolones are generally not recommended in pregnancy and among children aged <18 years (CIII). However, >200 cases of ciprofloxacin use in pregnancy have been reported to various pregnancy registries, and its use has not been associated with arthropathy or birth defects after in utero exposure. Thus, quinolones can be used in pregnancy for drug-resistant TB, if required based on susceptibility testing (CIII). Para-aminosalicylic acid (PAS) has been associated with occipital bone defects when administered during pregnancy to rats . PAS is not teratogenic among rats or rabbits. A possible increase in limb and ear anomalies was reported among 143 pregnancies with first trimester exposure in one study . No specific pattern of defects and no increase in rate of defects have been detected in other human studies, indicating that this agent can be used with caution if needed (CIII). Ethionamide has been associated with an increased risk for several anomalies among mice, rats, and rabbits following high dose exposure; no increased risk for defects was noted with doses similar to those used among humans, but experience is limited with use during human pregnancy. No data are available from animal studies or reports of cycloserine use in humans during pregnancy.