The Centers for Disease Control and Prevention convened two panels in the past year to consider guidelines for managing HIV-related tuberculosis, and the recommendations from these meetings were published in October 1998 [MMWR 1998;47]. This article will summarize the major findings from that document, regarding the treatment of active tuberculosis, drug interactions, and preventive therapy.

The extensive report from the CDC reemphasizes some important aspects of tuberculosis control in HIV-infected individuals, including the importance of early diagnosis and screening for latent infection by tuberculin skin testing with provision of preventive therapy to those latently infected. The major thrust of the guidelines, however, is the appropriate regimens for treating tuberculosis in patients receiving combination antiretroviral therapy and new options for preventive therapy with short-course regimens.

Treatment of Active Tuberculosis

For HIV-infected patients with suspected or confirmed tuberculosis, prompt treatment with a multi-drug regimen is essential to both effectively treat the patient and reduce transmission. Patients with HIV infection and tuberculosis should be evaluated for the appropriateness of highly active antiretroviral therapy (HAART) given the dramatic impact that this therapy has on the clinical course of HIV disease. For patients in whom HAART is not recommended because of clinical or adherence criteria, treatment with a standard 4-drug regimen including isoniazid, rifampin, pyrazinamide and ethambutol or streptomycin should be initiated, and use of HAART should be reconsidered within three months. For patients already receiving HAART or who are candidates to start HAART, a 4-drug regimen should be started, and rifabutin should be substituted for rifampin using appropriate dose adjustments of the PI or efavirenz. Ritonavir, nevirapine, (Fortov)ase and delavirdine should not be used.

All patients with HIV-related tuberculosis should receive directly observed therapy (DOT), as two studies have shown improved survival with this treatment modality compared to self-administered therapy. For patients who are unable to take rifamycins, or whose physicians feel rifamycins should not be used because of concerns about drug interactions, a 9-month regimen of isoniazid, pyrazinamide, ethambutol and streptomycin given daily or thrice weekly may be used. A 3-drug regimen without a rifamycin or aminoglycoside should not be used. The duration of treatment for HIV-related tuberculosis is 6 months when rifampin or rifabutin is used. Completion of all scheduled doses is essential, and therapy should be extended for patients whose treatment is interrupted for compliance or toxicity reasons. Therapy for patients who are still culture-positive at 2 months of therapy should be extended to include 4 months of therapy after culture conversion.

Drug Interactions

Drug interactions between rifamycins and protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) pose a serious problem in patient management. For example, rifampin lowers the serum concentration of all PIs except ritonavir by >80% and lowers ritonavir levels by 35%. With NNRTIs, rifampin lowers levels of nevirapine by about 40% and delavirdine by 96%; rifampin lowers efavirenz levels by 13-20%. Rifampin is contraindicated in any patient taking a PI or NNRTI. Rifabutin is a less potent inducer of P450 cytochromes than rifampin and therefore has a less dramatic effect on levels of drugs metabolized through this pathway. Rifabutin reduces levels of Fortovase, indinavir, nelfinavir and amprenavir. PIs, to the contrary, result in increases in serum concentrations of rifabutin by 2-3 fold, thereby potentially increasing the risk of toxicity. Rifabutin lowers delavirdine levels by 80%, nevirapine levels by 16% and has no effect on efavirenz levels. However, efavirenz lowers rifabutin levels by 32%. Thus, if rifabutin is used in patients receiving HAART, dosage adjustments are recommended. As noted above, rifampin has only a modest effect on efavirenz levels (and efavirenz has no effect on rifampin levels), but the guidelines state that these two drugs should not be used together. Some experts feel that use of rifampin with efavirenz is a reasonable risk but would increase the efavirenz dose to 800-1,000 mg daily. This dose is not currently recommended or approved, however, and data from a drug interaction study will be available shortly, hopefully.

Two very important differences in the treatment of HIV-infected individuals with tuberculosis were included in the new guidelines. First, pregnant women with HIV and tuberculosis should be treated with a 4-drug regimen including pyrazinamide. Although this drug is recommended around the world for pregnant women with tuberculosis, the U.S. has not endorsed its use because of perceived inadequate safety data. The new guidelines state that the potential risk of pyrazinamide use during pregnancy in a woman with HIV infection is outweighed by the likely benefit. Second, children with HIV and tuberculosis should be treated with a 4-drug regimen including ethambutol. Previously, ethambutol use has been strongly discouraged in children too young to be evaluated for ocular toxicity from this agent but, again, the benefit in this setting was felt to outweigh the potential risks. The dose of ethambutol in children should be 15 mg/kg/day. *

Dr. R Chaisson, The Hopkins HIV Report - 5.99