Tuberculosis (TB) continues to kill approximately 2 million people per year, and is a major cause of HLV-related morbidity and mortality in developing countries. In addition, TB appears to cause a more rapid progression of HIV disease even when it is successfully treated, as active TB causes upregulation of HIV replication through several mechanisms. Although the World Health Organization has promoted a strategy of treatment of active TB as the principal weapon for TB control, accumulating evidence indicates that preventive therapy is required, particularly in countries with a high HIV burden. Both isoniazid (INH) and rifampin and pyrazinamide (RIF/PZA) have been shown to be effective in reducing the short-term incidence of TB in HIV-infected, tuberculin positive people, but the long-term benefit is not clear. Moreover, the implementation of TB preventive therapy programs in developing countries has been hindered by multiple factors. Establishment of clinical infrastructures to provide preventive therapy, concerns about adherence to treatment regimens, and a high likelihood of reinfection with subsequent increased risk of primary TB have been suggested as reasons not to implement preventive programs for HIV-infected populations. The purpose of this trial is to determine the effectiveness of three novel treatments on the risk of TB in a population of HIV-infected adults receiving clinical care and follow up in Soweto, South Africa. We will randomize 1141 adults with HIV infection and a reactive tuberculin skin test to receive weekly rifapentine and INH (RPT/INH) for 12 weeks, twice-weekly rifampin and pyrazinamide (RIFIPZA) for 8 weeks, continuous INH daily indefinitely (INH-C), or the internationally accepted standard of INH daily for six months (INH-6) for the prevention of TB. RPT is a rifamycin-S derivative with antimicrobial activity similar to rifampin, but with a longer half-life. RPT is efficacious in the treatment of non-H IV-related TB, and has been shown in animal models to be a highly promising agent for treating latent TB. We hypothesize that the increased tuberculocidal activity and programmatic advantages of supervised, once- or twice- weekly regimens with rifamycin-based combinations will be more effective than INH-6. We also hypothesize that a continuous course of INH will be more effective than INH-6 because elimination of latent TB will be more thorough and prophylaxis will provide ongoing protection against incident TB infection. By studying TB preventive therapy in a setting of comprehensive HIV care for adults in a developing country setting, we will be able to generate critically important data on alternative therapeutic options for TB control among HIV-infected people that will be applicable throughout the world.
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