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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048526-04
Application #
6749585
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Laughon, Barbara E
Project Start
2001-09-07
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
4
Fiscal Year
2004
Total Cost
$768,345
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Martinson, Neil A; Gupte, Nikhil; Msandiwa, Reginah et al. (2014) CD4 and viral load dynamics in antiretroviral-naïve HIV-infected adults from Soweto, South Africa: a prospective cohort. PLoS One 9:e96369
Levison, Julie H; Wood, Robin; Scott, Callie A et al. (2013) The clinical and economic impact of genotype testing at first-line antiretroviral therapy failure for HIV-infected patients in South Africa. Clin Infect Dis 56:587-97
Venkatesh, Kartik K; de Bruyn, Guy; Lurie, Mark N et al. (2012) Sexual risk behaviors among HIV-infected South African men and women with their partners in a primary care program: implications for couples-based prevention. AIDS Behav 16:139-50
Martinson, Neil A; Hoffmann, Christopher J; Chaisson, Richard E (2011) Epidemiology of tuberculosis and HIV: recent advances in understanding and responses. Proc Am Thorac Soc 8:288-93
Martinson, Neil A; Barnes, Grace L; Moulton, Lawrence H et al. (2011) New regimens to prevent tuberculosis in adults with HIV infection. N Engl J Med 365:11-20
Chaisson, Richard E; Churchyard, Gavin J (2010) Recurrent tuberculosis: relapse, reinfection, and HIV. J Infect Dis 201:653-5
Venkatesh, Kartik K; de Bruyn, Guy; Lurie, Mark N et al. (2010) Decreased sexual risk behavior in the era of HAART among HIV-infected urban and rural South Africans attending primary care clinics. AIDS 24:2687-96
Shah, Maunank; Martinson, Neil A; Chaisson, Richard E et al. (2010) Quantitative analysis of a urine-based assay for detection of lipoarabinomannan in patients with tuberculosis. J Clin Microbiol 48:2972-4
Hanrahan, Colleen F; Golub, Jonathan E; Mohapi, Lerato et al. (2010) Body mass index and risk of tuberculosis and death. AIDS 24:1501-8
Shah, Maunank; Variava, Ebrahim; Holmes, Charles B et al. (2009) Diagnostic accuracy of a urine lipoarabinomannan test for tuberculosis in hospitalized patients in a High HIV prevalence setting. J Acquir Immune Defic Syndr 52:145-51

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