This is a revised competing continuation application for NIAID grant R01 AI48526, Novel TB Preventive Regimens for HIV Infected Adults. The purpose of this trial is to determine the efficacy of three novel treatments on the risk of TB in a population of HIV-infected adults in Soweto, South Africa. Over the past 4 years, we have built a productive research team in Soweto and have recruited 1150 HIV/latent TB co- infected adults into this trial. We have randomized these patients with HIV infection and a reactive tuberculin skin test to receive weekly rifapentine and INH (RPT/INH) for 12 weeks, twice-weekly rifampin and INH (RIF/INH) for 12 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-HIV-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. The current mean follow up for patients in the study is 1.4 years, and there have been 24 incidence cases of TB, for a rate of 1.5 cases per 100 person-years. We now propose to extend follow up for another 3 years, so that all participants will be followed at least 3 years, with a mean of 4.4 years. With a type I error of 0.05, we have power of 85-99% to detect superiority of the 3 experimental regimens vs. the control regimen, INH-6. This trial of TB preventive therapy in a setting of comprehensive HIV care for adults in a developing country setting will 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 #
5R01AI048526-07
Application #
7263960
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Decarlo, Ellen S
Project Start
2000-05-01
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
7
Fiscal Year
2007
Total Cost
$544,836
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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