UNAIDS estimates that 14,000 persons are newly infected with HIV every day throughout the world, of which one half are between the ages of 15 and 24. New infections occur despite widespread awareness of the modes of HIV-1 transmission, and the protection afforded by condom use. Novel concepts for HIV-1 prevention are urgently needed. We propose to evaluate the safety and efficacy of chemoprophylaxis for HIV prevention in a randomized and blinded trial of daily oral tenofovir 300 mg versus placebo among men in Peru, who have extremely high risk of acquiring HIV infection. Daily oral tenofovir 300 mg is selected for evaluation because it is FDA-licensed for human use, allows once- a-day dosing, is well-tolerated, is active against many drug resistant HIV-1 strains, and was demonstrated to be effective for prevention in non-human primate models. We propose to enroll 2100 men who will be randomized 1:1 to receive daily oral tenofovir 300 mg versus placebo and followed for 13 months for HIV-1 seroconversion (aim 1), adverse events (aim 2), and viral load, drug resistance and CD4 T cell count after seroconversion (aim 3). Study sites are selected in Peru because of their well-developed prevention research infrastructure and their demonstrated ability to recruit men at high risk for HIV infection with outstanding rates of retention. Recruitment will be derived from 3 cities in Peru that had the highest incidence of HIV-1 infection in two recent surveys, have the required infrastructure to support a closely monitored clinical trial, and represent enormous genetic and geophysical diversity. The sample size is sufficient to detect cost-effective levels of HIV-1 prevention. The trial also aims to evaluate the safety of this agent in HIV uninfected persons, including the incidence of mild renal insufficiency and liver inflammation. Chemoprophylaxis may involve durable benefits or risks as well, possibly leading to an attenuated course of infection due to early inhibition of viral replication or drug resistance. The proposed research addresses important gaps of knowledge directly, including the safety and efficacy of daily oral tenofovir chemoprophylaxis among men exposed to HIV after rectal exposure. This unique and essential information bears directly on HIV prevention in the Americas and will not be available after the completion of other studies planned for the United States, Asia and Africa. The safety and efficacy of chemoprophylaxis may differ in men and women due to differences in reproductive biology, the mucosal surfaces that are typically exposed to HIV, behavioral differences, and pharmacokinetics. This research ultimately aims to break the epidemic cycle of HIV-1 by protecting men at risk for HIV, and may spare their sexual partners and their future children. PERFORMANCE SITE(S) (organization, city, state) Gladstone Institute of Virology and Immunology, Asociacion Civil Impacta Salud y Educacion The J. David Gladstone Institutes Lima, Peru San Francisco, CA Center for AIDS Prevention Studies, University of California, San Francisco, Asociacion Civil Amazonica San Francisco, CA Iquitos, Peru Institute Sur Peruano de Infectologia Arequipa, Peru KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name Organization Role on Project Grant, Robert M. The J. David Gladstone Institutes Principal Investigator Casapia, Martin Glidden, David V. Goicochea, Pedro Disclosure Permission Statement Asociacion Civil Selva Amazonica Co-Investigator University of California, San Francisco Co-Investigator Asociacion Civil Impacta Salud y Educacion Co-Investigator Applicable to SBIR/STTR Only. Seeinstructions. D Yes l No [unreadable]PHS 398 (Rev. 05/01) Page 2 Form Page 2 Lama, Javier R. Lucchetti, Aldo Page-Shafer, Kimberly Sanchez, Jorge Zamalloa, Victoria Principal Investigator/Program Director (Last, first, middle): Asociacion Civil Impacta Salud y Educacion Asociacion Civil Impacta Salud y Educacion University of California, San Francisco Asociacion Civil Impacta Salud y Educacion tnstituto Sur Peruano de Infectologia Grant, Robert M. Co-Principal Investigator Co-Investigator Co-Principal Investigator Co-Investigator Co-Investigator PHS 398/2590 (Rev. 05/01) Page _3_ Continuation Format Page Use 1/2-inch MARGINS. Number pages consecutively at the bottom throughout the application. Do noluse suffixes such as 3a, 3b. Principal Investigator/Program Director (Last, first, middle): Grant, Robert The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. Type density and size must conform to limits and specifications provided in the PHS398Instructions. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description, Performance Sites, and Personnel Table of Contents Detailed Budget for Initial Budget Period Budget for Entire Proposed Period of Support Budgets Pertaining to Consortium/Contractual Arrangements 7-17 Biographical Sketch-Principal Investigator/ProgramDirector (Not to exceed four pages). 38-41 Other Biographical Sketches (Not to exceed four pages for each) 42-65 Other Support N/A Resources 66-72 Research Plan 73 Introduction to Revised Application (Not to exceed 3 pases) 73-75 Introduction to Supplemental Application (Not to exceed one page). A. Specific Aims 76 B. Background and Significance 76-83 C. Preliminary Studies/Progress Report/ (Items A-D: not to exceed 25 pages') 83-89 Phase I Progress Report (SBIR/STTR Phase II ONLY). D. Research Design and Methods 89-100 E. Human Subjects 101-108 Protection of Human Subjects (Required if Item 4 on the Face Page is marked "Yes") 104-107 Inclusion of Women (Required if Item 4 on the Face Page is marked "Yes") 107 Inclusion of Minorities (Required if Item 4 on the Face Page is marked "Yes") 107 Inclusion of Children (Required if Item 4 on the Face Page is marked "Yes") 108 Data and Safety Monitoring Plan (Required if Item 4 on the Face Page is marked "Yes" and a Phase I, II, or III clinical trial is proposed 108 F. Vertebrate Animals 110 G. Literature Cited 110-115 H. Consortium/Contractual Arrangements 116 I. Consultants 116-118 J. Product Development Plan (SBIR/STTR Phase II and Fast-Track ONLY) 118 Checklist 121 * SBIR/STTR Phase I applications: Items A-D of the Research Plan are limited to 15 pages. Appendix (Five collated sets. Nopage numbering necessary for Appendix.) Check if Appendix is Appendices NOTPERMITTED forPhase I SBIR/STTR unless specifically solicited. Included Number of publications and manuscripts accepted for publication (not to exceed 10) Other items (list): Letters of Support PHS 398 (Rev. 05/01) Page 4 Form Page 3