Emtricitabine/Tenofovir Disoproxil Fumarate for HIV Prevention in Men

• Anti-HIV seroconversion [ Time Frame: At 36 months ] [ Designated as safety issue: Yes ]
• Safety endpoints, including Grade 1 or higher creatinine toxicity; Grade 3 or higher phosphorous toxicity; Grade 2, 3, or 4 laboratory adverse events; or Grade 2, 3, or 4 clinical adverse events; or HIV seroconversion [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]

• HIV seroconversion
• Grade 2, 3,or 4 laboratory or clinical adverse events
• HIV infection as measured by seroconversion
• Grade 1 or higher creatinine toxicity
• Grade 3 or higher phosphorus toxicity

• Hepatitis flares among hepatitis B virus (HBV) infected persons during and after chemoprophylaxis [ Time Frame: At 42 months ] [ Designated as safety issue: Yes ]
• Changes in bone mineral density, body fat distribution, or fasting triglyceride and cholesterol levels [ Time Frame: At 42 months ] [ Designated as safety issue: Yes ]
• Among HIV infected participants: viral load, drug resistance, and CD4 count [ Time Frame: At 42 months ] [ Designated as safety issue: Yes ]
• Proportion of missed doses by pill count and by estimate during CASI interview [ Time Frame: At 36 months ] [ Designated as safety issue: No ]
• Risk behavior, including number of sexual partners with HIV positive or unknown status, total number of sexual partners, and condom use before, during, and after use of study medication [ Time Frame: At 42 months ] [ Designated as safety issue: Yes ]
• Prevalence of sexually transmitted infections (STIs) before, during, and after use of study medication [ Time Frame: At 42 months ] [ Designated as safety issue: Yes ]

• Hepatitis flares among hepatitis B virus (HBV) infected persons during and after chemoprophylaxis
• changes in bone mineral density or body fat distribution
• among HIV infected participants: viral load, drug resistance, and CD4 cell counts
• attitudinal and behavioral correlates of chemoprophylaxis failure or success
• risk behavior including condom use before, during, and after use of study medication
• the prevalence of sexually transmitted infections (STIs) before, during, and after use of study medication

The purpose of this study is to determine whether daily use of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) can prevent HIV infection in men who also receive HIV counseling, condoms, and treatment for other sexually transmitted infections (STIs).

The Joint United Nations Programme on AIDS estimates that 14,000 persons are newly infected with HIV every day worldwide; one half of these infections occur in people between the ages of 15 and 24. New infections occur despite widespread awareness of the modes of HIV transmission and the protection afforded by condom use. Effective interventions for HIV prevention are urgently needed. This study will evaluate the safety and efficacy of chemoprophylaxis for HIV prevention in men who have sex with men (MSM) who are at high risk for HIV infection despite using condoms, receiving HIV counseling, and receiving treatment for STIs, particularly hepatitis B virus (HBV) infection. A daily combination dose of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) has been selected for evaluation because it has a well-established safety record in previous studies and was demonstrated to be effective for HIV prevention in primate models. These medications have long half-lives that allow daily dosing and do not have known interactions with hormonal contraception, methadone, or tuberculosis therapies.

Once on the study drug, participants will be followed for a variable length of time, starting within 4 weeks of their screening visit and lasting up to 144 weeks. All participants will be followed for at least 8 weeks after stopping study drug. Participants who are reactive to a Hepatitis B surface antigen (HBsAg) test will be followed for hepatic flares for 16 additional weeks for a total of 24 weeks after stopping study drug. If enrolled in the optional substudy of bone mineral density, fat distribution, and fasting lipids, the participant will be asked to return for one additional visit 24 weeks after stopping study drug. Participants who HIV seroconvert during their participation will also be followed until the end of the study.

All study visits will be at 4 week intervals. At study entry, high risk, HIV uninfected MSM will be randomly assigned to receive either daily FTC/TDF or placebo, in addition to standard HIV counseling, condoms, and sexually transmitted infection (STI) management. The study will closely monitor biological and behavioral safety, including careful analysis of drug resistance, kidney and liver function, and risk behavior.

At the screening visit, participants will undergo HIV antibody and HBV testing, a medical history, a medical exam, blood and urine collection, risk behavior assessment, and STI testing. At study entry, participants will be given study medication; tested for HCV; and offered the HBV vaccine, if applicable. At all study visits, there will be HIV antibody testing, pill counts, adherence checks, study medication distribution, HIV counseling, and condom distribution. A medical history and blood will be taken on selected visits, along with STI testing and treatment if needed. Testing and treatment of STIs will be provided at no cost to the participant.

All study participants will be encouraged to join a substudy that will assess interactions between HBV infection, bone mineral density and fat distribution, and immune function. If enrolled in the substudy, the participant will be asked to return for one additional visit 24 weeks after stopping the study medication. All participants in the substudy will undergo dual energy x-ray absorptiometry (DEXA) scans, and HIV infected participants will undergo additional blood collection.

Sites will have the option of participating in the following four substudies:

The Hair Substudy: Participants who are receiving FTC/TDF will be eligible to enroll. At each 12-week follow-up study visit, hair samples will be collected and questionnaires will be completed.

The Urine Substudy: For all participants who elect to enroll in this substudy, additional testing will occur on blood and urine samples collected at each 24-week follow-up visit. An additional urine collection will occur 8 weeks after participants stop receiving FTC/TDF.

The Semen Substudy: Participants who seroconvert during the study may elect to participate in this substudy. One semen sample will be collected at participants' next study visit when plasma viral load testing is performed.

The Gonorrhea and Chlamydia Substudy: Participants in this substudy will undergo rectal and oropharyngeal swab procedures and urine collection at the 24-week study visit.

After the randomized phase ends, if the daily oral FTC/TDF arm is shown to be beneficial and safe, participants will be given the option of participating in an open label extension phase. During this extension phase, study participants will receive daily oral open-label FTC/TDF, in addition to standard counseling, condoms, and STI management.

• Drug: Emtricitabine/tenofovir disoproxil fumarate
  Fixed-dose coformulation of 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate
• Drug: Placebo
  Placebo for emtricitabine/tenofovir disoproxil fumarate

• Experimental: 1
  Daily oral emtricitabine/tenofovir disoproxil fumarate
  Intervention: Drug: Emtricitabine/tenofovir disoproxil fumarate
• Placebo Comparator: 2
  Daily oral placebo
  Intervention: Drug: Placebo

• Grant RM, Buchbinder S, Cates W Jr, Clarke E, Coates T, Cohen MS, Delaney M, Flores G, Goicochea P, Gonsalves G, Harrington M, Lama JR, MacQueen KM, Moore JP, Peterson L, Sanchez J, Thompson M, Wainberg MA. AIDS. Promote HIV chemoprophylaxis research, don't prevent it. Science. 2005 Sep 30;309(5744):2170-1. No abstract available.
• Grant RM, Wainberg MA. Chemoprophylaxis of HIV infection: moving forward with caution. J Infect Dis. 2006 Oct 1;194(7):874-6. Epub 2006 Aug 29. No abstract available.
• Lama JR, Sanchez J, Suarez L, Caballero P, Laguna A, Sanchez JL, Whittington WL, Celum C, Grant RM; Peruvian HIV Sentinel Surveillance Working Group. Linking HIV and antiretroviral drug resistance surveillance in Peru: a model for a third-generation HIV sentinel surveillance. J Acquir Immune Defic Syndr. 2006 Aug 1;42(4):501-5.
• Liu AY, Grant RM, Buchbinder SP. Preexposure prophylaxis for HIV: unproven promise and potential pitfalls. JAMA. 2006 Aug 16;296(7):863-5. No abstract available.
• Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, Goicochea P, Casapía M, Guanira-Carranza JV, Ramirez-Cardich ME, Montoya-Herrera O, Fernández T, Veloso VG, Buchbinder SP, Chariyalertsak S, Schechter M, Bekker LG, Mayer KH, Kallás EG, Amico KR, Mulligan K, Bushman LR, Hance RJ, Ganoza C, Defechereux P, Postle B, Wang F, McConnell JJ, Zheng JH, Lee J, Rooney JF, Jaffe HS, Martinez AI, Burns DN, Glidden DV; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Dec 30;363(27):2587-99. Epub 2010 Nov 23.

Inclusion Criteria:

• Male sex (at birth)
• HIV uninfected
• Age having reached the local age of consent
• High risk for HIV infection including any of the following: 1) No condom use during anal intercourse with a male HIV-positive partner or a male partner of unknown HIV status during the last 6 months; (2) anal intercourse with more than 3 male sex partners during the last 6 months; (3) exchange of money, gifts, shelter, or drugs for anal sex with a male partner during the last 6 months; (4) sex with a male partner and STI diagnosis during the last 6 months or at screening, or (5) sexual partner of an HIV-infected man with whom condoms are not consistently used in the last 6 months.
• Able to provide a street address of residence for themselves and one personal contact who would know their whereabouts during the study period
• Healthy enough to work, as indicated by score of 80 or greater on the Karnofsky scale
• Certain laboratory values
• A urine dipstick with a negative or trace result for both glucose and protein within 28 days of enrollment.
• Ability to understand and local language for which an informed consent form has been approved by a local IRB and registered with the study sponsor.

Inclusion Criteria for Open-Label Extension:

• Participated in a randomized, placebo-controlled, PrEP trail
• Has been unblinded
• Has provided informed consent

Exclusion Criteria:

• Previously diagnosed active and serious infections, including tuberculosis infection, osteomyelitis, or infections requiring parenteral antibiotic therapy
• Active clinically significant medical problems including heart disease (e.g., symptoms of ischemia, congestive heart failure, arrhythmia), lung disease (steroid-dependent chronic obstructive pulmonary disease), diabetes requiring hypoglycemic medication, or previously diagnosed cancer expected to require further treatment
• Acute HBV infection at the screening visit or presence of treatment indications for hepatitis B based on local practice standards; or clinical signs of hepatic cirrhosis
• History of pathological bone fractures not related to trauma
• Receiving ongoing therapy with certain HIV/AIDS-related medications or other medications as determined by the investigator
• Definitely or possibly received an anti-HIV vaccine while participating in a blinded clinical trial
• Current alcohol or drug use that, in the opinion of the investigator, may interfere with the study
• Current participation in a clinical trial or cohort study other than sub-studies of this protocol
• Any condition at enrollment that, in the opinion of the investigator, would make participation in the study unsafe or would interfere with the study
• Sites may utilize additional criteria that restrict enrollment to a subset of people who meet the protocol-defined enrollment criteria.

Exclusion Criteria for Open-Label Extension:

- Site leadership believes participant will have difficulty completing requirements