The purpose of this study is to examine safety and tolerability of daily tenofovir use in HIV-uninfected men.

This study will assess the clinical and behavioral safety and tolerability of oral daily TDF use as pre-exposure prophylaxis (PrEP) to prevent HIV infection in uninfected men.

Inclusion Criteria:

• Healthy biologic male (male at birth)
• 18-60 years of age
• HIV-1 negative by licensed, commercially available, FDA-approved whole blood rapid enzyme immunoassay (EIA) at screening and enrollment
• Reports any anal sex with a man in the last 12 months
• Able to understand and pass comprehension assessment questionnaire
• Able to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures
• Able to understand English
• Adequate renal function: calculated creatinine clearance of at least 70 mL/min
• Hepatic transaminases (AST and ALT) less than or equal to 2x upper limit of normal (ULN)
• Total bilirubin less than or equal to 1.5 mg/dL
• Absolute neutrophil count at least 1,500/mm3;
• Platelets at least 100,000/mm3;
• Hemoglobin at least 9.5 g/dL
• Serum amylase less than or equal to 1.5 x ULN
• Biochemical profile: within normal limits for serum phosphorus, potassium, sodium, and calcium.
• Hepatitis B surface antigen negative
• Normal urine dipstick or urinalysis (UA)

Exclusion Criteria:

• Active untreated syphilis
• Current uncontrolled hypertension (blood pressure > 160/100 mmHg)
• Mutually monogamous for > one year with a known HIV antibody negative partner
• History of chronic renal disease, known osteoporosis, osteomalacia, or osteopenia
• Current or expected participation in other longitudinal HIV behavioral or biomedical research study
• Current HIV antiretroviral use
• Receiving or planning to receive on-going therapy with any nephrotoxic agents or experimental/investigational agents
• Previous or expected requirements for the administration of immunosuppressive/ immunomodulatory therapy (e.g. chronic systemic steroids, interferon, interleukins, chemotherapy, radiation).
• Evidence of a gastrointestinal malabsorption syndrome or chronic nausea or vomiting which may confer an inability to receive an orally administered medication.
• Current alcohol or substance abuse judged by the investigator to potentially interfere with participant compliance.
• Imminently life-threatening medical conditions (malignancy, immunosuppressive disease [e.g. lymphoma]), or other serious disease or conditions (e.g. cardiovascular, renal, diabetes) within the last 5 years or that are unstable and/or require chronic medication that would impede compliance with study requirements and complicate the interpretation of adverse events
• Expected to be non-compliant with study visits or planning to move within 24 months to an area where the study will not be conducted
• Any other clinical or social condition, prior therapy, occupation, or other responsibility, that, in the opinion of the investigator, would interfere with, or serve as a contraindication to study participation or compliance with the dosing requirements.

400 participants enrolled (200 in San Francisco, 121 in Atlanta, and 79 in Boston). 201 were randomized to TDF and 199 to placebo. Participants were distributed similarly in terms of age, ethnicity, education, no. male partners in previous 3 mo., and no. of unprotected anal sexual contacts within the previous 3 mo.

Maximum time period on drug of 24 months for immediate arm participants and 15 months for delayed arm participants.

Treatment emergent cohort: participants enter cohort when study drug is initiated, and exit at the first occurence of one of these events: 1) completion of study visits, 2)30 days after loss to follow up, or 3)30 days after start of permanent drug interruption.