Emtricitabine/Tenofovir Disoproxil Fumarate for HIV Prevention in Men

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.

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