Evaluating the Safety and Tolerability of Antiretroviral Drug Regimens Used as Pre-Exposure Prophylaxis to Prevent HIV Infection in At-Risk Men Who Have Sex With Men and in At-Risk Women

Several clinical trials are currently under way evaluating the safety and efficacy of
ARV-based PrEP for preventing HIV infection. In 2010, the results of the first efficacy
trial of ARV-based PrEP showed 44% fewer HIV infections among study participants receiving
the study drugs (TDF and FTC) than among those receiving placebo. Although these results are
promising, concerns about poor adherence, drug resistance, and toxicity prompt further
exploration of ARV PrEP regimens. This trial will evaluate the safety and tolerability of
PrEP using four ARV regimens in reducing HIV transmission in at-risk men who have sex with
men and in at-risk women.

Participants will be randomly assigned to one of four arms: Arm 1, Arm 2, Arm 3, or Arm 4.
Arm 1 will receive MVC, FTC placebo, and TDF placebo orally once daily from Week 0 through
48. Arm 2 will receive MVC, FTC, and TDF placebo orally once daily from Week 0 through 48.
Arm 3 will receive MVC, FTC placebo, and TDF orally once daily from Week 0 through 48.
Participants in Arm 4 will receive MVC placebo, FTC, and TDF orally once daily from Week 0
through 48.

Study visits will occur at enrollment and Weeks 2, 4, 8, 16, 24, 32, 40, 48, and 49. All
study visits will include a physical examination, blood collection and storage, and HIV
counseling and testing. Select study visits will include adherence counseling, surveys,
behavioral assessments (including sexual behavioral assessments), urine collection, and
dual-energy x-ray absorptiometry (DXA). Participants will also undergo sexual behavioral
assessments randomly 12 to 13 times through Week 48 via short message service (SMS). Some
female participants may opt into taking part in an interview at Week 48.

Participants who enroll in this study may also consent to be a part of two subset
evaluations as part of this study: the Drug Interaction Subset or the Tissue Subset.
Enrollment in these subsets will involve additional study procedures. The Drug Interaction
Subset will undergo blood collection before and after a directly observed dose of study drug
at the Week 2 visit. Participants in the Tissue Subset will take part in additional study
procedures at select visits, including blood collection, hair collection, and rectal tissue
and fluid collection (required for men; optional for women). Women involved in the Tissue
Subset will also undergo cervical tissue and cervicovaginal fluid collection at select
visits.

Inclusion Criteria:

- For participants in the men's component of the study, born male. For participants in
the women's component of the study, born female.

- 18 years or older at the time of screening

- Willing to provide informed consent for the study

- Able to read at a level required for the study components (e.g., computer-assisted
self-interview [CASI] and short message service [SMS], per the judgment of the study
investigator)

- For men, a history of receptive or insertive anal intercourse without use of condoms
with at least one HIV-infected male partner or male partner of unknown HIV serostatus
within 90 days of study entry (provided by self-report)

- For women, a history of vaginal intercourse or receptive anal intercourse without use
of condoms with at least one HIV-infected male partner or male partner of unknown HIV
serostatus within 90 days of study entry (provided by self-report)

- The following laboratory values must be from specimens obtained within 45 days prior
to study enrollment: Nonreactive HIV test results (more information on this criterion
can be found in the protocol); hemoglobin (men) greater than 11 g/dL; hemoglobin
(women) greater than or equal to 10.5 g/dL; absolute neutrophil count greater than
750 cells/mm^3; platelet count greater than or equal to 100,000/mm^3; for men and
women, calculated creatinine clearance greater than or equal to 70 mL/minute using
the Cockcroft-Gault equation; alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) less than 3 times the upper limit of normal (ULN); total
bilirubin less than 2.5 ULN; urine protein less than 2+; and hepatitis B surface
antigen (HBsAg) negative.

- No alcohol or substance use that, in the opinion of the study investigator, would
interfere with the conduct of the study (e.g., provided by self-report or found upon
medical history and examination or in available medical records)

- No medical condition that, in the opinion of the study investigator, would interfere
with the conduct of the study (e.g., provided by self-report or found upon medical
history and examination or in available medical records)

- Willing to undergo all required study procedures (including sexual assessment by
CASI, use of the drug monitoring device, and SMS [i.e., texting])

- For all women participants: If of reproductive potential (defined as girls who have
reached menarche and pre-menopausal women who have not had a sterilization procedure
per self-report (e.g., hysterectomy, bilateral oophorectomy, tubal ligation or
salpingectomy), must have a negative serum or urine pregnancy test performed within
48 hours before initiating the protocol-specified medication(s). More information on
this criterion can be found in the protocol.

- For all women participants: If participating in sexual activity that could lead to
pregnancy, must agree to use a form of contraception from the following list during
the trial and for 30 days after stopping the study medication: condoms (male or
female) with or without a spermicidal agent, diaphragm or cervical cap with
spermicide, IUD, or hormone-base contraceptive.

Inclusion Criteria for the Tissue Subset:

- For men and women participating in the rectal component, willing to abstain from
receptive anal intercourse and practices involving insertion of anything in the
rectum (drug, enema, penis, or sex toy) for 3 days prior to rectal biopsy and for 7
days post-biopsy, to minimize risk of HIV-1 infection and bleeding complications
after each procedure

- For women participating in the vaginal component, willing to abstain from vaginal
intercourse and practices involving insertion of anything in the vagina (drug,
douche, penis, or sex toy) for 3 days prior to cervical biopsy and for 7 days
post-biopsy, to minimize risk of HIV-1 infection and bleeding complications after
each procedure

- For women only, per participant report at screening, usual menstrual cycle with at
least 21 days between menses (does not apply to participants who report using a
progestin-only method of contraception at screening, e.g., Depo-Provera)

- For women, satisfactory Pap results in the 12 calendar months prior to enrollment
consistent with Grade 0 according to the Female Genital Grading Table for Use in
Microbicide Studies Addendum 1 to the DAIDS Table for Grading Adult and Pediatric
Adverse Events, Version 1.0, December 2004 (Clarification dated August 2009), or
satisfactory evaluation with no treatment required of Grade 1 or higher Pap result
per American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines in the
12 calendar months prior to enrollment. If there is no document of satisfactory Pap
results, the participant should be offered to have the test performed by the site
prior to the enrollment visit. If they refuse, they are not eligible.

Exclusion Criteria:

- One or more reactive HIV test results at screening or enrollment, even if HIV
infection is not confirmed

- Coenrollment in any other HIV interventional research study (provided by self-report
or other available documentation) or prior enrollment and receipt of active arm
(i.e., NOT a placebo) of an HIV vaccine trial (provided by available documentation)

- Use of ARV therapy (e.g., for post-exposure prophylaxis [PEP] or PrEP) in the 90 days
prior to study entry

- Prior history of a gastrectomy, colostomy, ileostomy, or any other procedure altering
the gastrointestinal tract or drug absorption (provided by self-report or obtained
from medical history or records)

- Receipt of prohibited medications as described in the study drug package inserts or
listed in the Study-Specific Populations (SSP) Manual (provided by self-report or
obtained from medical history or medical records)

- Ongoing intravenous drug use: episodic use or any use in the past 90 days (as
assessed by the study investigator)

- Known medical history of allergy to soy (soya or soybeans) or peanuts

- Weight exceeding 300 pounds (exceeds weight limit of DXA scanners)

- For women, pregnancy or currently breastfeeding

Exclusion Criteria for the Tissue Subset:

For Men and Women:

- The following applies to men, and only to women who opt for rectal sampling:
Abnormalities of the colorectal mucosa or significant colorectal symptom(s), which in
the opinion of the study investigator represent a contraindication to biopsy
(including but not limited to presence of any unresolved injury, infectious or
inflammatory condition of the local mucosa, and presence of symptomatic external
hemorrhoids)

- Per participant report at screening, anticipated use and/or unwillingness to abstain
from the following medications during the period of study participation: Heparin,
including Lovenox®, Warfarin, Plavix® (clopidogrel bisulfate), or any other drugs
that are associated with increased risk of bleeding following biopsy procedures in
the opinion of the study investigator

- The following applies to men, and only to women who opt for rectal sampling: Per
participant report at screening, anticipated use and/or unwillingness to abstain from
rectally administered medications (including over-the-counter products) for 3 days
prior to rectal biopsies and for 7 days after biopsies

- Per participant report at screening, anticipated use and/or unwillingness to abstain
from the following medications for a period of 10 days before a biopsy procedure:
aspirin (daily use of low-dose aspirin [no more than 81 mg] is allowed at the
discretion of the Investigator of Record) or non-steroidal anti-inflammatory drugs
(NSAIDS)

- Abnormal laboratory results for coagulation tests that may indicate an increased risk
of bleeding (in the opinion of the investigators)

- Active untreated syphilis, gonorrhea, or chlamydia infection

For Women Only:

- Carcinoma in situ of the cervix or invasive cervical cancer. Abnormalities of the
vaginal mucosa or significant vaginal symptom(s), which in the opinion of the study
investigator represent a contraindication to biopsy (including but not limited to
presence of any unresolved injury, and infectious or inflammatory condition of the
local mucosa).

- Hysterectomy

- Per participant report at screening, anticipated use and/or unwillingness to abstain
from vaginally administered medications (including over-the-counter products) and
vaginal douching for 3 days prior to cervical biopsies and for 7 days after biopsies