Pharmacokinetic Study of Dapivirine Gel Administered Rectally to HIV-1 Seronegative Adults

This study will evaluate the pharmacokinetics (PK) of dapivirine gel administered rectally to
HIV-1 seronegative adults.

Participants will be randomly assigned to two groups: Sequence A or Sequence B. Participants
in Sequence A will receive 2.5 g of dapivirine gel administered rectally via an applicator,
followed by a 2- to 4-week washout period. Participants will then receive a second dose of up
to 10 g of dapivirine gel administered rectally via a coital simulation device. Participants
in Sequence B will receive up to 10 g of dapivirine gel administered rectally via a coital
simulation device, followed by a 2- to 4-week washout period. Participants will then receive
a second dose of 2.5 g of dapivirine gel administered rectally via an applicator.

Participants will be in the study for approximately 1 month and will attend 7 study visits.
Study visits may include behavioral assessments, physical examinations, blood and urine
collection, throat and anorectal sample collection, and PK sampling.

Inclusion Criteria:

- Men and transgender women who are 18 years or older at Screening, verified per site
standard operating procedure (SOP)

- Able and willing to provide written informed consent

- HIV-1/2 uninfected at Screening and Enrollment, per applicable algorithm in Appendix
II of the study protocol and willing to receive HIV test results

- Able and willing to provide adequate locator information, as defined in site SOP

- Available to return for all study visits and willing to comply with study
participation requirements

- In general good health at Screening and Enrollment, as determined by the site
Investigator of Record (IoR) or designee

- At Screening, history of consensual receptive anal intercourse (RAI) at least once in
the past year per participant report

- Willing not to take part in other research studies involving drugs, medical devices,
genital or rectal products, or vaccines for the duration of study participation
(including the time between Screening and Enrollment)

- Willing to abstain from RAI, receptive oral anal stimulation (i.e., rimming), rectal
stimulation via fingers, as well as the insertion of any non-study products into the
rectum for 72 hours before and after each study visit

Exclusion Criteria:

- At Screening:

- Hemoglobin Grade 1 or higher*

- Platelet count Grade 1 or higher*

- White blood count Grade 2 or higher*

- Aspartate aminotransferase (AST) or alanine transaminase (ALT) Grade 1 or higher*

- Serum creatinine greater than 1.3 times the site laboratory upper limit of normal
(ULN)

- International normalized ratio (INR) greater than 1.5 times the site laboratory
ULN

- Positive for hepatitis C antibody

- Positive for hepatitis B surface antigen

- History of inflammatory bowel disease by participant report

- (*As per the Division of AIDS Table for Grading the Severity of Adult and
Pediatric Adverse Events Corrected Version 2.1, July 2017)

- Note: Otherwise eligible participants with an exclusionary test result (other
than HIV, hepatitis B virus (HBV) or hepatitis C virus (HCV)) can be re-tested
during the screening process. If a participant is re-tested and a
non-exclusionary result is documented within 30 days of providing informed
consent for screening, the participant may be enrolled.

- Known adverse reaction to latex or polyurethane (ever)

- Anticipated use of and/or unwillingness to abstain from the following medications
during study participation:

- Anticoagulant medications

- Aspirin (greater than 81 mg/day)

- Non-steroidal anti-inflammatory drugs (NSAIDS)

- Any other drugs that are associated with increased likelihood of bleeding

- Rectally-administered medications or products containing nonoxynol-9 (N-9) or
corticosteroids

- CYP3A inducer(s) and/or inhibitor(s) as specified in the MTN-033 Study Specific
Procedures (SSP) Manual

- Hormone-replacement therapy in tablet, patch, injectable or gel form

- Known adverse reaction to any of the components of the study product, applicator or
coital simulation device

- Use of pre-exposure prophylaxis (PrEP) for HIV prevention within 1 month prior to
Enrollment, and/or anticipated use and/or unwillingness to abstain from PrEP during
trial participation

- Use of post-exposure prophylaxis (PEP) for potential HIV exposure within the 6 months
prior to Enrollment

- Use of systemic immunomodulatory medications within the 6 months prior to Enrollment,
and/or anticipated use during trial participation

- RAI without a condom and/or penile-vaginal intercourse with a partner who is known to
be HIV-positive in the 6 months prior to Enrollment

- Non-therapeutic injection drug use in the 12 months prior to Enrollment

- Participation in research studies involving drugs, medical devices, genital or rectal
products, or vaccines within 30 days of the Enrollment Visit

- Per participant report at Screening, treatment of an anogenital sexually transmitted
infection (STI) (after diagnosis) within the past 3 months

- At Screening, participant-reported symptoms, and/or clinical or laboratory diagnosis
of active anorectal or reproductive tract infection (RTI) requiring treatment per
current CDC guidelines (http://www.cdc.gov/std/treatment) or symptomatic urinary tract
infection (UTI). Infections requiring treatment include symptomatic Neisseria
gonorrhea (GC), Chlamydia trachomatis (CT) infection, syphilis, active herpes simplex
virus (HSV) lesions, anogenital sores or ulcers, or symptomatic genital warts,
chancroid, trichomoniasis.

- Note: Otherwise eligible participants with an exclusionary UTI may be re-tested
during the screening process.

- At Enrollment, active anorectal infection or RTI requiring treatment per current CDC
guidelines (http://www.cdc.gov/std/treatment) or symptomatic UTI. Infections requiring
treatment include symptomatic GC, CT, syphilis, active HSV lesions, anogenital sores
or ulcers, symptomatic genital warts, trichomoniasis, chancroid.

- Note: HSV-1 or HSV-2 seropositive diagnosis with no active lesions is permitted
since treatment is not required.

- Has any other condition that, in the opinion of the IoR/designee, would preclude
informed consent, make study participation unsafe, complicate interpretation of study
outcome data, or otherwise interfere with achieving study objectives.