Intervention: Dapivirine
Trial phase: Phase 1
ATC code: G01AX17
SMILES: Cc1cc(C)c(Nc2ccnc(Nc3ccc(C#N)cc3)n2)c(C)c1
Sex: All
Age groups: Adult
Healthy volunteers: Accepts Healthy Volunteers
Participants at risk: 18
Group description: Participants will receive a single dose of dapivirine gel rectally, followed by 7 daily doses of dapivirine gel to be administered under direct observation in the clinic.

Dapivirine gel: Dapivirine gel (0.05%); administered rectally
Eligibility criteria:
Inclusion Criteria:

Age of 18 - 45 years (inclusive) 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 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
Per participant report, a history of consensual receptive anal intercourse (RAI) at least once in the past calendar year
Willing to not 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 be sexually abstinent for 72 hours prior to each study visit, during the study product use periods and for 72 hours after biopsy collection. Note: See Criteria 12 and 13 for additional restrictions for female participants
Willing to abstain from inserting any non-study products into the rectum for 72 hours prior to each study visit and during the study product use periods. Note: See Criteria 12 and 13 for additional restrictions for female participants

Females must also meet the following additional inclusion criteria to be eligible for study inclusion:

Women over the age of 21 (inclusive) must have documentation of a satisfactory Pap within the past 3 years prior to Enrollment consistent with Grade 0 according to the Female Genital Grading Table for Use in Microbicide Studies Addendum 1 (dated November 2007) to the DAIDS Table for Grading Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, or satisfactory evaluation with no treatment required of Grade 1 or higher Pap result
Willing to be sexually abstinent for 72 hours prior to each study visit and during the study product use periods and for 7 days after biopsy collection
Willing to abstain from inserting any non-study products into the vagina for 72 hours prior to each study visit, during the study product use periods and for 7 days after biopsy collection
Willing to use an effective method of contraception for at least 30 days (inclusive) prior to Enrollment and intending to continue use of an effective method for the duration of study participation; effective methods include: hormonal methods (except contraceptive ring), intrauterine device (IUD), sterilization (of participant and/or partner, as defined in site SOPs), or sexually abstinent for 90 days prior to Screening

Exclusion Criteria:

At Screening:

Hemoglobin Grade 1 or higher*
Platelet count Grade 1 or higher*
White blood count Grade 2 or higher*
Serum creatinine greater than 1.3× the site laboratory upper limit of normal (ULN)
International normalized ratio (INR) greater than 1.5× the site laboratory ULN
Aspartate aminotransferase (AST) or alanine transaminase (ALT) Grade 1 or higher*
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, HBV or HCV) can be re-tested during the screening process. If a participant is re-tested and a non-exclusionary result is documented within 45 days of providing informed consent for screening, the participant may be enrolled.

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

Heparin, including Lovenox®
Warfarin
Plavix® (clopidogrel bisulfate)
Aspirin (greater than 81 mg)
Non-steroidal anti-inflammatory drugs (NSAIDS)
Any other drugs that are associated with increased likelihood of bleeding
CYP3A inducer(s) and/or inhibitor(s) as specified in the MTN-026 Study-Specific Procedures (SSP) Manual
Hormone-replacement therapy in tablet, injectable or gel form
Known adverse reaction to any of the components of the study products
Use of post-exposure prophylaxis (PEP) for potential HIV exposure within the 6 months prior to Enrollment
Use of pre-exposure prophylaxis (PrEP) for HIV prevention within the 6 months prior to Enrollment, and/or anticipated use during trial participation
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 past 6 months
Non-therapeutic injection drug use in the 12 months prior to Screening and Enrollment
Participation in research studies involving drugs, medical devices, genital or rectal products, or vaccines within 45 days of the Enrollment Visit
At Screening, participant report of treatment for an anogenital STI within the past 3 months
At Screening, participant-reported symptoms and/or clinical or laboratory diagnosis of active anorectal or reproductive tract infection requiring treatment per current World Health Organization (WHO) guidelines (http://www.who.int/hiv/pub/sti/pub6/en/) 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, cervicitis, chancroid, pelvic inflammatory disease (PID), bacterial vaginosis (BV), symptomatic vaginal candidiasis, other vaginitis, trichomoniasis. Note: Otherwise eligible participants with an exclusionary UTI, BV and/or candida finding may be re-tested during the screening process.
At Enrollment, active anorectal or reproductive tract infection requiring treatment per current WHO guidelines (http://www.who.int/hiv/pub/sti/pub6/en/) or symptomatic urinary tract infection (UTI). Infections requiring treatment include symptomatic GC, CT, syphilis, active HSV lesions, anogenital sores or ulcers, symptomatic genital warts, bacterial vaginosis, symptomatic vaginal candidiasis, other vaginitis, trichomoniasis, chancroid, cervicitis and PID. 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.

Females who meet any of the following additional criteria will be excluded from the study:

Pregnant or breastfeeding at either Screening or Enrollment or intends to become pregnant or start breastfeeding during study participation. Note: A documented negative pregnancy test performed by study staff is required for inclusion; however, a self-reported pregnancy is adequate for exclusion from screening/enrollment into the study.
Last pregnancy outcome 90 days or less prior to Screening
Has had a hysterectomy
At Enrollment, has a clinically apparent Grade 1 or higher pelvic exam finding (observed by study clinician or designee) per the Female Genital Grading Table for Use in Microbicide Studies [Addendum 1, Dated November 2007]. Note: Cervical friability bleeding associated with speculum insertion and/or specimen collection judged to be within the range of normal according to the clinical judgment of the IoR/designee is considered expected non-menstrual bleeding and is not exclusionary.