Safety and Drug Detection Study of Dapivirine Vaginal Ring and Oral TRUVADA® in Breastfeeding Mother-Infant Pairs

This study will evaluate the safety and drug detection of the dapivirine (DPV) vaginal ring (VR) and oral Truvada in breastfeeding mother-infant pairs.

Mother-infant pairs will be randomly assigned to receive either the DPV VR or oral Truvada. Mothers randomized to the DPV VR will use the VR continuously for approximately one month (4 weeks), replacing the VR each month for approximately three months (12 weeks). Mothers using the Truvada tablet will take one tablet by mouth daily for approximately three months (12 weeks).

Study visits will occur at Day 0, Weeks 1 and 2, and Months 1, 2, 3, and 3.5. Study visits may include behavioral assessments; product acceptability assessments; infant feeding assessments; physical examinations; blood, urine, and breast milk collection; and pelvic examination and specimen collection.

Inclusion criteria

Inclusion criteria

- Mother

Participant mothers must meet all the following criteria to be eligible for inclusion in the study:

• Age 18 years or older at Screening, as verified per site Standard Operating Procedures (SOPs).
• At Enrollment, between 6 to 12 weeks postpartum (verified by birth records and/or similar supportive documentation and defined as between 42 - 84 days after delivery, inclusive).
• By participant report at Screening and Enrollment, currently exclusively breastfeeding one infant and willing and able to continue exclusively breastfeeding that infant for the duration of their participation in the study.

• Note: Exclusive breastfeeding will be defined as infant nutrition solely from breast milk, as determined by 7-day recall breastfeeding history. For the purposes of MTN-043, "breastfeeding" refers to all human milk feeding situations when an infant is fed with participant's own human milk whether the milk is received directly from the breast or as expressed milk.
• Consistently using an effective method of contraception per participant report at Enrollment, and intending to continue use of an effective method for the duration of study participation. Effective methods include contraceptive implants, intrauterine device, injectable progestin, oral contraceptive pills, and surgical sterilization.
• Able and willing to comply with all study requirements and complete all study procedures.
• Able and willing to provide the following:

• Written informed consent to be screened for and to take part in the study.
• Written informed consent for the breastfed infant to be screened for and take part in the study.
• Intention to stay within study catchment area for study duration and willingness to give adequate locator information, as defined in site SOPs.
• At Screening and Enrollment, HIV-uninfected based on HIV testing performed by study staff (per algorithm in the study protocol).
• At Screening and Enrollment, willing to be randomized at time of enrollment to either of the study products, and to continue study product use for at least 12 weeks.

Inclusion criteria

- Infant

Each mother eligible for MTN-043 will be asked to provide written informed consent for herself and her infant to participate in the study if the infant meets the following criteria:

• At Screening and Enrollment, infant is exclusively breastfed.

• Note: Exclusive breastfeeding will be defined as infant nutrition solely from breast milk, as determined by 7-day recall breastfeeding history. For the purposes of MTN-043, "breastfeeding" refers to all human milk feeding situations when an infant is fed with participant's own human milk whether the milk is received directly from the breast or as expressed milk.
• At Screening and Enrollment, the infant is generally healthy, according to the judgment of the investigator of record (IoR)/designee.
• At Enrollment, the infant is between the ages of 6 and 12 weeks postpartum (verified by birth records and/or similar supportive documentation with age defined as between 42 - 84 days after delivery, inclusive).

Exclusion criteria

Exclusion criteria

- Mother

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

• At Screening or Enrollment, breastfeeding infant ineligible for enrollment in the study.
• At Screening or Enrollment, participant reports any of the following:

• Known adverse reaction to any of the study products (ever).
• Known adverse reaction to latex and polyurethane (ever).
• Post-exposure prophylaxis (PEP) for HIV exposure within 6 months prior to Enrollment.
• Use of vaginal medications(s) or other vaginal products within five days prior to Enrollment.
• Non-therapeutic injection drug use in the 12 months prior to Enrollment.
• History of exposure to any investigational drug(s) during pregnancy, including participation in MTN-042.
• At Screening or Enrollment, has a positive HIV test.
• At Screening or Enrollment, Grade 2 or higher breast or genitourinary findings.
• At Screening or Enrollment, has a positive urinary pregnancy test.
• At Screening, has any of the following laboratory abnormalities:

• Positive for hepatitis B surface antigen (HBsAg).
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≥ Grade 2.
• Creatinine ≥ Grade 1.
• Estimated creatinine clearance ≥ Grade 2 (Cockcroft Gault formula).
• Diagnosed with urinary tract infection (UTI), pelvic inflammatory disease (PID), sexually transmitted infection (STI) or reproductive tract infection (RTI), requiring treatment per World Health Organization (WHO) Guidelines.

• Note: Otherwise eligible participants diagnosed during Screening with a UTI, PID or STI/RTI requiring treatment per WHO Guidelines - other than asymptomatic bacterial vaginosis (BV) and asymptomatic vulvovaginal candidiasis - are offered treatment consistent with WHO recommendations and may be enrolled after completing treatment if all symptoms have resolved. If treatment is completed and symptoms have resolved prior to obtaining informed consent for Screening, the participant may be enrolled. Genital warts requiring treatment also must be treated prior to enrollment. Genital warts requiring treatment are defined as those that cause undue burden or discomfort to the participant, including bulky size, unacceptable appearance, or physical discomfort.
• As determined by the IoR/designee, any significant uncontrolled active or chronic cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, psychiatric, endocrine, respiratory, immunologic disorder or infectious disease.
• 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 the study objectives.
• At Enrollment, participant reports any of the following:

• Participation in any research study involving drugs, vaccines, or medical devices 30 days or less prior to enrollment.
• Currently participating in other research studies involving drugs, vaccines, or medical devices.
• Expected to participate in other research studies involving drugs, vaccines, or medical devices during study participation.

Exclusion criteria

- Infants

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

• Note: Examples of exclusionary infant conditions include clinical evidence of stunting or illness.
• At Enrollment, according to the report of the mother, any of the following apply for the infant:

• Infants with birth weight less than 2000g.
• Participation in any research study involving drugs, vaccines, or medical devices since birth.
• Currently participating in other research studies involving drugs, vaccines, or medical devices.
• Expected to participate in other research studies involving drugs, vaccines, or medical devices for the duration of study participation.