MTN-008

Primary Objectives

• Assess the safety and tolerability of tenofovir 1% gel used daily for 7 days in third trimester pregnancy and lactation
• Assess the pharmacokinetics (PK) of tenofovir 1% gel used daily for 7 days in third trimester pregnancy and lactation

Study Summary
MTN-008 was the first study of repeat dosing of tenofovir 1% gel in pregnant and lactating women. Consistent with recommendations of the Institute of Medicine, the MTN-008 mother-infant pair study pursued critically valuable safety and PK data for microbicide use in HIV-uninfected women during pregnancy and breastfeeding, who represent a uniquely susceptible population of women in terms of HIV acquisition risk. The protocol assessed the presence of tenofovir in the blood of infants of women who enrolled in the Pregnancy and Lactation Cohorts and examined the impact of tenofovir 1% gel exposure on the presence of select organisms in the vagina.

MTN-008 completed follow-up on September 12, 2013. Results for the Lactation Cohort were first presented at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology (IDSOG) 2013 and results for the Pregnancy Cohort were first presented at IDSOG the following year. The two primary manuscripts were published in Antimicrobial Agents and Chemotherapy on August 22, 2016, and in Journal of the International AIDS Society on September 21, 2016, respectively. A total of three papers have been published from this study.

Primary Results
Lactation Cohort:  Seventeen healthy HIV-uninfected women who were breastfeeding a healthy infant between 4 and 24 weeks of age were enrolled. Serum tenofovir was detectable in all mothers, with median Cmax of 7.5 ng/mL after dose 1 and 5.6 ng/mL after dose 7. Breast milk tenofovir was quantifiable in 4 (4/16; 25%) mothers after dose 1, and in 6 (6/16; 37.5%) women after dose 7. Infant serum tenofovir was quantifiable in 6 infants (37.5%) at 6 hours after dose 1 and in 12 infants (75%) after dose 7. Nine (9/17; 53%) mothers had one or more adverse events (AEs). All maternal AEs were mild and over half (60%) were deemed unrelated. Four of 17 infants had one or more AEs for a total of 8 AEs, all of which were mild and typical for infancy. In summary, maternal PK values were similar to steady-state values in previous studies of observed dosing in non-lactating women. Tenofovir did not accumulate in breast milk following multi-day vaginal dosing and absorption of tenofovir in infants was low overall.

Pregnancy Cohort:  Ninety-eight healthy pregnant women were successfully and sequentially enrolled (first cohort at term, second cohort at late preterm) in a 2:1 ratio to tenofovir 1% vaginal gel versus HEC placebo gel. Most (>85%) maternal and neonatal AEs were low grade AEs, with no higher-grade AEs related to study product, and occurred at statistically equal rates in both gestational age cohorts and in both product arms. All maternal and neonatal primary endpoints also occurred in statistically equivalent proportions between the two study arms.  All women randomized to tenofovir gel in both gestational age cohorts had detectable serum tenofovir, with low overall median drug levels consistent with non-pregnant women. Overall, 16% of women and 25% of neonates had low but detectable TFV at delivery.  In summary, daily use of tenofovir 1% vaginal gel in term and late preterm pregnancy was well-tolerated, demonstrated a favorable safety profile and produced low serum levels consistent with those in non-pregnant women.