MTN-016

Primary Objectives

• Compare adverse pregnancy and delivery outcomes between participant mothers assigned to an active agent with those of mothers assigned to placebo/control
• Compare prevalence of major malformations identified in the first year of life between infants of mothers assigned to an active agent with those of infants of mothers assigned to placebo/control

Study Summary
The Prevention Agent Pregnancy Exposure Registry, also known as EMBRACE (Evaluation of Maternal and Baby Outcome Registry After Chemoprophylactic Exposure) was a prospective observational cohort study of maternal exposures to investigational HIV prevention agents. 460 pregnant participants and 413 infants were enrolled in the study. Participants are enrolled as early in pregnancy as possible to maximize data validity. The study population consisted of current or recent female participants identified as becoming pregnant during MTN microbicide or PrEP trials, or who have had planned exposures in pregnancy safety studies. This study included infants resulting from those pregnancies. This protocol assessed adverse pregnancy outcomes, evaluated growth parameters of infants during the first year of life, and collected information on the prevalence of major malformations in infants during the first year of life. It also evaluated the prevalence and persistence of HIV drug resistance mutations in plasma among HIV-infected infants and provided a cohort of infants not exposed to active study agents during pregnancy. The status of MTN-016 participants enrolled from the following parent protocols is as follows:

• MTN-002 protocol cohort completed follow-up on December 23, 2010
• MTN-003 protocol cohort completed follow-up on December 9, 2013
• MTN-008 protocol cohort completed follow-up on September 17, 2014
• MTN-020 protocol cohort completed follow-up on January 6, 2017
• MTN-025 protocol cohort completed follow-up on May 6, 2020

A total of two papers have been published from this study. Primary results from all cohorts are described below.

Primary Results
MTN-016/MTN-002 and MTN-008 cohorts’ results of obstetric and infant outcomes were presented at the 2014 HIV Research for Prevention (HIVR4P) meeting held on October 28-31, 2014, in Cape Town, South Africa. All 16 MTN-002 and 90% (88/98) of MTN-008 mothers were registered, with 25% (n=4) of MTN-002 and 97% (n=86) of MTN-008 participants enrolling prior to known pregnancy outcome. Demographics were similar for MTN-008 enrollees and non-enrollees in the registry. Infant retention at 12 months was 88% (MTN-002) and 80% (MTN-008). One defect (ear canal) was noted in MTN-002, a rate (6%) comparable to the 3% US background rate for malformations (p=0.51); no defects were noted in infants from MTN-008. Compared to placebo (n=30), TFV gel (n=58) was not associated with preterm delivery (1/58 (2%) vs. 2/30 (7%), p=0.27), postpartum hemorrhage (11/58 (19%) vs. 3/30 (10%), p=0.36), non-reassuring fetal status (3/58 (5%) vs. 1/30 (3%), p=1.0), chorioamnionitis (1/58 (2%) vs. 2/30 (7%), p=0.27), gestational diabetes (0/58 (0%) vs. 1/30 (3%), p=0.34), or abnormal infant physical exam findings in the first year of life (14/58 (24%) vs. 8 (27%), p=1.0).

MTN-016/VOICE cohort’s results of pregnancy incidence and outcomes were presented at International AIDS Society (IAS) held on July 19 - 22, 2015 in Vancouver, Canada. A total of 452 pregnancies occurred among 428 women who became pregnant while enrolled in VOICE (overall incidence of 8.2 per 100 person-years).  The median age at pregnancy was 23 years and did not differ by study arm. Among those who became pregnant, 1 (0.2%) was using an IUD, 289 (67.5%) were using oral contraceptives. 129 (30.1%) were using injectable contraceptives, and 11 (2.6%) were using implants. “Small for gestational age” or intrauterine growth restriction occurred in 10 out of 172 (5.8%) infants for whom classification was available. There were 263 (59%) full term live births, 22 (5%) premature births, 14 (3%) still births, 83 (19%) spontaneous abortions, 3 (1%) ectopic pregnancies, 60 (13%) elective abortions, and 3 (1%) other. Pregnancy rates and outcomes were equally distributed between study arms, but drug detection at visits associated with pregnancy diagnosis was too low to analyze pregnancy outcomes based on exposure.

Data regarding growth and development of infants born to VOICE participant mothers was presented at the HIV Research for Prevention (HIV R4P) conference, held on October 17-20, 2016, in Chicago, IL, USA. Of 199 live births in VOICE study participants, 185 (93%) were enrolled in MTN-016, of whom 14 (7.6%) were premature at birth and 6 (3.2%) died during follow-up. Most infants (88%) were evaluated within 10 days of birth and, of those enrolled, 87%, 93% and 89% completed visits at 1, 6 and 12 months respectively. After adjusting for pre-term gestation, there were no differences in growth over the first year among infants whose mothers were enrolled in study arms evaluating antiretroviral agents compared to placebos. Indications of developmental delay were rare: Denver II Screening results of “delay” or “caution” at 12 months were infrequent (2.5% gross motor, 0.6% fine motor, 1.9% language and 2.5% personal-social).

MTN-016/ASPIRE cohort’s results of pregnancy incidence and outcomes were presented at the Conference on Retroviruses and Opportunistic Infections (CROI) held on February 13 -17, 2017 in Seattle, WA. The primary manuscript was published in Journal of Acquired Immune Deficiency Syndromes on December 15, 2018. Of 2629 women enrolled in ASPIRE, 2551 were available for analysis (78 reported prior history of tubal ligation). Overall, a total of 179 pregnancies were detected in 169 women (dapivirine arm, n=86; placebo arm, n=93), resulting in 181 pregnancy outcomes. Pregnancy incidence was similar in the dapivirine and placebo arms (4.0 per 100 person-years, 95% CI 3.1-5.1 versus 4.3 per 100 person-years ,95% CI 3.4-5.5; HR=0.93, 95% CI 0.68-1.26). The distribution of pregnancy outcomes did not differ by study arm. Among 114 pregnancies that resulted in live births, data on potential congenital anomalies were available for 107 live births, with any anomaly seen in 4 infants (8%) in the dapivirine arm versus 4 (7%) in the placebo arm and no pattern of anomalies for those assigned to dapivirine. In summary, no differences were observed in the incidence of pregnancy between the dapivirine ring and placebo arms, and no adverse effects on pregnancy outcomes, infant congenital anomalies, or infant growth through the first year of life.

MTN-016/HOPE cohort’s results of pregnancy incidence and outcomes were summarized in the MTN-016 summary report by IPM. MTN-025 reported 71 pregnancies, of whom 38 participants were enrolled into MTN-016. Among them 33 completed the study and five discontinued the study early. Thirty-five participants ever used a ring and three never used one. The mean age of participants was 28.7 with 24 (63.2%) of them married. A total of 38 pregnancies were detected in 38 women, 30 (78.9%) full-term birth, 3 (7.9%) premature live birth, 2 (5.3%) stillbirth and 2 (5.3%) spontaneous abortions. There was no congenital anomaly reported in the HOPE cohort. Among 114 pregnancies that resulted in live births, data on potential congenital anomalies were available for 107 live births, with any anomaly seen in 4 infants (8%) in the dapivirine arm versus 4 (7%) in the placebo arm and no pattern of anomalies for those assigned to dapivirine. In summary, no differences were observed in the incidence of pregnancy between the dapivirine ring and placebo arms, and no adverse effects on pregnancy outcomes, infant congenital anomalies, or infant growth through the first year of life. No statistically significant difference was observed between the dapivirine group in HOPE and MTN-020 dapivirine and placebo groups for the Newborn/Initial Visit, Month 1, 6, and 12 Visits measurements of head circumference, weight, and length, indicating no reductions in growth of infants born to women with inadvertent exposure to dapivirine in early pregnancy compared to women in the placebo group. No HIV infections were reported for the participants from HOPE. No neonatal or infant deaths were reported for the dapivirine group in HOPE.