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. Author manuscript; available in PMC: 2025 Jan 1.
Published in final edited form as: J Acquir Immune Defic Syndr. 2024 Jan 1;95(1):65–73. doi: 10.1097/QAI.0000000000003312

DELIVER: A Safety Study of a Dapivirine Vaginal Ring and Oral PrEP for the Prevention of HIV During Pregnancy

Katherine Bunge 1, Jennifer E Balkus 2, Lee Fairlie 3, Ashley J Mayo 4, Clemensia Nakabiito 5, Nyaradzo Mgodi 6, Luis Gadama 7, Moleen Matrimbira 8, Catherine Anne Chappell 9, Jeanna Piper 10, Nahida Chakhtoura 11, Daniel w Szydlo 12, Barbra Richardson 13, Sharon L Hillier 14
PMCID: PMC11443417  NIHMSID: NIHMS1933114  PMID: 38055292

Abstract

Background:

Pregnancy represents a period of high HIV acquisition risk. Safety data for the monthly dapivirine vaginal ring (DVR) during pregnancy are limited. Here we report data from the first two cohorts of pregnant participants in MTN-042/DELIVER, a phase 3b, randomized, open-label safety trial of DVR and oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). MTN-042 is being conducted in three cohorts beginning with later gestational ages when risks of drug exposure are less.

Methods:

Eligible pregnant individuals aged 18 to 40 in Malawi, South Africa, Uganda, and Zimbabwe were randomized 2:1 to monthly DVR or daily TDF/FTC. Participants in cohort 1 initiated product use between 36 weeks 0 days (36 0/7 weeks) −37 6/7 weeks gestation; participants in cohort 2 initiated product use between 30 0/7– 35 6/7 weeks gestation. All participants continued product use until delivery or 41 6/7 weeks gestation. Pregnancy outcomes and complications were assessed and summarized using descriptive statistics and compared to local background rates obtained through a separate chart review.

Results:

One-hundred and fifty participants were enrolled into cohort 1 with 101 randomized to DVR and 49 to TDF/FTC. One-hundred and fifty-seven participants were enrolled into cohort 2 with 106 randomized to DVR and 51 to TDF/FTC. In both cohorts, pregnancy complications were rare and similar to local background rates.

Conclusion:

In this first study of a long-acting HIV prevention agent in pregnancy, adverse pregnancy outcomes and complications were uncommon when DVR and TDF/FTC were used in the third trimester of pregnancy suggesting a favorable safety profile for both prevention products.

Keywords: HIV prevention, pregnancy, safety, pre-exposure prophylaxis, dapivirine vaginal ring

Introduction

Pregnancy and postpartum are times of increased HIV acquisition risk1. One analysis of two HIV prevention trials found that the per-act probability of HIV acquisition was nearly three times higher for individuals in late pregnancy compared to their nonpregnant counterparts2. Biologically, hormonal changes are associated with increased innate immunity with associated inflammation and decreased adaptive immunity with fewer natural killer cells and reduced cytotoxic T-cell response3–7. The progesterone dominant genital environment is associated with mucosal thinning and increased CCR5 co-receptor expression. Behaviorally, condoms may be used less frequently during pregnancy and sexual partners may seek partners outside of their relationships8. Effective HIV prevention methods are essential for pregnant people, not only for the pregnant person’s health but also for the infant. Perinatal transmission is estimated to be as high as 18% with incident HIV infection during pregnancy9.

Oral daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) as pre-exposure prophylaxis (PrEP) was the first regimen clinically shown to prevent HIV-1 acquisition. Among nonpregnant reproductive-aged cisgender women, the Partners PrEP trial demonstrated a 66% reduction in HIV-1 incidence compared to placebo10. Subsequent demonstration projects reported even higher reductions (>95%) and confirmed high adherence. 11. Efficacy trials of TDF/FTC did not include pregnant and breastfeeding individuals; however, substantial data from pregnant and lactating individuals using TDF/FTC as treatment for HIV and Hepatitis B supported its safety12. When the United States Food and Drug Administration (FDA) approved TDF/FTC for HIV-1 prevention, it supported continuing or initiating use during pregnancy for women who might benefit 13 as did the World Health Organization (WHO) 14. Since 2012, more data have been generated from follow-up studies evaluating the safety and acceptability of TDF/FTC among HIV-negative pregnant persons and no safety concerns have been raised15–18.

The dapivirine vaginal ring (DVR) was demonstrated to reduce HIV acquisition in two large randomized placebo-controlled clinical trials and in post hoc analyses effectiveness was as high as 75% among women who had consistent use19–21. The DVR received a positive scientific opinion from the European Medicines Agency (EMA) under the Article 58 procedure in July 2020 and was recommend by WHO as an additional HIV prevention option in January 2021 as part of a combination prevention approach for “women at substantial HIV risk”22. It has since been approved by national regulatory authorities in Zimbabwe, South Africa, and Uganda, among others, for women 18–45 years old. Data available in pregnancy are limited to the peri-conception period from individuals participating in clinical trials who became pregnant23 and were instructed to stop using the DVR. Furthermore, the DVRs’ acceptability during pregnancy has not been assessed.

We implemented MTN-042/DELIVER, a phase 3b study of DVR and TDF/FTC to assess safety, adherence, and acceptability when used during pregnancy (MTN-042/DELIVER ClinicalTrials.gov number: NCT03965923). The trial was designed to provide safety data to inform policy makers charged with making product use recommendations during pregnancy as well as pregnant people and clinicians faced with weighing risks and benefits. The study is being conducted in three sequential cohorts, with cohort 1 enrolling pregnant participants from 36 0/7 weeks to 37 6/7 weeks gestation, cohort 2 enrolling from 30 0/7 weeks to 35 6/7 weeks gestation and cohort 3 from 12 0/7 weeks to 29 6/7 weeks gestation. Here we present details on study design and safety data from cohorts 1 and 2. Maternal safety data from cohort 3 will be presented at a later date. The last maternal participant exited the study in June, 2023, and infant follow-up will continue through May, 2024.

Methods

Community and Stakeholder engagement:

Given the complexity of conducting safety trials of investigational products during pregnancy, the Microbicide Trials Network (MTN), in partnership with AIDS Vaccine-Advocacy Coalition (AVAC), held a regional stakeholders consultation in April 2018 to gauge support for advancing DVR in both pregnant and breastfeeding populations and, if supported by regional stakeholders, to solicit input into protocol design24. Attendees included Ethics Committee (EC) and Institutional Review Board (IRB) Chairs, Ministry of Health representatives (MOH), National Drug Regulatory Authority representatives, Civil society and Non-Governmental Organization (NGO) representatives, a WHO representative, and other researchers with relevant expertise from Malawi, Uganda, South Africa, and Zimbabwe. Key recommendations are outlined in Table 1. Follow-up stakeholder consultations with additional support from local organizations took place in each of the four study countries between March 2019 and January 2020. Attendees included people who had used DVR and TDF/FTC, traditional leaders, representatives from faith-based organizations, male partners, representatives from maternal health and HIV NGOs, MOH, IRB and EC representatives, and midwives and physicians. The focus of these meetings was to discuss strategies for study implementation and to explore participants’ attitudes about the study’s relevance. Key recommendations included maximizing partner and family involvement, strengthening existing relationships with healthcare facilities, and providing community support and education around the protocol.

Table 1.

Stakeholder consultation recommendations for changes to MTN-042/DELIVER protocol

Recommendation Activity Outcome
Create valid comparator data Collect background pregnancy outcome data from the participating hospitals MTN-042B, chart review of 10,138 delivery records at facilities caring for the DELIVER study population29
Ensure Global South representation on the Interim Review Panel Include African pediatrician, obstetrician/gynecologist, midwife and public health experts on the Interim Review Panel The Interim Review Panel of nine experts included four African members
Mitigate non standardized reporting of pregnancy complications Adopt standardized definitions for pregnancy complications Standardized criteria derived from Brighton Collaboration38 were applied to both DELIVER and MTN-042B
Increase infant follow-up beyond 6 months Extend infant follow up to 1 year Protocol revised to extend infant follow-up
Consider mental health evaluation Include mental health evaluation as part of the safety evaluation Protocol revised to include mental health evaluation using Edinburgh Postpartum Depression Scale throughout study participation
Carefully describe causes of maternal and neonatal death Facilitate autopsies Developed study operations guidance at each site in the event of a maternal or infant death
Share interim study results with participants Inform participants in later cohorts about the results from previous cohorts Created communications materials for study participants after each cohort
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Study overview:

Healthy pregnant, HIV-negative people ages 18–40 were enrolled across four research sites: Blantyre, Malawi; Johannesburg, South Africa; Kampala, Uganda; and Chitungwiza, Zimbabwe (study protocol available at www.mtnstopshiv.org). The primary study objective was to describe maternal and infant safety profiles and pregnancy outcomes folllowing study product use during pregnancy. The protocol was approved by the Prevention Sciences Review Committee of the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health, and ethics review committees at each study site.

Study population:

Written informed consent was obtained for maternal participants (subsequently referred to as “participants”) and their infants. Eligibility criteria for both cohorts included HIV negative status and the intention to deliver at a health facility where adequate records could be obtained. Key exclusion criteria were current or prior pregnancy complication, genitourinary tract infection at enrollment, or significant laboratory or pelvic exam findings at enrollment. Cohort 1 required a viable singleton pregnancy between 36 0/7 to 37 6/7 weeks’ gestation as confirmed by ultrasound; cohort 2 required a viable singleton pregnancy between 30 0/7 to 35 6/7 weeks’ gestation at enrollment as confirmed by ultrasound. Infants were enrolled at birth without set inclusion or exclusion criteria.

Randomization and study products:

At enrollment, participants were randomized to monthly DVR or daily TDF/FTC assigned in a 2:1 ratio using a fixed-size block randomization, stratified by site. The DVR is an off-white, flexible silicone ring which contains 25 mg of dapivirine. The DVR is intended to be inserted monthly and provide a sustained release of drug over the month. Daily TDF/FTC is a fixed dose oral tablet containing 300 mg TDF and 200 mg FTC. Participants randomized to DVR were taught how to insert and remove the ring and instructed to remove the ring upon onset of labor (defined as start of contractions or rupture of membranes) or 41 6/7 weeks gestation, whichever came first. Standards of obstetric care in all of the site countries recommend that women be induced by 42 0/7 weeks gestation to avoid pregnancy complications. Participants were provided an instruction card in the local language for health care providers should they present for care with the ring in place.

Endpoints:

Primary endpoints for the study were composite maternal safety, composite infant safety, and pregnancy outcomes. Composite safety for both mother and infant encompassed all serious adverse events (SAEs) and grade 3 or higher adverse events (AEs) as per Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events25,26. Pregnancy outcomes were classified as either full term live birth (≥37 weeks), preterm live birth (<37 weeks), or intrauterine fetal demise ≥20 weeks. Secondary endpoints for the study included adherence, acceptability, infant drug levels and pregnancy complications. Regarding pregnancy complications, each participant was assessed for hypertensive disorders of pregnancy, chorioamnionitis, puerperal sepsis and endometritis, preterm premature rupture of membranes, hemorrhage, and fever of unclear etiology.

Congenital anomalies:

Congenital anomalies were included in SAE reporting although for cohorts 1 and 2, study product would not be implicated given the advanced gestational age at enrollment. We report this information here for reference and comparison for cohort 3. All potential congenital anomalies (both minor and major) were reported by sites and reviewed by an independent consultant geneticist masked to study arm who confirmed a final determination after reviewing infant history and photographic survey (process previously described)27. The European Surveillance of Congenital Anomalies (EUROCAT) Guide served as a reference for site clinicians28.

Study visits and procedures:

Pregnant participants returned for in-person visits every two weeks and had either in-person or telephone visits on alternating weeks until delivery. Safety related study procedures conducted in-person included HIV counseling and testing, medical history update, obstetric abdominal exam, and renal, hematologic, and hepatic laboratory evaluations. During telephone visits, clinicians assessed for adverse events (AEs) by history. A post-pregnancy outcome visit was scheduled in the clinic for both maternal and infant participants within two weeks of delivery. At this visit, maternal laboratory evaluations were conducted as needed; and infant serum creatinine was assessed for all infants. A final safety assessment for the mother was performed 6 weeks after delivery. Infant safety follow-up occurred at 6 weeks, 6-months, and 12-months of life.

Safety oversight.

A Protocol Safety Review Team (PSRT) composed of protocol chairs, DAIDS and National Institute of Child Health and Human Development medical officers, MTN safety physicians, and International Partnership for Microbicides and Gilead representatives met monthly to review AE data. After all pregnancy outcomes were collected from cohort 1, an external Interim Review Panel (IRP) comprised of seven members from both Africa and North America who are experts in pediatrics, obstetrics and gynecology, nursing, public health, statistics, and ethics, reviewed the safety data and issued an opinion as to whether the study should proceed into the next cohort. This process was repeated following the completion of cohort 2.

Sample size:

The total sample size for all three cohorts is approximately 550 pregnant participants: 150 participants each in cohorts 1 and 2 with 2:1 randomization to DVR: TDF/FTC and 250 in cohort 3 with 4:1 randomization. The sample size was determined based on the estimated minimum number of person-years needed for regulatory agencies to assess the safety of the DVR. While data on the safety of TDF/FTC in pregnancy are currently available, the TDF/FTC group was included here for reference.

Statistical analysis:

Using an intent-to-treat analysis, descriptive statistics were used to summarize the frequency of primary safety endpoints, pregnancy outcomes and complications by study arm. This report includes adverse event data ascertained through six weeks following the date of delivery for both participants and their infants in cohorts 1 and 2. Infant birth weight was also summarized using descriptive statistics. Potential congenital anomalies are reported for reference. Given that we expected some outcomes of interest to occur at low frequencies, no formal statistical testing by arm was performed. Rather, frequencies of outcomes were qualitatively compared to background rates ascertained as part of a formal multi-site, cross-sectional chart review (MTN-042B) conducted at maternal obstetric units where individuals participating in the DELIVER study were expected to deliver29.

Results

Study participants:

Between February 2020 and April 2021, 227 participants were screened for cohort 1, and 150 enrolled (101 DVR, 49 TDF/FTC; Supplemental Figure 1). Enrollment paused briefly early in the COVID-19 pandemic (March-May 2020) until sites implemented risk mitigation plans. The most common reasons for ineligibility were urogenital infection (n=10), no qualifying ultrasound (n=8), and a pregnancy outside the gestational age range (n=8). In cohort 2, of 218 participants screened, 157 were enrolled between September 2021 and March 2022 (106 DVR, 51 TDF/FTC; Supplemental Figure 1). The most common reasons for cohort 2 ineligibility were no qualifying ultrasound (n=18), hemoglobin ≥ Grade 2 (n=9), and urogenital infection (n=6). Select demographic characteristics, which were generally similar by cohort and arm, are presented in Table 2.

Table 2.

Participants characteristics at enrollment by study arm and cohort

Cohort 1 Dapivirine arm (n=101) TDF/FTC arm (n=49) Both arms (n=150)
Participant age (years), mean (SD) 25.4 (5.4) 25.1 (5.4) 25.3 (5.4)
Study site
 Blantyre, Malawi 18 (18%) 9 (18%) 27 (18%)
 Johannesburg, South Africa 28 (28%) 14 (29%) 42 (28%)
 Kampala, Uganda 30 (30%) 14 (29%) 44 (29%)
 Zengeza, Zimbabwe 25 (25%) 12 (24%) 27 (25%)
Had a prior pregnancy 66 (65%) 38 (78%) 104 (69%)
Number of prior full term live births, mean (SD) 1.7 (1.1) 1.5 (1.0) 1.6 (1.0)
Number of prior spontaneous abortions (<20 weeks), mean (SD) 0.2 (0.6) 0.2 (0.6) 0.2 (0.6)
Gestational age at enrollment (weeks), mean (SD) 36.4 (0.4) 36.4 (0.6) 36.4 (0.5)
Cohort 2 Dapivirine arm (n=106) TDF/FTC arm (n=51) Both arms (n=157)
Participant age (years), mean (SD) 26.2 (5.5) 26.7 (6.2) 26.4 (5.7)
Study site
 Blantyre, Malawi 26 (25%) 14 (27%) 40 (25%)
 Shandukani, South Africa 20 (19%) 8 (16%) 28 (18%)
 Kampala, Uganda 28 (26%) 14 (27%) 42 (27%)
 Zengeza, Zimbabwe 32 (30%) 15 (29%) 47 (30%)
Had a prior pregnancy 84 (79%) 35 (69%) 119 (76%)
Number of prior full term live births, mean (SD) 1.6 (1.0) 1.7 (1.0) 1.7 (1.0)
Number of spontaneous abortions (<20 weeks), mean (SD) 0.1 (0.3) 0.1 (0.3) 0.1 (0.3)
Gestational age at enrollment (weeks), mean (SD) 30.8 (1.1) 30.7 (1.1) 30.8 (1.1)
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Abbreviations: TDF/FTC= tenofovir disoproxil fumarate/emtricitabine; SD = standard deviation

Pregnancy Outcomes:

In cohort 1, pregnancy outcome data were available for 148 of 150 participants (99 of 101 in the DVR and 49 of 49 in the TDF/FTC arm). One participant was lost to follow-up and one participant withdrew consent. Most pregnancies resulted in full-term live births (98%) with only 3 (2%) preterm births, 1 (1%) in the DVR arm and 2 (4%) in TDF/FTC (Table 3). There was one stillbirth in the TDF/FTC arm. Pregnancy outcome data were available for 154 of 157 participants in cohort 2. One participant withdrew because of family pressures, one withdrew because of relocation, and one participant was lost to follow up. Despite singleton pregnancy being a requirement for inclusion, one participant was found to have twins after enrollment; as a result, there were 155 pregnancy outcomes in total. Most cohort 2 pregnancies resulted in full-term live births (94%) with 10 (6%) preterm births, 6 (6%) in the DVR arm and 4 (8%) in the TDF/FTC arm. There was one stillbirth in the DVR arm. Frequencies of pregnancy outcomes for both cohorts were similar to those observed in MTN-042B with the exception of stillbirth which was lower in the DELIVER cohorts.

Table 3.

Pregnancy outcomes by study arm and cohort

Cohort 1 Dapivirine arm (n=99)*
n (%)		 TDF/FTC arm (n=49) n (%) Both arms (n=148) n (%)
Live births 99 (100) 48 (98) 147 (99)
 Full term (≥ 37weeks) 98 (99) 46 (96) 144 (98)
 Premature (<37 weeks) 1 (1) 2 (4) 3 (2)
 Stillbirth/intrauterine fetal demise 0 (0) 1 (2) 1 (1)
Cohort 2 Dapivirine arm (n=104)* n (%) TDF/FTC arm (n=50) n (%) Both arms (n=154) n (%)
Live births 103 (99) 51 (100)** 154 (99)
 Full term (≥ 37weeks) 97 (94) 47 (92) 144 (94)
 Premature (<37 weeks) 6 (6) 4 (8) 10 (6)
 Stillbirth/intrauterine fetal demise 1 (1) 0 (0) 1 (1)
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*

Number of participants with obtainable pregnancy outcomes

Abbreviations: TDF/FTC= tenofovir disoproxil fumarate/emtricitabine

**

51 live births amongs 50 women as one woman had undiagnosed twins

Maternal Safety:

One percent of cohort 1 DVR users experienced one or more composite AEs while that percentage of DVR users in cohort 2 was 13.2%, similar to both TDF/FTC groups (Table 4). In cohort 1 there were four maternal SAEs reported (Table 4), one in DVR arm (urinary tract infection) and three in TDF/FTC arm (antepartum hemorrhage, preeclampsia, and perineal injury). In cohort 2, there were 11 maternal SAEs reported, nine in the DVR arm (two preeclampsia, two hemorrhage, and one each of the following: chorioamnionitis, gestational hypertension, oligohydramnios, COVID-19 infection, and postoperative wound infection) and two in the TDF/FTC arm (hemorrhage and gastroenteritis). No SAE in either cohort was deemed related to study product.

Table 4.

Maternal and infant serious adverse events and grade 3 or higher AEs by study arm and cohort

Cohort 1 Maternal adverse events Dapivirine arm (n=101) n (%) TDF/FTC arm (n=49) n (%) Both arms (n=150) n (%)
Participants with one or more composite AEs1 1 (1.0) 4 (8.2) 5 (3.3)
Nausea 0 (0) 1 (2.0) 1 (0.7)
Urinary tract infection 1 (1.0) 0 (0) 1 (0.7)
Perineal injury 0 (0) 1 (2.0) 1 (0.7)
Fetal distress syndrome 0 (0) 1 (2.0) 1 (0.7)
Hemorrhage in pregnancy 0 (0) 1 (2.0) 1 (0.7)
Preeclampsia 0 (0) 1 (2) 1 (0.7)
Cohort 1 Infant adverse events Dapivirine arm (n=99)n (%) TDF/FTC arm (n=48) n (%) Both arms (n=147) n (%)
Participants with one or more composite AEs1 12 (12.1) 6 (12.5) 18 (12.2)
Trisomy 21 1 (1.0) 0 (0) 1 (0.7)
Pneumonia 1 (1.0) 1 (2.1) 2 (1.4)
Underweight 6 (6.1) 3 (6.3) 9 (6.1)
Rectus diastasis 0 (0) 1 (2.1) 1 (0.7)
Hypoxic-ischemic encephalopathy 0 (0) 1 (2.1) 1 (0.7)
Jaundice 1 (1.0) 0 (0) 1 (0.7)
Acute kidney injury 1 (1.0) 0 (0) 1 (0.7)
Meconium aspiration syndrome 0 (0) 1 (2.1) 1 (0.7)
Neonatal asphyxia 2 (2.0) 0 (0) 2 (1.4)
Neonatal respiratory distress syndrome 1 (1.0) 0 (0) 1 (0.7)
Respiratory distress 0 (0) 1 (2.1) 1 (0.7)
Transient tachypnoea of the newborn 1 (1.0) 0 (0) 1 (0.7)
Cohort 2 Maternal adverse events Dapivirine arm (n=106) n (%) TDF/FTC arm (n=51) n (%) Both arms (n=157) n (%)
Participants with one or more composite AEs1 14 (13.2) 5 (9.8) 19 (12.1)
Anemia 0 (0) 1 (2.0) 1 (0.6)
Amniotic cavity infection 1 (0.9) 0 (0) 1 (0.6)
COVID-19 1 (0.9) 0 (0) 1 (0.6)
Gastroenteritis 0 (0) 1 (2.0) 1 (0.6)
Postoperative wound infection 1 (0.9) 0 (0) 1 (0.6)
Gestational hypertension 1 (0.9) 0 (0) 1 (0.6)
Hemorrhage in pregnancy 1 (0.9) 0 (0) 1 (0.6)
Oligohydramnios 1 (0.9) 0 (0) 1 (0.6)
Placenta previa hemorrhage 0 (0) 1 (2.0) 1 (0.6)
Post-partum hemorrhage 1 (0.9) 0 (0) 1 (0.6)
Preeclampsia 2 (1.9) 0 (0) 2 (1.3)
Premature labor 4 (3.8) 2 (3.9) 6 (3.8)
Preterm, premature rupture of membranes 1 (0.9) 0 (0) 1 (0.6)
Proteinuria 2 (1.9) 0 (0) 2 (1.3)
Cohort 2 Infant adverse events Dapivirine arm (n=102) n (%) TDF/FTC arm (n=51) n (%) Both arms (n=153) n (%)
Participants with one or more composite AEs1 17 (16.7) 7 (13.7) 24 (15.7)
Dysmorphism 1 (1.0) 0 (0) 1 (0.7)
Facial edema 1 (1.0) 0 (0) 1 (0.7)
Multiple organ dysfunction syndrome 1 (1.0) 0 (0) 1 (0.7)
Bronchiolitis 2 (2.0) 1 (2.0) 3 (2.0)
Gastroenteritis 1 (1.0) 0 (0) 1 (0.7)
Pneumonia 1 (1.0) 1 (2.0) 2 (1.3)
Fetal distress syndrome 2 (2.0) 0 (0) 2 (1.3)
Jaundice 1 (1.0) 0 (0) 1 (0.7)
Small for dates 9 (8.8) 6 (11.8) 15 (9.8)
Neonatal asphyxia 2 (2.0) 0 (0) 2 (1.3)
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1

Composite safety for both mother and infant encompassed all serious adverse events (SAEs) and grade 3 or higher adverse events (AEs) as per Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events24,25.

Abbreviations: TDF/FTC= tenofovir disoproxil fumarate/emtricitabine

Infant safety:

In cohort 1, median birthweight was 3.2 kg (interquartile range 3.0–3.4 kg). In cohort 2 median birthweight was 3.1 kg (interquartile range 2.8–3.4 kg). The percentage of infants with one or more composite AE was similar across cohorts and study arms. In cohort 1, amongst 147 infants, there were 10 infant SAEs reported (7 in the DVR arm and 3 in the TDF/FTC arm). There was one infant death at day of life two in the TDF/FTC arm and one Grade 4 event for hypoxic ischemic encephalopathy in the same infant (Table 4). In cohort 2, amongst 152 infants, there were 17 infant SAEs reported (14 in the DVR arm and 3 in the TDF/FTC arm). There was one neonatal death in the DVR arm of a female infant delivered by cesarean section at 34 6/7 weeks (1540 grams) for fetal distress. Upon delivery, the infant was noted to have multiple dysmorphic features and clinical features of rubella and cytomegalovirus infection. She died on the first day of life.

Congenital anomalies:

In cohort 1, there were 4 (3%) congenital anomalies reported by site staff, 2 (2%) in the DVR arm (scrotal hernia and left foot anonychia) and 2 (4%) in the TDF/FTC arm (umbilical hernia and congenital diastasis recti), of which only one anomaly was confirmed following geneticist review (left foot anonychia). In cohort 2, there were 10 (6%) congenital anomalies reported by site staff, 7 (7%) in the DVR arm (ankyloglossia, cryptorchidism, post-axial polydactyly, umbilical hernia (n=2), syndromic features, café au lait macule, and scrotal hernia,) and 3 (6%) in the TDF/FTC arm (laryngomalacia and umbilical hernias (n=2)). Four (2.5%) were ultimately confirmed (cryptorchidism, syndromic features, laryngomalacia, and post-axial polydactyly).

Pregnancy Complications:

The frequency of pregnancy complications by cohort and arm are displayed in Table 5 with available MTN-042B frequencies provided as a reference. Hypertensive disorders of pregnancy were the most commonly reported complication.

Table 5.

Maternal pregnancy complications by study arm and cohort

Cohort 1 Cohort 2 Local background frequencies (95% CI) of pregnancy complications1
Pregnancy complication Dapivirine arm (n=99) n (%) TDF/FTC arm (n=49) n (%) Dapivirine arm (n=106) n (%) TDF/FTC arm (n=51) n (%)
Any hypertensive disorder of pregnancy2 3 (3) 4 (8) 9 (8) 5 (10) 10.5% (10.0,11.3)
 Gestational hypertension 3 (3) 2 (4) 6 (6) 5 (10) 4.4% (4.0,4.8)
 Pre-eclampsia without severe features 0 (0) 1 (2) 1 (1) 0 (0) 2.2% (1.9,2.5)
 Pre-eclampsia with severe features 0 (0) 1 (2) 2 (2) 0 (0) 2.1% (1.9,2.4)
 Eclampsia 0 (0) 0 (0) 0 (0) 0 (0) 0.6% (0.5,0.8)
Peripartum/Antepartum hemorrhage 0 (0) 1 (2) 2 (2) 2 (4) --
Postpartum hemorrhage 2 (2) 1 (2) 2 (2) 0 (0) 3.2% (2.9,3.6)
Fever of unclear etiology 0 (0) 0 (0) 0 (0) 0 (0) 0.1% (0.1–0.2%)
Chorioamnionitis 0 (0) 0 (0) 1 (1) 0 (0) 0.2% (0.1–0.3%)
Postpartum endometritis 0 (0) 0 (0) 0 (0) 1 (2) 0.4% (0.3–0.5%)
Puerperal sepsis 0 (0) 0 (0) 0 (0) 2 (4) -
Other3 1 (1) 1 (2) 4 (4) 0 (0) -
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1

Data on background rates obtained as part of a published systematic chart review (MTN-042B).28 Peripartum/Antepartum hemorrhage and Puerperal sepsis were not assessed in MTN-042B.

2

Any hypertensive disorders is the total of the gestational hypertension, pre-eclampsia without severe features, pre-eclampsia with severe features, and eclampsia rows.

3

Others included placenta previa and postpartum anemia for cohort 1 and obstructed labor, oligohydramnios, placenta previa and wound cellulitis for cohort 2

Abbreviations: TDF/FTC= tenofovir disoproxil fumarate/emtricitabine; CI = confidence interval

IRP Review:

The IRP reviewed primary maternal endpoints through delivery and as available for the infants depending on the date of birth relative to the IRP review for each cohort. The IRP unanimously agreed on both occasions that there were no safety concerns and recommended that the study continue as planned. They noted that determining AE relationship to study product was inherently challenging and recommended continued vigilance for associations.

Discussion

In these first two cohorts of pregnant individuals using DVR or TDF/FTC in the third trimester, untoward pregnancy outcomes, adverse events, and pregnancy complications were uncommon, and outcomes were qualitatively similar to background rates in study communities29. As expected, the frequency of preterm birth for cohort 1 was lower than the estimated background rate since participants were enrolled at 36 weeks or beyond. Similarly, the rates of stillbirth were lower in both cohorts likely reflecting the inclusion criterion of a healthy singleton pregnancy. In the absence of safety concerns and with the support of the IRP, the third cohort of participants was enrolled and recently completed maternal follow up. Taken together, data from DELIVER will provide critical safety data for pregnant individuals, clinicians and regulators on use of DVR throughout pregnancy. This study provides the only human safety data of DVR beyond the periconception period of pregnancy. Makanani et al. compared the pregnancy incidence and outcomes by study arm in individuals participating in MTN-020 (ASPIRE) trial, where pregnancy tests were performed monthly and study product was withheld upon pregnancy detection23. During follow-up there were 181 pregnancy outcomes in 179 women with no difference in pregnancy incidence, pregnancy outcomes or frequency of congenital anomalies by study arm.

This study adds to the growing body of literature demonstrating the safety of TDF/FTC during pregnancy30. In a systematic review, Davey et al. identified five completed and nine pending studies investigating maternal and infant outcomes following TDF/FTC exposure during pregnancy18. Of five completed studies including 1,042 TDF/FTC-exposed pregnancies, four found no differences in pregnancy or infant outcomes in exposed versus unexposed. The Partners Demonstration Project found PrEP exposed infants had lower z-scores for length at 1-month which resolved by 1-year of life31. Nine ongoing studies, including DELIVER, will provide data on >6200 additional TDF/FTC-exposed pregnancies and assess perinatal, infant growth and bone health outcomes.

Historically, pregnant individuals have been classified as a “vulnerable population” and have been excluded from clinical trials of investigational products32. Most pregnancy safety data are collected several years post-licensure33. The DELIVER study illustrates that conducting safety trials of an investigational product in a pregnant population is possible, and DELIVER’s model of de-escalating risk through a cohort approach might serve as a valuable model for study of other investigational products in pregnancy.

Reassuring animal data, sponsor support, and pharmaceutical company’s willingness to advance a product in a pregnant population are all prerequisites to pregnancy trials; however, central to the success of this trial’s launch were the series of stakeholder engagement meetings held during protocol development and prior to implementation. Often “stakeholders” are limited to EC/IRBs, investigators, and sponsor. Expanding this list to include pregnant individuals, clinicians, faith-based organizations, NGOs, national drug authorities, ans policy makers, among others, from protocol development onward leads to a better protocol and a smoother regulatory process. It also helped to lay the groundwork for study implementation as representatives from many sectors of the community contributed to the development process. Having engaged in discussion about utility, feasibility, and ethics of study conduct at stakeholder meetings, community leaders were exceptionally well-informed about the study’s stepwise design with safety checks in place and were able to communicate this effectively to others in the community. The high retention rate, defined here as the proportion of participants participating in the study at the time of delivery, in both cohorts during the first two years of the COVID-19 pandemic highlights participants’ high level of interest as well as support from their communities and providers.

One strength of this study was the availability of complete background rates for pregnancy outcomes and complications from the formal chart review conducted prior to study initiation as was recommended by the African stakeholders. A second strength was the use of standardized definitions for pregnancy complications which minimized the challenges related to having variable definitions for common pregnancy complications34. Nonetheless, findings from DELIVER need to be interpreted in the context of several limitations. Only uncomplicated singleton pregnancies were included; furthermore, all study sites are in urban/peri urban settings. As a result, findings may not be generalizable to more complicated pregnancies or to pregnant individuals living in more rural settings. Because cohorts 1 and 2 only enrolled third trimester pregnancies by design, drug exposure was short. Lastly, the study population is too small to appreciate less common pregnancy and neonatal complications.

Cisgender women and other individuals with the capacity for pregnancy have the potential to spend a significant portion of their reproductive lives pregnant or breastfeeding35. Excluding pregnant and breastfeeding individuals from safety evaluations of new medications places them in a precarious position once the medication is licensed36–38. Together with their clinician, they must decide whether to use the medication without any available safety data in human pregnancy. Rather than releasing a medication to the market without safety data, pharmaceutical companies must evaluate the safety of medications during pregnancy with a safe and thoughtful approach. DELIVER is a valuable model, both for its centering of community stakeholders during study development and sequential approach to evaluating safety. Results from DELIVER suggest that the DVR and TDF/FTC are safe for use in late pregnancy – thus allowing patients and clinicians to effectively weigh risks and benefits of these HIV prevention options.

Supplementary Material

Supplemental Digital Content

Acknowledgements

The authors would like to thank the DELIVER participants and study communities without which this research would not be possible. This work is dedicated in memory of Dr. Bonus Makanani, who served as a protocol chair for DELIVER. Dr. Makanani worked tirelessly to improve the lives of pregnant and breastfeeding women and left this world a better place.

Source of Funding:

The study was designed and implemented by the Microbicide Trials Network (MTN). From 2006 until November 30, 2021, the MTN was an HIV/AIDS clinical trial network funded by the National Institute of Allergy and Infectious Diseases (UM1AI068633, UM1AI068615, UM1AI106707), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding:

The study was designed and implemented by the Microbicide Trials Network (MTN). From 2006 until November 30, 2021, the MTN was an HIV/AIDS clinical trial network funded by the National Institute of Allergy and Infectious Diseases (UM1AI068633, UM1AI068615, UM1AI106707), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

MTN-042/DELIVER Study Team

Study Sites:

Bonus Makanani±, MBBS, FCOG(SA) (Protocol Chair (PC), Investigator of Record (IoR)), Luis Gadama, MBBS, FCOG (SA), MMED UCT (IoR), Linly Seyama, Msc, RNM (Study Coordinator (SC)), Vitumbiko D. Mandiwa, MBBS (SC), Sufia Dadabhai, PhD (Clinical Research Site (CRS) Leader), and Taha E. Taha, PhD (Clinical Trials Unit Principal Investigator (CTU PI)), Johns Hopkins University (JHU) Research Project; Clemensia Nakabiito, MBChB, MMed (IoR), Phionah Bridget Kibalama Ssemambo, MBchB, MSc PH (SC), and Mary Glenn Fowler, MD, MPH (CTU PI), Makerere University - Johns Hopkins University (MU-JHU) Research Collaboration; Lee Fairlie, MBChB, FCPaeds (Protocol Co-Chair, IoR), Carlotta Mabuza, BS, PGDip, Dip (SC), Hermien Gous, PharmD (CRS Leader), and Ringson Ngozo, DipEd (Community Working Group (CWG) Representative), Wits RHI Shandukani Research Centre; Felix Mhlanga, MBChB, MMed (PC), Nyaradzo M. Mgodi, MBChB, Mmed, (IoR), Petina Musara, BSW (SC) and Z. Mike Chirenje, MD, FRCOG (CTU PI), University of Zimbabwe Clinical Trials Research Centre (UZ-CTRC)

Protocol Team:

Jeanna M. Piper, MD (DAIDS Senior Medical Officer (MO)), Naana Cleland, PhD, (Health Specialist Clinical Microbicide Research Branch (CMRB)), and Roberta Black, PhD (Chief, CMRB), National Institute of Allergy and Infectious Diseases (NIAID), Division of AIDS (DAIDS); Nahida Chakhtoura, MD, MsGH (NICHD MO), Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) National Institutes of Health (NIH); Dianne M. Rausch, PhD, (Director, DAIDS Research) and Teri Senn, PhD (Program Chief, Psychosocial Co-morbidities of HIV Prevention and Treatment), National Institutes of Mental Health (NIMH); James F. Rooney, MD (Vice President Medical Affairs), Gilead Sciences; Zeda Rosenberg, ScD (Chief Executive Officer), International Partnership for Microbicides; Craig Hendrix, MD, (Biomedical Science Working Group (BSWG) Representative, Protocol Pharmacologist) and Mark Marzinke, PhD, DABCC (LC Pharmacology Core), Johns Hopkins University; Lisa Noguchi, PhD, CNM (Director, Pregnancy Research), Johns Hopkins Bloomberg School of Public Health; Peter Anderson, PharmD (LC Pharmacology Core), University of Colorado School of Pharmacy; Abraham Johnson, MPH (Community Program Associate), Ashley J. Mayo, MPH (Sr. Clinical Research Manager (CRM)), Cheryl Blanchette, MS(Sr. Community Program Manager (CPM), Jontraye Davis, MHA (CPM), Rachel Scheckter, MPH (Sr. CRM), Tara McClure, MPH (Sr. CRM), and Lisa Levy, MPH, MTN Associate Director, FHI 360; Katherine Bunge, MD, MPH (PC), Catherine A. Chappell, MD, MSc (Protocol Safety Physician (PSP)), Richard H. Beigi MD, MSc (Advisory), and Sharon A. Riddler, MD, MPH (Protocol Physician), Magee-Womens Hospital and the University of Pittsburg Medical Center (UPMC); Devika Singh, MD, MPH(PSP), Division of Infectious Diseases, University of Vermont; Cindy Jacobson, PharmD (Director of Pharmacy Affairs), Edward Livant, BSMT (ASCP), MPH (MTN LC Research Manager), Lisa Rossi, BA (MTN Director of Communications), Luis Duran, DrPH, MPIA, (Project Manager), Mei Song, PhD (Project Manager), and Sharon Hillier, PhD (MTN Principal Investigator), Magee-Womens Research Institute-UPMC; Ariana Katz, MPH (Behavioral Research Coordinator), Alinda Young, MPH (Behavioral Research Coordinator), Elizabeth Montgomery, PhD (BRWG Representative), Imogen Hawley, MA, MSc (Behavioral Research Coordinator), and Marie Stoner, PhD (Behavioral Co-Investigator), RTI International; Ariane van der Straten, PhD, MPH (Behavioral Research Working Group (BRWG) Representative), University of California San Francisco; Ivan Balan, PhD (BRWG Representative), Florida State University College of Medicine; Barbra Richardson, PhD (Statistician), Jennifer Balkus, PhD, MPH (Protocol Epidemiologist), Daniel Szydlo, MS, (Statistical Research Associate), Lena Kemel, Pharm.D. (Clinical Safety Associate), Maricel Manalo, MD (Clinical Safety Associate), Tanya Harrell, BS (Clinical Data Manager), and Amanda Brown, MPH (Clinical Data Manager), Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center and the University of Washington ±Deceased

MTN-042 Interim Review Panel Members:

We would like to thank the members of the MTN-042 Interim Review Panel who donated their time to review safety data between study cohorts: Deborah M. Money, MD, FRCSC; Annie Lyerly, MD, MA; Richard Adanu, MB ChB, FWACS, MPH; Professor Ellen Chirwa, PhD MRNM; Paige Williams, PhD, MS; Charles Shey Wiysonge, MD, PhD; Dorothy Mbori-Ngacha, MBChB, MMed, MPH

Study Products:

The dapivirine vaginal rings used in this study were developed and supplied by the International Partnership for Microbicides (IPM). Oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) was donated by Gilead Sciences.

MTN-042/DELIVER Ethics approval:

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the following Institutional Review Boards/Ethics Committees and Drug Regulatory Authorities: Prevention Sciences Research Committee of the US National Institute of Allergy and Infectious Diseases; US Food and Drug Administration; College of Medicine Research and Ethics Committee; Johns Hopkins School of Public Health Institutional Review Board; Pharmacy, Medicines and Poisons Board of Malawi; Human Research Ethics Committee: (Medical), University of Witwatersrand, Johannesburg; South African Health Products Regulatory Authority; Joint Clinical Research Centre Institutional Review Board; Uganda National Council for Science and Technology; Johns Hopkins Medicine Office of Human Subjects Research Institutional Review Board; National Drug Authority of Uganda; Medical Research Council of Zimbabwe; Joint Research Ethics Committee for the University of Zimbabwe College of Health Sciences and Parirenyatwa Group of Hospitals; Research Council of Zimbabwe; Medicines Control Authority of Zimbabwe

C.A.C. has received research funding and served as a consultant to Gilead Sciences for work unrelated to this manuscript. B.R. serves on the board of two DSMBs for Gilead. S.L.H. receives support for her institution and herself from Merck.

Footnotes

Conflicts of Interest

For the remaining authors no conflicts of interest were declared

Contributor Information

Katherine Bunge, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA.

Jennifer E. Balkus, Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.

Lee Fairlie, Wits RHI, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Ashley J. Mayo, FHI360, Durham, NC, USA.

Clemensia Nakabiito, Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda.

Nyaradzo Mgodi, University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare, Zimbabwe.

Luis Gadama, Department of Obstetrics and Gynaecology, College of Medicine, University of Malawi, Blantyre, Malawi.

Moleen Matrimbira, University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare, Zimbabwe.

Catherine Anne Chappell, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA.

Jeanna Piper, Division of AIDS/NIAID/NIH, Bethesda, MD, USA.

Nahida Chakhtoura, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.

Daniel w. Szydlo, Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Center, Seattle, WA, USA.

Barbra Richardson, Departments of Biostatistics and Global Health, University of Washington, Seattle, WA, USA.

Sharon L. Hillier, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA.

Data Management:

Data management was provided by The Statistical Center for HIV/AIDS Research & Prevention (Fred Hutchinson Cancer Research Center, Seattle, WA) and site laboratory oversight was provided by the Microbicide Trials Network Laboratory Center (Pittsburgh, PA).

REFERENCES

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Digital Content
NIHMS1933114-supplement-Supplemental_Digital_Content.docx (47.6KB, docx)

Data Availability Statement

Data management was provided by The Statistical Center for HIV/AIDS Research & Prevention (Fred Hutchinson Cancer Research Center, Seattle, WA) and site laboratory oversight was provided by the Microbicide Trials Network Laboratory Center (Pittsburgh, PA).

RESOURCES