The first clinical trial specifically designed to test the safety of the monthly dapivirine vaginal ring in pregnant women has begun in southern and eastern Africa. The National Institutes of Health-funded study also will test the safety of a daily oral antiviral tablet for HIV pre-exposure prophylaxis (PrEP) in pregnant women and will assess how much they accept and use these two HIV prevention tools. The study will complement an ongoing NIH-funded trial of PrEP in adolescents and young women during pregnancy and the first six months after birth. PrEP is available in some countries and is being rolled out in others, while the dapivirine ring is under regulatory review by the European Medicines Agency for potential use in sub-Saharan Africa.
"Women need reliable HIV prevention methods that they know are safe during pregnancy for themselves and their babies," said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH. "This new clinical trial will provide important data on the safety of PrEP and the dapivirine ring during pregnancy and will help expectant parents make well-informed HIV prevention choices."
Studies have found that for women of reproductive age, the risk of acquiring HIV is two to four times greater during pregnancy and the first six months after childbirth than at other times. In sub-Saharan Africa, women tend to be pregnant for a substantial portion of their reproductive years, with an estimated 5.1 births per woman.
Limited evidence from earlier clinical trials and reports suggests that PrEP and the dapivirine ring are safe for pregnant women and their fetuses, but the safety of these tools during pregnancy has not yet been proven in a clinical trial designed specifically to address this question.
The new trial is called DELIVER: A Phase 3b Safety Study of the Dapivirine Ring and PrEP in Pregnant Women.
Using PrEP to prevent HIV involves taking an oral tablet containing two anti-HIV drugs, emtricitabine and usually tenofovir, once a day. Numerous studies have shown that PrEP is about 99% effective at protecting people from sexually acquiring HIV when taken daily.
The dapivirine vaginal ring slowly releases the anti-HIV drug dapivirine in the vagina and is replaced once a month. Two large, Phase 3 clinical trials demonstrated that the dapivirine ring is well-tolerated and roughly 30% effective overall at protecting women from acquiring HIV through vaginal sex.
Another NIH-funded trial that began in early 2019 has been studying whether PrEP drug concentrations in adolescents and young women aged 16-24 years are different during pregnancy than at other times. The trial, called IMPAACT 2009, soon will begin testing the safety, acceptability and feasibility of PrEP drugs during pregnancy and the first six months after birth in this population and their infants in southern and eastern Africa. Results are expected in 2022.
NIAID is sponsoring the DELIVER trial and co-funding it with the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, both part of NIH. The study, also known as MTN-042, is being conducted by the NIH-funded Microbicide Trials Network (MTN) at four sites in Malawi, South Africa, Uganda and Zimbabwe. Gilead Sciences, Inc., and the International Partnership for Microbicides, which developed the dapivirine ring, are donating PrEP medication and rings for the study, respectively.
The design of the DELIVER trial has been carefully reviewed and approved by the communities, national health authorities, ethicists and other key stakeholders where the study will take place. Data from DELIVER may help some countries decide whether and how to roll out PrEP among pregnant women. If the ring receives regulatory approval, the study may inform its rollout in that population as well.
Katherine Bunge, M.D., M.P.H., and Bonus Makanani, M.B.B.S., F.C.O.G.(SA) are leading the DELIVER study with Lee Fairlie, M.B.Ch.B., F.C.Paeds. Dr. Bunge is an assistant professor in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh School of Medicine, and Dr. Makanani is an associate professor of obstetrics and gynecology at the University of Malawi College of Medicine in Blantyre. Dr. Fairlie is the director of child & adolescent health in the Wits Reproductive Health and HIV Institute at the University of the Witwatersrand in Johannesburg.
The DELIVER study team plans to enroll 750 healthy, HIV-negative women aged 18-40 years who have an uncomplicated singleton pregnancy. The women will be assigned at random to receive either the dapivirine vaginal ring or PrEP in a 2-to-1 ratio and will be asked to use their assigned product until the end of their pregnancy or 42 weeks gestation, whichever comes first. The study team subsequently will enroll the mothers' newborn infants.
Out of an abundance of caution, the study team will enroll participants in four stages, beginning with women latest in pregnancy, and will pause to conduct a safety analysis before enrolling the next group. The first enrollment group, consisting of 150 women, will begin using their assigned product at 36 to 37 weeks gestation. The study team will follow these women through the end of their pregnancy and enroll their newborns for additional safety assessments. Then a panel of international experts unaffiliated with the trial will conduct an independent, interim safety analysis to determine if the next group of women can be enrolled or the study needs to stop early. If it is safe to proceed, this process will be repeated with a group of 150 women at 30 to 35 weeks gestation, 150 women at 20 to 29 weeks gestation, and 300 women at 12 to 19 weeks gestation. The participating women will be followed until approximately six weeks after their pregnancy ends, and the infants will be followed until they are approximately 1 year old.
The study team will record any medical problems and deaths among the women and infants, as well as birth defects in the infants. In addition, the team will track the frequency of full-term live births, premature live births and pregnancy losses. Investigators also will record pregnancy complications associated with exposure to PrEP or the dapivirine ring, measure levels of study drugs in the infants, and determine the extent to which women accept and use their assigned study product. Questionnaires will be used to assess the acceptability of the study products. Finally, the team will evaluate changes in women's genital microenvironment associated with the use of PrEP or the dapivirine ring during pregnancy.
A related NIH-funded clinical trial that is expected to begin in the coming months will test the safety of PrEP and the dapivirine ring in HIV-negative breastfeeding women and their infants. The trial, called B-PROTECTED or MTN-043, will enroll 200 women and their infants aged 6 to 12 weeks in Malawi, South Africa, Uganda and Zimbabwe. As in DELIVER, the data gathered during the B-PROTECTED study will help countries decide whether and how to roll out PrEP and the dapivirine ring, if approved, among breastfeeding women and will help these women make informed choices about HIV prevention.
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