The monthly anti-retroviral vaginal ring can be safely used to prevent HIV infection during late pregnancy and while breastfeeding, research has found, and should become available at selected clinics and private pharmacies this year alongside the HIV prevention injection and the HIV prevention pill, writes Laura Lopez Gonzalez for Spotlight.
Inserted at home, the silicon vaginal ring slowly releases the antiretroviral dapivirine and can reduce women’s risk of contracting HIV by 27% to 75%, says Katherine Bunge, assistant professor of obstetrics, gynaecology and reproductive sciences at the University of Pittsburgh School of Medicine in the United States.
The ring is one of three forms of pre-exposure prophylaxis (PrEP) that use antiretrovirals to prevent HIV infection. Currently, only the daily HIV prevention pill is widely available in South Africa and has been shown to slash a person’s risk of contracting HIV by around 99% when used as prescribed.
Still, in clinical trials, people who used an every-other-month injection of the antiretroviral cabotegravir were about 80% less likely to contract HIV than those on the HIV prevention pill – brand name Truvada.
The bi-monthly shot probably outperformed the pill because it was easier for people to take than daily pills, said the World Health Organisation. The injection is not a vaccine.
PrEP in pregnancy: new data, better options
South Africa has offered the HIV prevention pill to pregnant women since 2019. A study in The Lancet HIV confirmed that women who took the pill from as early as 14 weeks of pregnancy showed no increased risk of premature or underweight babies or stillbirths.
Similarly, early research found no risk to women who conceived on injectable cabotegravir but studies are ongoing.
Early but limited data in 2018 also suggested the vaginal ring to be safe during conception and early pregnancy. However, the research came from a study testing how well it worked and had not been specifically designed to evaluate safety during pregnancy.
Now, the first study examining the ring’s safety during pregnancy has found the ring can be safely used from at least the seventh month of pregnancy onwards, according to the research presented last week at the Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, United States. Findings from additional research from 12 to 29 weeks of pregnancy are expected later this year.
Meanwhile, a second study found the ring to also be safe for breastfeeding women and their babies.
Scientists say these latest findings pave the way for policymakers to feel confident about including pregnant and breastfeeding people in new national roll-outs or pilots of the ring slated for South Africa and other African countries such as eSwatini, Kenya and Zimbabwe.
In South Africa, the results are likely to fuel increasing calls for the government to offer PrEP to pregnant people and new mothers routinely.
Pregnant women are three times more likely to contract HIV than their non-pregnant peers, scientists finding that their HIV risk peaked during the six months after giving birth, when they were up to four times as likely to become infected. Experts believe biological changes during pregnancy and soon after lead to this increased risk.
Women who contract HIV during pregnancy or while breastfeeding are also more likely to pass the virus to their infants during labour via breast milk.
How the study worked
To confirm whether the dapivirine-containing vaginal ring was safe during pregnancy, researchers recruited about 300 healthy, pregnant women aged 18 to 40 in South Africa, Uganda, Malawi and Zimbabwe, who were randomised to take either the monthly vaginal ring or the daily HIV prevention pill.
Scientists then split the study into three sequential phases – the first among 150 women who were eight or nine months pregnant and were at the least risk of any side effects. Only once an independent expert panel reviewed data from this first phase and found no safety concerns did scientists start roughly an equal number of women who were about seven to eight months pregnant on to the study.
Bunge says that not only did this study design help protect women and their foetuses, but many women appreciated this added level of caution. It also allowed the study to report data sooner, as each phase was completed.
No increased risk in pregnancy
Researchers followed up with women until six weeks after delivery, to see whether they experienced higher than normal rates of miscarriages, or still/premature births. Additionally, participants were monitored for various conditions related to high blood pressure, haemorrhages, fevers and other infections.
The study found no risk of pregnancy or birth complications linked to either the pill or vaginal ring.
The study’s third phase will look at the safety of the ring and pill in women between three to about seven months of pregnancy. This ongoing phase is expected to conclude around May.
Safe during breastfeeding
The companion study on the vaginal ring’s safety during breastfeeding was conducted in the same countries and included about 200 breastfeeding mothers on PrEP and their six- to 12-week-old infants. Women were then randomly assigned to use the ring or the HIV prevention pill, which has already been shown to be safe during breastfeeding.
Very low concentrations of dapivirine were found in women’s breast milk and even lower amounts in their infant’s blood, posing no safety concerns for the babies.
“Women need safe and effective methods for HIV prevention to use at all times, perhaps especially when they are breastfeeding, a time of heightened risk for infection,” said researcher Maxie Owor, who helped lead the study, from Uganda’s Makerere University-Johns Hopkins University (MU-JHU) Research Collaboration centre. “This is why these results are so important.”
A right to access PrEP
The results are likely to strengthen calls for PrEP for expecting or new mothers to be better integrated into antenatal and early infant care.
Mathematical modelling has shown that offering PrEP to pregnant or breastfeeding people could prevent up to 136 000 new HIV infections between 2020 and 2030. Most of these averted infections would be among infants who would otherwise contract HIV via breast milk.
There have been repeated calls for PrEP to be made more readily available to women via antenatal clinics and after delivery.
Study details
DELIVER trial
DELIVER has already found use of the dapivirine ring during the third trimester of pregnancy posed no safety concerns, with pregnancy outcomes and complications experienced by participants in the first and second cohorts no different than what would be expected of women in the local communities where DELIVER is being conducted.
The vast majority of participants in both cohorts delivered full-term (between 37 and 42 weeks) live births, with only 2% of births delivered prematurely across both groups of women in Cohort 1 (those who used the dapivirine ring and those who used oral PrEP), and in Cohort 2, 6% of the births being premature, lower than the 13% premature birth rate expected within the trial site communities (though Cohort 1 were almost full term to begin with). There were two stillbirths, one in each cohort, neither of which was deemed related to use of the study product. In cohort 1, the stillbirth occurred in a participant assigned to Truvada as oral PrEP, whereas in Cohort 2 the stillbirth was experienced by a participant using the dapivirine ring. While based on data collected through the MTN-042B sub-study, 4% of pregnancies could be expected to result in a stillbirth, the frequency for each product and each cohort was well below this background rate. For Cohort 1, the frequency of stillbirth in the oral PrEP group was 2% and 0.7% for the cohort as a whole; and for Cohort 2, the frequency of stillbirth was 1% for the dapivirine ring and 0.6% for the Cohort as a whole.
Complications associated with high blood pressure (hypertensive disorders of pregnancy) were the most common complications experienced by study participants, but at rates lower than or similar to local background rates of 10.5% based on the records review. Hypertensive disorders of pregnancy were experienced by 3% of dapivirine ring users in Cohort 1 and 8% for Cohort 2; while for oral PrEP, these occurred in 8% of Cohort 1 and 10% in Cohort 2.
Study details
Microbicide Trials Network (MTN)-043 – Dapivirine ring and effects through breastmilk)
Maxensia Owor, Lisa Noguchi, Elizea Horne, Moleen Matimbira, Phionah Kibalama Semambo, Vitumbiko Madhlopa-Mandiwa, Rachel Scheckter, Holly Gundacker, Barbra Richardson, Mark Marzinke, Peter Anderson, Katherine Bunge, Nahida Chakhtoura, Jeanna Piper, Jennifer Balkus.
Presented at CROI (19-22 February 2023)
Abstract
Background
Global guidance supports exclusive breastfeeding for infants up to six months of age, continued breastfeeding with the introduction of complementary foods. World Health Organisation (WHO) guidance also supports provision of oral pre-exposure prophylaxis (PrEP) for breastfeeding people at substantial risk of HIV acquisition. In January 2021, WHO recommended the 25 mg dapivirine vaginal ring (DVR) as an HIV prevention choice as part of combination prevention approaches. However, data are limited on DVR safety and pharmacokinetics during breastfeeding, a period of increased risk for HIV acquisition.
Methods
Microbicide Trials Network (MTN)-043 was a phase 3b, randomised, open-label trial, with 12 weeks of exposure to monthly DVR or daily oral PrEP (200 mg emtricitabine [FTC]/300mg tenofovir disoproxil fumarate [TDF]). From September 2020 to July 2021, healthy, HIV-negative, exclusively breastfeeding, mother-infant pairs were enrolled 6-12 weeks after delivery at sites in Malawi, South Africa, Uganda, and Zimbabwe. Mother-infant pairs were randomized in a 3:1 ratio (DVR: PrEP). Adverse event data were collected for mothers and infants throughout product exposure and at two weeks following end of product use. Drug concentrations were measured in maternal plasma, maternal dried blood spots (DBS), breast milk, infant plasma, and infant DBS.
Results
We enrolled 197 mother-infant pairs (DVR: 148, PrEP: 49). Median infant age at enrolment was 9 weeks and >95% of visits were completed. No SAEs or ≥Grade 3 events in mothers or infants were deemed related to study product. Drug concentrations are presented in the Table. Results indicate high uptake of study product in both arms with extremely low concentrations of dapivirine (DVR arm) detected in infant plasma samples. In the oral PrEP arm, tenofovir diphosphate concentrations from infant DBS were all below the lower limit of quantitation.
Conclusions
In this first evaluation of DVR safety and drug detection during breastfeeding, few SAEs or ≥Grade 3 AEs occurred among mothers and infants and all infant AEs were deemed unrelated to study product. While dapivirine appears to concentrate in breastmilk, detection in infant plasma was low. This favorable safety profile, along with data demonstrating low dapivirine transfer to infants, supports updates to WHO and national guidelines to include breastfeeding people when recommending the DVR as an additional HIV prevention choice.
Microbicide Trials Network (MTN)-043 (Open access)
See more from MedicalBrief archives:
Dapivirine vaginal ring receives WHO prequalification for HIV prevention
SAHPRA approves ‘game-changer’ vaginal ring but DoH still undecided
Ring releasing ARV and contraceptive hormone well tolerated
REACH study: Adolescent girls and young women in Africa will use HIV prevention products