Dapivirine ring safe in late pregnancy and during breastfeeding
6 April 2023. Related: Conference reports.
Polly Clayden, HIV i-Base
The dapivirine vaginal ring appears safe when used in the third trimester of pregnancy and during breastfeeding – according to data presented at CROI 2023.
Pregnancy
Adverse pregnancy outcomes were uncommon when the dapivirine ring was used in the third trimester – in the first study of the monthly ring in pregnancy. [1]
Rates were also similar to those seen in the comparator arm – oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) – and in the communities where the study is being conducted. These data support plans for subsequent investigation of safety earlier in pregnancy.
Microbicide Trials Network (MTN)-042/DELIVER is a phase 3b, randomised, open-label safety trial of the dapivirine ring and oral TDF/FTC. The trial has a stepwise design working backwards from the third trimester. This includes an IRB review before moving to the next cohort:
- Cohort 1 – 36+ weeks (gestation); 2:1 randomisation/4–6 weeks
- Cohort 2 – 30–35 weeks; 2:1 randomisation/7–12 weeks
- Cohort 3 – 12 to 29 weeks; 4:1 randomisation/up to 30 weeks
The findings reported at the conference were safety data from the first two cohorts of pregnant participants.
Eligible pregnant women aged 18–40 in Malawi, South Africa, Uganda and Zimbabwe were randomised 2:1 to monthly dapivirine ring or daily TDF/FTC.
The evaluation assessed pregnancy outcomes and complications up to six weeks after delivery and summarised the findings using descriptive statistics. These were compared to local background rates from a systematic chart review: MTN-042B. This review included 10,138 records across four sites.
The trial started in January 2020 but was paused briefly March to May 2020, to ensure COVID-19 safety measures were in place.
The study enrolled 150 participants into cohort 1 (101 randomised to dapivirine ring and 49 to TDF/FTC) and 157 participants into cohort 2 (106 randomised to dapivirine and 51 to TDF/FTC).
Demographic and clinical characteristics were similar by study arm for each cohort.
In cohort 1, there was one stillbirth and one neonatal death, both in the TDF/FTC arm. One stillbirth and one neonatal death also occurred in cohort 2, both in the dapivirine ring arm. The prevalence of preterm delivery was 2% in cohort 1 and 6% in cohort 2.
In both cohorts, the most common outcome (93%) was a full-term, live birth. Pregnancy complications were rare, with hypertensive disorders being the most commonly reported (10.5%) and generally similar to local background rates.
There were no cases of fever of unclear etiology or preterm premature rupture of membranes. In cohort 2, there was 1 (1%) case of chorioamnionitis in the dapivirine ring arm and 1 (1%) of postpartum endometritis in the TDF/FTC arm, and 2 (4%) of puerperal sepsis in the TDF/FTC arm.
There were no seroconversions or maternal deaths during the reporting period. There was one infant death in each arm, neither were deemed to be associated to the study product.
Breastfeeding
Few adverse events were reported among mothers and infants in a related presentation showing the first evaluation of dapvirine ring safety and drug detection during breastfeeding. All infant adverse events were judged unrelated to study product. And although dapivirine appears to concentrate in breastmilk, detection in infant plasma was low.
A previous study, MTN-029/IPM 039, found a positive safety profile in lactating women and low likelihood of significant drug transfer to infants. Dapivirine was safe and well-tolerated among those who had weaned infants but were still able to produce milk. Median dapivirine concentrations were 676 pg/mL in breast milk, 327 pg/mL in plasma (milk/plasma ratio approximately 2.0). This study estimated extremely low infant exposure (74.3 ng/kg/day).
Following that study, additional research was recommended to evaluate safety of dapivirine use during breastfeeding.
MTN-043 was a phase 3b, randomised, open-label trial, with 12 weeks of exposure to monthly dapivirine ring or daily oral TDF/FTC. From September 2020 to July 2021, 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 randomised to 3:1 to the dapivirine ring or TDF/FTC. Adverse event data were collected for mothers and infants throughout product exposure and at two weeks after the end of product use.
Drug concentrations were measured in maternal plasma, maternal dried blood spots (DBS), breast milk, infant plasma, and infant DBS.
The study enrolled 197 mother-infant pairs. Infants were a median age of 9 weeks at enrollment.
Mean dapivirine concentrations in breast milk ranged from 698.3 pg/mL at week 1 to 596.1 pg/mL at month 3 (50.1pg/mL 2 weeks post-use). Extremely low concentrations of dapivirine were detected in infant plasma samples: 0 pg/mL week 1, 14.5 pg/mL week 2 and 10.7 pg/mL month 3 (BLQ 2 weeks post-use).
No serious adverse events or grade 3 and higher events in mothers or infants were considered to be related to study product.
In the TDF/FTC arm, tenofovir diphosphate concentrations from infant DBS were all below the lower limit of quantitation.
comment
The risk of acquiring HIV increases during pregnancy and is highest during the postpartum period.
These studies are excellent and provide important data from a new product to guide use in pregnant and lactating women that is usually absent (or very slow to obtain) in both treatment and prevention of HIV.
As the authors pointed out, typically development programmes rely on phase 3 trial results or post market surveillance.
Phase 3 studies usually include contraception requirements, so few pregnancies occur and participants who do get pregnant either discontinue the study or the study product. For example in MTN-020/IPM 027 (2629 women) there were 86 pregnancies in the dapivirine arm and in HPTN-084 (3224 women) 29 pregnancies in the cabotegravir long-acting arm.
Post-market surveillance depends on adequate reporting systems, results in substantial delay and shifts the risk-benefit to the user and clinician – pregnant women receive a new product in an uncontrolled and unconsented fashion.
A safety study, designed for a pregnant population, is the most efficient and rigorous way to collect safety data for an investigational product in pregnancy, so very welcome. These studies can be difficult and require support from the community, developers and donors.
MTN-042 is an example of good participatory practice. The study included a stakeholder meeting, with key opinion leaders from each trial site country, researchers and WHO after which recommendations were incorporated into the protocol (for example standardised definitions, background pregnancy outcome data and longer infant follow up). In-country meetings were also conducted with community groups and NGOs in each participating country.
Since early 2021, WHO recommends the dapivirine vaginal ring as part of combination prevention. [3] The guidance states: “The dapivirine vaginal ring may be offered as an additional prevention choice for women at substantial risk of HIV infection as part of combination prevention approaches”. This is a conditional recommendation with moderate-certainty evidence. It defines substantial risk of HIV infection as “HIV incidence greater than 3 per 100 person-years in the absence of PrEP.”
The ring is now approved by several national agencies including the Medicines Control Authority of Zimbabwe, Uganda National Drug Authority, and South African Health Products Regulatory Authority (as well as European Medicines Agency).
But there are substantial questions concerning the ring’s efficacy in reducing the risk of acquiring HIV. Although the WHO guideline summary of its review findings notes that a systematic review and meta-analysis of the ring trials demonstrated it to be effective, the two key randomised controlled trials, the Ring Study (IPM-027) and ASPIRE (MTN-020), showed only 33% and 27% relative reduction in HIV risk versus placebo.
The results from two open-label extension studies – DREAM and HOPE – found better efficacy (62% and 39% versus simulated control), compared to the randomised controlled trials. And a subgroup analysis by age did not demonstrate efficacy among women 18–24 years old, who had very low adherence.
Of note, in December 2021, The International Partnership for Microbicides (IPM) – who developed the ring – voluntarily withdrew its New Drug Application (NDA) from the US Food and Drug Administration (FDA), following feedback that current data are unlikely to support the ring’s approval by the agency. [4]
WHO followed this announcement with one saying it continues to support its conditional recommendation for the ring as an additional prevention option for women at substantial risk of HIV. [5]
References
- Bunge KE et al. DELIVER: A safety study of a dapivirine vaginal ring and oral PreP during pregnancy. CROI 2023. Seattle. Oral abstract 127.
https://www.croiconference.org/abstract/deliver-a-safety-study-of-a-dapivirine-vaginal-ring-and-oral-prep-during-pregnancy/ (abstract) - Balkus J et al. Dapivirine ring safety and drug detection in breastfeeding mother-infant pairs. CROI 2023. Seattle. Poster abstract 785.
https://www.croiconference.org/abstract/dapivirine-ring-safety-and-drug-detection-in-breastfeeding-mother-infant-pairs/ (abstract)
https://www.croiconference.org/wp-content/uploads/sites/2/posters/2023/CROI_2023_MTN043_poster_2023-02-10-133209613532694120.pdf (poster) - World Health Organisation. (2021). Guidelines: updated recommendations on HIV prevention, infant diagnosis, antiretroviral initiation and monitoring. World Health Organisation.
https://apps.who.int/iris/handle/10665/340190 - International Partnership for Microbicides. IPM Statement on US Food and Drug Administration Review of Dapivirine Vaginal Ring. 9 December 2021.
https://www.ipmglobal.org/content/ipm-statement-us-food-and-drug-administration-review-dapivirine-vaginal-ring - World Health Organisation. WHO continues to support its conditional recommendation for the dapivirine vaginal ring as an additional prevention option for women at substantial risk of HIV. 9 December 2021.
https://www.who.int/news/item/09-12-2021-who-continues-to-support-its-conditional-recommendation-for-the-dapivirine-vaginal-ring
This report was first published on 1 April 2023.