PrEP vaginal ring set for rollout after WHO endorsement
Significant step as WHO recommends the dapivirine vaginal ring as a new HIV prevention tool following promising trial results.
Last week (26 January), the World Health Organization (WHO) recommended the dapivirine vaginal ring as a new HIV prevention tool for women at heightened risk of HIV, as part of a package of other prevention tools.
While contraceptive vaginal rings have been available for several years, the monthly dapivirine ring - which releases an antiretroviral drug inside the vagina as pre-exposure prophylaxis (PrEP) - is the first ring to offer HIV prevention.
The soft, silicone ring is inserted into the vagina by women and worn continuously for a month. The ring is an important development because it is women-owned, long-acting, discrete and doesn't need a healthcare professional to insert.
In 2016, the Ring Study and ASPIRE – two Phase III trials of the dapivirine ring in Eastern and Southern Africa – found one-third fewer women contracted HIV who used the ring compared to women who used a placebo ring (the Ring Study reported a 35% reduction in HIV incidence and ASPIRE reported a 27% reduction). While certainly positive, low adherence to the ring among some age groups was disappointing. In sub-groups where adherence to the ring was high, HIV incidence was at least halved.
Results from two open-label extension studies, HOPE and DREAM, found that the ring reduced HIV infection by 50% overall. In these studies, all women were given the dapivirine ring and none received a placebo. Previous oral PrEP trials have shown a greater likelihood of using PrEP when there was no potential to be assigned a placebo. These real-world studies individually reported an HIV incidence reduction of 39% (HOPE) and 62% (DREAM), the result of higher uptake and use than in the original trials.
These peer-reviewed trial results were published this month (1 February) in The Lancet, although initial results were released last year and were used to inform a positive opinion from the European Medicines Agency (EMA) back in July 2020, and WHO pre-qualification in November.
Effectiveness and use of the ring in open-label extension trials
Running between 2016 and 2018, the HOPE study offered 12-month access to the dapivirine ring to 1,450 women in Malawi, South Africa, Uganda and Zimbabwe who had participated in the original ASPIRE trial. Their median age was 31 and roughly one in ten (12%) were younger than 25.
DREAM, the extension of the Ring Study, was conducted between 2016 and 2019 among 940 women in South Africa and Uganda. The median age in this cohort was 30 years.
Both studies began with monthly appointments, then saw participants every three months, providing them with rings to replace after 28 days. DREAM reported HIV incidence of 1.8 per 100 person-years. This was a 62% reduction in incidence compared to the Ring Study’s placebo group when matched on age, study site, and other demographics. In HOPE, HIV incidence was 2.7 per 100 person-years, 39% lower than the incidence in the matched ASPIRE placebo group.
In DREAM, 90% of women took the rings home and completed the trial to 12 months, compared to 73% in HOPE. Both studies tested the returned rings for residual amounts of dapivirine to measure adherence and found higher levels of adherence than in the Phase III trials. These remained consistently high over the study period, indicating that women continued to use the rings through the study.
Reasons for not using the ring included a preference for an alternative HIV prevention method, partners being unsupportive, work demands making it difficult to participate in the trial, and becoming HIV positive. Side effects were rarely reported as a reason not to use the ring.
Adherence levels reported by HOPE and DREAM are higher than those reported in oral PrEP trials with African women, which have reported 6-month and 12-month use between 20% and 50%.
No serious side effects occurred from ring use in either study. In DREAM, although 65% of women reported ‘adverse events’, ring use was not the cause in most cases. Only six incidents were associated with ring use and all were considered to be mild, such as pelvic discomfort.
In DREAM, five women (29%) who contracted HIV during the study had drug resistance. This is higher than the ASPIRE trial, which found 17% of women had drug-resistant HIV. Both sample sizes are small so this result should be viewed with caution. Both the Ring Study and ASPIRE found no difference in drug resistance between the ring and the placebo groups, and it may be possible that this increase in drug resistance reported by DREAM reflects a rise in the general prevalence of drug-resistant HIV.
As countries consider rolling out the dapivirine ring, the WHO calls for comprehensive training and support for providers to ensure they understand the ring’s risks and benefits and can pass this information on to women to help them make an informed choice about whether or not to use it.
The WHO is clear that the dapivirine ring should be used as 'a complementary prevention approach', in combination with other safer sex practices, such as condoms. It recommends that the ring is offered alongside other HIV prevention choices, contraceptive choices, STI diagnosis and treatment, voluntary partner services, HIV testing, and links to antiretroviral treatment if relevant.
Adolescent girls and young women and women from key populations may need more tailored support to use the ring. Further studies are needed to assess feasibility and effectiveness among these groups.
Real-world studies with women who have no previous experience of using the dapivirine ring are also needed to further analyse uptake and adherence. Research on whether the ring is safe to use during pregnancy and breastfeeding – something HOPE and DREAM did not examine – is also required.