Dapivirine Vaginal Ring Prevents HIV-1 Transmission

NEW YORK (Reuters Health) - The dapivirine vaginal ring is effective for HIV-1 prevention in women, according to results from two randomized controlled trials.

"I found the results tremendously encouraging - as real proof of concept that a microbicide could truly reduce the risk of HIV-1 infection," said Dr. Jared M. Baeten from the University of Washington's International Clinical Research Center in Seattle, who worked on one of the studies.

"We are accumulating fantastic tools for HIV-1 prevention, and having options will have the greatest impact - so patients can choose what will work best for them," he told Reuters Health by email.

Dapivirine is a non-nucleoside HIV-1 reverse transcriptase inhibitor with broad activity against HIV-1 subtypes. Vaginal rings incorporating dapivirine were shown to be safe and acceptable in phase 1 and 2 studies, with typical dapivirine plasma levels 1,000 times lower than those achieved with oral dapivirine.

Dr. Baeten and colleagues on the MTN-020-ASPIRE study team investigated the efficacy and safety of the dapivirine vaginal ring, replaced every 4 weeks, compared with a placebo ring, in a phase 3, randomized controlled trial funded by the National Institutes of Health. The team enrolled 2,629 African women.

During a median follow-up of 1.6 years, the incidence of HIV-1 infection was 27% lower (p=0.046) in the dapivirine group (3.3 per 100 person-years) than in the placebo group (4.5 per 100 person-years), the researchers report in The New England Journal of Medicine December 1.

HIV-1 protection was generally similar across subgroups, although dapivirine's efficacy differed significantly by age - 10% among women under the age of 25 years versus 61% among women 25 years of age or older.

Women who had evidence of higher rates of adherence experienced greater HIV-1 protection than did women with lower rates of adherence.

"That adherence was imperfect was not a surprise - the field has learned that not all prevention products will be workable for all people and that it can be hard to be adherent in a trial when a product is not yet proven to be safe or effective," Dr. Baeten said.

"The next step for this ring - 2 open-label studies are going on to assess uptake of and adherence to the ring now that it has been proven to be effective and safe," he said.

In the second study, also in The New England Journal of Medicine December 1, Neliƫtte van Niekerk from the International Partnership for Microbicides in Silver Spring, Maryland, and colleagues assessed the safety and efficacy of a dapivirine-containing vaginal ring for up to 24 months in 1,306 women from seven research centers in South Africa and Uganda.

Here, the incidence of HIV-1 infection was 31% lower (p=0.04) in the dapivirine group (4.1 seroconversions per 100 person-years) than in the placebo group (6.1 seroconversions per 100 person-years).

As in the other study, adherence influenced the apparent efficacy of the dapivirine rings. The rate of HIV-1 infection was 29% lower during adherent intervals between visits than during nonadherent intervals between visits.

Although dapivirine efficacy did not differ by age group, the HIV-1 incidence rate was higher among participants 21 years of age or younger than among those older than 21 years of age in both the dapivirine and placebo groups.

The cumulative incidence of adverse events did not differ significantly between the dapivirine and placebo groups in either study.

Dr. Adaora A. Adimora from the University of North Carolina School of Medicine, Chapel Hill, who wrote an accompanying editorial, told Reuters Health by email, "I was most surprised that the results of the two studies were so remarkably similar. Their similarity speaks to the excellent design, execution, and coordination of these two trials. I was also surprised by the low adherence among very young women; I would have thought young women would have liked the fact that they could insert the ring and not worry about it for a month instead of having to use a product every day or coordinate use of a product with intercourse."

"HIV prevention science is making progress," she said. "This new prevention modality - despite its modest efficacy - could protect women at high risk for HIV - if they are willing and able to use it consistently. It will be interesting to see what the next steps for this product will be."

Dr. José das Neves from Universidade do Porto in Portugal, who has published numerous reports regarding dapivirine, told Reuters Health by email, "The dapivirine ring may play an important role in protecting women from HIV infection. Although only shown moderately effective, the ring has the potential to empower women in settings characterized by gender inequality and to constitute an essential protection tool. The dapivirine ring, if approved, should be considered as an additional option to the ones already available."

"The ring will not meet all women's needs and preferences regarding protection from HIV infection," Dr. das Neves said, adding that alternative products are currently under development. "These include multiple purpose products, alternative dosage forms, or long-acting injectables."

Dr. Janneke van de Wijgert from the University of Liverpool, U.K., who has also conducted dapivirine studies, said, "When I first heard the results when they were presented at the Conference on Retroviruses and Opportunistic Infections (CROI), my initial reaction was excitement and relief, but also a bit of disappointment because the overall level of efficacy was only 27% in the ASPIRE trial and 31% in the Ring Plus trial."

"However, I was reassured when I saw the subanalyses by adherence level, which clearly showed that better adherence resulted in better efficacy," Dr. van de Wijgert told Reuters Health by email.

"I have heard many public health officials argue that only the overall results matter, but I strongly disagree," she said. "Some women (especially young women) do not feel vulnerable, some women do not prioritize HIV prevention because of the many other difficulties in their lives, some women don't care, but there is also a large group of women who do want to protect themselves and would protect themselves if they had the means to do so. When I lived in Zimbabwe, I first and foremost wanted to help this latter group of women."

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"We already knew that male and female condoms and oral pre-exposure prophylaxis (PrEP) can protect women from HIV, but we now know that vaginal application of antiretroviral drugs is also efficacious," Dr. van de Wijgert said. "We are all well aware of the problems associated with condom use (low acceptability, requires male cooperation, prevents pregnancy), and oral PrEP may cause systemic toxicity with long-term frequent use. It is therefore important that these additional methods of HIV prevention for women are now becoming available."

She added, "I think that it is important to point out that a main advantage of applying antiretroviral drugs vaginally is to minimize systemic toxicity. While I support role out of oral PrEP in groups of men and women at high risk who cannot or will not use condoms, I do not believe in a rollout in general populations because of potential systemic toxicity with long-term frequent use. I think that vaginal application of antiretroviral drugs is much safer and could therefore be used by larger groups of women."

Ms. van Niekerk did not respond to a request for comments.

SOURCE: http://bit.ly/2hegrXW, http://bit.ly/2hbboqK and http://bit.ly/2gINB0N

N Engl J Med 2016.

References
SOURCES:

Dapivirine Vaginal Ring Prevents HIV-1 Transmission. Medscape. Dec. 14, 2016.

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