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Results presented at the 2016 Conference on Retroviruses and Opportunistic Infections from two large Phase III clinical trials suggest that a monthly vaginal ring containing the antiretroviral drug dapivirine (and no contraceptives) can safely help prevent HIV-1 infection in women.
Results presented at the 2016 Conference on Retroviruses and Opportunistic Infections from two large Phase III clinical trials suggest that a monthly vaginal ring containing the antiretroviral drug dapivirine (and no contraceptives) can safely help prevent HIV-1 infection in women.1-2
Developed by the Silver Spring, MD-based nonprofit International Partnership for Microbicides (IPM), the monthly ring is the first long-acting HIV prevention method designed for women, who bear the greatest burden of the global HIV/AIDS epidemic. Results from the Ring Study, led by IPM, indicate that the monthly dapivirine ring safely reduced HIV infection overall by 31% compared to a placebo.1 Similar results were seen in the second study dubbed ASPIRE, headed by the Microbicide Trials Network (MTN), which was funded by the U.S. National Institutes of Health. Data from the ASPIRE study suggest the ring safely reduced infection by 27% overall.2 (Contraceptive Technology Update reported on the genesis of both studies. Access the story “Dapivirine vaginal ring eyed for HIV prevention,” which was in the October 2012 issue, at http://bit.ly/1pEMTG3.)
The Ring Study enrolled 1,959 HIV-negative women ages 18-45 at seven sites in South Africa and Uganda, while the ASPIRE study enrolled 2,629 HIV-negative women ages 18-45 at 15 sites in Malawi, South Africa, Uganda, and Zimbabwe. The ASPIRE study began in 2012 and ended in 2015. While the Ring Study also began in 2012, it released its results early after its independent data safety and monitoring board recommended the study proceed to final analysis.
The Ring Study employed a 2:1 randomization design: For every two women who used the dapivirine ring, one woman used the placebo. Of the 1,300 participants who used the dapivirine ring and were included in the study’s final analysis, 77 acquired HIV. Of the 650 who used a placebo ring, 56 acquired HIV (31% efficacy). In the ASPIRE study, which used a 1:1 randomization design, of the 1,308 participants who used the dapivirine ring and were included in the final analysis, 71 acquired HIV. Of the 1,306 who used a placebo, 97 acquired HIV (27% efficacy). All women in both studies received regular HIV testing and counseling, treatment for sexually transmitted infections, and condoms. Participants were instructed on how to insert and remove the ring, which they replaced every four weeks.
Both studies saw differences in efficacy by age and consistency of ring use, or adherence. Results from the ASPIRE study indicate the ring cut HIV risk by 61% in women older than age 25 and by 56% in women older than age 21 in a post-hoc analysis.2 These findings were statistically significant and supported by a trend in The Ring Study, which also showed higher efficacy (37%) for women older than age 21.1
However, scientists in both studies saw little to no protection in women ages 18-21; just 15% in the Ring Study and no protection in ASPIRE.1-2 The lack of protection seen in this age group, which is likely due to lower adherence, is not unique to these two studies, scientists believe. Previous ARV-based prevention efficacy trials with tenofovir gel and tenofovir-based oral PrEP also saw lower protection among younger male and female participants due to lower adherence.3-4 With daily oral PrEP, however, adherence increased for younger participants in subsequent post-trial studies, in which participants knew that PrEP already had been proven effective and that they were receiving the active product.5
IPM plans to conduct an open-label extension (OLE) study that will provide the dapivirine ring to previous Ring Study participants. How might such a study help to answer critical questions about the product?
“First, the OLE study would demonstrate how women would use the monthly dapivirine ring now that they know it can safely help prevent HIV when it is used consistently, and help us to better support adherence,” says Zeda Rosenberg, ScD, IPM chief executive officer. “In an open-label research setting, we could follow women’s ring use patterns individually and talk to them directly about their experiences, which would help us fully understand what factors discourage adherence and, just as importantly, what motivates it.”
In addition, the study will help scientists understand why women age 21 and younger had such low protection in the Phase III ring studies, notes Rosenberg. Was it solely because they were not able to use the ring consistently, or are there other biological factors at play? Results from the OLE study will help develop methods to overcome barriers to protection for the youngest women, she states.
“The high HIV incidence rates we saw in women of all ages in both ring studies underscore the great risk women in these communities face every day — and the urgent need to find effective solutions they can use to protect their health,” states Rosenberg.
As sister studies, ASPIRE and the Ring Study were designed to provide the strength of evidence to support potential licensure of the dapivirine vaginal ring for preventing HIV in women. Because at least two Phase III efficacy trials usually are needed for a product to be considered for regulatory approval, ASPIRE and the Ring Study were conducted in parallel to accelerate the timeline to the ring’s potential approval. IPM is compiling all data on the ring to submit it for product licensure in the first quarter of 2017.
Dapivirine belongs to a class of antiretroviral drugs referred to as non-nucleoside reverse transcriptase inhibitors that bind to and disable HIV’s reverse transcriptase enzyme, a key protein needed for HIV replication. The ring, made of a flexible silicone material, slowly releases the drug over a month, with minimal absorption elsewhere in the body.
The ring’s development was made possible by a public-private partnership with Dublin-based Janssen Sciences Ireland UC, a Janssen pharmaceutical company of Johnson & Johnson, which granted IPM a royalty-free license in 2004 to develop dapivirine as a microbicide for women in developing countries. The license has been expanded since then to a worldwide rights agreement.
What characteristics of the dapivirine ring might make it an attractive option for HIV prevention, particularly for at-risk women? Two characteristics stand out, says Jared Baeten, MD, PhD, vice chair of global health and professor of allergy and infectious diseases, public health, and epidemiology at the Seattle-based University of Washington School of Public Health.
“First, the ring is under a woman’s control and can be used discretely,” says Baeten, who served as protocol chair for the ASPIRE study. “Second, it is safe, with very little systemic absorption of the medication. The drug is concentrated in the vagina, where it is needed.”
Financial Disclosure: Consulting Editor Robert A. Hatcher, MD, MPH, Nurse Reviewer Melanie Deal, Editor Rebecca Bowers, and Executive Editor Joy Dickinson report no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.