A vaginal ring containing an antiretroviral (ARV) drug called dapivirine that women use for a month at a time was safe and helped protect against HIV in a large-scale clinical trial involving more than 2,600 women in Africa, researchers who conducted the trial, known as ASPIRE, reported.
The study, which was led by the National Institutes of Health (NIH)-funded Microbicide Trials Network (MTN), found the dapivirine ring reduced the risk of HIV infection by 27% overall – there were 27% fewer women who acquired HIV in the group assigned to use the dapivirine ring than in the group assigned to use a placebo ring containing no active drug.
The risk of HIV was reduced significantly more among the study’s older participants, who also used the ring most consistently. Women in the dapivirine group who were 25 and older were 61 percent less likely to acquire HIV than women of the same age in the placebo group. Intrigued with this finding, the researchers conducted additional analyses. These drew a more precise line of demarcation, with lack of protection being confined to women between the age of 18 and 21, and women older than 21 seeing their risk of HIV cut by more than half (56 percent).
ASPIRE enrolled HIV-negative women ages 18 to 45 at 15 clinical research sites in Malawi, South Africa, Uganda and Zimbabwe.
Results of the ASPIRE study were announced at the Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, together with similar findings from a second trial of the dapivirine ring, two days ahead of their scheduled presentation.
The University of Cape Town’s Professor Linda-Gail Bekker, the South African National Protocol Chair for The Ring and ASPIRE studies, tod Swedish Radio that she hoped vaginal rings would now be accepted as one of the alternative means of HIV protection when condoms are not used.
In the second trial, called The Ring Study, HIV risk was reduced by 31% overall, and by 37% among participants older than 21. The International Partnership for Microbicides (IPM), which developed the monthly dapivirine ring, is conducting The Ring Study in South Africa and Uganda among 1,959 women. Although still ongoing, The Ring Study is reporting results early, following a recommendation of its independent data and safety monitoring board that the study proceed to final analysis.
“This is a glass half-full moment,” said Dr Jared Baeten, of the University of Washington, who as protocol chair led the ASPIRE study. “The HIV prevention field for women has struggled in the last few years – at times the glass had seemed almost completely empty. Now, for the first time, we have two trials demonstrating that a female-controlled HIV prevention method can safely help reduce new HIV infections. I’m optimistic about what these results might mean for women worldwide.”
Women account for nearly 60% of adults with HIV in sub-Saharan Africa, where unprotected heterosexual sex is the primary driver of the epidemic. While several studies have shown that ARVs are highly effective in preventing HIV, other studies – such as VOICE and FACTS 001 – suggest that for young, at-risk women in Africa, ARVs delivered as a vaginal gel or as a tablet may not be acceptable. Products must be used to be effective, and that was not the case for most of the participants in those previous studies.
Vaginal rings are flexible products that fit high up inside the vagina where they release a medication slowly over time. They are already used in the US and Europe to deliver hormonal contraception. Women can insert and remove the ring themselves. The dapivirine ring adapts that medical technology by using an ARV instead of contraception as a way to offer women potentially longer-acting protection against HIV.
ASPIRE was conducted between August 2012 and June 2015 and enrolled 2,629 women who were randomly assigned to use either the dapivirine ring or placebo ring for a month at a time throughout the study. Participation averaged 18 months, with some using their assigned monthly ring for up to 34 months. Women received a new ring at each monthly visit, plus condoms and HIV prevention counselling. They learned how to insert and remove the ring when they began the study and received additional guidance on its correct and consistent use throughout.
“Despite having never seen or used a vaginal ring, a number of study participants told us they were very comfortable inserting and removing the ring. A vaginal ring for HIV prevention can be used by African women. Expanding the number of HIV prevention options is important for women globally,” said Dr Thesla Palanee-Phillips, ASPIRE protocol co-chair who also directed the research site at the Wits Reproductive Health and HIV Institute (Wits RHI) in Johannesburg, South Africa.
To determine whether the ring was effective in preventing HIV, researchers compared the number of HIV infections that occurred in each group. Overall, 168 women in the study acquired HIV – 97 in the placebo group and 71 in the dapivirine ring group, representing a 27% reduction in HIV. An additional analysis, which was planned early into the study, excluded data from two of the trial’s 15 sites that had less than ideal retention and adherence. In that second analysis, there were 139 HIV infections – 85 in the placebo ring group and 54 in the dapivirine ring group, resulting in a 37% reduction in HIV infections. Results of both analyses were statistically significant. Additional analyses, both pre-planned and post-hoc, found the reduction in HIV risk exceeded 50% in women older than age 21.
The study found no safety concerns associated with the dapivirine ring, and among women who acquired HIV during the study, there were no differences in the number of cases or type of drug resistance between the dapivirine and placebo groups.
“Our results make it all too clear that we must do more to address the unique needs of the youngest women in our study, who represent one of the highest-risk groups. Why didn’t the ring work for them? We need to understand if it is adherence alone or biological or physiological factors. The blinded nature of the trial, with a placebo arm, also could have played a role, as we know from prior studies that some women may be nervous using a product before it is proven to be safe and effective,” explained Baeten. In open-label studies of Truvada as oral pre-exposure prophylaxis (PrEP), both adherence and effectiveness were higher than in the original Phase III trials.
“Both ASPIRE and The Ring Study have raised important scientific questions about the susceptibility of very young women to HIV, as well as their willingness to use prevention products. Further research can address these knowledge gaps. With the number of new infections in women each year, time is not on our side. We cannot lose momentum in the search for products to reduce the spread of HIV,” commented Dr Sharon L Hillier, of the University of Pittsburgh and principal investigator of the MTN.
The National Institute of Allergy and Infectious Diseases (NIAID), the primary NIH institute that funds the MTN, has indicated it will convene a panel of experts to provide advice on the future of NIH-funded dapivirine ring research.
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 are usually 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.
Dapivirine, also known as TMC-120, belongs to a class of ARVs called non-nucleoside reverse transcriptase inhibitors (NNRTIs) that bind to and disable HIV’s reverse transcriptase enzyme, a key protein needed for HIV replication. The ring’s development was made possible by a public-private partnership with 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. That license has since expanded to a worldwide rights agreement.
Antiretroviral medications that are used as prophylaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials among African women, the incidence of HIV-1 infection was not reduced, probably because of low adherence. Longer-acting methods of drug delivery, such as vaginal rings, may simplify use of antiretroviral medications and provide HIV-1 protection.
We conducted a phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor, involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe.
Among the 2629 women who were enrolled, 168 HIV-1 infections occurred: 71 in the dapivirine group and 97 in the placebo group (incidence, 3.3 and 4.5 per 100 person-years, respectively). The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval [CI], 1 to 46; P=0.05) than that in the placebo group. In an analysis that excluded data from two sites that had reduced rates of retention and adherence, the incidence of HIV-1 infection in the dapivirine group was lower by 37% (95% CI, 12 to 56; P=0.007) than that in the placebo group. In a post hoc analysis, higher rates of HIV-1 protection were observed among women over the age of 21 years (56%; 95% CI, 31 to 71; P<0.001) but not among those 21 years of age or younger (−27%; 95% CI, −133 to 31; P=0.45), a difference that was correlated with reduced adherence. The rates of adverse medical events and antiretroviral resistance among women who acquired HIV-1 infection were similar in the two groups.
A monthly vaginal ring containing dapivirine reduced the risk of HIV-1 infection among African women, with increased efficacy in subgroups with evidence of increased adherence.
Oral presentations of results will be Wednesday, 24 February and can be viewed online approximately 24 hours later.
Notably, both studies saw important differences in efficacy by age and consistency of ring use, or adherence. ASPIRE showed that the ring reduced HIV risk by 61% in women older than age 25, and in a post-hoc analysis by 56% in women older than 21, who also appeared to use the ring more consistently. These findings were statistically significant and supported by a trend in The Ring Study which also showed higher efficacy (37%) for women over 21.
Conversely, little to no protection was seen in women ages 18-21 across both studies – 15% in The Ring Study and no protection in ASPIRE. This underscores the urgent need to overcome barriers to HIV prevention for the youngest women. IPM and MTN are working to understand how ring use, and potential biological and other factors may have influenced the different levels of protection seen by age in these studies.
Following guidance from the regulatory authority in South Africa, IPM will close The Ring Study’s placebo arm in that country and provide all women still enrolled with the active dapivirine ring for the remainder of their participation. IPM is seeking similar approval in Uganda.
“These findings give new hope to many women at high risk who need more and different options to effectively protect themselves from HIV,” said Dr Zeda Rosenberg, founding CEO of IPM. “IPM will seek regulatory approval for the monthly dapivirine ring and work with partners to determine its role in strengthening HIV prevention efforts. We are also hopeful we can learn more about how to help women who want to use the ring do so consistently, which could help increase protection. A planned follow-on study would help answer key questions about how women would use the ring when they are aware it can safely help offer protection.
“Our thanks go out to the women who participated in the studies, and their families and communities for their commitment to finding a solution to this devastating epidemic. IPM also extends its deepest thanks to the research teams that expertly conducted these multi-year studies, and to its donors and civil society partners for their investment of time and resources in women’s health.”
The monthly dapivirine ring, which IPM developed over the past decade, is the first to adapt a medical technology commonly used to deliver hormones to women – the vaginal ring – to instead deliver an ARV drug to prevent HIV. The flexible ring is easy for a woman to insert herself and provides sustained-release of dapivirine locally to the site of potential infection during vaginal sex.
“I welcome the results from the ASPIRE and Ring Study, which investigated the extent to which the dapivirine ring protects women from acquiring HIV,” said South Africa’s Minister of Health, Dr Aaron Motsoaledi. “Every advance in science that empowers women to protect themselves from the virus should be considered for rapid adoption and implementation.”
Women in sub-Saharan Africa remain at high risk for HIV despite global progress against the disease. Ending the epidemic will require multiple prevention options that meet women’s needs and fit within the context of their lives. IPM hopes the monthly dapivirine ring will join other new innovations such as oral pre-exposure prophylaxis (PrEP) as part of a comprehensive HIV prevention package, alongside continuing development of next-generation vaginal and rectal microbicides, long-acting injectables, vaccines and other strategies.
Both studies found the ring to be safe, with no statistical difference between the active and placebo arms. Previous IPM studies have shown that absorption of dapivirine is largely confined to vaginal tissue with low systemic exposure, which may help minimize side effects.
The Ring Study and ASPIRE also found no evidence that use of the dapivirine ring increased the presence of ARV-resistant HIV. As we continue to examine the data, we are also focusing on what more we can learn about the relationship between adherence and efficacy. Both studies used objective markers to measure adherence, including dapivirine levels in blood plasma and residual drug left in used rings of women in the dapivirine ring arms of the studies.
Overall, adherence and, in turn, HIV protection improved over time in ASPIRE. This finding was supported by a post-hoc analysis of The Ring Study exhibiting a strong trend toward higher efficacy in women with less drug remaining in the ring. Taken together, these data suggest that the ring must be used continuously to achieve protection – and that greater protection could be achieved with more consistent use.
“Women who volunteered for these studies live in communities with some of the highest rates of HIV in the world, and we saw that across women of all ages in both studies. Today, we have turned a corner in HIV prevention,” said Dr Annalene Nel, chief medical officer of IPM and study director for The Ring Study. “We have seen the potential of an ARV ring, and must now work to fully realize this potential for women worldwide.”
The majority of women in both studies were young, with a mean age of 26, and unmarried. Importantly, the studies showed that women of all ages were at very high risk for HIV. Across both studies, rates of new HIV infection in the placebo group were up to 8.2% for women ages 18 to 21, 7.3% for women between ages 21 and 25, and 4.3% for women older than 25.
Based on the results, IPM is pursuing the following steps:
• Open-label extension (OLE) study: IPM is planning an OLE study that would provide previous Ring Study participants with the dapivirine ring, and help answer critical questions about the product and its use while it is under regulatory review for licensure. We hope that knowledge of the ring’s safety and efficacy would encourage its use, as seen in oral PrEP OLEs. Pending approvals, this study could begin as soon as April 2016. Discussions are taking place about a similar OLE study for ASPIRE participants.
• Regulatory submission: As the ring’s regulatory sponsor, IPM is compiling all data on the ring and plans to submit the comprehensive dossier of evidence regulators require for product licensure in Q1 2017.
• Access planning: IPM is committed to working with governments, donors, communities and civil society to fully understand the findings from The Ring Study and ASPIRE, determine the appropriate role for the ring in HIV prevention programs in Africa and prepare for affordable access, should the ring be approved.
This is the first time a vaginal ring has been used to effectively deliver an ARV, and opens the door to next generation prevention products. IPM is advancing a three-month dapivirine-only ring, another ring designed to prevent both HIV and unintended pregnancy, and combination ARV rings designed to increase efficacy.