In a major finding, HIV microbicide researchers have found new and encouraging evidence that the antiretroviral drug dapivirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), is not impacted by a woman's vaginal microbiome composition when administered as a vaginal gel or film.
This study, presented by Sharon Hillier, Ph.D., from the University of Pittsburgh at the 9th Annual IAS Conference in Paris, should come as a relief for microbicide researchers, as it indicates that dapivirine will likely work even among women who have bacterial vaginosis (BV), a common type of inflammation caused by overgrowth of certain vaginal bacteria.
"I have been funded by the [National Institutes of Health] to develop and evaluate vaginal products for prevention of HIV since 1995," Hillier told TheBodyPRO.com. "I have never been more optimistic about this approach as I am today. With the completed trials of the vaginal rings containing dapivirine, we now know that [antiretrovirals] applied vaginally in tiny doses can substantially reduce women's risk of acquiring HIV."
For years, researchers have been investigating the promise of vaginal rings and gels: products loaded with antiretroviral medication that can be inserted into the vagina, giving women more control over their HIV exposure. This research is important because HIV remains a leading cause of death among women in sub-Saharan Africa, despite the billions of condoms that have been distributed.
However, this approach has been dogged by efficacy concerns, with results varying widely among different groups. Recently, researchers hit on a piece of the puzzle with new evidence that specific composition a woman's vaginal microbiome might significantly impact the efficacy of tenofovir (Viread), a nucleoside analog reverse transcriptase inhibitor, or "nuke."
Tenofovir and dapivirine are both used in HIV microbicide applications. In 2010, a study called CAPRISA 004 found tenofovir gel to reduce HIV infections by 39% on average. In addition, a subsequent analysis revealed that among women with vaginal microbiomes dominated by "good" bacteria, Lactobacillus, the gel was 78% protective in women who used it properly. Yet, in women with microbiomes dominated by Gardnerella vaginalis, which is associated with BV, the drug was only 26% protective.
Despite the mixed efficacy in CAPRISA 004, Hillier and other researchers involved in the FAME (Film Antiretroviral Microbicide Evaluation) research group suspected that other drugs might be less vulnerable to Gardnerella vaginalis.
"Our hypothesis was that, because dapivirine is a nonnucleoside reverse transcriptase inhibitor, it would not be as vulnerable to metabolic degradation by the bacteria and would therefore not be impacted by vagina microbiome," said Hillier during her presentation at IAS.
To investigate this hypothesis, Hillier and her colleagues enrolled 66 healthy, non-pregnant women from the Pittsburg, Pa., area to participate in a research study. These women were all using contraception and tested negative for HIV, chlamydia, gonorrhea and trichomoniasis.
Most of the women were not married; 67% were white; and 27% were black. On the first day of the study, women were asked to come to a clinic and apply either tenofovir or dapivirine-based film or gel microbicides under supervision. Then, they were given several doses to take home and apply independently over six days. On the seventh day, they came back to the clinic to apply the final dose, and researchers took samples of plasma, cervicovaginal lavage and vaginal fluid, as well as cervical biopsies to check for drug levels.
For the women given tenofovir, those with BV were more likely to have lower drug levels than those without BV across tissue samples, indicating that the bacteria responsible for BV were metabolizing, or breaking down, tenofovir. Yet, among women given dapivirine-based microbicides, the composition of the vaginal microbiome did not appear to impact efficacy.
According to the findings, there was no association between the concentration of Gardnerella vaginalis (BV-causing bacteria) and dapivirine concentrations in vaginal tissue, cervical tissue, cervicovaginal lavage or plasma. In addition, the Nugent criteria, used to determine BV, were not associated with lower cervicovaginal lavage, tissue or plasma concentrations of dapivirine.
"Fortunately, we found that vaginal bacteria did not impact how much dapivirine penetrated the genital tissues, which is a good surrogate for whether the drug will work in reducing the risk of HIV," said Hillier. "This means that the dapivirine ring should work equally well whether or not women have bacterial vaginosis."
This research is heartening for the ongoing microbicide campaigns in sub-Saharan Africa, where women remain vulnerable to HIV. Although other effective prevention methods -- such as condoms or oral pre-exposure prophylaxis (PrEP) -- exist, researchers have been searching for a long-acting prevention method that does not require women to regularly visit a clinic.
Compared with PrEP, the vaginal ring approach is extremely safe because the total drug exposure is tiny, only 4 mg over an entire month, compared with 300 mg per day for PrEP, said Hillier. Also, unlike PrEP, with vaginal rings there's no need to monitor kidney function regularly, she added.
"For some women, the vaginal ring containing dapivirine could be a great option -- just insert it and forget a month at a time," said Hillier "At the IAS meeting, we also reported the results of a study we performed among U.S. 15-17 year olds who found the ring to be easy to use, and they were able to use it consistently over six months. This tells us that the ring may be an option for young women who have struggled with adherence to daily product use."
Hillier and her colleagues are already looking ahead to the next generation of vaginal products, including longer-acting rings that are just now entering clinical trials.
"These include vaginal rings that could work for 90 days at a time, meaning that a woman could get four rings and that would provide an entire year of HIV protection!" Hillier said.
There are also next-generation rings that combine HIV prevention with contraception, and the first of these studies has just been completed, Hillier said.
"Women in Africa tell us that they want a product that will do more than one thing for them, and we believe that for some women, the combination ring will be really important," she added.
Finally, Hillier said, there are new products designed for women who only need sporadic protection to use "on demand."
"There are some really exciting prototype film products (kind of like the contraceptive film or a Listerine breath-mint strip) just entering clinical trials, which could be applied by women intravaginally and could release an [antiretroviral] slowly over a week," she said.
"The bottom line is that women everywhere need options that work in their lives," Hillier said. "We hope that by creating a real range of products, more women will be able to have sex and stay healthy. This is the ultimate empowerment -- to give women the tools they need to stay healthy."