Topical PrEP Gel Can't Withstand Vaginal Flora; Oral PrEP Does

Nichole Klatt, Ph.D., Assistant Professor, in both the Department of Pharmaceutics and in Pathobiology, presents research on the effect of gardnerella on Tenofovir

Diverse communities of microbes in the vagina may have a role in a woman's vulnerability to HIV; however, they don't keep oral PrEP, or pre-exposure prophylaxis, pills from doing their job. These reassuring findings were presented at the Conference on Retroviruses and Opportunistic Infections (CROI), the world's largest HIV research meeting, in February 2017, where the vagina and its numerous microbial inhabitants were a hot topic.

Perhaps you've heard of bacterial vaginosis, or BV: It's the most common vaginal infection, affecting 29 percent of women ages 14 to 49; it can come with a thin discharge, an itching or a burning sensation in the vaginal area, the notorious fishy odor around which an industry of feminine products is based—or no symptoms at all. What you may not know is that BV is defined by what's happening with microbial communities in the vagina—called the vaginal microbiome or, more poetically, vaginal flora. As with the digestive system, an array of bacteria are a normal part of how the vagina functions.

BV is not caused by one specific germ; it's what happens when there's a disruption in the delicate balance of bacteria in a woman's vagina. BV is associated with having frequent sex without condoms and having multiple sex partners, especially if they're uncircumcised; but nonsexual everyday activities can also be culprits: Menstruation, diet and even smoking can lead to changes in the vaginal microbiome. Imbalances in vaginal flora can also result from douching, which, ironically, is often done to mask BV-like symptoms.

Vaginal microbiota dominated by Lactobacillus (a probiotic of which there are many species, some used to make yogurt) are considered "optimal," while microbiota with more diverse bacterial profiles are considered "BV-like" (although they may not necessarily cause symptoms). Vaginal flora varies by race and ethnicity: Specifically, White people's vaginal flora is more likely to be dominated by Lactobacillus, while the vaginal microbiota of Black women tend to be more diverse. Black women are not only more than twice as likely to be diagnosed with BV as their white counterparts; Black women also more frequently experience BV's most troubling effects, including preterm birth and increased vulnerability to HIV and other sexually transmitted infections.

While many of the factors that render a person vulnerable to BV are known to do the same for HIV—what researchers call "confounding variables"—factors such as vaginal inflammation also likely add to BV's role in increased HIV risk.

"Hide the Tenofovir": One of BV's Many Tricks

Vaginal flora was at the center of several discussions at CROI. These were further explorations of groundbreaking findings that had been presented at the International AIDS Conference in Durban, South Africa, last summer, by the CAPRISA consortium of South African and North American researchers. These are the folks who brought the world the first exciting proof that a tenofovir-based gel as topical PrEP could have efficacy, even if not a great deal of it. It's been bad news for this particular microbicide agent ever since. While the secondary analyses from the study that were presented in Durban kept with that trend, they also provide vital lessons in the long game of providing HIV prevention options for women.

One of the analyses showed a significant reason that tenofovir gel didn't work for many women in the study: While women with vaginal flora dominated by Lactobacillus experienced HIV protection from this topical PrEP agent, women whose vaginas were home to a higher concentration of another bacteria, Gardnerella vaginalis, saw paltry protection. Gardnerella essentially "ate" tenofovir, resulting in less drug available to prevent HIV in the vaginal tract.

University of Pittsburgh School of Medicine reproductive-infectious-disease specialist Sharon Hillier, Ph.D., who has been working to understand relationships between the vaginal microbiome and HIV for more than 20 years, presented results at CROI that tested these findings in an environment where she was able to control for factors such as sexual activity and adherence. Hillier checked participants' tenofovir levels at two time points over the course of a week. The second check came two hours after the final dose of gel, which was administered at the clinic. At both points, Hillier saw the same results as those reported in CAPRISA.

"Quite frankly, this surprised me," she explained in her CROI presentation. "After a direct application of that much tenofovir, one wouldn't have imagined that the bacteria could so speedily alter the amount of drug that could get into the tissue and into the plasma."

What About Truvada?

The question then became, would tenofovir-containing oral PrEP pills, approved for HIV prevention since 2012, meet the same fate when mixed with diverse flora in the vaginal tract? According to the findings presented by epidemiologist Renee Heffron, Ph.D., the answer is no. It's important to remember that oral PrEP has already shown in large studies and demonstration projects that it's effective for women when taken as directed—including in areas where BV rates are high.

Heffron and colleagues analyzed data from women with BV in the Partners PrEP study. They found that there was no significant difference in effectiveness between those with diverse, BV-like vaginal flora and those whose vaginal communities were dominated by Lactobacillus.

The difference has to do with application of a gel versus a pill: With PrEP pills, the drug is taken by mouth and reaches all other parts of the body through the bloodstream (known as systemic administration of a drug), rather than being applied topically to a single spot (in this case, the vaginal tract).

"Our results are strong," Heffron asserted in a recent email. "It makes sense that a systemic route of protection from PrEP would not be modulated by vaginal microbiota in the same way that vaginal microbiota could interrupt the tenofovir gel."

The takeaway from Heffron's results appears to be: Keep calm and adhere to oral PrEP. The daily pill remains a vital tool in overcoming factors, including BV, that contribute to Black women's 18-fold greater chance than White women's (pdf) of becoming HIV positive.

As for the immediate future of topical PrEP, look to the vaginal ring, another promising generator of buzz in the HIV research community. These results show the importance of looking at how the drug in the ring interacts with vaginal flora. Hillier, at the CROI press conference discussing Heffron's and her results, gave a teaser for findings on BV and the ring. She hopes that those results will be ready for presentation at the International AIDS Society Conference in Paris this summer.

That gives clinicians and community supporters of women-controlled HIV prevention options something to look forward to—and hope for.

Olivia G. Ford is a freelance writer and editor currently based in New Orleans. She has been engaged with HIV-related media since 2007.