The rectal microbicide pipeline and how to proceed.

As the first phase II rectal microbicide study, MTN 017, wraps up, the prevention field is poised to consider what’s next. Some key considerations are: As highly effective oral PrEP becomes available, how will a rectal microbicide fit into combination prevention? And what might be the best rectal microbicide candidate?

The lead rectal tenofovir-based candidate is not the most potent against HIV in the test-tube. Other compounds look better in these “in vitro” analyses, giving researchers hope that they might also provide protection in humans. But clinical trials are needed to get real answers. Previous studies have shown that vaginal tenofovir gel can lower HSV-2 risk in women but other compounds in early research, such as Griffithsin, are active against HIV, HSV-2 and HCV. There are also questions about what types of delivery systems are most desirable and effective—gel, enema, nanofiber, quick-dissolving tablet, etc.

IRMA and AVAC convened a stakeholder consultation at the South African AIDS Conference in Durban, in June, to grapple with these very issues. South African advocates, clinicians and researchers weighed in, declaring the desire for more prevention options and helping to shape an agenda in support of the development of safe, effective, acceptable and accessible rectal microbicides for men, women and transgender individuals. The consultation was held in collaboration with the Desmond Tutu HIV Foundation (DTHF) and the Microbicide Trials Network.

IRMA and AVAC are pleased to share with you the six detailed PowerPoints presented by Ian McGowan and Ross Cranston of the Microbicide Trials Network, José Romero of the Population Council, Brian Kanyemba of the Desmond Tutu HIV Foundation, and Jim Pickett of IRMA. DTHF researcher Linda Gail Bekker co-chaired the event with Pickett.

Check them out here: rectalmicrobicides.org/community.php and below.

• An introduction to rectal microbicide development: Ian McGowan, Microbicide Trials Network
• An overview of MTN-017 and an introduction to MTN-026: Ross Cranston, Microbicide Trials Network
• Beyond HIV: Rectal microbicides to prevent HIV and other STIs: José Romero, Population Council
• Moving the rectal microbicide agenda forward; results from a scientific, ethical, and community consultative process: Ian McGowan
• Community Perspectives on Rectal Microbicides; Forward, Ever Forward: Brian Kanyemba, Desmond Tutu HIV Foundation and Jim Pickett, IRMA

Manju Chatani-Gadi is an AVAC staff member.

Disappointed but not defeated – reflected the mood of many microbicides advocates at the recently concluded AVAC 2015 Partners Forum. At CROI 2015, results were announced from the FACTS 001 study that involved over 2000 mostly young women in South Africa. It found no effect for vaginal tenofovir gel overall in the trial. A month later, at the Partners Forum, many long-time microbicides advocates were still smarting from the results – having put a lot of heart and work into preparing for the results and hoping for success. In that context, participants in a breakout session to discuss the dapivirine vaginal rings studies were a little cautious in discussing how to best prepare for the trial results.

Earlier discussions at the Forum focused on the importance of advocating for women’s access to oral PrEP as a proven intervention. However, the need for a wide array of tools and options for women remains important and the group gathered for this breakout were also interested in non-systemic options for women like vaginal microbicides.

At the breakout session, an IPM colleague shared updates on the ASPIRE (MTN 020) and the RING (IPM 027) studies, reviewed the timeline for study results and plans for follow on trials. Both trials are studying a vaginal ring containing the antiretroviral drug dapivirine that is designed to be inserted into the vagina and remain there for roughly a month. Together, the two ongoing efficacy trials have enrolled over 4500 participants in Malawi, South Africa, Uganda and Zimbabwe. Results are expected in late 2015 or early 2016.

The research teams are planning for success, actively engaging regulators in each country as well as at the global level to discuss the timeline and requirements for licensure, should the results be positive. There are also plans for open-label extension trials to provide former study participants access to the dapivirine ring while it is undergoing regulatory review.

The open-label trials are still research studies that would seek to understand more about the safety and women’s use of the ring, issues important for broader implementation of the ring should it be approved. IPM is also collaborating with key partners to help ensure the ring would then be made available to women in developing countries at a low cost and as soon as possible. The earliest possible regulatory decision would be in 2017 or 2018.

Some participants at the breakout session were interested to know what kinds of adherence measures were being used in the Ring studies. Previous microbicide and PrEP trials – including FACTS 001, VOICE and FEM-PrEP – reported difficulties in participants adhering to trial dosing regimens. They were curious if the Ring study teams were talking to other researchers to learn about how to address adherence issues found in earlier trials. Several participants were concerned on what it would mean for the field if the ring trials did not show positive results, and a few talked about fatigue to disappointing results.

There was animated discussion about whose role it was to prepare for results with policy makers, media and community groups. “Are we doing the work of the trial teams?” one participant asked, “Why aren’t they preparing better?”, “Are we giving false hope?”, and “What if it doesn’t work?” One view that helped to rally the room is that advocates need to be poised to respond to the results – if positive, to advocate for quick passage to licensure and then into the hands of those who most need prevention tools; and if not – to ensure the urgent need for more tools for women does not fall off the radar.

In discussing how to prepare for the ring results expected late 2015 or early 2016, many in the room pointed to existing platforms that could be built on: the in-country mechanisms through which groups prepared for the FACTS 001 results; the ad-hoc groups brought together for the Ring consultations conducted last year by IPM, MTN, AVAC and country partners; and AVAC’s materials and ongoing processes to help prepare advocates for results.

There was a clear call for early planning and for materials that were specific to each country’s context. The group called on the research teams and AVAC to help ensure that advocates had a good understanding of the research to be able to react, and to develop materials and messages. They also called for simple information on results from past trials to be able to refer to. Many advocates in the room committed to have meetings when they got back home to develop more detailed plans.

Cautiously optimistic, advocates and allies left the room still discussing what they learned and felt from FACTS 001 – and how to re-energize for the Ring results.

Cindra Feuer is an AVAC staff member.

The Partners’ Forum rectal microbicide breakout session could not have come at a more strategic time. By the latter part of this year, the first Phase II rectal microbicide gel study, MTN 017, will come to an end with results expected in early 2016. However, it doesn’t seem likely that this product—which is a reformulated, reduced-glycerin cousin of the 1% tenofovir vaginal gel evaluated in CAPRISA 004, VOICE and, most recently FACTS 001—will move into the Phase III efficacy trial that has been discussed as the next step after MTN 017.

There are many reasons why the Phase III may not happen. There has been anecdotal evidence from MTN-017 and community gel discussion that the gel is not really lube-like (the applicator used to apply the gel means that it ends up in a different part of the rectum than what is lubricated during anal sex). There has also been criticism of the pre-filled applicator (the same one used in the trials of vaginal gel), with some finding it uncomfortable and burdensome to carry around and use. MTN 017 was designed to gather this kind of feedback. These reports are part of what has caused the field to pause. The recent disappointment from the FACTS trial has added to this.

FACTS 001 found that, even though women used the gel about 50 percent of the time, this level of adherence wasn’t high enough to reduce risk of HIV. In the meantime, daily oral PrEP is available today for people at risk of HIV, including the same men and transwomen who might want a rectal microbicide; long-acting injectable ARVs for prevention and treatment are also on the horizon.

The breakout session on rectal microbicides at the AVAC Partners Forum deliberated on new directions, demands and next steps for the rectal microbicide field. Participants felt strongly that there was a need and desire for rectal microbicides even with the advent of oral PrEP. They declared strongly that research should continue.

The second key message took some serious consideration, weighing the urgency of the need and desire for a rectal microbicide against the realities of what is available today, and the promise of the longer-term pipeline. But in the end, the group decided that its recommendation was that anecdotal evidence from MTN 017 should be taken seriously and rectal tenofovir gel shouldn’t move into phase III because of lack of acceptability of the applicator and the fact that the gel does not function like a lubricant—meaning two products would still need to be used. The group heard a description of Microbicide Trials Network’s (MTN) proposed Phase II Adonis Study design comparing different strategies for delivering a rectal microbicide, looking beyond the current applicator.

The group also weighed in on longer-term efforts and agreed on the need to: Keep a robust pipeline moving through development, including dapivirine gel Phase I to start this year; douche microbicides; and preclinical compounds especially Griffithsin, a non-ARV microibicide.

And, of course, the group was all in favor of continuing rectal microbicide research in South Africa, one of the homes to MTN 017, the first rectal gel study on the continent.

There was recognition for a revived African advocates voice in support of these demands on the IRMA listserv, which is closely followed by a range of researchers and leaders in the field, including scientists at the MTN and NIH—as well as PrEP, vaccine and all-around prevention researcher Linda-Gail Bekker of the South African Desmond Tutu HIV Foundation who declared at the Forum, “If you aren’t following IRMA, you haven’t lived!”

This post was written by Yvette Raphael in South Africa a few days following the announcement of the FACTS 001 microbicide gel trial results. Yvette is a 2014 AVAC Fellow working at Johns Hopkins Health and Education in South Africa. She is a leader in South Africa’s HIV prevention movement for young women.

For years women’s failure to protect themselves from HIV was exacerbated by their inability to navigate through young womanhood. I fell into that same cycle: I did not negotiate my first sexual debut and not using a condom was surely not my choice. I now know that I was coerced into not using one. I learnt the hard way that that his compliments on my beauty were to make me feel OK about having unprotected sex with someone who knew he was HIV positive but not virally suppressed.

In 2010 the CAPRISA 004 trial showed a microbicide is possible. It was just the news I wanted to hear even if this news was almost 10 years too late for me and a marketable product would be even much later. A microbicide gel was one of the many prevention methods being tested and all were at different stages but I was particularly excited about this one for many reasons. The research for this was happening in South Africa, my country. The women who were in the trial represented me at the age I got infected and they would have gone through the same struggles as I did. If the gel worked for them, it would work in the South African context and most likely work for woman elsewhere in the world. What was particularly exiting was the regimen, in which the gel is delivered by applicator before and after sex. I thought of this as a power tool for women—something women could put in their handbag, almost like a Taser, and protect themselves. I was excited that our government made an investment in the research and I was excited that the team of lead researchers were women who I looked up to.

I waited for the results of the FACTS 001 trial results like an excited toddler would wait for Santa Clause. Then, in February, the call came directly from fellow advocates attending the session where the long-awaited results were released at the 2015 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle. The results were flat. A microbicide gel in an applicator used before and after sex did not work for women. That was certainly not the news I wanted to hear. My heart sank. I wanted to run away. I wanted to hide. So many women were looking forward to this. The emails started, the press releases, the commentary from all angles. Everyone had something to say except the women.

I was following CROI with keen interest mostly for the FACTS results. But like with soccer, when your team loses, you support your next favourite team. I started to follow what was coming out of CROI about PrEP.

The Partners Demonstration Project among discordant heterosexual couples showed that PrEP and treatment in couples reduced the negative partner’s risk of HIV by 96 percent. Both the PROUD study in the UK and IPERGAY in France, looking at PrEP in gay men, showed an 86 percent reduction in risk.

What does all this mean for women? Would PrEP be the option that will finally liberate young women and girls? How do we advocate for PrEP to be made available to women in South Africa—where HIV prevalence is nearly twice that of men?

Jim Pickett, Director of Prevention Advocacy and Gay Men’s Health at AIDS Foundation of Chicago and chair of IRMA (International Rectal Microbicide Advocates), is a long-time advocate for new HIV prevention technologies for men, women, and transgender individuals.

I’ve been a microbicide advocate before I could pronounce the term. And while I am associated closely with rectal microbicides, I was a vaginal microbicide advocate well before I had a clue there was any back-door research going on—and I still am.

The microbicide field has a lot of experience with trials that don’t yield the results we’ve all been hoping for, and working so very hard to achieve. We’re used to being sad, disappointed, heartbroken. We’ve learned to manage our expectations—not always an easy task. And we’ve wiped our tears, tended to our bruises and gotten right back in the game. We don’t wallow.

When I heard the FACTS results—I was sad. SAAAAAAAD. I felt heartbroken—reflecting on the 2,000+ African women who volunteered for this study in the hopes they could be part of HIV prevention history, and help change the trajectory in a setting that so, so, so desperately needs new protective strategies for women.

I felt frustrated for the hundreds of clinical trial staff who gave this thing their all. But microbicide researchers and advocates—a pretty fabulous, resilient, hard-core bunch—don’t tend to linger at the pity party. There is no time to wallow. Our communities don’t have the luxury of wallowing—and we don’t either. We’re learning a lot from FACTS, and I look forward to the qualitative research that comes out and helps us better understand the lives of young African women, so we can do better. We have to do better.

Meanwhile, we have Truvada as PrEP—proven to work with women. And we have two Phase III dapivirine ring studies (the Ring Study and ASPIRE) in the field. And a robust pipeline of films, fibers and multi-purpose technologies. We’re not stopping. We’re not giving up. FACTS hurt us—but it didn’t break us. We all have work to do—and we’re getting on with it.