October 23, 2018
Along with #metoo and many others, #believewomen is one of the social media rallying cries of the past months (and years) as women and allies have taken a stand against violence, assault and the power structures that protect perpetrators, be they an aspiring Supreme Court justice or an employee at the UN agency charged with coordinating the global AIDS response. If silence is violence, #believewomen is the response. At this week’s HIV R4P conference in Madrid, we are hearing both silence and the challenge. In this first of a series of updates from the conference, we bring you a set of session updates, and this overall observation: #believewomen has no borders. It is everywhere. Even when the discourse is polite. Here in Madrid: Skilled, esteemed speakers are saying a lot and… silence speaks volumes.
Many of the silences occur in spaces where the lives and bodies of women, girls, gay and trans people are on the line. A Monday PrEP satellite (SA16 Current State of Play: PrEP Implementation Update and Challenges) focused on experiences delivering oral PrEP in diverse countries and started with an update on implementation progress from WHO’s Michele Rodolph. She emphasized that PrEP works for men and women and that programs should be selective and permissive: targeting the strategy but also offering it to anyone who comes into a clinic asking for the strategy. She also reminded us that the primary areas of scale-up are in the US and Europe, where gay men are the predominant population accessing PrEP.
As John Brooks from the US Centers for Disease Control and Prevention noted in that session, the patterns of access do not mirror the patterns of incidence: black and brown gay men and other men who have sex with men are at the highest risk of HIV and are least likely to access PrEP. Reports from the Jilinde project in Kenya by Daniel Were and the South African National Department of Health by Hasina Subedar—some of the most well-resourced and advanced PrEP programs in sub-Saharan Africa—showed that low uptake and continuation is slowly giving way to incremental increases in use by young women and female sex workers. A presentation by Mike Cohen of the HIV Prevention Trials Network started with the statement that PrEP works in men and women, but then turned to an exploration of data on the ability to offer women a precise estimate of protection associated with daily oral PrEP, and ended with a bullet point stating that “concerns about potential limitations of TDF-FTC prevention in women have been noted, and will likely be clarified through ongoing studies (e.g. HPTN 082) and observational data.
This was a head-spinning destination compared to Rodolph’s curtain-raising talk. The silences in these sessions is deafening. No one remarked on the degree to which racism and white supremacy drive HIV risk in the US. Nor did anyone raise the possibility that it is time, now, for African women—versus American men—to use available data to decide whether PrEP works for them, and to determine whether questions about whether daily oral PrEP work in women help or hinder HIV prevention.
Unfortunately, these silences recurred in the opening ceremony where a spirited yet respectful intervention by advocates called for continued research investment in daily and monthly methods in the category of microbicides—which includes the ARV-containing dapivirine vaginal ring—by the US government and all research funders. Dr. Anthony Fauci, the head of the US National Institute of Allergy and Infectious Diseases, spoke directly after this action and did not address the demands. Instead, he stated that the ring was a non-starter and also did not use the word microbicides, to the great dismay of the African women who had helped lead the action. Dr. Fauci also identified black and brown American men as a clear “demographic hotspot” without addressing structural issues. Silence on racism, silence on women’s desires—happily and profoundly broken by Gcobisa Madlolo, the recipient of the Omololu Falobi Award, who stated that her award was for all women who do not have control over their bodies, and by Linda-Gail Bekker (Desmond Tutu HIV Foundation and President of the International AIDS Society) who, on receipt of the 2018 Desmond Tutu Award for HIV Prevention Research and Human Rights, reminded the audience that the anti-Apartheid archbishop for whom the award was named was clear on the necessity of activism to propel social change. Speak truth to power.
These themes of gaps, questions, unuttered possibilities and implications continued in a robust plenary on Tuesday morning, which included an animated (literally) tour by Tom Hope of Northwestern University regarding early events in HIV infection. This led to some evaluation of so-called topical PrEP (perhaps better known as a microbicide), specifically an intravaginal ring, compared to daily oral PrEP and its ability to reduce risk of HIV. Hope used a single high-dose challenge in non-human primates to evaluate protection provided by the ring and the pill in rhesus macaques. He noted in passing that the high-dose model was sure to raise questions, as it does not mimic actual patterns of exposure. He did not return to this potentially significant limitation as he drew the conclusion that the levels of drug were localized in the vaginal tract, leaving some areas susceptible to infection, at least in the context of the high-dose challenge. Some of the actual human women in the trials of the ring have been protected from HIV—a reality that is worth uttering, and that does not diminish the need to continue to explore markers of protection and early events of infection.
Subsequent Tuesday plenary speakers shed more light on early and local vaginal events. Thumbi Ndung’u’s presentation on the FRESH cohort in South Africa involved insights from a group of young women who visit the clinic twice a week for job skills, educational training and blood draws to identify HIV in its very earliest stages of infection. Over five years of the cohort, incidence has remained very high—at over 8 percent. Women who do acquire HIV based on sensitive tests start ART immediately and some of these women have never seroconverted—meaning infection has not been established in the blood. Ndung’u and colleagues isolated the “founder” virus from these women in early infection and found that single broadly neutralizing antibodies did not block all viral activity of all of these isolates. Right now, the bNAb in efficacy trials (VRC01) is a single monoclonal; combinations are in the pipeline but farther down the road. Based on this, Ndung’u observed that combinations will be what’s needed for efficacy. Unasked questions: what would happen if the site offered PrEP on-site along with its training programs and intensively supported adherence, versus referring out for PrEP? Given that there has been no incidence reduction, yet DREAMS and She Conquers programs (South Africa’s nationally driven version of DREAMS) in the country have shown reductions, albeit, modest, in new diagnoses, is there a standard of care that could be adapted on site to help drop incidence? Given that combo bNAbs are needed and are many years away, can the world really afford not to say the word “microbicide” and act on the ring?
“We are entering the era of the microbiome,” said Sharon Achilles from the University of Pittsburgh, the final plenary speaker, before moving into a deep exploration of the role of vaginal bacteria in HIV risk. Picking up from Ndung’u, she noted FRESH cohort findings that the presence of unhealthy vaginal bacteria associated with bacterial vaginosis was associated with HIV risk. She then looked at how different contraceptive methods impacted presence of these bacteria. Oral and hormonal contraceptives decreased presence of these unhealthy bacteria; the copper IUD increased detectable BV-associated bacteria. This information makes the upcoming results from the ECHO trial, a randomized, controlled trial of the copper IUD, DMPA and the Jadelle implant to directly measure impact on HIV risk, all the more important. Sadly, Dr. Achilles did not mention the trial at all.
Other highlights from the conference included:
Voices in the long-acting PrEP movement
Showing how the voices of possible users of long-acting prevention were and could be listened to during different stages of product design and development was the theme of a session aimed at fostering dialogue between different groups represented at the session. The speakers included people from pharmaceutical companies such as Alex Rinehart from ViiV and Mike Robertson from Merck, researchers such as Elizabeth Montgomery and Leah Johnson from RTI, Maggie Keane from IAVI and Anabel Gomez from AVAC. There was much interest in how to ensure getting feedback from people who may use the products before clinical trials, and a consensus that there is a need for better human-centric research earlier in the development process particularly to identify possible behavioral factors that could affect adherence. Participants identified a key question related to figuring out how to ensure that information about the behavior and preferences of users of today’s products is gathered in a way that is relevant to future products.
GPP a must in clinical trials: Nelson Michael
“Community engagement is not just “nice to have”; it’s essential to clinical research,” Rt Col. Dr. Nelson Michael of the US Military HIV Research Program (MHRP) said. He addressed a group of GPP implementers, advocates and other research team staff at a GPP focused session on Monday, October 22. Michael shared how lessons learned during the RV144 vaccine trial in Thailand are informing MHRP’s work in Germany today.
Cate Hankins of the Amsterdam Institute for Global Health & Development (AIGHD) and AVAC’s Stacey Hannah facilitated the satellite, which delved into 10 years of implementation of Good Participatory Practice (GPP) in biomedical research, with interactive discussion around successes, challenges, and strategic directions for the future. The meeting explored consensus on GPP as a standard in clinical trials, and its measurement. Participants received tutorials of new innovative GPP tools, such as the Engage! online platform for the GPP Community of Practice and the new Engagement in Ethics Review online course.
“If you don’t work with the community, you’ll fail,” said Michael, who served on the Obama Presidential Commission for the Study of Bioethical Issues.
What’s next for bNAbs for prevention?
A pre-conference session reviewed where we are in the next stage bNabs for prevention beyond the VRC01 antibody currently being tested in AMP. There is increasing emphasis on the likely need for more than one antibody for any prevention formulation (possibly 3 or more) to avoid existing or developed resistance seen in bNAb for treatment. bNAb combos might need to be matched regionally to provide better breadth (e.g. a clade C passive immunization), The durability of antibodies for prevention is being explored. Gene modifications of the LS region could extend half-life four times as long from the current two months but might take slightly longer to reach effectiveness after infusion.
The AMP trial testing VRC01 in two trials in Africa and the Americas is fully enrolled as of October 7 with no serious adverse events after 30,000 infusions. Larry Corey suggests that VRC01 is possibly the safest bNAbs treatment ever.
At a satellite session on HIV Prevention for Pregnant and Breastfeeding Women, Renee Heffron summarized data that pregnant women are 2- to 3-fold more at risk then women who are not pregnant, with the risk rising 4-fold in post-partum women. Yet the dearth of research and hence data on the safety of drugs for pregnant women often mean that their safety is only captured in post-marketing evaluations and off-label use. There’s a palpable tension between providing access to PrEP to pregnant women now due to the urgent need vs. ensuring there is enough safety data before use. Dr. Abednego Musau described Jhpiego’s experience in providing PrEP to pregnant and breastfeeding women in Kenya while Dr. Bonus Makanani described planned MTN trials to study PrEP and dapivirine ring use in 4 cohorts of pregnant women (MTN 042) and in breastfeeding women (MTN 043). Research in this community has traditionally had a protectionist attitude but this is changing with more and more ethicists challenging that we need to move from assumed exclusion to presumed inclusion, of women in clinical trials. Advocates are urging that US regulations be revisited so that pregnant women are able to reap the same benefits from research as other populations and have a right to safe, efficacious, appropriately dosed therapies that have been studied specifically in pregnant and breastfeeding women. All women—in all stages of their reproductive and sexual life—have the right to use safe and efficacious drugs that have been studied specifically for them.
Stay tuned for additional updates as the week unfolds!