Last Friday marked the end of HIVR4P Virtual, and as AVAC reported last week, there are a number of excellent sources of news to catch up on all that was shared at the conference including coverage from aidsmap and Bhekisisa. In addition, AVAC roundups are available on our special HIV R4P page where you’ll also find recordings from the many great sessions hosted at the Advocates’ Corner, covering topics like vaccine hesitancy, research ethics, “the tail” in CAB-LA research and more. Consider checking out the Advocates’ Corner sessions you missed and continue the conversation on Engage!
Read on for a take on some of the key themes from the second week.
Prevention Unmasked: The second week of HIVR4P
by Emily Bass
Contents:
Masks are omnipresent these days: a public health tool, a commodity that’s a given for some, a luxury for others and—in politicized environments like in the United States—a symbol of one’s relationship to science and even vaccines. Masks were on my mind as I attended the second week of HIVR4P. What’s on the surface, what’s underneath? These were the questions that recurred, or seemed to, throughout the second week. Here are some ways the complexities and challenges in the field today appeared to me.
The mucosa remain mysterious and critical to understanding early events in HIV
For all the decades of research on HIV, with increasingly sophisticated techniques, assays and approaches, there are enduring unanswered questions—especially about the earliest events following the acquisition of HIV. In the context of sexual transmission, these events occur at the mucosa—the lining of the vagina, rectum and penis. A presentation involving long-term follow-up of participants in the Thai vaccine trial known as RV144 provided insights into when and how vaccine “boosts” deliver immune responses at mucosal tissue—a site that wasn’t sampled in the original trial. Alexandra Schuetz reported the finding that participants who received the boost at 12 and 15 or 18 months after their last shot had stronger immune responses, including at mucosal surfaces, than those who received it at 6 months. The timing of follow-up shots, and their impact on the types and location of immune responses is another area where there’s still a lot to learn—in HIV, COVID and other research arenas. Other research described below homed in on how STIs harm, and lactobacillus helps, mucosal barriers that block HIV infection, and explored the possibility that infections might start and remain contained for some time in this region.
Community-based research and activism: “Inside out” and “Outside in”
There’s a tendency in many fields to draw a distinction between “researchers” and “community”—one that many AVAC partners help to disrupt and redefine. One invaluable contribution to this effort came in an R4P presentation on the place of Black researchers in French and American institutions, which are shaped by white supremacy. Tashuna Albritton presented findings from the ETOILE study (Experiences of Tensions in Organizations and Interventions Leveraged for Empowerment and Prevention), a Franco-American study evaluating the community of researchers. The presentation featured the perspective of one Black PhD candidate who said, “You can have the same degree and yet what you are contributing to the conversation is not considered as legitimate.” ETOILE yielded a plainspoken reality: en Francais or in English, Black researchers are given the most labor-intensive and time-consuming tasks, and work in white-dominated power structures (while R4P works diligently to reflect the diversity of the field in its panels and program, there were instances of white-dominated panels at this conference, too). In these hierarchies, white senior researchers select white collaborators more often than Black ones. The mere fact that Albritton presented this work at HIV R4P helped unmask racism within the organizations where research is designed and conducted. The next conference will be a chance to take stock of how the organizers absorbed the messages.
Challenging traditional structures and distribution of power was also central to talks by Clever Chilende (TALC, Zambia) and Jacque Wambui (NEPHAK/independent activist, Kenya), who described two successful civil society efforts to challenge and change the way that research teams engage with community.
The PopART trial, also known as HPTN 071, was a “treatment as prevention” trial that measured HIV incidence in communities in Zambia and South Africa. Participants were randomized to one of three trial arms—Arm A received a combination prevention intervention with universal ART initiation on diagnosis; Arm B included the prevention intervention with ART according to local treatment guidelines; and Arm C was standard care. Researchers compared the rate of HIV incidence in trial communities to incidence in communities where ART was provided according to national guidelines. PopART started before universal test and treat became standard; midway through the trial national guidelines changed, the trial design shifted and ART became available on-demand to people in both Arms A and B. In Zambia, Chilende and his colleagues pressed PopART investigators to engage people living with HIV (PLHIV) as activists, advocates and watchdogs. They pursued an “outside-in” approach, whereby civil society advocates worked with the trial team and study communities to create forums for input, research literacy and independent monitoring. “The outside-in approach has the potential to improve transparency and accountability at a range of stakeholder levels,” Chilende concluded.
Jacque Wambui went beyond the role of trial communities, in her presentation on civil society engagement related to the ECHO trial, which evaluated the impact of three contraceptive methods on HIV risk. Wambui described how a Global Community Advisory Group, or GCAG, was convened by the ECHO trial team. Comprised of women from the trial countries and other geographies, the GCAG worked in tandem with an independent advocacy working group that brought together advocates from a range of countries and disciplines to share information and build consensus on key issues related to contraception, HIV risk and choice-based programming. The interplay between the GCAG and the advocacy working group (jointly convened by AVAC and ICW-EA) helped build civil society power. On the GCAG, a small number of individuals consulted directly with the trial team, ensuring a wide array of voices contributed to the conversation. (In the interest of full disclosure, I was part of the GCAG and helped co-convene the advisory group with ICW-EA. I cheered on Wambui as I watched from my tiny home office, pumping my fist and shouting “Womandla!”)
Masks and partial, practical prevention
In my neighborhood, most of us wear masks, but in other parts of New York City and in many parts of the US, many people don’t. Now that COVID-19 vaccines have arrived for some people in this country—even as the epidemic sky rockets in many other countries—Americans are in the privileged, if delusional, position of having conversations about when things will go back to “normal”. In other words, they want to know when they can take off their masks. If the HIV field has offered clarity on anything, it’s that there’s no single solution to a global pandemic. No new technology is ever going to supplant the need for action on multiple fronts, whether it’s safeguarding the human rights of key populations—as Johns Hopkins professor Chris Beyrer so eloquently described in his talk—or offering a range of options, which as Ram Prasad of Final Mile said in an insight-filled talk about the prevention needs and perspectives of South African adolescent girls and young women, include not just condoms or PrEP or any biomedical option, but “trust,” “partner loyalty,” and, yes, ‘periods of abstention.”
No single technology will supplant an array of approaches and, as presenters described, new options will need to be tested in a world where there is a larger array of HIV prevention strategies than at any point in the history of the epidemic. In a satellite session on “next generation” trial design convened by AVAC and partners, advocates and researchers described what trials might look like in a world where all the options are on the table. Mike Robertson from Merck described the design of a pair of trials known as IMPOWER-22 and IMPOWER-24 that will test a once-monthly oral ARV called islatravir for PrEP. In both trials, participants will receive both a monthly pill and a daily pill; in one arm of each trial, the monthly pill will be the active drug islatravir and the daily pill will be the placebo, while in the other, participants will receive active daily tenofovir-based PrEP and a placebo monthly pill in place of islatravir. This double-dummy, double-blind design means that participants will not know whether they received islatravir or tenofovir-based PrEP.
Because oral PrEP reduces incidence when taken correctly and consistently, and monthly islatravir may as well, rates of new HIV diagnoses could be very low in both arms of the trial. As Robertson described, Merck is planning to use recency assays—which detect very early HIV infection—in the communities where the trials take place to estimate what incidence would be among participants, if they were not in the trial. Robertson said the recency assays drawn from the community is “the best way to estimate incidence,” since incidence is expected to be extremely low in the trials.
In the same session, Moupali Das of Gilead Sciences presented their plans for two efficacy trials of their six-monthly injectable Lenacapavir that will also rely on recency assays to estimate background incidence in the same communities and populations where the trial will be carried out. Participants who remain HIV negative at the end of the initial phase will be offered the chance to be randomized into one of the trial arms. One of these trials will be conducted among cisgender women to study both injectable Lenacapavir and oral T/TAF as PrEP. The second is studying Lenacapavir among men who have sex with men, transgender women and gender non-binary individuals.
Recency assays have implications for people who test positive—it may pinpoint from whom someone acquired HIV. This raises a host of questions and could entail the need for critical supports including provider training, communications for communities and individuals and monitoring of potential harms to individuals receiving recency test results and to their partners—who might be identified as sources of HIV infection. Particular attention will need to be paid to use of recency testing in contexts where laws that criminalize HIV exposure or transmission are on the books. As AVAC and amfAR wrote in an issue brief on new HIV testing strategies and human rights concerns, including the use of recency testing, “potential harms that can come with such testing [include] a false sense of security and potential misuse as evidence of transmission.” The AVAC-convened Advocates’ Trial Design Academy and other allies raised these concerns in early consultations with Merck about the islatravir trials; in those discussions, the drug company said that it was open to suggestions and recommendations. With 2021 launch dates for these trials, the time is ripe for civil society engagement, which might include ensuring that all trials using recency assays have documentation on the legal environment regarding HIV criminalization in relevant communities; adequately-resourced, independent community oversight; and specific, proactive approaches to documenting adverse events such as gender-based or intimate-partner violence, disclosure or other outcomes that might emerge from use of recency testing.
In other words, these new trial designs aim to get answers about the range of products people want and need—but it will only work if “outside-in” advocacy is a reality. Its work that’s going to be critical and complex, and AVAC and partners including the Advocates’ Trial Design Academy are committed to doing this work. (The consultations related to the F/TAF trial design were also presented during the first week of R4P by my colleague Daisy Ouya.)
PrEP unmasks longstanding questions about sexual pleasure and prevention of STIs
One of the most delightful and, yes, downright pleasurable sessions of week two was a round of “speed debates” on key topics related to PrEP, pleasure and other sexually transmitted infections. In studies of communities where PrEP use is climbing, rates of HIV are dropping. In many of these same communities, rates of STIs like chlamydia, gonorrhea and syphilis are climbing—a trend that was underway prior to PrEP but that may also be impacted by changes in condom use as people rely on PrEP for HIV prevention and/or by the increasing rates of testing that come with PrEP programs. PrEP doesn’t protect people against those and other sexually transmitted infections, which has had some people arguing that a PrEP-plus-condom message was the best public health approach. Wear condoms and avoid STIs, Edwina Wright said, arguing (in character for the sake of debate) that most women don’t enjoy sex with another person anyway. Understand that PrEP makes sex pleasurable for people—and pleasure must be at the center of sexual health programming, said Mitzy Gafos, Alongside preventing and treating STIs, Gafos argued that research and programs must go beyond condoms to support peoples’ full range of needs and priorities.
The debate was high-spirited, the stakes serious: as Gladys Macharia described, in a cohort of East and Southern African men and women (part of IAVI’s protocol C) having an STI increased the risk of acquiring multiple strains of HIV, versus a single founder virus. Infection with multiple strains of HIV was associated with a faster CD4 cell decline. Having an STI, and treating it, can also disrupt the vaginal microbiome, as Eric Armstrong described in a close look at how, exactly, lactobacillus helps keep the vaginal microbiome healthy. While STIs disrupt the vaginal epithelium, a protective layer of tissue, lactobacillus helps keep it robust, at least in lab-based tissue cultures. Lactobacillus also recruited anti-inflammatory immune responses—the kinds of defenses that may help the body ward off HIV on its own. As people use more PrEP and, sometimes, fewer condoms, the message should be, “Here’s how to get pleasure and be safe.” The specifics of that remain to be seen.
A debate on whether to abandon the WHO-endorsed “syndromic management” approach to STIs saw an audience poll overwhelmingly in favor of moving to an approach that treats “etiologically”. Syndromic management involves offering treatment for the most likely infection based on symptoms, while an “etiological” approach refers to precise treatment for a confirmed infection e.g., chlamydia. Whether this shift will happen, what it will cost and what it will look like remains to be seen—but prevention and treatment of STIs must be a part of the expanded PrEP rollout that will happen as new strategies become available.
Masks and the current pandemic moment
Since the beginning of 2020, masks have gone well beyond metaphor. They are life-saving, essential protections as the world faces down the global COVID-19 pandemic. Scientists and advocates are striving toward a dual agenda for HIV and COVID-19 during key sessions at HIVR4P and at a one-day IAS COVID-19 Prevention Conference, open to R4P attendees. It wasn’t always easy. A session at the COVID-19 conference featuring GAVI leader Seth Berkley, activist Fatima Hassan from South Africa’s Health Justice Initiative and Peter Sands of the Global Fund to Fight AIDS, TB and Malaria got quickly to the heart of the matter: like AIDS, COVID-19 is a pandemic of global inequities, defined by grotesque imbalances in access to COVID-19 vaccines, lack of transparency on pricing, and intellectual property provisions that, until waived, favor patent-holding corporations over people.
In a satellite session at R4P, HIV researchers looked at what they could learn from COVID-19 and vice versa. Galit Alter from Harvard Medical School urged the field to let go of the “herd mentality,” and start thinking outside the box. Linda-Gail Bekker from the Desmond Tutu Health Foundation leapt in to say she’d be beating the herd from behind—urging greater speed, in line with the toll AIDS still plays worldwide.
Masked infections: A new mystery from the AMP trial
In the final session on the final full day of the conference, a frank and fascinating exchange among scientists, during a discussion on the antibody-mediated prevention (AMP) trial, explored the possibility of “masked HIV infections” among participants in AMP. Here, the term refers to an infection that occurred while a trial participant was receiving the active experimental product, but that was not diagnosed while the person was using the product. How might that happen? See the very first item in this write-up about the mysteries of the mucosa.
The very early events of HIV infection are still not well understood, but in the context of sexual exposure, HIV starts in the genital tract and then moves—often via immune cells—throughout the body. It’s long been hypothesized that a prevention strategy or even the body’s own defenses might be able to contain HIV in the genital tract, preventing it from establishing infection throughout the body. If a drug or antibody played a key role in that containment, would HIV infection progress when those agents are no longer present? In such a scenario, someone who previously tested HIV-negative would now test HIV-positive. “We have data in the higher-dose VRC01 group—more cases occurred in the tail of the study than in the placebo arm,” offered Peter Gilbert from Fred Hutchinson Cancer Research Center.
One reason this might have happened, session moderator Carl Dieffenbach of NIAID said: VRC01 might have had “a weak antiviral effect.” In other words, the bump in what looked like new infections at the end, or tail, of the study in people who received VRC01 might have actually been the appearance, in the bloodstream of HIV that VRC01 had previously contained in a localized area, remaining undetected until VRC01 had washed out of the body. In intriguing new-to-me remarks, panelist Mike Cohen of the HPTN chimed in that masked infections might have happened in the CAB-LA trials, too. AVAC is following up to clarify and understand these hypotheses, but in that session, Cohen suggested that “masked infections” may be a reality in long-acting prevention. “That phenomenon almost certainly exists,” said Cohen, who went on to say that CAB-LA trials had 15 men versus and four women in the CAB-LA trials diagnosed with what he described as “a not-easily detectable infection.” Hearing investigators think aloud about what they’ve seen in trials—particularly what’s perplexing them—can be enormously revealing. In this case, there’s clearly far more to understand and learn.
Advocates have experience with the possibility of “false positive” HIV tests—especially in the context of HIV vaccine trials where the vaccine induces antibodies that cause a positive result on HIV-antibody tests. But a “false negative” is new terrain. What does the possibility of a false negative mean for informed consent processes, post-trial follow-up, the potential need for more sensitive HIV tests in the context of HIV programs, public health messaging, and community understanding of product efficacy? These critical questions began buzzing as soon as the session ended in an advocates’ debrief, and will be hashed out for months to come.
The AMP session also left open questions about how to use and describe the assay devised to study cases of HIV acquired among participants in the AMP study. That assay, known as the TZM-bl neutralization assay, involved sequencing the genes of viruses from participants, and then isolating genetic sequence encoding the envelope protein, known as “env”. The env sequences from participants were then used to form a new viral particle known as a “pseudotype”—which contains the isolated env sequence along with standardized, lab-adapted viral proteins. Making pseudotypic particles—in which the only difference is the env sequence—allows researchers to make controlled comparisons. In this case, the primary question was how the pseudotypes viruses from AMP participants responded to VRC01—whether the antibody neutralized it and, if so, at what concentration. The AMP investigators say that the trials validated the TMZ-bl assay as a means of predicting the breadth and potency of future bNAbs, or bNAb combinations, against a range of viruses. This predictive ability could be used to select bNAbs alone or in combination for future studies. Not so fast, said panelist Michel Nussenzweig, from the Rockefeller University who said that the field had to see AMP as “a disappointment,” and warned that for some bNAbs in development their ability to neutralize viruses was markedly different, depending on whether they were tested against pseudotypes or whole viruses, isolated and cloned from human samples. The investigators jousted back and forth about the relevance of the assay—settling for “both/and”—TZM-bl isn’t a total solution, but it’s an advance that moves the field a step in the right direction, if not across the finish line.
And that, in a way, is the best one can ask for right now—steps in the right direction, a realistic expectation of what a “finish line” might look like, and the understanding that we might still be wearing masks—real and metaphorical—on the other side. That’s especially true if the work doesn’t align with principles of justice and equity. In her talk last Wednesday, Dazon Dixon Diallo offered a quote from Paolo Freire, the anthropologist and theorist of inequality, that is as succinct and powerful a summation of this reality as any I know. And at the end of this roundup, of this most unusual conference in this most perilous time, Freire, via Dixon Diallo, has the last word: “Attempting to liberate the oppressed without their reflective participation in the act of liberation, is to treat them as objects to be saved from a burning building.”
