Among the world’s top scientific conferences on HIV, the Conference on Retroviruses and Opportunistic Infections (CROI) stands among the most prestigious. Only a handful of the top submissions of new scientific data are deemed worthy of stage time. Submissions deemed less worthy are relegated to the poster halls with endless rows of dense text, charts and graphs.
It was in such an inauspicious place that Martin Delaney, Project Inform’s founding director, stumbled upon a tucked away poster claiming that an HIV-positive stem cell transplant recipient had gone for months without antiretroviral therapy (ART) with no return of the virus. Recognizing the possibility of the world’s first documented HIV cure, Marty hastily contacted the scientist behind the study and in tandem with others set off what is now a furious race to find a cure that will work for many — or something that is a significant step on the way.
Though Marty died in 2009, a little more than a year later, his lifetime of brilliant research activism was recognized not only by the National Institutes of Health — by dedicating its flagship HIV cure research effort in his name — and by CROI — with the placement of a yearly memorial lecture for young scientists.
In February, I had the truly humbling honor to present on the role of the community in HIV cure research at the session named after Marty, who was my friend and greatest mentor. The session, focused on Good Participatory Practices (GPP), was organized by community engagement guru for CROI, Mark Hubbard, and presented jointly along with Stacey Hannah from AVAC, and Deborah Barron from RFI in Johannesburg, South Africa. No doubt, some of those new investigators probably had the following question when noting our session as part of their training: “What is GPP and why should I worry about it?”
It’s not necessarily an unreasonable question. But if HIV cure research can take a cue from prevention research, it grows more clear with each passing day that the community must not merely be involved in helping recruit for trials or review informed consent documents, it must also be involved at the very beginning of the discovery process, to ensure that experimental interventions are worth pursuing, and help to anticipate and plan for how to proceed quickly when things go right, and how to proactively prepare for what to do when things go wrong from a safety, ethical and social stand point.
I use the term “HIV cure research” somewhat reluctantly and have for some time. Social science research — both my own and others — has indicated that for most people living with HIV a “cure” means that the virus is eliminated entirely from their bodies, that an HIV antibody test will be negative, and that they cannot transmit the virus to a sex partner or baby (more on those in a minute). What’s more, a cure must also render a person invulnerable to becoming infected with HIV again. I never say never, but it will be a formidable scientific challenge to achieve all four and many scientists now conclude that a much humbler goal for now is to achieve a suppression of the virus to very low levels for extended periods of time without ART.
The case I tried to make at the session, however, is that if the community is not deeply involved now in shaping cure research and how it is implemented, we not only carry the risk of developing a product that does not work for many who need it most or be greatly delayed in doing so, but that we may also harm people unintentionally in the process.
As for the first point, pioneers such as Rowena Johnston with amfAR and Eileen Scully from Johns Hopkins University have demonstrated that cisgender women (people who were assigned female sex at birth and continue to identify as female) might maintain the hidden reservoir of HIV differently than cisgender men due not only to the presence of estrogen and estrogen-like hormones, but also due to the genetic influence of how many estrogen receptors are present on immune cells. We know this, because of research carried out by John Karns — first reported in 2015 — and new research by Scully presented this year at CROI. This means that not only could it be more difficult to poke and wake up the hidden reservoir of virus in cisgender women, but also that interventions designed to do so might not work as well in them, at least during certain periods of the menstrual cycle.
If we don’t think carefully and push for HIV cure-related research in women living with HIV now, we might not only fail to develop a product that will work in more than half of the global population of people living with HIV, we might mistakenly discard an effective product due to testing it at the wrong moment in a woman’s cycle of hormonal production.
Yet as bad is this sounds, there are further implications that go beyond sex. A majority of people living with HIV globally don’t carry strains of the virus that are present in the United States, Western Europe, Canada and other high-income nations where the vast majority of cure research has taken place. Neither the people carrying those other strains, nor their cells and tissue, have received the same degree of scientific scrutiny.
The bottom line, if we fail to equip HIV-positive women and people living with HIV in sub-Saharan Africa and other regions with the tools to participate in shaping and setting priorities and directions of HIV cure research, we could either delay the development of a promising cure strategy or end up with an intervention that is much less useful for a large number of people living with HIV on the planet.
Empowering people living with or affected by HIV with the information, skills and resources to participate in the research process ensures that GPP, a roadmap for comprehensive multi-stakeholder participation, can be followed. I look at GPP as the solution to the ancient fable of the blind men who can only feel different parts of an elephant. To one of the blind men who feels the elephant’s leg he is feeling a tree, to another, feeling only the elephant’s trunk, it is a thick rope. No one, whether medical scientists, social scientists or members of the community, has the capacity on their own to “see” the whole elephant of a path to a promising cure. GPP helps ensure that we work cooperatively to put the individual pieces together as a whole.
But GPP is also a bit like disaster planning. Even the most rigorous planning can’t prevent something bad from happening, but it can minimize the chance of negative outcomes and ensure that if the unexpected occurs, we are ready to limit the damage quickly and effectively. That’s what GPP grew out of, a failure to effectively and proactively work with all critical stakeholders in the midst of the controversies and disasters that were spawned when three prevention trials ground to a halt in the mid-2000s.
With HIV cure research, three looming threats have already emerged and we don’t yet have answers to them. All are related to what might occur when we interrupt ART in people who participate in studies. Most scientists agree that for now the only way to prove that a cure (or remission) strategy has worked is to stop HIV treatment for some time. This is not without consequences, however.
Here are just a few, some of which have already occurred.
Imagine that we take extensive care to ensure that study participants understand that whatever we are testing is highly unlikely to cure them. Quite the opposite, we labor to convince them that it probably won’t — at least in the long-term. But even if we are successful at convincing them at the outset of a study, how will they feel if they stop ART and go weeks or months without HIV returning to measurable levels? Will they grow more and more sure that they are cured and how will they respond if the virus does come roaring back?
We’re getting so good at identifying people at risk for HIV within the first days after becoming infected, that more and more are being put on ART the same day they are tested. In such people, though we can measure bits of the virus there isn’t enough of it to provoke a strong antibody. Thus, they will “test negative” in common parlance. A treatment interruption, however, could and has resulted in the virus levels climbing high enough to provoke the body to generate HIV antibodies. These people now test positive on a standard HIV test, and some of them live in countries where an HIV-positive test result can mean the loss of a job offer or the termination of employment. Testing positive can have even worse consequences,
Finally, multiple studies now confirm that viral suppression from effective ART makes HIV transmission highly unlikely. However, if a person stops ART during a study, we certainly test for a return of the virus often enough to preserve their own health, but what about ART’s ability to prevent transmission? If a person has a viral spike, will it be possible to transmit HIV to their partner? If so, how frequently should viral load testing occur? If we test very frequently in a study, how frequently will we need to test when an intervention goes into wider use, and how would we ever do so in countries that struggle to even provide viral load tests at all?
A number of activists such as myself — the vast majority of us being lay scientists — are working with researchers on the technical details of the biomedical research, and we are mentoring and building a new cohort of others who can do the same. However, if these efforts are unlinked to thoughtful planning for the psychological and social impact of a cure intervention going into wide study or being approved, the new intervention might never accomplish what people with HIV most hope for.
At last year’s International AIDS Conference, a group of us created a booth in the Global Village, which is open not only to conference goers, but to the local community. Inspired by the thinking of the brilliant Ugandan activist, Moses “Supercharger” Nsuguba, we built a huge cardboard tree trunk and branches, and provided paper leaves and tape to visitors who were asked to write on them the answer to the following question:
“If a cure were found tomorrow, and was available to all free of charge, what would it mean to you or to the people with HIV you love or care for?”
There were so many leaves on the tree by the end of the conference that they extended nearly into the adjacent booths. The answers varied widely, but the most predominant answer by far was related to the concept of freedom — freedom from fear, anxiety, stigma, oppression and isolation.
What this tells me is that we should be aiming for not only a biological outcome or delivery of an HIV cure intervention, but the resulting freedom from all of the things that still afflict our booth’s visitors and those they love. Without early and consistent partnership with the community in our efforts to incrementally develop a cure for HIV, one guided by GPP principles, we may never achieve what people with HIV most hope a cure will offer them.