It is crucial to apply principles of racial and gender equity to participation in HIV cure trials, a qualitative study has concluded. Beyond the lack of scientific rigour and potentially variable effectiveness of a future cure among different groups, these exclusions highlight issues such as medical mistrust.
Gender and power dynamics also need to be considered, as the heightened risk of HIV transmission introduced by trials that involve a treatment interruption may endanger participants and their sexual partners.
The US Food and Drug Administration (FDA) will soon require researchers to take active steps to ensure greater diversity among late-stage clinical trial participants. Scientists have applauded the change, because while the number of White women in clinical trials has increased over the past decade, progress has stalled for racial and ethnic minority groups.
According to recent figures released by the Treatment Action Group, women only made up 20% of those participating in global HIV cure-related clinical trials, although more than half of all people living with HIV globally are women and girls. However, an HIV cure might work differently based on biological sex. Thus, generalising findings from studies with only male participants would be scientifically unsound and may not benefit those disproportionately impacted by HIV globally.
Black people made up around 23% of participants, while there was only a total of 19 trans participants across the 124 clinical trials. Many of these trials took place in the US, where Black Americans comprise over 40% of new annual HIV diagnoses (while only making up 13% of the population), and an estimated 44% of Black trans women, and 26% of Latinx trans women are living with HIV. Thus, trial participation also inadequately reflects the racial HIV health disparities and the intersection of race and gender.
As part of the informed consent process, potential study participants need to be made aware that studies working towards an HIV cure are at an early stage; participants are unlikely to achieve HIV remission or otherwise personally benefit by taking part. Moreover, a growing number of HIV cure trials require participants to stop taking HIV antiretroviral treatment (ART) during the trial, to see if an experimental intervention is effective at preventing viral replication. This is known as an analytical treatment interruption (ATI) – a supervised pause in taking daily ART during which a participant is monitored for viral rebound. One of the central risks of participating in an ATI study is the loss of the benefits of undetectability; there is a danger of passing HIV on to sexual partners during this time.
To investigate considerations for increasing diversity in HIV cure studies that involve an ATI, Dr Karin Dubé and colleagues conducted 21 in-depth interviews in 2020 with five types of informants: two bioethicists, nine community members (people living with HIV and their advocates), six biomedical HIV cure researchers, three socio-behavioural scientists, and one HIV care provider. Just over half of the participants identified as male (52%) and most were White (62%).
Women in analytical treatment interruptions
While no trans women were interviewed, the researchers considered the participation of both cis and trans women in ATIs in their interview questions. Interviewees described different benefits, concerns and risks, depending on whether women were trial participants or their sexual partners.
Bioethicists viewed the under representation of women in ATI studies generally as a matter of gender equity and justice, especially considering that a cure may possibly work differently based on biological sex.
The risk of HIV transmission during ATIs was raised – both in instances where a woman is the participant or the sexual partner of one. Community members expressed the need for clarity on the distinction between sex assigned at birth and how a person identifies in terms of gender. They also recommended more detailed screening questions for potential study participants:
“If she’s having insertive sex with a male, vaginal sex with a person who is [male]… is she having sex with someone where there’s a likely high transmission risk, even if she is detectable? What type of sex is she having? What’s going on with her partner? I think we need to dig more deeply into these things with women, and it might result in having different types of screening questions or different kinds of scripts that will be more effective.” – Community member
"Pregnancies happening, they’re going to happen, so how will a study team deal with it, right?"
Of central importance for some was the potential for pregnancy in those assigned female at birth, as participation in an ATI may result in vertical HIV transmission. One HIV cure researcher expressed this in an unambiguous manner:
“Obviously, if the [cisgender] woman could come up with a new STI during a cure trial, they can also become pregnant during a cure trial, and acute infection and rapid viral replication during early pregnancy would be a disaster for mother-to-child transmission. But for a baby, I think that’s kind of non-negotiable... For cure trials, female participants have to be on reliable birth control, just full stop.”
However, community members felt the issue was more complex:
“But… you don’t always have control over your ability to not become pregnant. And we have to do better as an infrastructure to contend with that reality. Pregnancies happening, they’re going to happen, so how will a study team deal with it, right? Until we get past that, we’ll continue to debate this issue. We’re now 40 years into this epidemic... I have to say that we’ve miss[ed] the mark when we speak broadly about including women and not having a basic plan in place to meaningfully include women aside from making her promise to not get pregnant, well she does not impregnate herself.”
Whether female participants had shared their HIV status with sexual partners added another layer of complexity. While it might be most protective to tell participants that their partners should take HIV pre-exposure prophylaxis (PrEP) for the duration of the study, this would also mean disclosure of HIV status. This raised the question of whether disclosure was a necessary pre-requisite for participation in these studies and the issue of intimate partner violence.
“It brings together so many colliding issues, right? When you talk about the rates of domestic violence or intimate partner violence against women with HIV, they are exponentially higher than that of the general population. And so, to bring into play a partner’s participation in her trial… it just, it increases her level of vulnerability. We want to do the ethical thing and offer PrEP to a partner, but we must first evaluate the woman’s ability to have an open dialogue with her partner about her participation in the clinical trial.” – Community member.
Socio-behavioural scientists raised the issue of intersectionality for women of colour participating in ATIs:
“If you add in the element of race, African American women, for example, pretty much are doing the worst when it comes to reaping the benefits of all of these advancements in HIV treatments... So, I think there’s an intersectional issue of racism and also sexism when it comes to why Black women are experiencing some of those challenges... We’re also talking about issues around medical mistrust and also very real healthcare discrimination when they do access care.”
People of colour in analytical treatment interruptions
While most interviewees wished to see increasing racial diversity in ATI studies, there was also recognition of the historical context of medical experimentation on vulnerable groups in the US. Medical mistrust plays a central role for many people of colour when deciding to participate in trials or not.
“Given where the cure field is… sometimes I certainly hear treatment interruptions or cure studies characterized as ‘‘more experimental’’ than other kinds of research. And I think that communities of colour, trans individuals, members of particularly vulnerable and under-represented populations are particularly vulnerable to exploratory and experimental research, and/or that kind of lights up historical trauma from that work in the past. So, I think that just requires great deal of sensitivity and consideration as we move forward.” – HIV cure researcher.
One bioethicist raised a point regarding the current lack of individual benefit of trial participation:
“I am a little less concerned than others in the sort of HIV cure ethics or maybe HIV research ethics area about the diversifying of the pool of participants. In a word, in the setting, study participation is hardly a benefit. Arguably just really risky and so it’s not… when I root for minority rights or women’s rights or whatever, I usually do that for benefits, not for harms. It’s a little more complex… it’s not a case of some huge benefit that we’re depriving people of.”
Nonetheless, for most community members, increasing diverse participation was centrally important, and they provided suggestions for how to achieve it:
“This is where it’s crucial for research teams to partner with trusted community-based organizations, grassroots community-based, maybe health and social services or whatever organizations…”
“Designing with intentionality around diversity is critical. And, we have very few examples of that, honestly, in HIV most trials have typically [been] enrolling older, whiter populations, and men. I think the HPTN 083 trial that just is now ending early for injectable cabotegravir as prevention had specific benchmarks for both age and diversity.”
Regarding medical mistrust, interviewees spoke about historical breaches of trust between researchers and communities of colour in the US. They emphasised that trial participation had to be viewed in the context of current US health disparities. Any potential risks and benefits need to be adequately explained, with an acknowledgement of current realities. According to one community member:
“We tend to simplify this issue... People that has been suffering from access to care or… health disparities...if I’ve been a person that has suffered from health disparities my whole life, is it fair to be asked to participate in a clinical trial in which I’m gonna risk my life?... I don’t know if that’s fair to ask minorities to join clinical trials in which we’re not very clear about how it’s gonna benefit them… You need to think about intersectionalities.”
"Study participation is hardly a benefit… When I root for minority rights, I usually do that for benefits, not for harms."
Of central importance for some community members was the issue of HIV criminalisation in the US: people living with HIV can be prosecuted for a range of criminal acts in most states, from not disclosing their status to alleged HIV transmission. As one community member said, Black people are disproportionately impacted by these laws:
“[T]he stigma of coming off of one’s medication in order to participate in an ATI-involved study has huge ramifications for HIV criminalisation laws in this country, in the United States and globally. That’s a huge, you know, structural and systemic barrier to engaging under-represented communities, and I’m specifically naming Black communities, who already have, disproportionate involvement, or shall I say are, disproportionately, inequitably, targeted by the criminal justice system in the United States.”
Both researchers and community members emphasised the need to understand the dynamics of participants’ sexual relationships. They also recommended using a trauma-informed approach to research, especially when participation could result in intimate partner violence.
“The risk of him getting infected versus the risk of him beating her. If I were a clinical participant, I’d want to be the one making that judgment. I think this is about empowering [the] individual to help her help us navigate through that scenario. I think it’s somewhat paternalistic for the trial team to say, ‘Oh. We don’t want you in the trial because we’re afraid you might get beaten up or because we think you might transmit.’… We’re grappling with your safety and his HIV potential seroconversion. Let’s talk about that. How would you like to handle that?” – Community member
“To know that kind of dynamic in a community where you’re conducting an ATI up front, will inform the kinds of counselling and conversation that you have in the informed consent with a potential participant who is living in that community, who may or may not be living in that specific dynamic, but is living in that community… but you do not know the dynamics that that particular individual is in.” – Cure researcher
“We found that engaging diverse communities in HIV cure research with ATIs will require closer attention to issues of equity, trust, and outreach in the design of such research (e.g.,
enrolment targets, recruitment efforts, and promoting safety and well-being), as well as gender, power, and partnership dynamics in plans that are used in this research to reduce the likelihood of harm (i.e., asking partners to seek PrEP),” the researchers conclude.
“Ideally, ATI trials are also implemented within a racial and social justice equity framework, where there are genuine community partnerships built to earn the trust of communities due to lasting sociohistorical traumas involving experimental medicine. Furthermore, more socio-behavioural research will be necessary to understand the effect of ATI trials on stigma for people living and their sexual partners, including with people living with HIV of diverse racial, ethnic, sexual, and gender identities. Finally, partner protection strategies should also be acceptable to both participants and their sexual partners, and robust community engagement will also be necessary to ensure acceptability.”
Dubé, K et al. Considerations for Increasing Racial, Ethnic, Gender, and Sexual Diversity in HIV Cure-Related Research with Analytical Treatment Interruptions: A Qualitative Inquiry. AIDS Research and Human Retroviruses, 38: 50-63, 2022.