MEXICO CITY — For Wendy Armstrong, MD, who still sees patients die from complications of AIDS, news of monthly injectable HIV treatment, simplified regimens, and better tolerated antiretroviral drugs are exciting. But they're also frustrating.
"All these ideal populations don't help us at all think about how we actually treat real-world patients," said Armstrong, from the Emory University School of Medicine in Atlanta, Georgia.
These "ideal populations," as seen in clinical trials, are often white, male, cisgender — people whose identity matches the sex they were assigned at birth — and have ready access to healthcare. It's a group representative of those devastated by the early AIDS epidemic.
But even as they eagerly await the upcoming International AIDS Society (IAS) 2019 Conference on HIV Science, Armstrong along with other physicians, scientists, government agencies, and companies are questioning whether the way they've always recruited for clinical trials still serves patients.
"This gets back into what we need to do to end the epidemic," said Carl Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Health's National Institute of Allergy and Infectious Diseases (NIAID). "These questions are critical. We can't just answer them with cohorts from the 80s."
It wasn't that long ago that the participants of an HIV drug trial would have had the following demographic characteristics: 15% women, 15% non-white, and 0% transgender. Those are the demographics for the 2013 SPRING-2 trial that proved the effectiveness of dolutegravir (DTG) (Tivicay, GlaxoSmithKline).
For the 2015 IPERGAY trial of on-demand preexposure prophylaxis (PrEP) for gay men, the demographics was 0% women, 8.5% non-white, and 0% transgender. To date, it's the only trial for on-demand PrEP.
For pharmaceutical companies, the goal has been to "complete the study as quickly as possible," said Vani Vannappagari, PhD, MBBS, MPH, global head of epidemiology and real-world evidence at ViiV Healthcare. "That means, historically, that white MSM [men who have sex with men] populations really were the participants in clinical trials."
In 2017, white men who have sex with men accounted for 18% of new HIV infections. Black and Latino men who have sex with men composed 44.3%.
Women account for 19% of new HIV diagnoses in the United States, although worldwide, they represent the majority. In the United States, black women account for 59% of the new HIV diagnoses among women.
HIV rates for transgender women have been difficult to determine, but a 2008 meta-analysis of available data put the HIV rate among transgender women at 27.7%.
This disconnect means that "we have products that haven't been tested in all types of people, even though they are going to be used in all types," said Linda-Gail Bekker, MBChB, PhD, of the Desmond Tutu Center, the University of Cape Town, South Africa, who is former president of the IAS.
It also means that someone still has to figure out how these drugs work for women who become pregnant or are pregnant, for people of trans experience, and for black Americans, among others.
"When companies don't do it, it falls to doctors," said Rebecca Zash, MD, of Beth Israel Deaconess Medical Center in Boston, Massachusetts.
"Then it's left up to researchers to figure out how to get all that [clinic-level] data" on how drugs affect those who were not included in large numbers in trials, she explained. "Doctors aren't all in our studies, so we have to figure out how to get the information, rather than having a system in place."
Zash should know. At last year's International AIDS Conference, she reported that there was evidence of an increase in neural tube defects in infants born to women who were taking the drug dolutegravir at the time of conception. She will present updated data on that evidence at the upcoming conference.
Ironically, when women who were participating in the trial became pregnant, they were excluded from the study, as happens with all clinical trials.
"It's something that I hope to hear at every trial of a new ARV [antiretroviral], long-acting ARV, an antibody or immune strategy — basically, what's the plan to figure out whether this is safe for women who could become pregnant?" Zash said.
And it's not just women of reproductive potential. It's people in sub-Saharan Africa, women, adolescents and, Bekker added, "especially transgender people who get left out but then in whom we want to use these products."
This exclusion from trials has had real-world impact.
A 2017 NIAID study found that transgender women have shied away from using PrEP because of fear that it interacts with hormone therapy.
And then, of course, there's the dolutegravir–neural tube signal, which wasn't detected when the rate at which cisgender women were included was 15%.
Widening the Protocols for Clinical Trials
At the beginning of 2019, the US Food and Drug Administration issued draft guidance for drug companies seeking approval of their medicines. The guidance called for a broadening of the protocols for clinical trials.
Regulators are questioning whether some of the criteria included in phase 2 trials must also be included in phase 3 efficacy trials, and they suggest that "it may be possible in some cases to have the development program include specific studies in higher risk populations conducted at sites with expertise in working with such participants."
This has pharmaceutical companies reaching for solutions.
In a statement, Gilead Sciences pointed out that 13.4% of DISCOVER's US participants were black or of mixed black race. They touted the 1% of the DISCOVER cohort that is transgender, calling it "an important clinical achievement."
A year ago, ViiV's Vannappagari became the company's first head of epidemiology and real-world evidence. She's in charge of post-approval studies in populations that weren't the focus of the original trials. ViiV has begun requiring sites in which ViiV's research is being conducted to stop enrolling men until a target goal for enrollment of women is reached. The company has also begun providing transportation and childcare to make participation in clinical trials possible for women, she said.
"We can say to sites, 'You have already enrolled 50 men. Now wait to enroll more until you get 15 women,' " she said. "That we can do. We have started doing that."
Vannappagari said that ViiV has a goal of having women make up 20% to 25% of participants in all future clinical trials. This goal was met in the ATLAS and FLAIR trials, with 30% and 22% participation by women. Having a quarter of participants be women should be sufficient to determine efficacy, she said. "For some rarer events, it might not be enough," she noted.
With NIAID and other funders, ViiV is also cosponsoring a study of the use of long-acting cabotegravir for prevention in women. They are also cosponsoring a new efficacy trial of long-acting cabotegravir that is injected into the thigh instead of the buttocks. This will enable participation by transgender women who have received posterior saline implants as part of their medical transition.
Still, these trials drew criticism at the Conference on Retroviruses and Opportunistic Infections (CROI) 2019. Audience members for DISCOVER focused on what they considered to be low recruitment of black men who have sex with men from the South. FLAIR and ATLAS drew criticism, as reported by Medscape Medidcal News, that a decade ago, a trial already included 30% participation by women.
This is where NIAID has come in in the past, said Dieffenbach. NIAID and other public funders have sponsored studies of tenofovir/emtracitabine (Truvada, Gilead Sciences) and topical HIV prevention drugs, such as a dapivirine ring for use by African women.
"We do the research that individual companies can't or won't do," he said.
Dieffenbach has adopted a phrase coined by HIV activists to describe the groups that have traditionally been excluded from clinical trials: the hardly reached.
Something for Everyone
"We aren't going to say 'hard to reach,' " he said. "This puts the burden on us as physician-scientists. We have the problem. We need to solve this."
Aadia Rana, MD, from the University of Alabama at Birmingham, is in the thick of figuring out how. She's protocol co-chair of the Long-Acting Therapy to Improve Treatment Success in Daily Life (LATITUDE) trial, which is looking to do something that has rarely been done before: enroll the very people who are almost never included in clinical trials. These are people for whom daily pills haven't worked and who are most affected by the HIV epidemic today.
Two months into recruitment, 70% of participants are black, and almost 40% are women. Each site involved in the study must have a plan to recruit and retain participants, as well as a dedicated outreach worker to help participants stay in the trial. The goal is to enroll 350 people.
Whether it will prove successful remains to be seen, said Rana. But what is clear is that the study represents "a paradigm shift," one that she hopes to see in other trials.
"We are going to have to go outside the box of the prior paradigm, where interested participants knocked on the door to be included," she told Medscape Medical News. "This is going to require active recruitment and active retention."
Vannappagari is an employee of ViiV Healthcare. Dieffenbach, Armstrong, Zash, Bekker, and Rana have disclosed no relevant financial relationships.
International AIDS Society (IAS) 2019 Conference on HIV Science.
Medscape Medical News © 2019
Cite this: The New Face of HIV and Treating the 'Hardly Reached' - Medscape - Jul 17, 2019.