PrEP Success Breeds Complexity in HIV Prevention Trials

Heather Boerner

October 18, 2016

CHICAGO — For years, HIV researchers and advocates have worked toward a gold-standard method of HIV prevention that is more effective than condoms, a robust HIV-prevention pipeline that features a variety of investigational medications and novel delivery methods, and advances that no one could have predicted.

"We worked for decades to get to this place," Jim Pickett, director of gay men's health at the AIDS Foundation of Chicago, told Medscape Medical News.

But "this place" is complicated. With the success of the combination of tenofovir and emtricitabine (Truvada, Gilead) in clinical trials, the World Health Organization and the Centers for Disease Control and Prevention now recommend pre-exposure prophylaxis (PrEP) for all people at high risk for HIV. And regulatory agencies around the world are beginning to consider or have approved the drug.

This means the design of next-generation HIV-prevention trials has to change.

To that end, statisticians, trial designers, regulators, and advocates gathered during a noncommercial satellite-conference panel here at HIV Research for Prevention (HIVR4P) 2016 to discuss the complexity of organizing clinical trials in the era of highly effective PrEP.

Complicating Future Studies

Clinical trials of HIV-prevention methods have always included a prevention package of risk-reduction counseling and condoms. Now, that package might include PrEP.

That complicates placebo-controlled trials. How do you determine whether new agents, such as long-acting cabotegravir injections, provide protection when people in the placebo group are taking PrEP and are more than 90% protected from HIV infection?

The alternative is to scrap placebo-controlled trials altogether, and instead build PrEP into the design. The result will be a noninferiority or superiority trial with PrEP as the control or comparator group. The PrEP combination has become the standard against which all other prevention methods will be judged.

That is exactly the way the study of long-acting cabotegravir was designed.

 
This is a pretty big deal.
 

"This is a pretty big deal," said Deborah Donnell, PhD, from the vaccine and infectious disease division at the Fred Hutchinson Cancer Research Center in Seattle.

"When you do your first noninferiority trial, your first active-comparator trial, there are a lot of unknowns, a lot of things you have to adapt to as the trial goes on," she told Medscape Medical News. "We're going to be watching this very closely. It's kind of a new world to us."

The Antibody Mediated Prevention (AMP) Study of broadly neutralizing antibodies against HIV, which began enrolment in July, has already accrued hundreds of men and women, Myron Cohen, MD, director of the Institute for Global Health and Infectious Diseases at the University of North Carolina in Chapel Hill, announced during the opening-night plenary.

The aim is to compare 2700 men or transgender people who have sex with men in Brazil, Peru, and the United States with a parallel study of women in Sub-Saharan Africa.

"The enthusiasm for the trials among participants" has been "surprising," Dr Cohen said.

Although the AMP trials are placebo-controlled, PrEP will be provided in accordance with regulations of the specific countries they are working in, the investigators report.

In some countries, like South Africa, Truvada PrEP has been approved, but only for sex workers and men who have sex with men. This means that men who have sex with men will receive PrEP in trials like AMP, but women will have to be referred to a demonstration projects for access.

Uneven PrEP Access Raises Alarms

This uneven availability of back-up prevention has raised alarms among advocates and ethicists, including Jeremy Sugarman, MD, professor of bioethics and medicine at Johns Hopkins University in Baltimore.

"What we provide in a trial [as prevention] has to be effective, has got to be reasonably accessible, and has to be achievable," he said.

Some advocates have argued that the cost of PrEP, which can be more than $1000 a month in the United States, is a barrier to study participants. Others have argued that the solution is not in the trial design, but instead is in implementation science, so that the most effective methods of PrEP get to the people who need it most.

"It's not the job of clinical science to solve healthcare inequalities," said David Evans, director of research advocacy at the nonprofit organization Project Inform. "Yet, at the same time, I don't think clinical science can ignore healthcare inequalities."

When asked by an audience member if it is possible to do a vaccine trial in the age of PrEP, David Glidden, PhD, professor of biostatistics at the University of California, San Francisco, said it has to be.

"We need a vaccine and we need a vaccine trial," said Dr Glidden, who was statistician on iPrEx, the seminal PrEP trial. "AMP gives us a sense of how we might do these trials" with regard to PrEP backup.

"PrEP is not contraindicated in these studies; I think of them as add-on studies," he explained. "We'll have to accept some heterogeneity in the standard-of-care prevention packages in those contexts."

But that heterogeneity — where some trial participants are informed that PrEP exists, others are referred to a demonstration project and may or may not get PrEP for free, and others are offered PrEP — might not be fair to participants who are offering themselves in the interest of science, said Peter Godfrey-Faussett, senior science advisor at UNAIDS.

"It's a really interesting time for prevention research," he told Medscape Medical News. "On the one hand, we urgently need new prevention tools, and we need innovation and research to get there. But at the same time, it's really important that we protect the interest of research participants, and ensure that research participants get the best possible standard of prevention within a trial."

A "Door to a New World"

While these discussions are taking place, innovation in HIV research is continuing. Promising results from a monkey study of an antibody against the cell receptor alpha4beta7 integrin were presented by Anthony Fauci, MD, director of the National Institute for Allergy and Infectious Diseases at the National Institutes of Health, during his plenary talk.

In the small study, the monkeys received standard antiretroviral therapy, followed by antiretroviral therapy plus an infusion of the antibody against a4b7, then the infusion alone, and then no treatment (Science. 2016;354:197-202). Two of seven monkeys were able to fully suppress the virus for more than a year; the rest, after blips in viral load, were also able to suppress the virus naturally.

"The animals are not cured," Dr Fauci told the packed room. "There's still replication-competent virus in the animals."

But, he reported, he and his team are quickly moving on a human study of 15 to 25 people, and enrolment has begun. They will use vedolizumab, a drug approved by the US Food and Drug Administration to treat Crohn's disease and ulcerative colitis, which is similar to the antibody used in the monkey trial.

Dr Fauci told Medscape Medical News that he's not sure he would go that far, but he is hopeful.

"The reason I'm circumspect about it is twofold," he explained. First, "even though the effect is striking and there are several potential mechanisms we discuss, we still haven't nailed it down 100%."

And second, "it's an animal study. I don't mean to belittle animal studies, because I'm doing them, but I think this would not be the first time that you saw something in an animal that might not be [the same] in a human," he pointed out.

Still, he added, "if we discontinue therapy in 15 people and four don't rebound, that's the best anyone's ever seen."

The idea of this kind of treatment for HIV is brand new and represents a whole new way of thinking, said Carl Dieffenbach, PhD, director of the division of AIDS at the National Institutes of Health.

It has "literally opened a door to a new world that we're just stepping into it for the first time," he explained.

Dr Fauci, Dr Dieffenbach, Mr Godfrey-Faussett, Dr Glidden, Dr Donnell, and Mr Pickett have disclosed no relevant financial relationships. Dr Cohen reports receiving advisory board honorariums and/or travel reimbursement from Janssen Global Services, Roche Molecular Systems, and Merck Research. Mr Evans reports that his organization receives unrestricted but project-specific funding from Gilead Sciences, ViiV, and Merck. Dr Sugarman reports receiving grants from the National Institutes of Health, serving on the Merck KGaA bioethics advisory panel and stem cell research oversight committee, consulting on bioethics for Novartis, and being a member of Quintiles' ethics advisory panel.

HIV Research for Prevention 2016. Abstracts SA15 and PL01. Presented October 17, 2016.

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