Px Wire: April-June 2017

Volume 10, Number 2

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AVAC's Take

New trials, new terms, new times

Talking about biomedical HIV research used to be as easy as . . . 1, 2, 3. A product started in a small Phase I safety trial, moved to a bigger Phase II trial for expanded safety, and then on to a Phase III efficacy trial to see if it actually worked. It was a tidy framework, and it worked well enough—for a while. But the real world is a messy, complicated place. And that’s where prevention research happens. About a decade ago, the HIV prevention field started talking about Phase IIb trials, which aren’t licensure trials but do provide “proof-of-concept”—a hint or indication that a candidate works.

Beginning in 2006, trials of new biomedical strategies started to show efficacy and the world got even more complicated—in a good way. The new strategies changed prevention programs and prevention research. Countries and communities are adapting and inventing new approaches to delivering these tools, like oral PrEP and voluntary medical male circumcision (VMMC). And the research field is grappling with how these new approaches impact HIV prevention trial design.

Adjustments must be made on (at least) two fronts. First, once something is introduced in a country (whether PrEP as a pilot program or VMMC as a national campaign), that strategy has to be considered for inclusion in the standard package of prevention services offered to every participant who joins a trial. What gets added when? The UNAIDS/WHO guidance document on ethical considerations in biomedical HIV prevention trials states that “New HIV risk-reduction methods should be added... as they are scientifically validated or as they are approved by relevant authorities.” But that doesn’t settle the question entirely. The wording allows the possibility that a tool could be added before local approval.

Second, some new strategies may be part of the design of the trial. When a strategy is included in the trial design and used as an active comparison to the experimental product, it’s not a background option, but rather a key part of a trial designed to find out whether the experimental product is better or as good as the existing option. How does that work? This issue of Px Wire—including the centerspread—is your guide to the evolving world of HIV prevention trial design. —AVAC

Next-Generation PrEP Trials

The age of “active controls”

A medicine you get only every two months to reduce HIV risk sounds like a great deal for some people. This could be an option in the future, but only if two big efficacy trials of long-acting injectable cabotegravir (CAB-LA) find that one shot of this long-acting antiretroviral in the buttocks every eight weeks shields trial participants from HIV.

The first of two efficacy trials, HPTN 083, launched in December 2016. It tests injectable CAB-LA as PrEP among men who have sex with men (MSM) and transgender women. A companion study among women—HPTN 084—is due to start later this year. Both of these trials have a design that’s known as “double-dummy double-blind”. Each is designed to compare CAB-LA to daily oral PrEP. HPTN 083 is a “non-inferiority trial” and HPTN 084 is a “superiority” trial. Do these terms sound familiar? They might not. (See the centerspread for a lexicon and illustrations.) The advent of daily oral PrEP as a WHO-recommended prevention strategy has propelled changes in trials of other prevention strategies.

Why? While the comparison isn’t exact—and the history is controversial—consider research on prevention of vertical transmission of HIV. At one time, a lengthy regimen of AZT showed efficacy. A trial began that sought to test a simpler strategy—single doses of nevirapine for the mother and newborn. But this trial came under intense scrutiny for a design that included a placebo arm, an arm with proven efficacy (the AZT regimen) and an arm with a regimen with unproven efficacy (short-course nevirapine). Many stakeholders felt that a placebo arm was unethical, and it was ultimately dropped. The trial went forward testing an unproven and a proven strategy head-to-head, even as concerns persisted about about asking some women to use an unproven strategy when a proven one existed. In part, researchers rationalized that less complex strategies were needed. The trial went on and ultimately found efficacy, providing an additional, valuable option for prevention of vertical transmission, as well as lessons about the difficulties of post-placebo trial design.

Similar issues are in play with PrEP today. Daily oral PrEP is effective when taken correctly and consistently. But additional options are needed, such as an injection. Both oral and injectable PrEP are designed to be used on their own. So a trial with “background” oral PrEP given to all participants isn’t a great option, as injectable-oral PrEP combos are not in the works.

HPTN 084, the planned trial of CAB-LA in African women, is an example of the complexities of trials in the post-placebo era. It was originally designed as an open-label study (see centerfold). In this design, some women would have been randomly assigned to receive daily oral PrEP, others to receive the injection. With this design, researchers hoped that women randomized to receive oral PrEP would use it more consistently than women did in some of the PrEP efficacy trials. In some of those trials, women’s adherence was quite low, perhaps because they did not know whether they were receiving an active product, or whether that product worked. (However, there is now evidence from PrEP projects that women can and will take daily oral PrEP consistently.) Each group would have known what they were receiving and been counseled accordingly.

Regulatory authorities raised concerns about the open-label design and the possibility that it would introduce bias into the research. When participants aren’t blinded and know what they are receiving, they may change their behaviors in ways that impact the validity of the results (e.g., if women receiving oral PrEP who understood that it was a proven tool increased their risk behaviors or women receiving the experimental injection increased condom usage). In both open-label and blinded trials, people are assigned to study arms by chance. The difference is that in blinded trials participants don’t find out what they are receiving. The argument for this design is that it offers a more fair comparison of two options versus unblinded trials.

Regulators’ concerns were discussed within the scientific community and in a community consultation that AVAC helped to organize with the HPTN 084 trial team. There was rich discussion in these meetings about the trial design. Ultimately, the HPTN 084 design changed to the double-dummy double-blind design (same as HPTN 083). The DISCOVER trial of a different drug being tested for oral PrEP, F/TAF, is also using this design. Time will tell whether future trials of PrEP strategies can utilize such a design.

It’s complex territory, and AVAC will continue to work with our partners in research and civil society to ensure that the trial designs are ethical, the goals well understood, and the outcomes on track to achieve the ultimate goal—a sustained end to epidemic levels of new HIV infections worldwide.