Effective HIV Interventions Have Changed the Approach to Trials

In the past, individuals who were at high risk for HIV infection and who were enrolled in placebo-controlled prevention trials had been typically randomly assigned to either an experimental agent or placebo. However, that trial design—and the way those trials were interpreted—has shifted.

This was the topic of discussion during David Dunn’s session yesterday at the Conference on Retroviruses and Opportunistic Infections (CROI) 2019. Dunn is a researcher at University College London in the United Kingdom.

“The HIV landscape has changed fundamentally with the development of effective intervention,” said Dunn. “There is overwhelming evidence that oral [TDF-FTC] is highly effective in preventing HIV infection when taken as prescribed, so it is no longer ethical to do a study with a placebo arm.”

Instead, researchers are now replacing the placebo arm with an active control agent arm.

Now, with the use of active-control pre-exposure prophylaxis (PrEP) trials, Dunn says the knowledge of the hypothetical placebo HIV incidence is essential in the trials’ interpretation.

There are several ways to estimate the hypothetical placebo incidence, each with its own limitations, but 2 of the more popular ways are by estimating the “force of infection” from tests on baseline samples and assessing the ecological association between HIV and sexually transmitted infection (STI) incidence.

“STIs really play a critical role in PrEP studies because they are such strong markers for HIV risk behaviors,” said Dunn.

Dunn also suggests that there is a fundamental problem with using rate ratio when analyzing the trials. To account for this, Dunn recently described a new measure for active-controlled trials called the averted infections ratio.

“[The averted infections ratio] formally involves the hypothetical placebo incidence rate and avoids the logical inconsistencies of the rate ratio,” he explained. “It measures the proportion of infections that would be averted by using the experimental agent rather than the control agent.”

While placebos are no longer used in PrEP trials, they still do have a role in trials that aim to estimate vaccine efficacy since there is no clearly effective HIV vaccine available.

However, Dunn says that while the participants’ use of PrEP might complicate the design and analysis of these studies, the ethics of not having participants on PrEP still need to be considered.

—Colleen Murphy

Reference:

Dunn D. Designing & interpreting HIV prevention trials in the era of effective interventions. Paper presented at: Conference on Retroviruses and Opportunistic Infections; March 4-7, 2019; Seattle, WA. http://www.croiconference.org/sessions/designing-interpreting-hiv-prevention-trials-era-effective-interventions. Accessed March 5, 2019.