Taken every 2 months, the long-acting injectable drug cabotegravir prevented more HIV infections than daily oral pre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine (TDF/FTC), according to newly announced results from a major Phase 3 study.
The data show that the experimental drug is noninferior to the current standard-of-care PrEP drug, which may open the door for a new biomedical HIV prevention option aimed at those who would prefer a shot six times a year over taking a daily pill.
On May 18, the HIV Prevention Trials Network (HPTN) held a press briefing by phone announcing results from the HPTN 083 trial. Interim data so convincingly showed non-inferiority—with results even approaching superiority for injectable cabotegravir—that the trial was stopped and results were reported early, according to the briefing.
“Demonstrating conclusively that long-acting injectable cabotegravir is highly effective almost two years earlier than originally expected is exciting news,” said HPTN 083 protocol chair Raphael J. Landovitz, M.D., in a press release. “It is inspiring that we may soon have additional HIV prevention options for at-risk individuals who have difficulty with or prefer not to take pills. We are indebted to our study participants and clinical research sites.”
The Phase 3 study enrolled 4,570 cisgender men who have sex with men (MSM) and transgender women who have sex with cisgender men in seven countries: Argentina, Brazil, Peru, South Africa, Thailand, the U.S., and Vietnam. Two-thirds of the study participants were under the age of 30, and 12% were transgender women. Of the U.S. study enrollees, half were Black or African-American.
“We did this study in a population of individuals who are not normally included in these trials,” said Kimberly Smith, M.D., a senior vice president and the head of research and development at ViiV Healthcare. HIV advocates have critiqued other biomedical HIV prevention studies for lacking diversity, or for not enrolling groups who are more vulnerable to acquiring HIV.
HPTN 083 Study Construction and Early Results
For this double-blinded, double-dummy study, participants were enrolled in one of two arms:
- One group received injectable cabotegravir once every 8 weeks, following a lead-in period in which they received daily oral cabotegravir for 5 weeks, then their first two injections at 4-week intervals. These participants also took a daily oral placebo pill.
- One group received daily oral TDF/FTC. Participants also received cabotegravir placebo pills and injections following the same schedule as the other group.
Participants were observed for two years of follow-up.
Researchers found that a total of 50 people contracted HIV during the course of the study—38 in the daily oral TDF/FTC arm, and 12 in the CBT arm, with incidence rates of 1.21% and .38% respectively.
“We observed roughly three times the HIV incidence rate in the TDF/FTC arm than in the [cabotegravir] arm,” said Landovitz, who is also a professor of medicine in the division of infectious diseases at the University of California-Los Angeles (UCLA) David Geffen School of Medicine and associate director of the UCLA Center for Clinical AIDS Research & Education.
Researchers noted that while the gap in the HIV incidence rate between the two arms looks dramatic, the initial analysis showed that cabotegravir was merely noninferior to TDF/FTC; it fell just shy of demonstrating superiority. Regardless, the findings were so convincing that the data and safety monitoring board (DSMB) for this study decided to stop the study and announce the preliminary results.
The researchers said that all participants will be notified of the study results and be told which medication they received. Any participant in the long-acting cabotegravir arm will be offered the ability to continue their injectable PrEP or switch to daily oral TDF/FTC. Participants in the TDF/FTC arm will be able to stay on daily oral PrEP, but can switch to long-acting cabotegravir once it becomes available.
Smith noted during the press briefing that ViiV shared the results of this study with the U.S. Food and Drug Administration (FDA), but no details regarding a filing for FDA approval or the timing of a potential approval were announced.
Last December, the FDA declined to approve a new drug application for a long-acting injectable HIV treatment regimen (cabotegravir/ripilvirine) due to technical manufacturing issues, but not for lack of safety or efficacy. No updated announcements have been regarding when monthly injectable treatment for HIV will be available.
Despite Positive Cabotegravir-as-PrEP Findings, Questions Linger
One looming question regarding injectable PrEP is on the status of long-acting cabotegravir studies in cisgender women. HPTN does have a study still running (HPTN 084) that is looking at the same prevention drug in women. The study was started a year later than HPTN 083, and the DSMB decided that the study in women needed to continue before it could re-evaluate its results.
“We look forward to studies showing efficacy in women and adding this to the toolbox of interventions for HIV prevention,” said Smith. “We will be in discussions with FDA on filing. In an ideal world we’d love to file for all men and women, but we’re still waiting on the results of the 084 study. There is still a tremendous amount of work to do.”
Danielle Campbell, M.P.H., a prevention research advocate, agrees. “Data from the HPTN 083 trial demonstrates great promise for global HIV prevention among populations of cisgender men and transgender women,” she noted in an emailed statement. “In addition, as most of us who are still smarting from recent HIV prevention trial data that did not include cisgender women, I will temper my excitement in anticipation of results planned for later this fall for the sister study in cisgender women, HPTN 084.”
But even if a long-acting HIV prevention drug is approved for all sexually active people, there are still remaining questions about implementation. Shots will likely have to be administered by trained clinicians, which will add clinical visits to the schedules of providers who already are stretched thin. And during a COVID-19 pandemic where clinics and public health programs are looking at ways to provide more care without face-to-face visits, advocates say more needs to be done to prepare for scale-up of injectable prevention and treatment.
“Operational research to find out how communities and individuals can best be supported to access the drug and how health systems can be strengthened to deliver [injectable PrEP], should it be approved for use, is a critical next step while we await complete data from all populations that would inform a regulatory submission,” said Mitchell Warren, the executive director of AVAC, in a press release. “This is essential work that can and must begin now so that we don’t repeat the same kind of delays that have slowed daily oral PrEP rollout over the past eight years.”