Follow-up study affirms efficacy of injectable cabotegravir for PrEP, though questions remain on hypertension, resistance

The unblinded phase of the HPTN 083 trial affirmed the efficacy of long-acting cabotegravir (CAB) for HIV prevention, but issues remained and merit further study, including questions around the potential for hypertension and the possible risk of integrase inhibitor resistance among CAB recipients who acquire HIV.

About This Study

“Efficacy and safety of long-acting cabotegravir compared with daily oral tenofovir disoproxil fumarate plus emtricitabine to prevent HIV infection in cisgender men and transgender women who have sex with men 1 year after study unblinding” was published online on Nov. 9, 2023, in The Lancet HIV. The lead author is Raphael J. Landovitz, M.D., of the Center for Clinical AIDS Research and Education at the David Geffen School of Medicine of the University of California Los Angeles. The study was funded partly by ViiV Healthcare and Gilead Sciences, the manufacturers of the two study drugs.

A related commentary, “Long-acting cabotegravir PrEP: a time for cautious optimism” by David W. J. Griffin, MBBS, Ph.D., proffesor Jennifer F. Hoy, and associate proffesor James H. McMahon, of the Department of Infectious Diseases at Alfred Hospital and Monash University in Melbourne, VIC, Australia, was published in the same issue.

Key Research Findings

The study reported on the first year of unblinding in the HPTN 083 clinical trial of injectable CAB for pre-exposure prophylaxis (PrEP). The blinded trial included 4,488 participants, 3,290 of whom remained on their original regimen during the unblinded portion. All participants are cisgender men (87%) or transgender women (13%) who have sex with men.

During the blinded phase, HIV incidence on injectable CAB was 0.41/100 person-years (PY) vs. 1.29/100 PY on daily oral tenofovir disoproxil fumarate/emtricitabine (TDF). During the first year of unblinding, HIV incidence rose in both arms, to 0.82/100 PY for CAB and 2.27/100 PY for TDF, while adherence to both study products dropped.

Most seroconversions were associated with treatment interruptions or poor adherence, although in the injectable CAB group, two breakthrough infections were from HIV virus with pertinent resistance mutations, and one seroconversion occurred in a participant who had persistently low CAB levels despite on-time injections. New-onset hypertension and dyslipidemia were more common in the CAB than the TDF arm.

Discussion Highlights and Implications for Practice

Study limitations reported included incomplete adherence data for the TDF group and delays in HIV diagnosis in the CAB group due to the drug’s long-acting nature.

The researchers summarized these new findings by saying that that these additional data “reaffirmed the relative efficacy observed in the primary study report, showing a consistent reduction in risk of infection by roughly two-thirds for long-acting compared with daily oral PrEP… .”

But while these results affirm the effectiveness of long-acting PrEP, caution is warranted due to the higher risk of hypertension, possibly suboptimal CAB levels despite adherence, and the potential for INSTI mutations if seroconverting within six months of the last injection, the researchers said.

Adherence is key for any biomedical HIV prevention. “Hence, the optimal PrEP modality for a person is the one that they can access and take consistently,” opinion authors noted.

By Barbara Jungwirth