Long-acting injectable HIV prevention with cabotegravir was superior to daily oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate-emtricitabine (TDF/FTC; Truvada) in men who have sex with men (MSM) and transgender women, a randomized trial found.

Among more than 4,500 participants in the phase IIb/III trial, 13 incident infections occurred in the cabotegravir group compared with 39 in the TDF/FTC group (HR 0.34, 95% CI 0.18-0.62), reported Raphael Landovitz, MD, of the University of California Los Angeles, and colleagues with the HPTN-083 trial group.

While the injectable was safe, four incident infections occurred despite on-time administration and adequate levels of cabotegravir, raising questions about the potential for PrEP failure, as well as the specter of integrase strand-transfer inhibitor (INSTI) resistance, the authors wrote in the study in the New England Journal of Medicine.

Interim data from HPTN-083 were previously presented at the 2020 International AIDS Conference, where researchers showed a 66% lower incidence in HIV infection with cabotegravir. As previously reported, the trial was stopped early on the basis of efficacy by a data and safety monitoring board.

Researchers analyzed the data within the blinded phase of the trial, from December 2016 up through May 2020. Participants were adult cisgender MSM and transgender women who have sex with men at high risk of HIV acquisition in 43 sites in the U.S., Latin America, Asia, and Africa. They were healthy, with a negative HIV serologic test, an undetectable HIV viral load, and a creatinine clearance of 60 ml or more per minute.

The primary efficacy endpoint was incident HIV infection, and the primary safety endpoint was an adverse event of grade 2 or higher. As previously noted, the non-inferiority margin was a hazard ratio of 1.23.

There were 4,566 participants in an intention-to-treat analysis, 87% of whom were MSM. Participants had a median age of 26, and 37% came from the U.S., where half of the participants were Black. Median follow-up was 1.4 years.

As previously reported at the Conference on Retroviruses and Opportunistic Infections in March 2021, several HIV incident infections were reclassified as breakthrough infections during a post-hoc analysis. Identifying one baseline infection dropped the HIV incidence rate in the cabotegravir group to 0.37 (95% CI 0.19-0.65), with a revised hazard ratio of 0.32 (95% CI 0.16-0.58).

HIV infections in the cabotegravir group were classified into four groups:

• Baseline infections

• Infections after a long hiatus after last administration of cabotegravir

• Infections occurring during the oral lead-in phase of the trial

• Infections occurring despite on-time administration of cabotegravir and expected plasma cabotegravir concentrations

“The risk of PrEP failure may be influenced by low plasma cabotegravir concentrations between initial injections, low cabotegravir concentrations in rectal tissue, rectal inflammation related to sexually transmitted infection, or a combination of these factors,” the authors wrote.

They also detected INSTI resistance in five cabotegravir patients, one with baseline infection and four with incident infections. Landovitz’s group said that risk of resistance can be reduced potentially through using more sensitive HIV assays to “minimize the interval between HIV infection and diagnosis.”

Regarding safety, 93% of participants reported grade 2 adverse events, while 33% reported grade 3 adverse events. About 5% of participants reported serious adverse events, which were well balanced between groups. These included seizures and liver-related events leading to discontinuation of medication in both groups.

Eleven participants in the TDF/FTC group and four in the cabotegravir group died. The authors noted that one death in the TDF/FTC group was from cardiovascular disease that was potentially treatment related.

While 81% of participants reported an injection-site reaction, just 2.4% discontinued due to such events, the authors said, noting that most were mild or moderate.

The overall incidence rates of sexually transmitted infections were 21.36 per 100 person-years for new urethral or rectal chlamydia, 16.69 per 100 person-years for new syphilis infections, and 13.49 per 100 person-years for new rectal or urethral gonorrhea.

Landovitz’s group also noted that there are additional trials of cabotegravir in cisgender women, such as HPTN-084, which was recently unblinded after cabotegravir showed superiority versus oral PrEP, and an adolescent study is also in the works.