Long-acting cabotegravir/rilpivirine (Cabenuva; CAB/RPV-LA) appeared superior to daily oral antiretroviral therapy (ART) in maintaining viral load suppression for people living with HIV who have trouble adhering to oral ART, according to an interim analysis of a phase III trial.

At 52 weeks, numerically fewer patients assigned to monthly injections of CAB/RPV-LA experienced regimen failure — defined as the earliest occurrence of virologic failure or treatment discontinuation — compared with those kept on standard oral ART (24.1% vs 38.5%).

Though that primary endpoint narrowly missed on statistical significance (-14.5% difference, 98.75% CI -29.8 to 0.8), the totality of evidence from the so-called LATITUDE study supported the long-acting injectable for this patient population, reported Aadia Rana, MD, of the University of Alabama at Birmingham, at the Conference on Retroviruses and Opportunistic Infections.

“CAB/RPV-LA demonstrated superiority when compared to daily oral standard-of-care ART in persons with HIV in the U.S. who face barriers to adherence and have a prior history of virologic non-response or loss to follow-up,” Rana told attendees.

“Those of us that take care of inner-city drug users are used to suboptimal adherence, and they have multiple comorbidities, which is why we’ve developed monthly administered addiction medicines, monthly administered antipsychotic medications,” commented Brian Conway, MD, of Simon Fraser University in Burnaby, British Columbia. “I could easily see a study or an intervention where HIV-infected, inner-city drug users get their monthly Sublocade in their belly, their Clopixol in their arm, and their [CAB/RPV-LA] in their backside, capitalizing on the infrastructure that’s already there to take care of them.”

“I think that sort of combination adherence support — a biomedical-behavioral combo — is exactly what we need to end this epidemic,” Rana replied. She said that 5% of the study population were current injection drug users and 9% had reported recent or prior drug use.

Once-monthly injectable CAB/RPV was first FDA approved as an alternative to oral ART regimens in 2021. It is only indicated for people with HIV who have achieved virological suppression on a stable antiviral regimen with no history of treatment failure. A recent label change now allows for injections every 2 months with a higher dose of the product as well.

Last month, the NIH and drugmaker ViiV Healthcare announced that LATITUDE had been stopped for efficacy, following the recommendation of an independent data and safety monitoring board; all eligible participants were offered CAB/RPV-LA.

Results of key secondary endpoints in the trial also favored the long-acting agent, with 7.2% of those receiving CAB/RPV-LA experiencing virologic failure versus 25.4% of those receiving standard oral ART. Also, 9.6% in the CAB/RPV-LA group experienced treatment-related failure compared with 26.2% in the standard-of-care group.

The overwhelming majority of monthly injections (93%) were administered on time and only 3% of the injections were missed, Rana pointed out.

The study was designed using a four-step approach. Eligible participants enrolled in Step 1 for up to 24 weeks, during which time they received treatment adherence support and conditional economic incentives for achieving viral suppression on oral ART. Those who achieved viral suppression in Step 1 moved to Step 2 and were randomized to either CAB/RPV-LA every 4 weeks or to continuation of standard of care for 52 weeks.

Step 3 was an open-label crossover continuation that provided CAB/RPV-LA for participants without confirmation of virologic failure in Step 2. Step 4 was an oral therapy observation step, for any participant who received at least one CAB/RPV-LA injection but prematurely discontinued injectable treatment.

Rana pointed out that while participants did have to achieve a suppressed viral load in order to become eligible for randomization at Step 2, 17% of the participants in the CAB/RPV-LA arm and 7% of the participants in the standard-of-care arm had a viral load of greater than 200 copies at the randomization visit itself. In fact, eight participants in the CAB/RPV-LA arm had a viral load greater than 10,000 copies at randomization.

Referring to the requirement for study participants to attain viral suppression at Step 2, Monica Gandhi, MD, MPH, of the University of California San Francisco, pointed out during a Q&A session that “adherence-challenged patients, by definition … are often viremic.” Gandhi, who was not associated with the trial, asked whether clinical trials investigating therapeutics in patients with HIV and difficulties with adherence would be more informative if the trials included participants with active viremia.

“I think it’s something that may be outside of a clinical trial,” Rana replied. “I think it’s an ongoing discussion, and I think that also is potentially an opportunity for novel study designs, particularly for this population.”

Clinical Trial Details

The LATITUDE trial, also known as ACTG 5359, enrolled 434 participants from 33 sites across the U.S., including Puerto Rico. No participant was excluded because of active substance use, alcohol use, or unstable housing. Participants had a median age of 40, but 20% were age 30 or younger. Thirty percent were female sex assigned at birth and 5% identified as transgender. A majority (64%) were Black or African American and 17% were Hispanic. Fourteen percent reported either current or prior injection drug use. Participants were not excluded based on their CD4⁺ T-cell counts or viral load levels. In fact, 14% of Step 1 participants had a viral load of greater than 100,000 copies at entry. The median CD4⁺ count at entry was 270.

The rate of adverse events was similar in both the CAB/RPV-LA group and the standard-of-care group, Rana said. Overall, 57% of participants in the CAB/RPV-LA group had at least one injection site reaction in Step 2, and the most common reactions reported were pain, tenderness, and nodules. Three participants in the CAB/RPV-LA group had grade 3 or higher injection site reactions. One participant with a grade 1 injection site reaction discontinued treatment for this reason.

Rana noted limitations of the study, most importantly that there was a need for viral suppression before eligibility for randomization and that only injections administered every 4 weeks were evaluated.

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