DENVER — Long-acting cabotegravir/rilpivirine (Cabenuva) injectable therapy resulted in similarly high levels of viral suppression to oral antiretroviral therapy (ART) in African patients with HIV, a phase IIIb randomized, open-label trial showed.

At 48 weeks, 96.9% of participants receiving cabotegravir/rilpivirine had a viral load of less than 50 copies/mL compared with 97.3% of those receiving standard first-line ART, meeting the noninferiority criterion, reported Nicholas Paton, MD, of the National University of Singapore and the London School of Hygiene and Tropical Medicine, during the Conference on Retroviruses and Opportunistic Infections.

Injectable cabotegravir/rilpivirine has been recommended for individualized HIV-1 treatment in regions with ample resources. However, there has long been reticence about long-acting injectable therapy programs in Africa because of concerns about its potential viability given wide variation in demographic factors, viral subtypes, prior treatment exposure, pre-existing antiviral drug resistance, and treatment approaches.

For example, people with HIV in Africa are predominantly Black African women, who differ demographically from the mostly male North American and European participants in the ATLAS and FLAIR trials that originally established monthly injectable therapy as noninferior to oral ART.

“This study essentially enrolled a pretty substantial proportion of the exact type of participants that the earlier phase III studies suggested may not benefit the most from long-acting injectables,” Aadia Rana, MD, of the University of Alabama at Birmingham, told MedPage Today.

Many of the patients who failed in ATLAS and FLAIR had baseline rilpivirine resistance mutations and higher body mass index (BMI), said Rana, who moderated the session but was not involved in the study. In this study, 21% of patients had a BMI of 30 or higher, and 74% had prior exposure to non-nucleoside reverse transcriptase inhibitors (NNRTIs), which increases the likelihood of resistance to rilpivirine.

“I think this study is pivotal because it speaks to a lot of the reservations that people have about implementing long-acting injectables in sub-Saharan Africa with this background of resistance” and other factors, she noted.

Paton said that this trial is the “essential first step” in exploring the possibility of a public health strategy using injectable cabotegravir/rilpivirine.

“Despite many reasons why one might have questioned whether that was achievable, that’s an extraordinary result,” he said. “We’ve shown it works in our setting, and now we can have the discussions about what the programs might need to do, what the cost issues are, the practicalities about delivering this, etc., but potentially, it’s a very exciting development in Africa.”

The current study, CARES (Cabotegravir and Rilpivirine Long-Acting in Africa Study), included 512 adults from Uganda, Kenya, and South Africa who were HIV-positive and stable on first-line ART: tenofovir disoproxil fumarate (Viread) with lamivudine/emtricitabine and dolutegravir (Tivicay)/nevirapine/efavirenz (Sustiva). Participants needed to have a viral load of less than 50 copies/mL for at least 4-12 months before screening with no history of hepatitis B infection or virology failure. Pregnant patients were also excluded.

More than half of the participants (57.6%) were women, and median age was 42. They had been on first-line ART for a median 8 years. The vast majority were on the integrase strand transfer inhibitor (INSTI) regimen (92%) at screening.

Based on archived DNA analysis, 56.5% of the participants had viral subtype A1. In addition, 13.5% had rilpivirine resistance mutations (10.1% with intermediate/high-level resistance), and 16.1% had cabotegravir resistance mutations (8.3% intermediate/high-level).

The 255 patients in the injectable arm had an optional 4-week lead-in of oral cabotegravir/rilpivirine before receiving injections of 600-mg cabotegravir and 900-mg rilpivirine every 8 weeks. The other 257 patients remained on the oral ART. Trial retention at 48 weeks was 99%. Because the trial was testing a public health approach, viral load was monitored every 24 weeks instead of the once-monthly monitoring done in the licensing studies.

A sensitivity analysis confirmed the noninferiority of injectable cabotegravir/rilpivirine to oral ART, with an adjusted difference of -0.3% (95% CI -3.0 to 2.3).

The one patient who had confirmed virological failure at week 48 (8,608 copies/mL) was a female with subtype A1 and no NNRTI or INSTI mutations in the injectable group, and her viral suppression returned when she restarted oral ART. An additional male participant with subtype D in the injectable arm had unconfirmed virological failure (44,984 copies/mL) but died of non-HIV-related causes before he could return to oral ART. At baseline, he had no INSTI mutations but had the NNRTI resistance mutations K103N/S and E138A.

The unexpectedly low rate of virologic failure in this trial may have occurred because the public health approach of far less frequent monitoring meant fewer opportunities to capture virologic failure, Rana said, “but at the end of the day, you’re looking at noninferiority, and both arms had very high viral suppression.”

Significantly more patients experienced grade ≥3 adverse events in the cabotegravir/rilpivirine group than the oral ART group (9.4% vs 3.9%), but the difference was non-significant for grade ≥3 adverse events related to the study drug (1.2% vs 0.8%). More adverse events overall occurred in the cabotegravir/rilpivirine group (86.3% vs 62.6%), but the difference lost significance after excluding injection-site reactions. Most injection-site reactions were grade 1 or 2, with only one patient experiencing a grade 3 nodule.

“Most people regarded the benefits of being on this therapy to far outweigh the transient pain and injection-site reactions,” Paton said. Based on the HIV Treatment Satisfaction Questionnaire change version, treatment satisfaction scores increased in both groups but significantly more in the injectable group than in the oral ART group, with an adjusted mean difference of 10.4 (95% CI 8.7-12.2).

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