Long-acting monthly injectable HIV therapy cabotegravir and rilpivirine was non-inferior to oral HIV antiretroviral therapy (ART), two phase III randomized trials found.
Monthly injections of cabotegravir/rilpivirine as part of an HIV treatment regimen were non-inferior to oral therapy, both in the proportion of patients with viral load higher than 50 copies/mL and those who achieved viral suppression, reported Chloe Orkin, MD, of Queen Mary University of London in England, and colleagues, writing in the New England Journal of Medicine.
“Prolonged daily regimens can engender dissatisfaction, contribute to stigma, and increase the risk of nonadherence to treatment and treatment failure,” the authors wrote. “Surveys indicate that many patients would prefer therapeutic alternatives.”
Cabotegravir is an investigational integrase strand-transfer inhibitor (INSTI) and rilpivirine is a non-nucleoside reverse-transcriptase inhibitor (NNRTI) with an approved oral formulation (Edurant), the investigators noted. Prior research found that viral suppression was maintained through week 96 in 87% of patients who switched to the long-acting therapy versus 84% who continued oral therapy.
Notably, the team found that 83% of patients on long-acting therapy were virally suppressed through week 160 of treatment.
Orkin and co-authors conducted the First Long-Acting Injectable Regimen (FLAIR) study, an open-label trial randomizing HIV patients with a viral load of 1,000 copies/mL or greater. All patients received 20 weeks of daily oral induction therapy with dolutegravir-abacavir-lamivudine.
At week 16, virally suppressed patients were either randomly assigned to oral cabotegravir plus rilpivirine therapy for 1 month, followed by monthly injections of long-acting cabotegravir plus rilpivirine, or assigned to continue on oral therapy.
Overall, 566 were randomized during the maintenance phase: 283 to eventually switch to monthly injections of long-acting therapy, and 283 to continue on oral therapy. Participants across treatment groups were a median age of 34, 22% were women, and about three-quarters were white. Around 20% had an HIV viral load higher than 100,000 copies/mL at baseline, and prior to the induction phase, about 70% had a CD4+ lymphocyte count of 350 per microliter or higher, which increased to 90% at the start of maintenance therapy, the authors said.
At week 48, six participants did not achieve viral suppression in the intervention group versus seven in the control group (2.1% vs 2.5%, respectively, adjusted difference -0.4 percentage points, 95% CI -2.8 to 2.1), meeting the six percentage point margin for non-inferiority.
Likewise, 93.6% of patients in the intervention group achieved a viral load of 50 copies/mL or less compared with 93.3% of controls (adjusted difference 0.4 percentage points, 95% CI -3.7 to 4.5), which met the -10 percentage point non-inferiority margin.
Four participants in the long-acting therapy group had confirmed virologic failure, with three of four developing NNRTI and INSTI resistance mutations. Three participants in the oral therapy group had confirmed virologic failure without the development of resistance mutations, the authors noted.
Other than injection site reactions, nasopharyngitis, headache, and upper respiratory tract infection were the most common adverse events in the intervention group. Serious adverse events occurred in 6% of participants in the long-acting therapy group and 4% in the oral therapy group. Adverse events leading to withdrawal from the trial occurred in nine participants receiving long-acting therapy and four receiving oral therapy.
Long-Acting Therapy Works in Treatment-Experienced Patients, Too
A second phase III open-label randomized trial in NEJM by Susan Swindells, MBBS, of the University of Nebraska Medical Center in Omaha, and colleagues, found long-acting injectable therapy was non-inferior among patients who were virally suppressed for at least 6 months on standard oral ART.
In the Antiretroviral Therapy as Long Acting Suppression (ATLAS) trial, 616 patients with HIV RNA levels less than 50 copies/mL for at least 6 months were randomized to either continue their standard therapy or be switched to monthly injections of long-acting cabotegravir and rilpivirine.
Five patients in the long-acting therapy group and three in the oral therapy group had HIV RNA levels of 50 copies/mL or higher (1.6% vs 1.0%, respectively, adjusted difference 0.6 percentage points, 95% CI -1.2 to 2.5), which met the non-inferiority margin of six percentage points.
Similarly, 92.5% of participants in the long-acting group had HIV RNA of less than 50 copies/mL versus 95.5% of those in the oral therapy group (adjusted difference -3.0 percentage points, 95% CI -6.7 to 0.7), which also met the non-inferiority margin of -10 percentage points.
Most participants in the long-acting therapy group also had injection site reactions, with three experiencing virologic failure in the long-acting group and four in the oral therapy group.
An accompanying editorial by Judith Currier, MD, of UCLA Medical Center in Los Angeles, noted another finding of both studies: namely that participants in both trials preferred monthly injectable therapy with daily oral therapy.
“When approved by regulators, this major advance in treating HIV infection will provide a new option for a select group of patients who currently have viral suppression while taking ART and represents the first step toward making less-frequent dosing of ART a reality,” she wrote.
She noted that the ongoing ATLAS-2M trial is currently evaluating this therapy with a dosing schedule of every 8 weeks.
“Differentiated models of care, wherein injections are provided outside the conventional clinic setting, deserve evaluation,” Currier wrote. “We need creative approaches that will allow us to deploy injectable treatment in the absence of virologic suppression in order to have the greatest effect on ending the HIV epidemic.”
The cabotegravir/rilpivirine combination is under development by Viiv Healthcare. The company had submitted a U.S. marketing application last year; the FDA sent it back in December because of perceived issues with the product’s manufacturing.
Orkin disclosed support from ViiV Healthcare, GlaxoSmithKline, Gilead, Janssen, and MSD; co-authors disclosed support from ViiV Healthcare, GlaxoSmithKline, Gilead Sciences, Janssen Research and Development, Johnson & Johnson, MSD, Torii Pharmaceuticals, Janssen Pharmaceuticals, Japan Tobacco/Torii Pharmaceutical, Theratechnologies, and Merck.
Swindells disclosed support from ViiV Healthcare; co-authors disclosed support from AbbVie, Gilead, Janssen, Sanofi, MSD, ViiV, GlaxoSmithKline, Merck, and TaiMed.
Currier disclosed support from Merck and being the head of the AIDS Clinical Trials Group.