New Long-Acting Two-Drug Injectable Regimen for Maintaining HIV Suppression

Therapy with monthly injections of long-acting cabotegravir plus rilpivirine was noninferior to once-daily oral therapy for maintaining HIV-1 suppression, according to 2 study results published in the New England Journal of Medicine.^1,2

Simplifying therapy for people with HIV-1 infection with a long-acting injectable regimen to maintain HIV suppression was the focus of two phase 3, open-label, multicenter, noninferiority trials (FLAIR¹ and ATLAS²; ClinicalTrials.gov identifier: NCT02938520 and NCT02951052, respectively). Patients who had an HIV-1 RNA level of <50 viral copies/mL after 16 weeks¹ and 6 months² were randomly assigned in a 1:1 ratio to continue their current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly injections of long-acting cabotegravir plus rilpivirine.

In the FLAIR trail,¹ treatment-naïve patients (n=566; median age, 34 years; 22% women; 74% white) with plasma HIV-1 RNA level ≥1000 copies/mL at screening received oral induction therapy with a fixed-dose combination of dolutegravir-abacavir-lamivudine once daily for 20 weeks. Patients who had an HIV-1 RNA level of <50 copies/mL after 16 weeks were randomly assigned to either the current oral therapy group or the investigational treatment group (n=283 for each).

In the ATLAS trial,² patients (n=618; median age, 42 years; 33% women; 32% non-white) who received antiretroviral drugs in an uninterrupted regimen without virologic failure and without a change in medication for at least 6 months before screening were randomly assigned to either their current oral therapy group or the investigational treatment group (n=308 for each; 2 patients withdrew before starting treatment). Acceptable current antiretroviral regimens included 2 nucleoside or nucleotide reverse-transcriptase inhibitors plus one of the following drugs: an integrase strand-transfer inhibitor, a non-nucleoside reverse-transcriptase inhibitor, a boosted protease inhibitor, or unboosted atazanavir. To increase generalizability of the ATLAS trial, patients taking fixed-dose combination of dolutegravir-abacavir-lamivudine were excluded from the study since this was covered in the FLAIR trial.

Patients in the long-acting therapy group received 30 mg of oral cabotegravir plus 25 mg of rilpivirine once daily with food for the first 4 weeks (oral lead-in period) to assess safety and adverse events. At week 4, patients received initial doses of 600 mg of cabotegravir and 900 mg of rilpivirine (3 mL each) by injection into the gluteus muscle, followed by injections of 400 mg of cabotegravir and 600 mg of rilpivirine (2 mL each) every 4 weeks through week 52 of the maintenance phase.

The primary endpoint in both trials was the percentage of patients who had an HIV-1 RNA level of 50 viral copies/mL or higher at week 48 of the maintenance phase.

At week 48 in the FLAIR trial, an HIV-1 RNA level ≥50 copies/mL was found in 2.1% of patients who received long-acting therapy and 2.5% of patients who received oral therapy (adjusted difference, -0.4%; 95% CI, −2.8 to 2.1). Similarly, in the ATLAS trial, 1.6% of patients who received long-acting therapy and 1.0% of patients who received oral therapy had an HIV-1 RNA level ≥50 viral copies/mL (adjusted difference, 0.6%; 95% CI, -1.2 to 2.5). These results met the criterion for noninferiority for the primary endpoint (noninferiority margin, 6%).

In the FLAIR trial, an HIV-1 RNA level of <50 copies/mL at week 48 was found in 93.6% of patients who received long-acting therapy and in 93.3% of patients who received oral therapy (adjusted difference, 0.4%; 95% CI, -3.7 to 4.5). In the ATLAS trial, 92.5% of patients receiving long-acting therapy and 95.5% of patients receiving oral therapy had an HIV-1 RNA level of <50 copies/mL at week 48 (adjusted difference, -3.0%; 95% CI, -6.7 to 0.7). These results met the criterion for noninferiority for this endpoint (margin, -10%).

Adverse events were more common in the long-acting therapy group and included injection-site pain. In the FLAIR trial, grade 3 or higher adverse events and events that met liver-related stopping criteria occurred in 11% and 2%, respectively, of patients who received long-acting therapy and in 4% and 1%, respectively, of patients who received oral therapy. In the ATLAS trial, serious adverse events were reported in no more than 5% of patients in each group.

Treatment satisfaction as measured with the HIV Treatment Satisfaction Questionnaire, change version increased after patients switched to long-acting therapy. At week 48, 91% and 86% of patients preferred long-acting therapy over daily therapy in the FLAIR and ATLAS trials, respectively.  

More trials are needed to fully define the clinical role of a long-acting regimen in a spectrum of patients with HIV, including patients who do not have a stably suppressed HIV infection, with adherence challenges, or with gastrointestinal absorption issues, concluded the investigators.

Disclosure: These clinical trials were supported by ViiV Healthcare and Janssen. Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

References

1. Orkin C, Arasteh K, Hernández-Mora MG, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection [published online March 4, 2020]. N Engl J Med. doi:10.1056/NEJMoa1909512

2. Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression [published online March 4, 2020]. N Engl J Med. doi:10.1056/NEJMoa1904398