Research Summary

Monthly Long-Acting Cabotegravir–Rilpivirine Reduces Regimen Failure in US Adults with HIV

Key Highlights

  • In a randomized phase 3 trial, monthly cabotegravir–rilpivirine reduced 48-week regimen failure vs standard oral ART.
  • Virologic failure occurred in 6 participants receiving injectables vs 34 receiving standard care.
  • Randomization was stopped early due to demonstrated superiority in secondary efficacy outcomes.

Monthly injections of long-acting cabotegravir plus rilpivirine significantly reduced the risk of regimen failure compared with standard oral antiretroviral therapy (ART) in adults with HIV who had adherence challenges, according to the results of the phase 3 randomized clinical trial published in the New England Journal of Medicine.

Long-acting injectable ART has been approved for virologically suppressed patients but has not been rigorously evaluated in randomized trials among individuals with ongoing adherence barriers. The LATITUDE trial addressed this gap by enrolling participants with documented nonadherence and comparing monthly injectable therapy with continued oral ART.

In this open-label, multicenter, US trial, 820 adults were screened and 453 enrolled in step 1, which provided up to 24 weeks of adherence support, conditional economic incentives, and standard oral ART. Eligible participants were aged 18 years or older, had HIV without a hepatitis B coinfection, had previously received ART, and had evidence of nonadherence within 18 months before entry.

Participants who achieved HIV-1 RNA levels ≤200 copies/mL during step 1 were randomized 1:1 in step 2 to either continue standard oral ART or switch to monthly, long-acting cabotegravir–rilpivirine for 52 weeks. The primary outcome was regimen failure, defined as confirmed virologic failure (2 consecutive HIV-1 RNA measurements >200 copies/mL) or permanent treatment discontinuation.

Study Findings

Among the 453 participants enrolled in step 1, 306 (68%) underwent randomization in step 2 (152 to cabotegravir–rilpivirine and 154 to standard care). The median age was 40 years; 63% were Black, 29% had been assigned female sex at birth, and 14% reported current or prior injection drug use. The median follow-up was 48 weeks.

Regimen failure occurred in 29 participants (19%) in the cabotegravir–rilpivirine group and 55 participants (36%) in the standard-care group. The cumulative incidence of regimen failure at week 48 was 22.8% with cabotegravir–rilpivirine and 41.2% with standard care, for a between-group difference of −18.4 percentage points (98.4% CI, −32.4 to −4.3; P = .002).

Virologic failure occurred in 6 participants in the cabotegravir–rilpivirine group and 34 participants in the standard-care group, corresponding to a −21.4 percentage-point difference in cumulative incidence at week 48 (98.4% CI, −33.5 to −9.3). Treatment-related failure occurred in 9 and 34 participants, respectively. Resistance-associated mutations developed in 2 participants with confirmed virologic failure in each group.

At least 1 adverse event occurred during step 2 in 34% of participants receiving cabotegravir–rilpivirine and 30% receiving standard care. The cumulative incidence of an adverse event at week 48 was 43.5% and 42.4%, respectively (between-group difference, 1.1 percentage points; 95% CI, −12.7 to 15.0). Injection-site reactions were reported in 60% of participants, most commonly pain, swelling, tenderness, or nodules. Two deaths occurred in the cabotegravir–rilpivirine group and were deemed unrelated to study treatment.

Clinical Implications

According to the study authors, monthly, long-acting cabotegravir–rilpivirine was superior to standard oral ART in reducing regimen failure among persons with HIV who faced adherence barriers. The authors noted that the trial provided randomized clinical evidence supporting the use of long-acting injectable ART as a strategy for individuals in whom oral ART has not been effective.

Expert Commentary

“The results of this trial showed that long-acting cabotegravir–rilpivirine was superior to standard care in reducing the risk of regimen failure among persons with HIV who faced barriers to adherence,” the researchers concluded.

Reference
Rana AI, Zheng L, Castillo-Mancilla J, et al. Cabotegravir plus rilpivirine for persons with hiv and adherence challenges. N Engl J Med. Published online February 18, 2026. doi:10.1056/NEJMoa2508228