Long-Acting Injectable HIV Therapy Reduces Regimen Failure in Patients with Adherence Challenges

Monthly injections of long-acting cabotegravir–rilpivirine were superior to standard oral antiretroviral therapy (ART) in reducing the risk of regimen failure among persons with HIV who had adherence challenges, according to phase 3 trial results published February 18, 2026. The cumulative incidence of regimen failure by week 48 was 22.8% in the cabotegravir–rilpivirine group and 41.2% in the standard-care group (difference, −18.4 percentage points; 98.4% confidence interval [CI], −32.4 to −4.3; P=0.002).

The LATITUDE trial (Long-Acting Therapy to Improve Treatment Success in Daily Life; ClinicalTrials.gov number NCT03635788) was conducted as an open-label, randomized trial involving persons with HIV who had inadequate adherence to ART (a persistent HIV-1 RNA level of >200 copies per milliliter or loss to follow-up). In step 1 of the trial, 453 participants who satisfied nonadherence eligibility criteria underwent a period of induction with a standard of care oral ART regimen for up to 24 weeks using conditional economic incentives and adherence support. The median age was 40 years, 63% were Black, and 29% had been assigned female sex at birth.

Participants who achieved virologic suppression (HIV-1 RNA level ≤200 copies per milliliter) in step 1 were eligible to enter step 2 of the trial. In step 2, 306 participants who were able to achieve viral suppression were randomly assigned in a 1:1 ratio to receive injectable cabotegravir + rilpivirine every 4 weeks (n=152) or continue taking daily oral ART (n=154). The primary outcome was regimen failure, defined as confirmed virologic failure (two consecutive HIV-1 RNA measurements of >200 copies per milliliter) or treatment discontinuation during step 2.

Step 2 randomization was stopped early on the basis of the superiority of cabotegravir–rilpivirine to standard care in secondary outcomes at a prespecified analysis performed after a median follow-up of 48 weeks. Regimen failure was reported in 29 cabotegravir–rilpivirine patients (5 with virologic failure and 24 with permanent treatment discontinuation as their first event) and 55 oral ART patients (32 with virologic failure and 23 with permanent treatment discontinuation as their first event).

The long acting injectable was also found to be superior to daily oral ART for the following key secondary endpoints: cumulative probability of virologic failure was 6.8% vs 28.2% (difference, -21.4% [98.4% CI, -33.5, -9.3]); cumulative probability of treatment-related failure was 8.9% vs 28.1% (difference, -19.2% [98.4% CI, -31.6, -6.9]); and cumulative probability of permanent discontinuation of treatment was 19.8% vs 28.2% (difference, -8.4% [98.4% CI, -21.3, 4.5]).

The cumulative incidence of an adverse event was 43.5% in the cabotegravir–rilpivirine group and 42.4% in the standard-care group (difference, 1.1 percentage points; 95% CI, −12.7 to 15.0). Resistance-associated mutations developed in 2 participants with confirmed virologic failure in each group.

In 2021, the Food and Drug Administration approved the combination of long-acting injectable cabotegravir plus rilpivirine (cabotegravir–rilpivirine) for the treatment of virologically suppressed HIV-1 infection in persons receiving oral ART, which is administered once a month or once every 2 months. However, phase 3 trials of cabotegravir–rilpivirine generally excluded persons with HIV who had viremia and challenges with adherence to oral ART. To date, randomized clinical trials evaluating this treatment strategy in this population are lacking.

Cabenuva (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) is currently approved as a complete regimen for the treatment of HIV-1 infection in adults and adolescents aged 12 years and older and weighing at least 35kg to replace current ART in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable ART with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine.

The trial was funded by the National Institute of Allergy and Infectious Diseases.