Rana AI, Zheng L, Castillo-Mancilla J, et al. ACTG A5359 LATITUDE Trial Team.  Cabotegravir plus Rilpivirine for Persons with HIV and Adherence Challenges.  N Engl J Med.  2026 Feb 18:10.1056/NEJMoa2508228.  doi:10.1056/NEJMoa2508228.  PMID: 41707171

ACTG A5359 LATITUDE investigators describe safety and efficacy of monthly CAB/RPV versus daily oral ART in adults with a history of adherence challenges.  In Step 1, participants received adherence support and were eligible for conditional economic incentives; in Step 2, participants achieving virologic suppression in Step 1were switched to CAB/RPV or continued oral ART for 52 weeks (with continued adherence support but no incentives).  453 participants enrolled in Step 1: median age 40 years, 29% assigned female at birth, 63% Black and 17% Hispanic/Latinx, and 14% with current/prior injection drug use.  306 participants enrolled in Step 2: 152 assigned to CAB/RPV and 154 standard oral ART (16% of participants in the CAB/RPV group and 7% in the oral ART group had RNA > 200 copies/mL at the randomization visit).  94% of maintenance injections were administered on time, and 34-46% of oral ART participants reported no missed doses in the 30 days before study visits.  Virologic failure occurred in 6 participants on CAB/RPV vs. 34 on oral ART (corresponding to a -21.4% difference in week 48 cumulative incidence), and permanent treatment discontinuation occurred in 26 participants on CAB/RPV and 37 on oral ART (-8.4% difference).  Among participants experiencing virologic failure, INSTI mutations developed in 2/5 (40%) on CAB/RPV and 2/22 (9%) on oral ART; primary risk factors were higher BMI and lower CAB and RPV concentrations early in treatment.  For the 2 participants on CAB/RPV with emergent INSTI mutations, both developed E138K and Q148K.  There was no significant difference in cumulative incidence of adverse events.  All participants in the CAB/RPV group who experienced virologic failure suppressed on oral ART (except for 1 lost to follow-up).

Preliminary data from this randomized trial, presented at CROI 2024, helped shape updated treatment guidelines to support consideration of long-acting injectable CAB/RPV for people with adherence challenges.  Details published in this study affirm how impactful long-acting injectable therapies can be for people with HIV and adherence challenges, a population that has often been overlooked in large clinical trials.  Additional studies examining whether q-2month CAB/RPV demonstrates similar efficacy (particularly among people starting CAB/RPV with viremia) can further guide optimal implementation of CAB/RPV.