Featured Literature
Koethe JR, Lake JE, Kantor A, et al. A 48-week, Randomized Controlled Trial of Doravirine for Individuals with HIV and Obesity on Integrase Inhibitors and Tenofovir Alafenamide: The Do IT Study (ACTG A5391). Clin Infect Dis. 2026 March 18:ciag196. doi:10.1093/cid/ciag196.
ACTG A5391 is an open-label, multi-center trial designed to assess whether a switch from INSTI-based combinations to a DOR-containing regimen, as well as from TAF- to TDF-, leads to weight reduction and improved metabolic health parameters among U.S. adults with HIV and obesity. People on TAF/FTC plus either bictegravir, dolutegravir, or raltegravir for over a year with virologic suppression were eligible for randomization to: DOR plus TAF/FTC; DOR plus TDF/FTC; or no change in therapy. There were 145 participants who initiated study treatment (47 in the DOR plus TAF/FTC group; 49 in the DOR plus TDF/FTC group; and 49 in the INSTI plus TAF/FTC group). Median BMI at entry was 34.9 kg/m2, waist circumference 111 cm, 49 percent were female, 53 percent Black, and 18 percent Hispanic/Latinx. Out of all participants, 65 percent had experienced an unintentional ≥ 10 percent weight gain in the first one to three years of INSTI use.
The primary efficacy analysis population included 127 participants who completed 48 weeks of follow-up. Although over half of participants in all groups lost some weight (estimated mean change in weight was -0.47% for DOR plus TAF/FTC, -2.73% for DOR plus TDF/FTC, and -1.84% for INSTI plus TAF/FTC), CI limits for the treatment difference in weight change did not exceed the pre-specified five percent threshold. Estimated mean treatment differences in waist circumference changes were not significant; similarly, there were no significant changes in total fat, trunk fat, or total lean mass as measured by DEXA.
Commentary
For people with HIV and obesity who had been taking INSTI-based regimens for over a year, switching to a DOR-based combination (with or without TDF) did not lead to significant weight reductions over 48 weeks. Subgroup analyses examining changes according to sex at birth, gender, race/ethnicity, age, and historical ART-related weight gain also did not reveal any significant treatment differences. Comprehensive strategies and interventions outside of ART-related modifications will be necessary to effectively prevent and manage unintentional weight gain for people with HIV.
Featured Literature
Havens JP, O’Neill J, Kubat M, et al. Scalability Metrics and Effort Requirements for a Long-Acting Injectable Antiretroviral Treatment Program. Open Forum Inf Dis. 2026 March 4. https://doi.org/10.1093/ofid/ofag116.
This study describes staff effort, resource allocation, and scalability based on implementation of a long-acting injectable program at a Ryan White-funded HIV specialty clinic housed within an academic center. The primary outcome was estimated staff effort required for program support: this was calculated based on direct observation, interviews, and department records (information specific to role and task categories was also collected). Scalability metrics (i.e., patients/FTE and injections/FTE) were calculated annually to assess changes in program efficiency. The site utilized the “buy and bill” mechanism for medication procurement. From May 2022 to December 2024, 113 adults receiving LA-CAB/RPV were included in this analysis. The number of injections increased from 68 (second half of 2022) to 301 (CY23) and 515 (CY24), representing a 657 percent increase.
Prior to program launch, the initial start-up period required ~0.24 FTE to manage protocol development, workflows, and medication access/ordering. After program initiation, total dedicated effort increased from 1.0 FTE to 2.25 FTE and effort distribution across roles evolved as the program gained experience and scaled up. The program coordinator remained the single largest component (comprising 33-50% of total FTE each year). Clinician effort decreased over time, from 42 percent to four percent. Administrative effort shifted, with the addition of various roles: access coordinator, benefits/billing specialists, and outreach and technology staff. With these refinements, program efficiency improved: the number of patients managed and injections per dedicated FTE both increased (27 to 50 and 68 to 229, respectively). No virologic failures were observed and the discontinuation rate was less than three percent.
Commentary
Information from this “real world” analysis can help guide resource planning and allocation to support long-acting injectable therapy scale up. Although the clinic had prior experience as a trial site and utilized a “buy and bill” mechanism for CAB/RPV procurement (and therefore its experiences may differ from other clinics and practice models), the program was able to demonstrate successful growth and efficiency gains over a relatively short time. It achieved this by gradually shifting FTE toward program/administrative personnel, encouraging multidisciplinary collaboration and flexibility, optimizing health information technology use, and investing in a dedicated program champion/coordinator.
Featured Literature
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 1 were switched to CAB/RPV or continued oral ART for 52 weeks (with continued adherence support but no incentives). Of the 453 participants enrolled in Step 1: median age 40 years, 29 percent assigned female at birth, 63 percent Black and 17 percent Hispanic/Latinx, and 14 percent with current/prior injection drug use. Of the 306 participants enrolled in Step 2: 152 were assigned to CAB/RPV and 154 had 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). Ninety-four percent of maintenance injections were administered on time, and 34 to 46 percent of oral ART participants reported no missed doses in the 30 days before study visits. Virologic failure occurred in six participants on CAB/RPV versus 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 two out of five (40%) on CAB/RPV and two out of 22 (9%) on oral ART; primary risk factors were higher BMI and lower CAB and RPV concentrations early in treatment. For the two 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 one lost to follow-up).
Commentary
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.
Featured Literature
Makinson A, Bani-Sadr F, Palich R, et al; DAT’AIDS Study Group. Switch to BIC/TAF/FTC or DTG + TDF/FTC in virologically suppressed PWH: outcomes in real-world setting with and without tenofovir resistance. Clin Inf Dis. 2026 Jan 9:ciaf726. doi:10.1093/cid/ciaf726.
DAT’AIDS investigators evaluated whether switching to BIC/TAF/FTC or DTG plus TDF/FTC in people with virologic suppression increased risk of virologic failure and whether this was influenced by tenofovir resistance. Participants included people suppressed on ART for over 12 months who had no history of DTG or BIC exposure: individuals were excluded if they had no available genotypes or known DTG or BIC resistance based on cumulative RNA and DNA resistance testing. People who transitioned to DTG-based dual therapy or paired DTG with backbones other than TXF plus XTC were censored.
There were 1,393 people who switched to the combinations of interest (“switchers”) and they were compared to 8,434 “non-switchers”: switchers had a longer duration of ART, higher number of prior regimens, and higher proportion of M184V/I and possible or definite tenofovir resistance. There were 75 (5.4%) cases of virologic failure (primary outcome was defined as VL > 200 copies/mL) among switchers and 523 (6.2%) in non-switchers. Among VF cases in the switch group, 60 (80%) continued their combination and suppressed after a median of 1.4 months. Two people in the switch group with VF acquired DTG or BIC resistance. In logistic regression analyses, there was no association of switching to BIC/TAF/FTC or DTG plus TDF/FTC with VF (out to 60 months) and no association of tenofovir resistance with VF.
Commentary
In this real-world analysis of treatment experienced people with HIV who switched to a second generation INSTI plus TXF/XTC backbone, two-year rates of virologic failure remained low. Additionally, the presence of tenofovir resistance and/or M184V/I mutations was not associated with virologic failure after switch – providing further evidence to support the robustness of these combinations across diverse populations of people with HIV. Broad access to these well-tolerated and highly effective options remains vital to advance progress in HIV care.
