Integrase inhibitor regimen showed non-inferiority and fewer adverse events versus boosted protease inhibitor in advanced HIV

BACKGROUND: To date, clinical trials have been underpowered to assess which antiretrovirals perform best in people with advanced HIV disease. We aimed to investigate the efficacy and safety of an integrase inhibitor-containing versus a boosted protease inhibitor-containing regimen for this population. METHODS: In this open-label, multicentre, non-inferiority trial in seven European countries (Spain, France, Italy, Germany, Belgium, Ireland, and the UK), therapy-naive adults with advanced HIV disease were randomly allocated (1:1) to receive either bictegravir, emtricitabine, and tenofovir alafenamide (integrase inhibitor group) or darunavir, cobicistat, emtricitabine, and tenofovir alafenamide (boosted protease inhibitor group) for 48 weeks. Randomisation was computer generated in permuted blocks within strata with block sizes of four and stratified by country and baseline CD4 cell count. The primary composite outcome (time to first occurrence of specified virological or clinical events) and its components were evaluated by Kaplan-Meier and Cox regression analyses in both modified intention-to-treat (mITT) and per-protocol populations. The mITT population included all randomly allocated participants who received at least one dose of the study drug, whereas the per-protocol population excluded those who received incorrect treatment. Non-inferiority of the integrase inhibitor-based regimen versus the boosted protease inhibitor-containing regimen was declared if the upper limit of the 95% CI of the hazard ratio (HR) for the primary composite endpoint was less than 1·606, corresponding to a 12% difference in the cumulative probability of the composite primary endpoint. Adverse events, a secondary endpoint, were recorded at eight visits in all participants. This trial is registered with ClinicalTrials.gov, NCT03696160, and is completed. FINDINGS: Between May 13, 2019, and June 26, 2023, 222 people were randomly assigned to the integrase inhibitor group and 225 to the boosted protease inhibitor group. Of these 447 recruited participants, 442 (99%) participants with a median CD4 count of 41 cells per μL (IQR 17-79) received at least one dose. 358 (81%) of the 442 treated participants self-reported as male and 84 (19%) female, and 276 (62%) were of White ethnicity, 83 (19%) Black, and 83 (19%) other. In the mITT analysis, the 48-week composite primary outcome event occurred in 49 (22%) of 220 participants in the integrase inhibitor group versus 70 (32%) of 222 participants in the boosted protease inhibitor group (adjusted HR 0·70 [95% CI 0·48-1·00]; non-inferiority shown). The per-protocol analysis gave a similar estimated adjusted HR of 0·69 (0·48-1·00; non-inferiority shown). By mITT, drug-related adverse events (grade ≥2) occurred in 16 (7%) of 220 participants in the integrase inhibitor group versus 32 (14%) of 222 in the boosted protease inhibitor group (p=0·043). The rates of serious adverse events or adverse events leading to study discontinuation did not differ between groups. 12 deaths occurred during the study (nine in the integrase inhibitor group and three in the boosted protease inhibitor group), not related to the study drugs. INTERPRETATION: In people with advanced HIV disease, bictegravir, emtricitabine, and tenofovir alafenamide was shown to be non-inferior to darunavir, cobicistat, emtricitabine, and tenofovir alafenamide and resulted in fewer adverse events, supporting its use as a preferred first-line antiretroviral regimen in this vulnerable population. FUNDING: Gilead Sciences and Janssen Pharmaceuticals.