Integrase versus protease inhibitor therapy in advanced HIV disease (LAPTOP): a multicountry, randomised, open-label, non-inferiority trial - 01/12/25

Doi : 10.1016/S1473-3099(25)00681-4

Georg M N Behrens, ProfMD ^a,^b,^c,⁎ , Lambert Assoumou, ProfPhD ^d, Geoffroy Liegeon, MD ^e,^f, Andrea Antinori, ProfPhD ^g, Rafael Micán, MD ^h, Francesco G Genderini, MD ⁱ, Frank A Post, ProfPhD ^j, Jürgen K Rockstroh, ProfMD ^k, Lisa Hamzah, PhD ^l, Pere Domingo, PhD ^m, Adrian Curran, PhD ⁿ, Montserrat Laguno, PhD ^o, Carl Fletcher, BSc ^p, Jack Moody, BSc ^p, Anton Pozniak, ProfMD ^q,^r
on behalf of the
NEAT-ID Foundation
Georg M N Behrens, Brenda Crabtree, Nikos Dedes, Carlo Giaquinto, Beatriz Grinsztejn, Esteban Martinez, Jean-Michel Molina, Anton Pozniak, Jürgen K Rockstroh, Francois Venter

and
LAPTOP Study Team^{^†}
Members listed at the end of the Article
Andrea Antinori, Cristina Gómez Ayerbe, Georg M N Behrens, Phil Bright, Mar Masia Canuto, Antonella Castagna, Aoife Cotter, Alberto Díaz De Santiago, Pere Domingo, Adriàn Curran Fabregas, Julie Fox, Lucio Jesus Garcia-Fraile, Francesco Giovanni Genderini, Andrea Giacomelli, Juan Gonzalez, Giovanni Guaraldi, Lisa Hamzah, Elbushra Herieka, Guillen Sirera Jiménez, Margaret Anne Johnson, Christine Katlama, Stephen Kegg, Chris Kenyon, Hernando Knobel, Karine Lacombe, Montserrat Laguno, Clara Lehmann, Pierre Leroy, Alain Makinson, Patrick Mallon, Giulia Marchetti, Rob Miller, Jean-Michel Molina, Roya Movahedi, Chloe Meave Orkin, Federico Pulido Ortega, Jose Luis Casado Osorio, Patrick Philibert, Joaquín Portilla, Frank Alexander Post, Francois Raffi, Jose Ramon Blanco Ramos, Iain Reeves, Jürgen Rockstroh, Karen Rogstad, Maria Saumoy, Guido Schäfer, Sarah Schoeman, Christoph D Spinner, Christoph Stephan, Janina Trauth, Andrew Peter Ustianowski, Linos Vandekerckhove, Alan Winston

^a Department of Rheumatology and Immunology, Hannover Medical School, Hanover, Germany
^b Centre for Individualized Infection Medicine, HZI–Hannover Medical School, Hanover, Germany
^c German Centre for Infection Research Partner Site Hannover–Braunschweig, Hanover, Germany
^d Sorbonne University, Inserm, Pierre Louis Institute of Epidemiology and Public Health, Paris, France
^e Paris Cité University and Sorbonne University, Paris, France
^f Department of Infectious and Tropical Diseases, Saint-Louis and Lariboisière Hospital, Paris, France
^g Clinical and Research Department, IRCCS Lazzaro Spallanzani National Institute for Infectious Diseases, Rome, Italy
^h Infectious Diseases Unit, La Paz University Hospital, Madrid, Spain
ⁱ Infectious Diseases Department, Saint-Pierre University Hospital, Brussels, Belgium
^j Department of Sexual Health and HIV, Kings College Hospital NHS Foundation Trust, London, UK
^k Department of Internal Medicine, University Hospital Bonn, Bonn, Germany
^l Department of Clinical Infection, St George’s Hospital, London, UK
^m Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
ⁿ Department of Infectious Diseases, Vall d’Hebron University Hospital, Barcelona, Spain
^o Infectious Diseases Service, Hospital Clinic de Barcelona, Barcelona, Spain
^p Research Organisation (KC), London, UK
^q Chelsea and Westminster Hospital, London, UK
^r London School of Hygiene & Tropical Medicine, London, UK

^*Correspondence to: Georg M N Behrens, Department of Rheumatology and Immunology, Hannover Medical School, Hanover 30625, GermanyDepartment of Rheumatology and ImmunologyHannover Medical SchoolHanover30625Germany

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Monday 01 December 2025

Summary

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.