Ogbuagu O.Segal-Maurer S.Ratanasuwan W.Avihingsanon A.Brinson C.Workowski K.Antinori A.Yazdanpanah Y.Trottier B.Wang H.Margot N.Dvory-Sobol H.Rhee M.S.Baeten J.M.Molina J.M.Molina J.M.Molina J.M.DeJesus E.Richmond G.J.Berhe M.Ruane P.J.Sinclair G.I.Lichtenstein K.Ramgopal M.N.Wiznia A.Workowski K.Sanchez W.Brinson C.McGowan J.P.Creticos C.M.Berger D.S.Wheeler D.A.Hagins D.Crofoot G.E.Sims J.Osiyemi O.Hodge T.Zurawski C.Ogbuagu O.Segal-Maurer S.Ratanasuwan W.Siripassorn K.Chetchotisakd P.Castagna A.Castelli F.Ronot-Bregigeon S.Molina J.M.Trottier B.Brunetta J.Shirasaka T.Yokomaku Y.Koenig E.Mallolas J.Stellbrink H.J.Hung C.C.Rassool M.Mahidol University2023-08-132023-08-132023-08-01The lancet. HIV Vol.10 No.8 (2023) , e497-e505https://repository.li.mahidol.ac.th/handle/20.500.14594/88313BACKGROUND: Lenacapavir, a first-in-class HIV-1 capsid inhibitor, is in development as a long-acting agent for treating and preventing HIV-1. We aimed to evaluate the efficacy and safety of lenacapavir with an optimised background regimen in adults living with multidrug-resistant HIV-1 up to 52 weeks. METHODS: This ongoing, international, phase 2/3 trial at 42 sites included adults living with multidrug-resistant HIV-1. In cohort 1, 36 participants were randomly assigned (2:1) to add oral lenacapavir (600 mg, days 1 and 2; 300 mg, day 8) or placebo to an existing failing regimen. At day 15, those on oral lenacapavir received subcutaneous lenacapavir 927 mg every 26 weeks; those on placebo started lenacapavir (2-week oral lead-in then subcutaneous). Cohort 1 started an optimised background regimen on day 15. In cohort 2 (non-randomised), 36 participants started an optimised background regimen concurrent with lenacapavir (oral to subcutaneous). Here we report the secondary endpoints of plasma HIV-1 RNA of less than 50 copies per mL or less than 200 copies per mL at week 52 (US Food and Drug Administration snapshot algorithm) in cohort 1 along with results for cohorts 1 and 2 combined. This trial is registered with ClinicalTrials.gov, NCT04150068, and clinicaltrialregister.eu, EudraCT 2019-003814-16 and is ongoing. FINDINGS: Of 72 participants, 46 (64%) had CD4 counts of less than 200 cells per μL and 38 (53%) had no more than one fully active antiretroviral drug at baseline. In cohort 1, 30 of 36 participants (83%, 95% CI 67-94) had less than 50 HIV-1 RNA copies per mL and 31 of 36 participants (86%, 71-95) had less than 200 HIV RNA copies per mL, at week 52. In all, nine participants (four in cohort 1, five in cohort 2) had emergent lenacapavir resistance; four resuppressed (HIV-1 RNA <50 copies per mL) while maintaining lenacapavir use. One participant discontinued study drug owing to injection site reaction. INTERPRETATION: In participants with multidrug-resistant HIV-1, subcutaneous lenacapavir in combination with an optimised background regimen resulted in a high rate of virological suppression up to 52 weeks. FUNDING: Gilead Sciences.Immunology and MicrobiologyArticleSCOPUS10.1016/S2352-3018(23)00113-32-s2.0-851666533192352301837451297