BackgroundTenofovir containing antiretroviral therapy regimens may bring long-term toxicity-related side effects. We aimed to assess the virological efficacy of co-formulated darunavir-ritonavir plus lamivudine compared to darunavir-ritonavir plus tenofovir and emtricitabine or lamivudine. MethodsThe ANDES study was a 48-week, phase 4, randomized, open-label, non-inferiority trial in naïve adults living with HIV. Patients were randomized 1:1 to receive a daily oral regimen of either dual therapy based on a generic co-formulation of darunavir-ritonavir (800/100 mg) plus a generic lamivudine 300 mg pill, or triple therapy with darunavir-ritonavir plus tenofovir/emtricitabine (300/200 mg) or tenofovir/lamivudine (300/300 mg). The primary endpoint was the proportion of patients with a viral load of less than 50 copies/mL at week 48 in the intention-to-treat population. We used the FDA snapshot algorithm and a non-inferiority margin of -12%. Secondary objectives included safety analysis in the per-protocol population. This study is registered at ClinicalTrials.gov, NCT02770508. ResultsBetween November 2015 to October 31, 2020, 336 participants were randomly assigned either to the triple therapy arm (165) or the dual therapy arm (171). After 48 weeks, 153 patients in the triple therapy group (93%) and 155 patients in the double therapy group (91%) achieved virological suppression (difference -2·1%, 95%CI -7·0 to 2·9). Drug-related adverse events were more common in the triple therapy group (p=0·04). Two toxicity-related events led to discontinuation in each group. InterpretationCo -formulated darunavir/ ritonavir plus lamivudine has shown non-inferiority and a safer toxicity profile compared to a standard-of-care triple regimen including tenofovir in treatment-naïve patients.