Short-cycle 4-days-per-week maintenance two-drug therapy in people living with HIV (ANRS-177 DUETTO): a randomised, open-label, multicentre, non-inferiority trial.

BACKGROUND: Previous trials have validated the strategy of short-cycle three-drug (triple) antiretroviral therapy for HIV treatment. The main objective of ANRS-177 DUETTO was to assess whether a two-drug (dual) regimen taken on 4 consecutive days per week (4/7-days) was virologically non-inferior to standard dual therapy regimen taken 7 days per week (7/7-days) in participants with HIV and sustained viral suppression. METHODS: This open-label, randomised, parallel, multicentre, non-inferiority trial enrolled adults (aged ≥18 years) living with HIV-1 at 36 ANRS clinical research hospital sites in France. Participants were on dual therapy, for 6 months or more, with plasma viral loads less than 50 copies per mL for more than 12 months, and no resistance to their current therapy. Individuals with CD4 counts of 250 cells per μL or less or with chronic hepatitis B were excluded. Participants were randomly assigned (1:1) to continue their current dual therapy on a 4/7-days or 7/7-days regimen. The primary endpoint was virological failure at week 48 in the modified intention-to-treat (mITT) population, using the US Food and Drug Administration snapshot algorithm with a 5% non-inferiority margin. The Cochran-Mantel-Haenszel test, adjusted for baseline regimen, was used to compare virological failure proportions between groups. Non-inferiority was confirmed if the 95% CI for the adjusted difference in virological failure (4/7-days minus 7/7-days) was less than 5% in both the mITT and per-protocol populations. The trial is completed and was registered with ClinicalTrials.gov (NCT04867083) and EudraCT (2020-003951-13). FINDINGS: Between June 21, 2021, and Jan 24, 2022, 487 individuals were screened. After exclusions, 441 participants were randomly assigned to treatment groups and 433 went on to participate in the study (219 to 4/7-days, 214 to 7/7-days) and were included in the mITT analysis. Median age was 53 years, and 350 (81%) were male. Virological failure occurred in eight (4%) of 219 participants in the 4/7-days group and none of 214 in the 7/7-days group (adjusted difference of 3·7%, 95% CI 1·2-6·2). The per-protocol analysis yielded a similar result (3·7%, 95% CI 1·2-6·3), meaning that non-inferiority was not demonstrated. Grade 3-4 adverse events occurred in ten (5%) of 219 participants in the 4/7-days group and 11 (5%) of 214 in the 7/7-days including one study treatment discontinuation and one death. INTERPRETATION: The 4/7-days short-cycle dual therapy strategy did not demonstrate non-inferiority for virological failure and is not recommended for routine use. FUNDING: Agence Nationale de Recherche sur le Sida et les Hépatites Virales, Maladies Infectieuses Emergentes (Inserm ANRS-MIE). TRANSLATION: For the French translation of the abstract see Supplementary Materials section.