A 4-days-on and 3-days-off maintenance treatment strategy for adults with HIV-1 (ANRS 170 QUATUOR): a randomised, open-label, multicentre, parallel, non-inferiority trial.

Background: Intermittent (on 4 days per week) antiretroviral therapy (ART) for patients with HIV-1 might be more convenient, better tolerated, and cheaper than continuous treatment. We aimed to establish the efficacy and safety of a 4-days-on and 3-days-off (intermittent) maintenance regimen versus a standard 7 day (continuous) maintenance regimen.

Methods: In a randomised, open-label, multicentre, parallel, non-inferiority trial, we randomly assigned (1:1) adults with HIV-1 infection with a plasma viral load (pVL) of less than 50 copies per mL for more than 12 months and no drug-resistance mutations to either the intermittent regimen or their existing continuous maintenance regimen, with stratification according to third therapeutic agent (protease inhibitor, non-nucleoside reverse transcriptase inhibitor, or integrase-strand transfer inhibitor). Participants were recruited from 59 hospitals throughout France. The main exclusion criteria were CD4 cell count lower than 250 cells per μL and chronic hepatitis B virus infection. The primary endpoint was the proportion of participants in the modified intention-to-treat (mITT) population who started the study strategy presenting treatment success at week 48 (pVL <50 copies per mL without strategy modification), estimated using the US Federal Drug Administration snapshot approach, with a 5% non-inferiority margin. The study was registered with ClinicalTrials.gov (NCT03256422) and EudraCT (2017-000040-17). The trial is now closed.

Findings: From Sept 7, 2017, to Jan 22, 2018, 850 potential participants were screened for eligibility. 647 participants were enrolled and randomly assigned (1:1) to either the intermittent or the continuous treatment group. The mITT population included 636 participants (318 per group). At week 48, in the mITT population, treatment success was recorded in 304 (96%) of 318 participants in the intermittent treatment group and 308 (97%) of 318 in the continuous treatment group (adjusted difference -1·3%, 95% CI -4·2 to 1·7). Six (2%) participants in the intermittent treatment group and four (1%) participants in the continuous treatment group had virological failure. Grade 3-4 adverse events were reported in 29 (9%) participants in the intermittent treatment group and 39 (12%) participants in the continuous treatment group (p=0·320). Daily life satisfaction improved in 153 (59%) of 258 participants in the intermittent treatment group versus 19 (7%) of 255 in the continuous treatment group (p<0·0001). ART costs were 43% lower in the intermittent treatment group than in the continuous treatment group (p<0·0001).

Interpretation: These findings show the non-inferiority of the treatment strategy of 4-consecutive-days-on and 3-days-off strategy maintenance regimen relative to standard continuous ART triple therapy over 48 weeks. 4 days on and off treatment represents a workable, effective alternative strategy for patients with high adherence to ART, and using a drug combination with a high genetic barrier to resistance.

Funding: Institut National de la Santé et de la Recherche Médicale Agence Nationale de Recherche sur le Sida et les Hépatites Virales, Maladies Infectieuses Emergentes.

Competing Interests: Declaration of interests RL has received honoraria from Gilead and ViiV Healthcare and personal grants for attending meetings and travel from ViiV Healthcare, Merck, and Gilead. PDT has received honoraria from Gilead and ViiV Healthcare and personal grants for attending meetings and travel from Gilead, MSD, and ViiV Healthcare. BL has received honoraria for a seminar of medical sales representatives from Gilead. CA has received honoraria for lectures and presentations from ViiV Healthcare, Gilead, Janssen, and MSD and support for attending meeting or travel from Gilead, MSD, and Janssen. CK has received honoraria from MSD and ViiV Healthcare, grants or contracts from ViiV Healthcare and MSD, support for attending meetings and travel from ViiV Healthcare and Gilead and participation on a data safety and monitoring board or advisory board from MSD and ViiV Healthcare. JMM has received grants or contracts for his institution from Gilead, royalties or licenses from Gilead, ViiV Healthcare, and Merck, and a payment for participating on a DSMB or advisory board from Aelix. JC has received research grant for her institution from MSD and ViiV Healthcare, and payment for lectures from Gilead, MSD, and ViiV Healthcare. MD has received grants or contracts from Gilead, ViiV Healthcare, and Abbvie, honoraria from Gilead, ViiV Healthcare, and Merck and support for attending meetings or travel from Janssen and Gilead. LMJ has received honoraria for advisories or invited talks to conferences from Gilead, Merck, MSD, Janssen, and ViiV Healthcare, and support for attending meetings or travel from Gilead, Merck, and MSD. DC has received grant or contracts for HIV grant for her institution from Janssen, and honoraria for two HIV lectures from Gilead. All author authors declare no competing interests.

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