ABSTRACT: Objectives:To assess the safety and tolerability as well as antiretroviral impact of ABX464, an oral investigational drug with a novel mechanism of HIV-1 inhibition (ClinicalTrials.gov NCT02735863). Methods:Randomised, double-blind, placebo-controlled, Phase IIa study in individuals living with HIV-1 on antiretroviral therapy at six clinical centres in Spain, France and Belgium. ABX464 was administered once a day to 22 fully controlled HIV-1-positive participants at two doses (50?mg, n=6 and 150?mg, n=16) versus placebo, which was given to eight participants for 28 days in combination with a boosted protease inhibitor (darunavir/ritonavir or darunavir/cobicistat). The primary objective of the study was to assess ABX464 safety and tolerability when used in combination with darunavir boosted therapy. The secondary objective was to study antiretroviral efficacy on viral reservoirs using time to viral rebound following treatment interruption. The impact of ABX464 on HIV-1 reservoirs was further assessed by measuring levels of total HIV-1 in peripheral blood mononuclear cells (PBMCs) in the intervention arm versus placebo. A positive response was defined as an absolute reduction in HIV-1 DNA of at least 50 copies/106 PBMCs and a relative decrease >25% of HIV-1 DNA level. Results:Twenty-six of the 30 randomly allocated participants completed the study according to the study protocol. ABX464 was found to be safe and well tolerated with the majority of adverse events (AEs) being mild or moderate. Of the participants, 22 (73.3%) experienced treatment-associated AEs (93.8%, 66.7%, 37.5% in the ABX464 150-mg, 50-mg dose and placebo arms, respectively). Percentages for combined grade 3/4 AEs for the three arms were 6.3%, 0% and 12.5%, respectively. Median time (Kaplan-Meier estimates) to viral rebound for ABX464 150-mg, 50-mg and placebo arms were 12.0 (95% confidence interval [CI]: 10-15), 15.5 (95% CI 14-22) and 15.5 (95% CI 1-22) days, respectively with no significant difference between the 150-mg treatment arm and placebo. Median changes in total HIV-1 DNA copies/106 PBMCs for ABX464 150-mg, 50-mg and placebo arms after 28 days of treatment were -40 (range -434 to +194), -115 (range -116 to -114) and 25 (range -35 to +218), respectively, showing a decrease in the intervention arms. There were 6/14, 2/2, and 0/4 responders for ABX464 150?mg, 50?mg and placebo, respectively. No significant difference was seen between treatment arms and placebo with respect to these virological parameters. Conclusions:This small controlled study confirmed the good safety and tolerability of ABX464 and provides some evidence of a potential reduction of the HIV-1 reservoir in terms of HIV-1 DNA levels in PBMCs when it was added to an HIV-1 protease inhibitor-based regimen. These results will need to be confirmed in a larger study.
