Time to HIV rebound after antiretroviral therapy interruption: a double-blind randomised placebo-controlled trial of long-acting broadly neutralising antibodies; The RIO Trial

BackgroundHIV-specific broadly neutralising antibodies (bNAbs) can maintain viral control after interrupting antiretroviral therapy (ART). We investigated the duration and efficacy of Fc-engineered long-acting bNAbs (LS-bNAbs) in maintaining ART-free HIV control compared with placebo. MethodsRIO is a 1:1 randomised double-blind placebo-controlled trial of two LS-bNAbs (3BNC117-LS & 10-1074-LS) in individuals virally suppressed on ART initiated since early-stage HIV. Eligible participants interrupted ART after receiving blinded infusions of either both LS-bNAbs (Arm-A) or placebo (Arm-B). A second optional blinded infusion was offered after 20 weeks for participants who remained virally suppressed without ART. The primary outcome was time to viral rebound 20 weeks after ART interruption, defined as either the first of six consecutive plasma HIV RNA >1,000 copies/mL, or two measurements >100,000 copies/mL. Secondary outcomes included adverse events, long-term viral control and bNAb pharmacokinetics. FindingsSixty-eight participants were randomised, thirty-four to each arm. By week 20, viral rebound had occurred in 8 Arm-A and 30 Arm-B participants; 75% (95% CI, 61 - 92) of Arm-A participants had not rebounded, compared to 11% (95% CI, 4-29) participants in Arm-B. Arm-A participants were 91% less likely to rebound compared to Arm-B participants (hazard ratio of rebound (HR): 0.09; 95% confidence interval (CI) 0.04 - 0.21, P < 0.001). ART-free viral control using the above endpoints beyond 96 weeks was evident in 7 (25%, 95% CI 13 - 48) Arm-A participants compared to 2 (11%, 95% CI 4 - 29) Arm-B participants (HR: 0.22, 95% CI 0.12 - 0.40, P < 0.001). These seven participants had predicted serum bNAb concentrations below the presumed therapeutic threshold of 10 g/mL at 96 weeks. Of nine serious adverse events, none were study-related. ConclusionLong-acting bNAbs can sustain extended ART-free viral control in people treated during early-stage HIV and represent a promising step towards achieving ART-free HIV remission. FundingThe RIO trial was funded by the Bill & Melinda Gates Foundation (grant ref. OPP1210792). Infrastructure support in the UK for this research was provided by the National Institute of Health Research (NIHR) Imperial Biomedical Research Centre (BRC), the NIHR Imperial Clinical Research Facility (ICRF) and the Oxford NIHR BRC. O_LIStudy/trial registration numbers and date of registration: {circ}UK Research Ethics Committee reference: 19/LO/1669 (11 Sep 2019) {circ}EudraCT: 2019-002129-31 (12 Dec 2019) {circ}EU CTR: 2024-514564-13-00 (02 Jan 2025) {circ}ClinicalTrials.gov Identifier: NCT04319367 (02 Mar 2020) {circ}UK IRAS: 266322 {circ}Sponsor Protocol Number: 19IC5249 {circ}Funder Reference: OPP1210792 C_LI Evidence in contextWe systematically searched Medline, Embase, and Web of Science databases until April 2024 with additional searches updated until January 2026. Combination therapy of HIV-specific broadly neutralising antibodies (bNAbs) has demonstrated periods of viral control for people living with HIV who interrupt their antiretroviral treatment. The development of long-lasting LS-bNAbs with Fc-receptor modifications has been shown to increase the serum half-lives by up to four-fold. To date, the clinical efficacy and duration of ART-free HIV control with LS-bNAbs has not been evaluated in a sufficiently powered human trial. Added value of this studyThe RIO trial; a prospective double blind randomised controlled study for the first time demonstrates that a single dose of two bNAbs 10-1074-LS and 3BNC117-LS was 91% more effective in maintaining ART-free viral control to twenty weeks compared to placebo. The long-term follow up to 96 weeks adds new data on the duration and frequency (25%) of viral control conferred by two doses of LS-bNAbs beyond the expected frequencies of post-treatment control in an early treated cohort of people living HIV. ART-free viral control beyond 96 weeks is likely due to post-bNAb induced mechanisms as modelled bNAb concentrations past this time were below presumed therapeutic thresholds. Administration of LS-bNAbs was safe and not associated with any Severe Adverse Events. Implications of all the available evidenceLS-bNAbs represent a major advance towards ART-free HIV control and remission as an achievable goal. These findings will inform future combination strategies to enhance the mechanisms of post-bNAb HIV control.