Background
The extent to which LS-broadly neutralizing antibodies (LS-bNAbs) maintain viral control off ART remains unknown. RIO tested the frequency and durability of viral control of LS-bNAbs compared with placebo in people with treated early HIV.
Methods
RIO is a double-blind randomised 1:1 placebo-controlled trial designed to investigate viral control in the absence of ART. Virally-suppressed participants (aged 18-60) who started ART during early HIV received up to two intravenous infusions >20 weeks apart of bNAbs (3BNC117-LS & 10-1074-LS) (Arm A) or placebo (Arm B), and undertook analytical treatment interruption (ATI). Participants were screened for resistance to 10-1074 based on HIV DNA env sequences. Viral rebound confirmed by an independent committee was based on the first date of 6 consecutive plasma HIV RNA >1,000 or two >100,000 copies/ml. Primary outcome was time to viral rebound at Week 20 after stopping ART, assessed using a Cox proportional hazards model. Secondary outcomes included adverse events, longer term viral suppression, bNAb pharmacokinetics, anti-drug antibody levels, predicted bNAb resistance and T-cell immunity.
Results
Of 145 participants screened, 68 were enrolled. 63/68 had no predicted significant baseline 10-1074 resistance; 5 failed to amplify. By Week 20, 25/68 had not rebounded: 22/34 in Arm A and 3/34 in Arm B. Arm A participants were 91% less likely to rebound over 20 weeks compared to Arm B (HR: 0.09; 95% CI: 0.04, 0.21, p<0.0001). In Arm A 13/34 and 7/34 had not rebounded out to 48 weeks and 72 weeks respectively after ATI, compared to 2/34 and 2/34 in Arm B. Nine SAEs were reported including one death, all unrelated to study drugs, ATI or protocol. There was no evidence of anti-drug antibodies or ART in plasma during the ATIs. Modelled 10-1074-LS and 3BNC117-LS levels remained above 10 µg/ml for 48 (±13 2SD) and 47 (±12 2SD) weeks after last bNAb dose, respectively; 6 participants in Arm A remained virally suppressed off ART beyond week 48 after last bNAb dose. HIV Gag-specific T-cell responses were enhanced following bNAb dosing in those remaining suppressed.
Conclusions
Two LS-bNAbs were safe and significantly improved viral control off ART compared to placebo. Sustained viral suppression after bNAb dosing associated with enhanced T cell immunity is consistent with an immunologically-driven post-bNAb effect.