Discussion
PWH, viral suppression
In this randomized, placebo-controlled HIV-1 cure trial among PWH on long-term ART who screened sensitive to the study bNAbs, we found that two doses of 3BNC117 and 10-1074 in the setting of ATI led to a significant delay in viral rebound compared to placebo. We also observed that 36% of individuals in the placebo/bNAb group compared to none in the placebo group maintained partial or complete virologic control at the end of the 25-week ATI. There were no differences in time to viral rebound or change in reservoir size between the placebo/placebo and the lefitolimod/placebo group or between the placebo/bNAb and lefitolimod/bNAb group. Thus, although there was no added clinical or immunological benefit of combining lefitolimod with bNAbs, antibody treatment alone led to a significant delay in viral rebound, and some bNAb-treated individuals experienced long-term ART-free virologic control.Single-arm trials show that bNAb-sensitive PWH on long-term ART receiving 3–8 infusions of 3BNC117 and 10-1074 maintain prolonged viral suppression in the absence of ARTOf note, we administered 10-1074 at 20 mg kgIn our study, 18% of participants (2/11) in the placebo/bNAb group maintained complete virologic control (HIV RNA <20 copies per milliliter) throughout the 25-week ATI, and both elected to continue off ART after the ATI ended. In previous trials using the same bNAb combination, 0% (0/7)Although virologic or immunological features characteristic of post-bNAb controllers have yet to be identified, pre-ATI HIV-1 reservoir size was seven-fold lower in post-ART controllers compared to non-controllers in a cohort studyAs expected, we found that HIV-1-specific CD8The combination of 3BNC117 and 10-1074 neutralizes a broad range of HIV-1 subtypes ex vivoLefitolimod alone or in combination with bNAbs did not significantly impact time to viral rebound or any of the immunological or virologic outcomes in this trial. Unexpectedly, co-administration of lefitolimod led to a faster decline in bNAb serum concentrationsThe combination of a TLR7 agonist and PGT121 was shown to induce long-term ART-free virologic control among 34–45% of NHPsDespite lefitolimod’s well-documented ability to enhance DC-mediated cross-presentation, upregulate IFN-stimulated genes and activate multiple innate and adaptive immune cell subsetsThe reported results have limitations and may not be generalizable to all PWH. Specifically, our ability to predict proviral bNAb sensitivity based on the PhenoSense assay or sequence analysis is limited. Undetected bNAb resistance leading to treatment failure may have clinical implications, particularly if bNAbs were to replace modern ART regimens as suppressive antiviral treatment or if used in combination with the new long-acting small-molecule-based injectable antivirals. Most enrolled participants were male. In contrast to some bNAb trialsAlthough lefitolimod and bNAbs were overall safe, the CD4In conclusion, although there was no added benefit of combining a TLR9 agonist with bNAbs compared to bNAbs alone, this was, to our knowledge, the first placebo-controlled, double-blinded trial to show prolonged ART-free virologic control during ATI in individuals receiving just two doses of bNAbs. This finding provides further support for investigating bNAbs as a component in long-acting treatment and HIV-1 curative strategies. However, additional interventions, optimization of bNAbs and bNAb drug combinations