Background:
Toll-like receptor 9 (TLR9) agonists stimulate innate antiviral immunity, prime adaptive immune responses and reverse latency in people with HIV-1 infection (PWH). Further, broadly neutralizing anti-HIV-1 antibodies (bNAbs) can boost HIV-specific immunity and enhance killing of infected cells through Fc-dependent mechanisms. Here, we evaluated the impact of the TLR9 agonist Lefitolimod and dual bNAb treatment on ART-free virological control.
Methods:
In a phase IIa multicenter, randomized placebo-controlled, double-blinded trial (TITAN study; NCT03837756), consenting PWH on suppressive ART were pre-screened for bNAb sensitivity and randomized into one of four groups: A) placebo /placebo; B) lefitolimod (LEFI) /placebo; C) placebo /bNAbs; or D) LEFI /bNAbs. LEFI (120 mg) or placebo were given subcutaneously (SC) weekly from week 1 through week 8. 3BNC117 at 30 mg/kg and 10-1074 at 20 mg/kg or placebo were given intravenously (IV) at week 3 and at week 6. Analytical treatment interruption (ATI) of antiretroviral therapy went from week 3 to 26, or viral rebound, whichever came first. The primary endpoint was time to loss of virological control (plasma HIV-RNA >1,000 c/mL for 4 weeks or confirmed >100,000 c/mL). Secondary endpoints were safety and rebound viral kinetics. bNAb sensitivity was assessed by PhenoSense and HIV envelope sequencing.
Results:
46 participants were randomized to either placebo/placebo (n=11), LEFI/placebo (n=11), placebo/bNAbs (n=12), or LEFI/bNAbs (n=12). The median time to loss of virological control was 32 days (interquartile range [IQR]:21-77) in group A, 35 days (IQR:28-42) in group B, 119 days (IQR:77-175) in group C, and 98 days (IQR:70-119) in group D. The groups receiving bNAbs had significant longer time to loss of virological control compared to placebo (log-rank, P< 0.0005). Six individuals did not meet ART restart criteria during the 24-week ATI (1 in B; 4 in C; 1 in D). The combination of LEFI and bNAbs vs. bNAbs alone did not result in improved virological control (log-rank, P=0.42). More mild adverse events were reported in group D. Two severe adverse events were reported (one vasovagal reaction [unrelated] and one infusion related reaction [considered related to 3BNC117]).
Conclusions:
In a double-blinded trial among PWH on suppressive ART, harbouring virus sensitive to study bNAbs, the dual bNAb treatment led to a significant delay in viral rebound during ATI, but there was no added effect on virological control of the TLR9 agonist, lefitolimod.