LAUSR

BACKGROUND AND AIMS To evaluate the hypothesis that increasing T-cell frequency and activity may provide durable control of hepatitis B virus (HBV), we administered nivolumab, a PD-1 inhibitor, with or without GS-4774, an HBV therapeutic vaccine, in virally-suppressed patients with HBeAg negative chronic HBV. METHODS In a Phase 1b study, patients received either single dose of nivolumab at 0.1 mg/kg (n=2) or 0.3 mg/kg (n=12), or 40 yeast units of GS-4774 at baseline and Week 4 and 0.3 mg/kg of nivolumab at Week 4 (n=10). The primary efficacy endpoint was mean change in HBsAg 12 weeks after nivolumab. Safety and immunologic changes were assessed through Week 24. RESULTS There were no grade 3 or 4 adverse events or serious adverse events. All assessed patients retained T-cell PD-1 receptor occupancy 6-12 weeks post-infusion, with a mean total across 0.1 and 0.3 mg/kg cohorts of 76% (95% CI 75,77), and no significant differences were observed between cohorts (p=0.839). Patients receiving 0.3 mg/kg nivolumab without and with GS-4774 had mean declines of -0.30 (95% CI, -0.46,-0.14) and -0.16 (95% CI, -0.33,0.01) log10 IU/mL, respectively. Patients showed significant HBsAg declines from baseline (p=0.035) with three patients experiencing declines of >0.5 log10 by end of study. One patient, whose HBsAg went from baseline 1173 IU/mL to undetectable at Week 20, experienced an ALT flare (grade 3) at Week 4 that resolved by Week 8 accompanied by a significant increase in peripheral HBsAg-specific T-cells at Week 24. CONCLUSIONS In virally suppressed HBeAg-negative patients, checkpoint blockade was well-tolerated and led to HBsAg decline in most patients and sustained HBsAg loss in one patient. Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) number: ACTRN12615001133527.