Benefit of transaminase elevations in establishing functional cure of HBV infection during nap-based combination therapy.

Treatment of HBV infection with nucleic acid polymers and pegIFN is accompanied by transaminase elevations in 95% of participants. HBV viral rebound, partial cure (HBV DNA < 2000 IU/mL, normal ALT) or functional cure (HBV DNA target not detected, HBsAg <LLOQ, normal ALT) occurred in 27%, 38% and 35% of participants. Correlations between ALT, AST and GGT elevations, virologic baseline, response during therapy and HBV therapeutic outcome were investigated. A retrospective analysis of all 40 participants in the REP 401 study (NCT02565719) included maxima and area under the curve for ALT, AST and GGT, baseline virology, HBsAg and anti-HBs response and HBV therapeutic outcomes. ALT, AST and GGT elevations were asymptomatic, independent of baseline virologic status and anti-HBs response but correlated with HBsAg reduction ≥3 log10 from baseline. Functional cure was associated with significantly lower HBsAg during the nadir of ALT flares versus viral rebound or partial cure. ALT elevations >3X ULN while HBsAg was <1 IU/mL occurred in 3/11 (27%), 11/15 (74%) and 14/14 (100%) of participants experiencing viral rebound, partial or functional cure. ALT elevation >3X ULN during HBsAg <1 IU/mL and <10 IU/mL were the best predictors of partial and functional cure. In conclusion, elevations in ALT, AST or GGT while HBsAg <10 IU/ml during therapy with REP 2139 + pegIFN are associated with partial and functional cure. More potent HBsAg reduction during flare nadir is associated with the establishment of functional cure, suggesting a critical role for HBsAg-specific immunity to achieve this outcome. These on-therapy milestones may have similar positive prognostic value with other combination therapies.