HBV serum RNA kinetics during nucleic acid polymers based therapy predict functional cure.

Abstract

Serum HBV-RNA is proposed to be a circulating marker of cccDNA transcriptional activity in hepatocytes. The combination of tenofovir-disoproxil-fumarate (TDF) and pegylated-interferon-alpha-2a (pegIFN) with nucleic-acid polymer (NAP) treatment was associated with a relatively high rate of functional cure (FC) 48 weeks after discontinuation of all therapy. We aim to characterize HBV RNA kinetics under TDF and pegIFN ± NAP combination therapies. Forty participants with chronic HBV in the REP401 phase-II clinical trial received 48 weeks of triple combination therapy with NAPs, pegIFN, and TDF. For 20 participants, triple combination therapy (TDF + pegIFN + NAPs) followed 24 weeks of TDF. For 20 other participants, triple combination therapy followed 24 weeks of TDF monotherapy and 24 weeks of dual therapy (TDF + pegIFN). The Abbott RUO assay for HBV RNA (LLoQ = 1.65 logU/mL) was performed every 4 weeks. Previously unrecognized HBV RNA kinetic patterns were identified with dual/triple therapy including (i) no change (ii) an increase followed by a new elevated plateau (only under dual therapy) and (iii) a transient increase followed by a spontaneous decline. All participants establishing a new elevated HBV RNA plateau level experienced a subsequent monophasic decline following the introduction of NAPs. Failure to reach HBV RNA LLoQ by 16 weeks of triple therapy had a negative predictive value of 100% for FC. The median HBV RNA half-life for participants in the virological-rebound group was significantly (p = 0.01) longer than in the partial and FC groups (5.7 vs 2.7 weeks, respectively). Achieving partial/functional cure is associated with a shorter HBV RNA half-life, which could reflect faster inactivation of cccDNA transcriptional activity.