Abstract

Background and Aims: Analyzing the interplay among serum HBV-DNA, HBsAg, anti-HBs, and ALT during nucleic- acid polymers (NAPs) based therapy for chronic hepatitis B provides a unique opportunity to identify kinetic patterns associated with functional cure.

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Methods: All participants with HBeAg-negative chronic HBV infection in the REP401 study (NCT02565719) first received 24 weeks of tenofovir-disoproxil-fumarate (TDF) monotherapy. The early-triple therapy group (n=20) next received 48 weeks of TDF+pegylated interferon-α2a (pegIFN)+NAPs. In contrast, the delayed-triple therapy group(n=20), next received 24 weeks of TDF+pegIFN prior to 48 weeks of triple therapy. Three participants discontinued treatment and were excluded. Functional cure (HBsAg and HBV DNA not detectable with normal ALT) was assessed at 48 weeks post-treatment. Different kinetic phases were defined by at least a 2-fold change in slope. A single-phase decline was categorized as monophasic and two-phase declines were categorized as biphasic.

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Results: Fourteen (35%) participants achieved functional cure. HBV DNA remained below or near undetectable for all participants by the end of TDF monotherapy and during subsequent combination therapies. Three HBsAg-kinetic patterns were found in both the early and delayed groups, non-responders (n=4 and n=4), monophasic (n=11 and n=11), and biphasic (n=4 and n=3), respectively. All participants who achieved a functional cure had a monophasic HBsAg kinetic pattern during triple therapy. Among participants with a monophasic HBsAg decline, those who had a functional cure had a shorter median time to HBsAg loss of 21weeks [interquartile range 11]) compared to those who did not achieve functional cure (median 27 [7] weeks) [p=0.012].

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Conclusions: Functional cure was associated with a rapid monophasic HBsAg decline during NAP-based therapy. A non-monophasic HBsAg-kinetic pattern had a 100% negative-predictive value for functional cure.