Nucleic acid polymer REP 2139 and nucleos(t)ide analogues act synergistically against chronic hepadnaviral infection in vivo

Abstract

Nucleic acid polymer (NAP) REP 2139 treatment was shown to block the release of viral surface antigen in DHBV–infected ducks and in patients with chronic HBV or HBV/HDV infection. In this preclinical study, a novel combination therapy consisting of REP 2139 with tenofovir disoproxil fumarate (TDF) and entecavir (ETV) was evaluated in vivo in the chronic DHBV infection model. DHBV-infected duck groups were treated as follows: normal saline (control); REP 2139-Ca; TDF; REP 2139-Ca + TDF; REP 2139-Ca + TDF + ETV. After 4-weeks of treatment, all animals were followed for 8 weeks. Serum DHBsAg and anti DHBsAg antibodies (anti-DHBs) were monitored by ELISA and viremia by qPCR. Total viral DNA and cccDNA were quantified in autopsy liver samples by qPCR. Intrahepatic DHBsAg was assessed at the end of follow-up by immunohistochemistry. On-treatment reduction of serum DHBsAg and viremia was more rapid when REP 2139 was combined with TDF or TDF and ETV and, in contrast to TDF monotherapy, no viral rebound was observed after treatment cessation. Importantly, combination therapy resulted in a significant decrease in intrahepatic viral DNA (> 3log) and cccDNA (> 2log), which were tightly correlated with the clearance of DHBsAg in the liver. Conclusion: Synergistic antiviral effects were observed when REP 2139 was combined with TDF or TDF + ETV leading to control of infection in blood and liver, associated with intrahepatic viral surface antigen elimination that persisted after treatment withdrawal. Our findings suggest the potential of developing such combination therapy for treatment of chronically infected patients in the absence of pegylated interferon. This article is protected by copyright. All rights reserved.

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