Abstract
SB 9200, an orally bioavailable dinucleotide, activates the viral sensor proteins, retinoic acid-inducible gene 1 (RIG-I) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) causing the induction of the interferon (IFN) signaling cascade for antiviral defense. The present study evaluated the overall antiviral response in woodchucks upon induction of immune response, first with SB 9200 followed by Entecavir (ETV) versus reduction of viral burden with ETV followed by SB 9200 immunomodulation. Woodchucks chronically infected with woodchuck hepatitis virus (WHV) were treated orally with SB 9200 (30 mg/kg/day) and ETV (0.5 mg/kg/day). Group 1 received ETV for 4 weeks followed by SB 9200 for 12 weeks. Group 2 received SB 9200 for 12 weeks followed by ETV for 4 weeks. At the end of treatment in Group 2, average reductions of 6.4 log10 in serum WHV DNA and 3.3 log10 in WHV surface antigen were observed whereas in Group 1, average reductions of 4.2 log10 and 1.1 log10 in viremia and antigenemia were noted. Both groups demonstrated marked reductions in hepatic WHV nucleic acid levels which were more pronounced in Group 2. Following treatment cessation and the 8-week follow-up, recrudescence of viral replication was observed in Group 1 while viral relapse in Group 2 was significantly delayed. The antiviral effects observed in both groups were associated with temporally different induction of IFN-α, IFN-β, and IFN-stimulated genes in blood and liver. These results suggest that the induction of host immune responses by pretreatment with SB 9200 followed by ETV resulted in antiviral efficacy that was superior to that obtained using the strategy of viral reduction with ETV followed by immunomodulation.
Highlights
Chronic infection with hepatitis B virus (HBV) is a major health problem and responsible for approximately 1.2 million deaths per year worldwide [1]
Immediate rebound in viremia and antigenemia was observed in Group 1, and woodchuck hepatitis virus (WHV) DNA and WHV surface antigen (WHsAg) returned to pretreatment within 2–6 or 3–8 weeks, respectively, indicating some variability among individual woodchucks
It is of note that serum WHsAg levels of four woodchucks of this group were near the lower limit of quantification of the ELISA assay (M4004, F4007 and M4010 at week 17 and M4008 at week 20), suggesting that continued sequential treatment beyond 16 weeks may result in much greater suppression of WHV viremia and antigenemia, including undetectable WHsAg
Summary
Chronic infection with hepatitis B virus (HBV) is a major health problem and responsible for approximately 1.2 million deaths per year worldwide [1]. Current antiviral therapies for chronic hepatitis B (CHB) are limited to nucleos(t)ides and interferon-alpha (IFN-α) which require prolonged administration for reducing viral load and for improving the long-term outcome of CHB, but rarely lead to a cure [4]. Use of these antivirals is further limited due to the emergence of drug-resistant variants during treatment, the risk of relapse upon treatment discontinuation, and unwarranted side effects [4]
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