Treatment with the Immunomodulator AIC649 in Combination with Entecavir Produces Antiviral Efficacy in the Woodchuck Model of Chronic Hepatitis B.

Kyle E Korolowicz,Xu Huang,Robin D Tucker,Stephan Menne,Xuebing Leng,Bhaskar V Kallakury,Changsuek Yon,Bin Li,Manasa Suresh

doi:10.3390/v13040648

Kyle E Korolowicz, Xu Huang + Show 7 more

Open Access

https://doi.org/10.3390/v13040648

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Abstract

As current interventions for chronic hepatitis B (CHB) rarely induce cure, more effective drugs are needed. Short-term treatment of woodchucks with the novel immunomodulator AIC649, a parapoxvirus-based stimulator of toll-like receptor 9 dependent and independent pathways, has been shown to reduce viral DNA and surface antigen via a unique, biphasic response pattern. The present study evaluated long-term AIC649 treatment in combination with Entecavir for potency and safety in woodchucks. AIC649 monotreatment induced modest reductions in serum viral DNA and surface and e antigens that were associated with the same biphasic response pattern previously observed. Entecavir monotreatment reduced transiently viremia but not antigenemia, while AIC649/Entecavir combination treatment mediated superior viral control. Undetectability of viral antigens and elicitation of antibodies in AIC649/Entecavir-treated woodchucks correlated with the expression of interferons and suppression of viral replication in liver. Combination treatment was well tolerated, and liver enzyme elevations were minor and transient. It was concluded that the AIC649-mediated effects were most likely based on an improvement and/or reconstitution of antiviral immune responses that are typically deficient in CHB. As a combination partner to Entecavir, the antiviral efficacy of AIC649 was markedly enhanced. This preclinical study supports future evaluation of AIC649 for treatment of human CHB.

Highlights

Chronic infection with the hepatitis B virus (HBV) is a major public health concern.It is estimated that 257 million individuals worldwide are chronic carriers of HBV who have an elevated risk of developing chronic hepatitis B (CHB), liver cirrhosis, and hepatocellular carcinoma (HCC) [1]
For assessing the therapeutic efficacy and safety of the immunomodulator AIC649, five woodchucks with established chronic woodchuck hepatitis virus (WHV) infection each were treated with the following regimens: Double placebo treatment (Control Group), AIC649 monotreatment (AIC649 Group), ETV monotreatment (ETV Group), and AIC649/ETV combination treatment (AIC649/ETV Group) (Figure 1)
In animals treated with AIC649 alone, WHV DNA levels initially increased by 0.31 log10 on average during the first two weeks of active treatment and declined transiently by 0.53 log10 during the two weeks, when compared to the Control Group

Summary

Introduction

Chronic infection with the hepatitis B virus (HBV) is a major public health concern.It is estimated that 257 million individuals worldwide are chronic carriers of HBV who have an elevated risk of developing chronic hepatitis B (CHB), liver cirrhosis, and hepatocellular carcinoma (HCC) [1]. Indirect evidence for treatment-induced reduction of this viral molecule includes the loss of HBV surface antigen (HBsAg), but even after five years of therapy with current NAs, induction of a functional cure, which is defined as clearance of circulating HBV DNA and HBsAg with or without subsequent seroconversion to antibodies against HBsAg (anti-HBs antibodies) [5], is a rare event and only achieved in 3–4% of patients on average [6,7]. One major goal to be achieved by new HBV therapeutics is to mimic the benefits of IFN-α therapy in regard to inducing a functional cure but in more than one-tenth of HBV-infected patients after a finite course of treatment, and without the side effects associated with the systemic administration of this pleiotropic cytokine

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