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Treatment with the Immunomodulator AIC649 in Combination with Entecavir Produces Antiviral Efficacy in the Woodchuck Model of Chronic Hepatitis B
by Kyle E. Korolowicz
1 [OrcID] , Manasa Suresh
1 [OrcID] , Bin Li
1, Xu Huang
1, Changsuek Yon
1, Xuebing Leng
1 [OrcID] , Bhaskar V. Kallakury
2, Robin D. Tucker
3 [OrcID] and Stephan Menne
1,* [OrcID]
1
Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA
2
Department of Pathology, Georgetown University Medical Center, Washington, DC 20057, USA
3
Division of Comparative Medicine, Georgetown University Medical Center, Washington, DC 20057, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Carla S. Coffin
Viruses 2021, 13(4), 648; https://doi.org/10.3390/v13040648
Received: 9 February 2021 / Revised: 6 April 2021 / Accepted: 7 April 2021 / Published: 9 April 2021
(This article belongs to the Special Issue Recent Advances in Management of Hepatitis B and towards Achieving a HBV Cure)
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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.
Keywords: parapoxvirus; TLR9; entecavir; woodchuck; chronic hepatitis B; antiviral efficacy; immune response |
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发表于 2021-4-26 12:49