title: Antiviral Efficacy and Host Immune Response Induction during Sequential Treatment with SB 9200 Followed by Entecavir in Woodchucks.
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.
authors.affiliation: Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, District of Columbia, United States of America.
authors.forename: Manasa
authors.initials: M
authors.lastname: Suresh
authors.affiliation: Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, District of Columbia, United States of America.
authors.forename: Kyle E
authors.initials: KE
authors.lastname: Korolowicz
authors.affiliation: Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, District of Columbia, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Balarezo
authors.affiliation: Spring Bank Pharmaceuticals, Inc., Milford, Massachusetts, United States of America.
authors.forename: Radhakrishnan P
authors.initials: RP
authors.lastname: Iyer
authors.affiliation: Spring Bank Pharmaceuticals, Inc., Milford, Massachusetts, United States of America.
authors.forename: Seetharamaiyer
authors.initials: S
authors.lastname: Padmanabhan
authors.affiliation: Spring Bank Pharmaceuticals, Inc., Milford, Massachusetts, United States of America.
authors.forename: Dillon
authors.initials: D
authors.lastname: Cleary
authors.affiliation: Spring Bank Pharmaceuticals, Inc., Milford, Massachusetts, United States of America.
authors.forename: Rayomand
authors.initials: R
authors.lastname: Gimi
authors.affiliation: Spring Bank Pharmaceuticals, Inc., Milford, Massachusetts, United States of America.
authors.forename: Anjaneyulu
authors.initials: A
authors.lastname: Sheri
authors.affiliation: Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, District of Columbia, United States of America.
authors.forename: Changsuek
authors.initials: C
authors.lastname: Yon
authors.affiliation: Department of Pathology, Georgetown University Medical Center, Washington, District of Columbia, United States of America.
authors.forename: Bhaskar V
authors.initials: BV
authors.lastname: Kallakury
authors.affiliation: Department of Comparative Medicine, Georgetown University Medical Center, Washington, District of Columbia, United States of America.
authors.forename: Robin D
authors.initials: RD
authors.lastname: Tucker
authors.affiliation: Spring Bank Pharmaceuticals, Inc., Milford, Massachusetts, United States of America.
authors.forename: Nezam
authors.initials: N
authors.lastname: Afdhal
authors.affiliation: Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, District of Columbia, United States of America.
authors.forename: Stephan
authors.identifier: http://orcid.org/0000-0001-6873-4084
authors.initials: S
authors.lastname: Menne
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017919:Hepatitis B Virus, Woodchuck / Q000187:drug effects / Q000276:immunology / Q000472:pathogenicity*; D008099:Liver / Q000821:virology; D008392:Marmota / Q000821:virology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; C413685:entecavir; D006147:Guanine