The guanine nucleoside analog penciclovir is active against chronic duck hepatitis B virus infection in vivo

Abstract

Ducks congenitally infected with duck hepatitis B virus (HBV) were treated with the antiviral guanine nucleoside analog penciclovir for 4 weeks at a dose of 10 mg/kg of body weight per day. The effects of treatment on viremia and intrahepatic viral genome replication, transcription, and translation were examined. In seven of eight penciclovir-treated ducks, viremia was barely detectable after a week of treatment. After 4 weeks of treatment, molecular hybridization studies showed that intrahepatic viral DNA, RNA, and protein levels were significantly reduced compared with those in placebo-treated controls. Synthesis of all viral replicative intermediates, including the normally persistent viral supercoiled DNA species, was inhibited by penciclovir treatment. Examination of liver tissue sections after in situ DNA hybridization or immunohistochemical staining confirmed that viral DNA and protein synthesis had been profoundly inhibited in most hepatic parenchymal cells. However, small subpopulations of cells, in particular the small bile duct epithelial cells, remained strongly positive for duck HBV antigens and DNA despite treatment. There was no evidence of toxicity associated with penciclovir therapy. This study confirms the safety and potent antihepadnaviral activity of penciclovir in vivo but indicates that further improvements in antiviral therapy will be required to completely eliminate HBV infection.

Clearance of Persistent Hepatitis B Virus Infection in Chinese Bone Marrow Transplant Recipients Whose Donors Were Anti–Hepatitis B Core– and Anti–Hepatitis B Surface Antibody–Positive

“…Previously, famciclovir was effective in reducing the intrahepatic replication of duck hepatitis B in vivo [19]. Famciclovir was the first nucleoside analogue shown to significantly reduce the level of viral covalently closed circular DNA species of duck hepatitis B virus, the key intermediate typically resistant to nucleoside analogue therapy [20]. In humans, famciclovir at a dosage of 500 mg three times a day for 16 weeks had a dose-dependent suppressive effect on HBV DNA replication [21].…”

Combination Therapy with Famciclovir and Interferon‐α for the Treatment of Chronic Hepatitis B

“…Penciclovir inhibits duck HBV replication in vitro and in animal experiments [2,3]. Recent clinical trials showed famciclovir to be well-tolerated and to suppress HBV replication in patients with chronic HBV infection [12,13].…”

“…Famciclovir has been approved for treatment of acute herpes zoster and herpes simplex virus infections. Penciclovir is also a potent inhibitor of the HBV DNA polymerase [2] and has been shown to inhibit HBV replication in vitro and in vivo [3].The aim of this pilot study was to evaluate the safety and antiviral and clinical effects of famciclovir alone and when used in combination with IFN-a in patients with chronic HBV infection who did not respond to previous therapy with IFN alone. …”

“…Famciclovir has been approved for treatment of acute herpes zoster and herpes simplex virus infections. Penciclovir is also a potent inhibitor of the HBV DNA polymerase [2] and has been shown to inhibit HBV replication in vitro and in vivo [3].…”

Treatment of chronic hepatitis B: New antiviral therapies

“…This phenomenon is most likely caused by intracellular persistence of circular HBV CCC DNA [90,91] and persistence of virus in nonhepatocyte reservoirs [72]. Monotherapy with these new antiviral agents is unlikely to be sufficient for the eradication of HBV infection in the majority of patients.…”