Oral famciclovir against duck hepatitis B virus replication in hepatic and nonhepatic tissues of ducklings infected in ovo

Abstract

Detection of hepadnaviral DNA in extrahepatic tissues of human and animal models of hepatitis B virus (HBV) has raised the question of whether virus replication in organs other than the liver could be targeted for the treatment of chronic hepatitis B. Since duck hepatitis B virus (DHBV) replication is dynamic in the liver, kidney, pancreas, and spleen of newly hatched ducklings infected in ovo, we used the duck model and the new antiherpesvirus agent, famciclovir (FCV), to determine whether antiviral effect of nucleoside analogues on DHBV replication is pluripotential. Day-old ducklings hatched from eggs laid by a DHBV-carrier duck were bled and administered FCV (25 mg/kg/bd) orally for periods of 1, 2, 3, 6, 9, and 12 days. Seventeen (17) hours after the last dose of each regimen the duckling(s) was bled and postmortem samples of liver, kidney, pancreas, and spleen were snap-frozen and stored at -70 degrees C. Analysis of plasma samples of ducklings treated for 2 days and longer by dot-blot hybridisation showed that levels of DHBV DNA were reduced significantly compared to levels in samples collected before treatment begun. Southern blot hybridisation of tissue DNA corroborated these results and showed that DHBV DNA replicative intermediates in all the tissues examined were reduced to levels that reflected the amount of virus released into the blood of each treated duckling. It is concluded from these results that if antiviral agents could be transformed to active metabolites in any infected tissues including the liver, replication of hepadnaviruses would be inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibitory Effect of Penciclovir-Triphosphate on Duck Hepatitis B Virus Reverse Transcription

“…These data confirm the activity of their respective nucleosides, which have a validated anti-HBV action in vivo and in tissue culture (Schalm et al, 1985;Ueda et al, 1989;Shaw et al, 1994;Tsiquaye et al, 1994Tsiquaye et al, , 1996Howe etal., 1996;Korba and Boyd, 1996;Kruger et al, 1996;Main et al, 1996). Penciclovir is a highly selective antiviral agent, having activity against herpesviruses (Boyd et al, 1987) and hepadnaviruses (Shaw et al, 1994;Tsiquaye et al, 1994) but being non-toxic to replicating cells (Vere Hodge and Perkins 1989;Boyd et al, 1993). In clinical trials famciclovir has a safety profile comparable to that of placebo (Saltzman et al, 1994) and is being further evaluated clinically as an anti-HBV agent (Kliiger et al, 1996;Main et al, 1996).…”

“…tured hepatocytes, and in vivo in animal models ofHBV infection (Shaw et al, 1994;Tsiquaye et al, 1994Tsiquaye et al, , 1996Korba and Boyd, 1996;Lin et al, 1996). It was also shown that K i for HBV DNA polymerase contrast with high K., for cellular polymerase giving rise to high selectivity (Korba and Boyd, 1996).…”

“…The development of new nucleoside analogues, with a potent anti-HBV activity and minimal cytotoxic effect, such as guanosine analogues (Schalm et al, 1985;Price et al, 1989;Fourel et al, 1994a,b;Sommadossi 1994;Hafk.emeyer etal., 1996;Howe et al, 1996) may provide a promising alternative for the therapy of chronic hepatitis B. Recently, the purine nucleoside analogue, penciclovir (9-(4-hydroxy-3-hydroxymethylbut-I-yl)guanine; BRL 39123), which is a highly selective antiviral agent, having activity against herpesviruses (Boyd et al, 1987;Vere Hodge and Perkins, 1989;Earnshaw et al, 1992), was also shown to have a potent anti-hepadnavirus activity in the animal models of HBV infection (Shaw et al, 1994;Tsiquaye et al, 1994;Lin et al, 1996). Penciclovir was shown to inhibit duck hepatitis B virus (DHBV) replication in vitro in primary duck hepatocytes infected with DHBV (Shaw et al, 1994) and to be a selective inhibitor of HBV replication in cultured human hepatoblastoma cells (Korba and Boyd, 1996).…”

“…Furthermore, results of in vivo experiments showed that the intraperitoneal administration ofpenciclovir induced a profound inhibition of viral DNA and protein synthesis in ducks congenitally infected with DHBV . Famciclovir, its oral form, was also shown to inhibit viral replication in congenitally DHBV-infected ducklings (Tsiquaye et al, 1994(Tsiquaye et al, , 1996. Preliminary evidence suggests that famciclovir may have clinical utility in the treatment of chronic HBV-infected patients (Main et al, 1996) and of HBV recurrence after orthotopic liver transplantation (Kruger et al,1996) In view of the low cytotoxicity of penciclovir and its potent antiviral activity against HBV, it is important to gain a better understanding of the mechanism of inhibition of HBV replication.…”

Inhibition of hepatitis B virus DNA polymerase by enantiomers of penciclovir triphosphate and metabolic basis for selective inhibition of HBV replication by penciclovir

“…These observations provide a mechanistic basis ple, PCV appears to be a more potent and specific inhibitor for the potent activity of PCV against HBV. (HEPATOLOGY of hepadnaviral replication, both in vitro 18 and in vivo 15,19,20 1996;24:996-1002.) than GCV, which is structurally identical except that PCV contains a methylene group in place of oxygen in the pentose ring (Fig.…”