Antiviral activities of oral 1-O-hexadecylpropanediol-3-phosphoacyclovir and acyclovir in woodchucks with chronic woodchuck hepatitis virus infection

Acyclovir triphosphate is a potent inhibitor of hepatitis B virus DNA polym erase, but acyclovir treatment provides no benefit in patients with hepatit is B virus infection. This is due in part to the fact that hepatitis B viru s, unlike herpes simplex virus, does not code for a viral thymidine kinase which catalyzes the initial phosphorylation of acyclovir. We synthesized 1- O-octadecyl-sn-glycero-3-phospho (3-P)-acyclovir and found that it was high ly active in reducing hepatitis B virus replication in 2.2.15 cells, while acyclovir was inactive, The greater antiviral activity of 1-O-octadecyl-sn- glycero-3-P-acyclovir appeared to be due to liver cell metabolism of the co mpound to acyclovir monophosphate (K. Y. Hostetler et al., Biochem. Pharmac ol. 53:1815-1822, 1997), However, a closely related compound without a hydr oxyl group at the sn-2 position of glycerol, 1-O-hexadecylpropanediol-3-P-a cyclovir, was more active and selective in 2.2.15 cells in vitro. In this s tudy, we treated woodchucks chronically infected with woodchuck hepatitis v irus with increasing oral doses of 1-O-hexadecylpropanediol-3-P-acyclovir a nd assessed the response to therapy versus acyclovir or a placebo. At a dos age of 10 mg/kg of body weight twice a day, the test compound significantly inhibited viral replication in vivo, as indicated by a 95% reduction in se rum woodchuck hepatitis virus DNA levels and by a 54% reduction in levels o f woodchuck hepatitis virus replicative intermediates in the liver, Higher doses were somewhat less effective. In contrast, 20 mg of acyclovir/kg twic e daily, a 5.3-fold-higher molar dosage, had no demonstrable activity again st woodchuck hepatitis virus. Oral 1-O-hexadecylpropanediol-3-P-acyclovir a ppeared to be safe and effective in chronic woodchuck hepatitis virus infec tion.