Valganciclovir and Human Herpesvirus–8
Ganciclovir is a nucleoside analogue of guanosine and is the mainstay of treatment against human cytomegalovirus (CMV), a γ‐herpesvirus. Ganciclovir is phosphorylated by herpes simplex virus thymidine kinase or the protein phosphokinase (UL97) of cytomegalovirus to form ganciclovir monophosphate. Cellular kinases then form ganciclovir triphosphate, which is a potent inhibitor of viral DNA polymerase. Ganciclovir triphosphate is an effective inhibitor of CMV replication, but it is not a chain terminator like acyclovir. In the presence of ganciclovir triphosphate, viral DNA replication is greatly slowed, but small fragments of CMV DNA around the origin of DNA replication continue to be made and ganciclovir monophosphate is incorporated into these small fragments of CMV DNA.
In clinical use, human CMV can become resistant to ganciclovir and resistance mutations are found in 2 CMV genes, the UL97 protein phosphokinase and the CMV DNA polymerase. The ganciclovir resistance mutations in the UL97 gene cluster at amino acids 460 and 520, as well as from 590–60. A ganciclovir‐resistant mutation results in a UL97 protein that is unable to phosphorylate ganciclovir. Only 6% of orally administered ganciclovir is bioavailable, which greatly restricts its oral use. By attaching a valine ester to ganciclovir (valganciclovir), the bioavailability of the orally administered drug is greatly increased to 68%. A valine esterase in the human gastrointestinal mucosa cleaves the valine and results in ganciclovir in the portal blood circulation. A daily oral dose of 900 mg of valganciclovir twice per day is equivalent to an intravenously administered dose of ganciclovir of 5 mg/kg twice per day.
The article by Casper et al. in this issue of the Journal provides evidence that valganciclovir can also inhibit replication of human herpesvirus–8 (HHV‐8), another γ herpesvirus. Ganciclovir has been shown to be phosphorylated in the presence of both the HHV‐8 thymidine kinase (open reading frame [ORF] 21) and the HHV‐8 phosphotransferase (ORF36). Two other reports, however, provide conflicting evidence, which suggests that the thymidine kinase of HHV‐8 does not phosphorylate ganciclovir. It is not completely clear, therefore, how ganciclovir is activated to ganciclovir triphosphate during HHV‐8 infection. Phosphorylation by a cellular enzyme remains a possibility. It has also been shown that ganciclovir, cidofovir, and foscarnet inhibit the production of HHV‐8 from latently infected cell lines upon stimulation, whereas acyclovir has little or no activity.