Most HHV-6 or HHV-7 infections in childhood require no specific antiviral therapy, but therapy is indicated for complicated infections especially in immunocompro-mised patients. HHV-6 and HHV-7 lack thymidine kinase and are resistant to acyclovir. The guanine analog Ganciclovir (GCV) is, however, active: 50% effective inhibitory concentration (EC50) for HHV-6A (GCV EC50 is 0.65 mg/mL), for HHV-6B (GCV EC50 is 1.33 mg/mL), and for HHV-7 (GCV EC50 >7 mg/mL). The HHV-7 GCV EC50 is greater than plasma concentrations of GCV routinely achieved with administration of GCV 5 mg/kg intravenously. The U69 gene product of HHV-6 and HHV-7 is a phosphotransferase analog of HCMV UL97, a GCV kinase. It is required to phosphorylate GCV so that it inhibits the viral DNA polymerase (the U38 gene product) (Fig. 2). The HHV-7 phosphotransferase is least efficient at phosphorylating GCV. Point mutations in the U69 and U38 are associated with GCV resistance. HHV-6 and HHV-7 can respond to GCV treatment, but a report exists of prophylactic GCV, administered to transplant recipients, failing to prevent HHV-7 replication despite adequate suppression of HCMV.
The pyrophosphate analog, phosphonoformic acid (Foscarnet, FSC), inhibits the DNA polymerase of all three viruses. It may be of particular use, as in HCMV, in the treatment of infections failing to respond to or resistant to GCV. The acyclic nucleoside phosphonate, cidofovir (CDF), also inhibits DNA polymerase; CDF EC50 is 0.3 mg/mL for HHV-6A, CDF EC50 is 1.2 mg/mL for HHV-6B, and CDF EC50 is 3 mg/mL for HHV-7. U38 mutations may also decrease susceptibility to this agent. Because of
Fig. 2 Mechanism of action of antiviral compounds against HHV-6 and HHV-7. Ganciclovir (G) is phosphorylated by a phosphotransferase (PT) to become the active triphosphorylated compound (aG). aG binds to the viral DNA polymerase (DP) and competitively inhibits the binding of deoxyguanosine triphos-phate (dG) to the polymerase. aG is incorporated into DNA resulting in retardation and cessation of chain elongation. Foscarnet (F) inhibits the binding of a range of deoxynucleotide triphosphates (dN) to the pyrophosphate-binding site of DP and blocks pyrophosphate cleavage. Foscarnet does not require intracellular phosphorylation. Cidofovir requires virus-independent intracellular diphosphorylation (aC). aC competitively inhibits the binding of deoxycytosine triphosphate to DP. aC is incorporated into DNA slowing elongation and, if two successive aC bind, terminating chain elongation. (View this art in color at www.dekker.com.)
nephrotoxicity, there is less experience with this agent in transplant recipients.
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