Comparative activity of selected antiviral compounds against clinical isolates of varicella-zoster virus

Sixteen freshly isolated varicella-zoster virus (VZV) strains were evaluated in vitro, in parallel with two reference strains expressing a functional thymidine kinase (TK+) (Oka and YS) and two thymidine kinase-deficient mutants (TK-) (07-1 and YS-R), for their susceptibility to a broad range of antiviral compounds. The following compounds were included: acyclovir (ACV), brivudine (BVDU), sorivudine (BVaraU), other BVDU congeners such as BTDU, CTDU, CVDC and CVDU, ganciclovir (GCV), FIAC, araT, araA, araC, foscarnet (PFA), phosphonoacetic acid (PAA), the acyclic nucleoside phosphonates HPMPC, cHPMPC, HPMPA, cHPMPA, HPMPc3A, PMEA and PMEDAP, the N7-isomeric acyclic nucleoside analogue N7AP, penciclovir (PCV), compounds 882C87 and H2G and two oxetanocin derivatives OXT-A and OXT-G. Fourteen of the 16 clinical isolates displayed the following order of decreasing selectivity against VZV: BVaraUBVDUCVDU approximately CVDCH2GN7AP approximately CTDU approximately BTDU approximately OXT-G approximately 882C87ACVFIAC approximately araTHPMPC approximately cHPMPC approximately HPMPA approximately HPMPc3A approximately cHPMPAPCV approximately GCV approximately OXT-APMEDAP approximately PMEAPFA approximately PAA approximately araAaraC. Two VZV strains (isolated from the cerebrospinal fluid of an AIDS patient) that were shown to have a truncated TK were clearly resistant to all the compounds that need the viral TK for their phosphorylation, while sensitivity to the acyclic nucleoside phosphonates, PFA, PAA, OXT-A and araA, remained unchanged. A slight (5- and 10-fold) increase was noted in the 50% inhibitory concentration of N7AP and OXT-G, respectively, for the TK- VZV strains as compared to the TK+ VZV strains. Ganciclovir and FIAC also showed a marked decrease in their activity against these two strains, but this was not as pronounced as for the other viral TK-dependent drugs. From our results, it appears that although acyclic nucleoside phosphonates may not have as favourable a therapeutic index as drugs requiring the viral TK, they should be considered for the treatment of TK- VZV life-threatening infections that are resistant to the viral TK-dependent drugs.