COMPARATIVE ACTIVITY OF SELECTED ANTIVIRAL COMPOUNDS AGAINST CLINICALISOLATES OF VARICELLA-ZOSTER VIRUS

Sixteen freshly isolated varicella-zoster virus (VZV) strains were eva luated in vitro, in parallel with two reference strains expressing a f unctional 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 inc luded: acyclovir (ACV), brivudine (BVDU), sorivudine (BVaraU), other B VDU congeners such as BTDU, CTDU, CVDC and CVDU, ganciclovir (GCV), FI AC, araT, araA, araC, foscarnet (PFA), phosphonoacetic acid (PAA), the acyclic nucleoside phosphonates HPMPC, cHPMPC, HPMPA, cHPMPA, HPMPc(3 )A, PMEA and PMEDAP, the N-7-isomeric acyclic nucleoside analogue N(7) AP, penciclovir (PCV), compounds 882C87 and H2G and two oxetanocin der ivatives OXT-A and OXT-G. Fourteen of the 16 clinical isolates display ed the following order of decreasing selectivity against VZV: BVaraU > BVDU > CVDU similar to CVDC > H2G > N(7)AP similar to CTDU similar to BTDU similar to OXT-G similar to 882C87 > ACV > FIAC similar to araT > HPMPC similar to cHPMPC similar to HPMPA similar to HPMPc(3)A simila r to cHPMPA > PCV similar to GCV similar to OXT-A > PMEDAP similar to PMEA > PFA similar to PAA similar to araA > araC. Two VN strains (isol ated from the cerebrospinal fluid of an AIDS patient) that were shown to have a truncated TK were clearly resistant to all the compounds tha t need the viral TK for their phosphorylation, while sensitivity to th e acyclic nucleoside phosphonates, PFA, PAA, OXT-A and araA, remained unchanged. A slight (5- and 10-fold) increase was noted in the 50 % in hibitory concentration of N(7)AP and OXT-G, respectively, for the TK- VZV strains as compared to the TK+ VZV strains. Ganciclovir and FIAC a lso showed a marked decrease in their activity against these two strai ns, 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 r equiring 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'