Novel agents for the therapy of varicella-zoster virus infections

Varicella-zoster virus (VZV), a member of the herpesvirus family, is respon sible for both primary (varicella or chickenpox) as well as recurrent (zost er or shingles) infections. Acyclovir has been the mainstay for treating VZ V infections in both immunocompetent and immunocompromised patients. Recent ly, newer anti-VZV drugs, i.e., valaciclovir (the oral prodrug form of acyc lovir) and famciclovir (the oral prodrug form of penciclovir) have been dev eloped and have enlarged the therapeutic options to treat VZV infections. B oth acyclovir and penciclovir are dependent on the virus-encoded thymidine kinase (TK) for their intracellular activation. Although emergence of drug- resistant strains does not occur in immunocompetent patients, several repor ts have documented the isolation of drug-resistant VZV strains following lo ng-term acyclovir therapy in immunocompromised patients. Mutations at the l evel of the Tg are responsible for development of resistance to drugs that depend on the viral TK for their phosphorylation (i.e., acyclovir and penci clovir). Foscarnet, a direct inhibitor of the viral DNA polymerase, which d oes not require activation by the viral TK, is the drug of choice for the t reatment of TK-deficient VZV mutants emerging under acyclovir therapy. Rece ntly, emergence of foscamet-resistant strains has also been reported. Both TK-deficient strains and foscarnet-resistant mutants are sensitive to the a cyclic nucleoside phosphonate cidofovir, CDV, HPMPC, (S)-1-(3-hydroxy-2-pho sphonylmethoxypropyl)cytsoine This agent does not depend on the virus-encod ed TK, but on cellular enzymes for its conversion to the diphosphoryl deriv ative, which then inhibits the viral DNA polymerase.