Antiviral therapy of herpes simplex virus infection: recent developments

Since 1981, the standard therapy of herpes simplex virus infections has been based on acyclovir. Valaciclovir, the l-valine ester of acyclovir and famciclovir, a pro-drug of penciclovir with an improved oral bioavailability have been recently licensed. HPMPC, an acyclic nucleoside phosponate, is highly active and shows a broad range of activity against all the herpes viruses, and it is far more efficient than ganciclovir against cytomegalovirus. Ribonucleotidase inhibitors have so far been unsuccessful in the treatment of acyclovir-resistant HSV infections. In the future, anti-sense oligonucleotides may play a role in the therapy of herpes virus infections and many efforts continue to be made to develop vaccines which may prevent recurrences in already infected individuals. Resistance to anti-HSV agents is almost exclusively encountered in immunocompromised patients. Failure of acyclovir therapy is mostly due to viral thymidine kinase (TK) deficiency as a result of mutation in the TK gene. Until now, the only alternatives for the treatment of acyclovir-resistant infections have been the intravenous administration of foscarnet, frequently associated with relatively severe side effects, or the topical application of trifluridine either as single agent or in combination with interferon alpha. In vitro observations suggest that the failure of antiviral therapy is not directly due to the emergence of resistant virus isolates. Reduced uptake or activation of acyclovir may represent a selective pressure for resistant isolates in immunocompromised patients. New prodrugs with increased bioavailability, such as valaciclovir and famciclovir will perhaps prevent or delay the emergence of drug resistant isolates in immunocompromised patients since higher intracellular levels of the active compound can be achieved.