HERPES-SIMPLEX VIRUS-RESISTANCE TO ACYCLOVIR - CLINICAL RELEVANCE

Herpes simplex virus (HSV) infections are very common in the general p opulation and can be treated with the nucleoside analogue acyclovir. A cyclovir is initially phosphorylated intracellularly in HSV-infected c ells by a viral-specific thymidine kinase to acyclovir-monophosphate. The monophosphate is subsequently di- and triphosphorylated by host ce llular kinases to the active form of the drug, which inhibits HSV DNA polymerase and incorporates into the elongating viral DNA and causes c hain termination. Acyclovir resistance has been increasingly described and is caused by mutations in either the thymidine kinase or the DNA polymerase genes. These mutations result in decreased or absent HSV th ymidine kinase production, altered affinity of the thymidine kinase fo r acyclovir-triphosphate, or altered affinity of the HSV DNA polymeras e for acyclovir-triphosphate. Thymidine kinase deficiency accounts for similar to 95% of acyclovir-resistant isolates. Clinical disease due to acyclovir-resistant HSV occurs primarily in immunocompromised patie nts and is usually characterized by a chronic, progressive ulcerative mucocutaneous disease with prolonged shedding of virus. Several large surveys have been done in an effort to determine the incidence of in v itro and clinical acyclovir resistance. Among immunocompetent hosts, e ven those who have received greater than or equal to 6 years of contin uous acyclovir, the prevalence of acyclovir-resistant isolates has rem ained stable at similar to 3%. Only three cases of clinical resistance of HSV to acyclovir have been reported. However, the incidence in imm unocompromised patients, particularly those with AIDS and those who ha ve had bone marrow transplants, is increasing. Transmission of acyclov ir-resistant isolates from person to person has not been documented, b ut due to the increased use of acyclovir and newer drugs, such as famc iclovir, there is great concern that this transmission might occur in the future. Continued surveillance in both immunocompetent and immunoc ompromised hosts for the development of clinical acyclovir-resistant H SV disease is necessary.