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Acyclovir-resistant Genital Herpes in an Immunocompetent Man

Acyclovir, in topical and oral form, has been available for a decade and has been used by millions of patients. There has been concern that strains of herpes simplex virus (HSV) or varicella-zoster virus (VZV) will develop resistance to acyclovir during therapy, and that drug-resistant strains will be transmitted to other persons, resulting in primary acyclovir-resistant HSV or VZV infections. To date, neither of these concerns has materialized to a significant degree. Approximately 4% of persons with HIV disease have infections with acyclovir-resistant HSV strains. In the majority of cases, these infections are successfully treated with foscarnet; if HSV infection recurs, it is often with a different strain, one that is acyclovir-sensitive. In comparison, little has been published on acyclovir-resistant HSV or VZV infections in immunocompetent persons.

This report describes the case of a 24-year-old immunologically normal man with frequently recurring, symptomatic, culture-positive outbreaks of genital herpes. He was an active homosexual and had sexual exposure to several HIV-infected men; the patient was reported to be HIV-seronegative. The initial genital herpes outbreak was treated with acyclovir (200 mg five times daily for five days) and promptly resolved. The first recurrence occurred five months later and was treated with long-term acyclovir therapy (200 mg twice per day). Within three months, another outbreak occurred despite suppressive therapy. The acyclovir dose was increased to 4.8 g per day, and despite sustained, appropriate serum drug levels, new lesions occurred. HSV isolates recovered from six sequential outbreaks were resistant to acyclovir. All isolates were identical according to multiple biochemical and molecular criteria.

For acyclovir to have antiviral activity the drug must first be converted to its monophosphate derivative by viral thymidine kinase; cellular kinases then convert the drug to its active triphosphate form, which inhibits viral DNA polymerase and viral reproduction. Resistance to acyclovir can arise either by mutations in the viral thymidine kinase gene, resulting in thymidine kinase-deficient (TK^-) virus strains, or by point mutations that alter the specificity of thymidine kinase for some of its potential substrates, leading to a thymidine kinase-altered (TK^A) viral phenotype. Acyclovir-resistant HSV isolates from the case reported here had a predominantly TK^A phenotype.

Comment: Because resistance to acyclovir was documented shortly after the patient started secondary acyclovir prophylaxis, it is possible that his primary infection was with an already acyclovir-resistant HSV strain, rather than that the resistance developed after long-term acyclovir therapy. Primary HSV infection with acyclovir-resistant strains has been rare, but could become more common in the growing population of sexually active immunocompromised patients with acyclovir-resistant HSV infections.

The FDA is currently deciding whether to permit sale of acyclovir as an over-the-counter drug. It is possible that more widespread use of acyclovir could facilitate development of resistance. However, from the experience of the past decade, it seems unlikely that acyclovir-resistance will emerge as a clinically significant problem during the next decade.

— RA Johnson

Published in Journal Watch Dermatology February 1, 1994

Citation(s):

Kost RG et al. Brief report: Recurrent acyclovir-resistant genital herpes in an immunocompetent patient. N Engl J Med 1993 329 1777-1781.

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