A 34-year-old man with advanced untreated HIV infection has extensive chronic perianal and oral herpes simplex lesions that have not improved despite four weeks of appropriately dosed intravenous acyclovir. Viral culture confirms HSV. The most likely mechanism of resistance is:

• A Mutation of the viral DNA polymerase reducing drug binding
• B Loss or alteration of the viral thymidine kinase enzyme ✓
• C Overexpression of cellular efflux pumps removing acyclovir triphosphate
• D Induction of viral uracil-DNA glycosylase degrading the nucleoside analog

Explanation

Acyclovir requires initial phosphorylation by the viral thymidine kinase; the monophosphate is then converted to the active triphosphate by host kinases. Most clinical HSV resistance arises from absence or alteration of viral thymidine kinase, so the drug is never activated inside the infected cell. Polymerase mutations occur but are far less common, and such strains usually remain susceptible to foscarnet, which bypasses thymidine kinase entirely.

Reference: Katzung's Basic and Clinical Pharmacology, 16th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.