## Mechanism of Acyclovir Resistance in HSV **Key Point:** Acyclovir requires viral thymidine kinase (TK) for phosphorylation to its active triphosphate form. Resistance arises primarily from TK-deficient or TK-altered mutants. ### Pathophysiology of Resistance 1. **Acyclovir-sensitive HSV** — possesses functional viral thymidine kinase - TK phosphorylates acyclovir → acyclovir monophosphate - Cellular kinases complete conversion to triphosphate - Triphosphate inhibits viral DNA polymerase 2. **Acyclovir-resistant HSV** — deficient or altered TK - Cannot phosphorylate acyclovir - Drug remains inactive - Viral replication continues unimpeded ### Distinguishing Features Table | Feature | Acyclovir-Sensitive | Acyclovir-Resistant | |---------|-------------------|---------------------| | **Viral TK** | Present and functional | Absent or non-functional | | **In vitro susceptibility** | IC₅₀ < 0.5 µM | IC₅₀ > 10 µM | | **Clinical response** | Rapid healing (3–5 days) | Persistent lesions despite therapy | | **Lesion severity** | Variable, unrelated to resistance | Variable, unrelated to resistance | | **Recurrence rate** | Normal pattern | Normal pattern | **High-Yield:** The **presence or absence of viral thymidine kinase** is the molecular discriminator. Clinical severity and recurrence patterns are determined by host immunity and viral strain virulence, not acyclovir susceptibility. **Clinical Pearl:** Acyclovir resistance is rare in immunocompetent hosts (~0.5%) but common in severely immunosuppressed patients (e.g., advanced HIV, post-transplant). Diagnosis requires **viral culture + susceptibility testing** or **PCR-based TK gene sequencing**. **Warning:** Do not confuse clinical failure to respond (may be due to poor absorption, inadequate dosing, or non-HSV etiology) with true acyclovir resistance (molecular defect in TK).
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