Repurposing Purine Analog Antivirals to Modulate Serum Uric Acid: Evidence From Real‐World Data

Xanthine oxidase (XO) inhibitors remain the standard pharmacologic therapy for hyperuricemia. However, additional enzymatic components of the purine degradation pathway may contribute to uric acid synthesis. Guanine deaminase (GD) catalyzes the conversion of guanine to xanthine, providing substrate for downstream oxidation by XO. Cyclovir antivirals (acyclovir, valacyclovir, and famciclovir) are guanine nucleoside analogues that function as alternative substrates for GD and may influence urate production through substrate-level interactions. We conducted retrospective analyses using two independent real-world data sources: the Merative MarketScan Research Databases with linked laboratory data and the US Veterans Health Administration. Patients exposed to cyclovir antivirals were compared with untreated controls with herpes simplex virus infection. The primary outcome was serum uric acid (sUA) measured approximately 1 year after index. Multivariable linear regression and inverse probability weighting were used to estimate adjusted differences in follow-up sUA. In the MarketScan cohort, associations were most pronounced among patients with elevated baseline sUA (≥ 6.8 mg/dL), with inverse probability-weighted analyses demonstrating an adjusted difference of -0.87 mg/dL (95% CI: -1.59 to -0.14; p = 0.02). In the Veterans Health Administration cohort, cyclovir treatment was associated with an adjusted difference of -0.87 mg/dL (95% CI: -1.43 to -0.30; p = 0.003). Cyclovir antiviral exposure was associated with modest reductions in serum uric acid in two independent real-world populations. Further mechanistic and prospective studies are warranted to clarify the role of GD and related pathway components in urate regulation.