Herpesvirus Infections in Patients Treated with the Mood Stabilizer Valproic Acid: A Nested Case-Control Study in the Spanish Primary Care Database, BIFAP

Purpose: The objective of this study is to evaluate the risk of infections for herpesviruses in patients exposed to Valproic acid and derivatives (VPA) in the Spanish research database BIFAP. Methods: We performed a case-control study nested in a primary cohort selected from the Spanish primary care population-based research database BIFAP over the period 2001 to 2015. The events of interest were those diseases caused by any of the herpesviruses known to infect humans, specifically. For each case, up to 10 controls per case matched by age, gender and calendar date were randomly selected using risk set sampling. A conditional logistic regression was used to compute adjusted odds ratios (OR) and their 95% confidence intervals (95%CI) for infection for herpesviruses associated to the use of VPA after adjusting for potential confounders. Results: Current use of VPA was associated with a trend towards a reduced risk of infection by herpesviruses as compared to non-users (OR 0.84; CI95% 0.7-1.0), being these differences marginally significant (p=0.053). Among current users, a trend to a decreased risk with treatment durations longer than 90 days was also observed. Conclusions: The results of this study show a trend to a reduced risk of infection for herpesviruses in patients exposed to VPA, especially in those with treatment durations longer than 90 days. These results are consistent with in vitro studies showing that, in cultured cells, VPA inhibits the production of infectious progeny of different enveloped viruses causing relevant human and veterinary diseases, including herpesviruses. Funding Statement: Work at Centro de Biologia Molecular Severo Ochoa was supported by grants from the Spanish Ministerio de Economia y Competitividad (AGL2014-52395-C2-1-R and AGL2017-84097-C2-1- R), and by an institutional grant from the Fundacion Ramon Areces and Banco Santander Central Hispano. Work at INIA (MAM-A) was supported by grant AGL2014-56518-JIN. Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The scientific committee of BIFAP granted a positive opinion to the study protocol (#08/2015). The investigators had access to only fully anonymized data, and under this condition, no specific ethics review was required according to Spanish law.