Neurotoxicity associated with acyclovir and valacyclovir: A systematic review of cases

Acyclovir and valacyclovir are commonly used antivirals with good general tolerance. Despite their good safety profile, they can cause systemic adverse effects, such as neurotoxicity, which are less frequent and known. The objective of this review was to collect all the reported cases of neurotoxicity associated with acyclovir and valaciclovir published in the literature and characterize their clinical course and interventions.

A systematic review of cases was carried out following the guidelines established by "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA). The research was carried out using the PubMed-Medline and Embase databases, between July 1984 and March 2021.

A total of 119 cases with neurotoxicity mainly related to acyclovir (n = 88; 73.9%), followed by valaciclovir (n = 35; 29.4%) were analysed. 49.6% (n = 59) were men with a mean age of 59.5 years ± 21.1 (0.5-88). In 83.3% of the cases, renal impairment was documented and 57.1% (n = 68) with end-stage renal disease. The administered dose was higher than the renal adjustment recommendations in 59.7% of the cases. The global mean of onset of symptoms was 3.1 days ± 4.3 (0.2-28) after the start of antivirals. The mean recovery time was 9.8 days ± 21.7 (0.2-180). 74.4% of the patients had a recovery of ≤7 days, 15.9% between 8 and 15 days and 9.8% > 15 days.

The neurotoxicity induced by acyclovir and its derivative valacyclovir is a poorly known and rare adverse effect that can occur mainly in patients with advanced age and impaired renal function. The most characteristic symptoms are confusion, altered level of consciousness, hallucinations, agitation and dysarthria. The basis of treatment is the discontinuation of the antiviral, and in some cases, it may require additional clearance by dialysis.