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

Abstract

What is known and objective 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. Methods 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. Results and discussion 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. What is new and conclusion 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.

Antiviral drugs

“…Of the 119 patients, 49.6% were men with a mean age of 59.6 years old. Additionally, 83.3% of these cases found documentation of renal impairment to support the increased risk of neurotoxicity in patients with renal dysfunction ( Brandariz-Nunez et al, 2021 ) [M]. A more recent finding highlighted polyuria as another complication secondary to renal dysfunction.…”

PharmGKB summary: acyclovir/ganciclovir pathway

“…It is characterized by neurologic and psychiatric symptoms such as confusion, lethargy, hallucinations, and seizures [37]. The mechanisms of ACV neurotoxicity are poorly understood, but it is associated with renal impairment and advanced age (>65 years) [38][39][40], which are responsible for prolonging the halflife of ACV. In addition, the concentrations of CMMG were significantly higher in the plasma of 93 patients who had neurologic side effects than in the plasma of patients without such symptoms (N = 49 vs. 44, CMMG concentration = 34.1 ± 39.4 mmol/µl and 4.7 ± 4.7 mmol/ µl, respectively; P < 0.001) [41].…”

Review of Pyrimidine Derivatives as Pharmacologically Active Compounds

“…по фармакодинамическому действию, показаниям к применению, побочным эффектам и т. д. валацикловир схож с ацикловиром, так как является его предшественником [15,16].…”