Drug-Induced Reactivation of VZV and HSV1-2 in Adult Patients with Multiple Sclerosis Receiving Disease-modifying Therapies: A SystematicReview and Meta-analysis

Introduction: Multiple Sclerosis (MS) patients treated with Disease Modifying Therapies (DMTs) are at risk of Herpes Simplex (HSV) and Varicella-Zoster (VZV) reactivation. This meta-analysis consolidates existing data on HSV and VZV reactivation in MS patients treated with DMTs to improve clinical strategies, including infectious disease screening, serological monitoring, and vaccination for MS patients on DMTs. We aimed to meta-analyze the incidence rates of clinically relevant VZV and HSV-1/2 reactivation in adults with multiple sclerosis treated with the included drugs, in comparison with unexposed patients. Methods: This systematic review and meta-analysis followed PRISMA and PICOST guidelines. Literature from 1996 to March 2024 was searched across five databases. Independent reviewers screened and extracted data, resolving conflicts with expert input. Risk of bias was assessed using ROB2 and the Newcastle-Ottawa Scale. Random-effects meta-analyses were conducted, reporting pooled incidence and heterogeneity, as well as risk ratios, where possible. Results: Seventy-eight studies were included in the review, with HSV/VZV reactivation most commonly reported for alemtuzumab (22), cladribine (11), and fingolimod (10). Meta-analyses showed that Fingolimod had HSV and VZV reactivation rates of 1.77 and 0.55 cases/100 persons, respectively, over mean follow-ups of 28.1 and 29.1 months, respectively. Alemtuzumab was associated with higher rates: 6.28 for HSV (4 studies) and 4.89 for VZV (11 studies) over 42 and 38.9 months, respectively. Meta-analysis of seven studies on natalizumab found a VZV reactivation rate of 0.29/100 person-years over 33.2 months, while five studies on rituximab reported a rate of 1.19/100 person-years over 33.0 months. Meta-analyses of placebo arms showed HSV reactivation at 1.10/100 persons and VZV reactivation at 0.50/100 persons over mean follow-up durations of 45.8 and 49 months, respectively. Discussion: This study may serve as a practical resource for clinicians to assess the risk of severe, disseminated, or fatal reactivations, especially in patients with additional risk factors, supporting more personalized infectious disease monitoring and prevention strategies. Conclusions: This study provides a comparative framework for evaluating herpetic reactivation rates during MS treatment with DMTs.