Varicella-Zoster Virus Infections in Patients Treated With Fingolimod

Abstract

IMPORTANCE Varicella-zoster virus (VZV) infections increasingly are reported in patients with multiple sclerosis (MS) and constitute an area of significant concern, especially with the advent of more disease-modifying treatments in MS that affect T-cell-mediated immunity.OBJECTIVE To assess the incidence, risk factors, and clinical characteristics of VZV infections in fingolimod-treated patients and provide recommendations for prevention and management.DESIGN, SETTING, AND PARTICIPANTS Rates of VZV infections in fingolimod clinical trials are based on pooled data from the completed controlled phases 2 and 3 studies (3916 participants) and ongoing uncontrolled extension phases (3553 participants). Male and female patients aged 18 through 55 years (18-60 years for the phase 2 studies) and diagnosed as having relapsing-remitting MS were eligible to participate in these studies. In the postmarketing setting, reporting rates since 2010 were evaluated.INTERVENTIONS In clinical trials, patients received fingolimod at a dosage of 0.5 or 1.25 mg/d, interferon beta-1a, or placebo. In the postmarketing setting, all patients received fingolimod, 0.5 mg/d (total exposure of 54 000 patient-years at the time of analysis).MAIN OUTCOMES AND MEASURES Calculation of the incidence rate of VZV infection per 1000 patient-years was based on the reporting of adverse events in the trials and the postmarketing setting.RESULTS Overall, in clinical trials, VZV rates of infection were low but higher with fingolimod compared with placebo (11 vs 6 per 1000 patient-years). A similar rate was confirmed in the ongoing extension studies. Rates reported in the postmarketing settings were comparable (7 per 1000 patient-years) and remained stable over time. Disproportionality in reporting herpes zoster infection was higher for patients receiving fingolimod compared with those receiving other disease-modifying treatments (empirical Bayes geometric mean, 2.57 [90% CI, 2.26-2.91]); the proportion of serious herpes zoster infections was not higher than the proportion for other treatments (empirical Bayes geometric mean, 1.88 [90% CI, 0.87-3.70]). Corticosteroid treatment for relapses might be a risk factor for VZV reactivation.CONCLUSIONS AND RELEVANCE Rates of VZV infections in clinical trials were low with fingolimod, 0.5 mg/d, but higher than in placebo recipients. Rates reported in the postmarketing setting are comparable. We found no sign of risk accumulation with longer exposure. Serious or complicated cases of herpes zoster were uncommon. We recommend establishing the patient's VZV immune status before initiating fingolimod therapy and immunization for patients susceptible to primary VZV infection. Routine antiviral prophylaxis is not needed, but using concomitant pulsed corticosteroid therapy beyond 3 to 5 days requires an individual risk-benefit assessment. Vigilance to identify early VZV symptoms is important to allow timely antiviral treatment.

Gender differences in safety issues during Fingolimod therapy: Evidence from a real‐life Relapsing Multiple Sclerosis cohort

“…Prevention and management of VZV infections, predominantly herpes zoster, in adults with MS receiving newer DMTs, is a topic of clinical relevance: symptomatic reactivation of latent VZV has been reported in patients who received Monoclonal Antibodies (natalizumab, alemtuzumab) (Coles et al., 2012; Fine, Sorbello, Kortepeter, & Scarazzini, 2013), and prophylactic aciclovir can reduce the proportion of patients who had herpes zoster (HZ) (Coles et al., 2012). Current data do not support the general use of antiviral prophylaxis in patients receiving FTY given the low incidence of HZ infection (Arvin et al., 2015). …”

Disseminated Cryptococcosis in a 63-year-old Patient with Multiple Sclerosis Treated with Fingolimod

“…Therefore, the mechanism of action of fingolimod-phosphate is to inhibit the S1P receptor function, thus preventing lymphocyte egress from the lymph nodes, reducing the number of lymphocytes in the peripheral blood and ultimately preventing them from entering the central nervous system (CNS) (9,10). Fingolimod induced a dose-dependent reduction in the peripheral lymphocyte counts to 20-30% of the baseline value (2), but it also increases the risk of infections, such as varicella zoster virus (3,4). Although fingolimod has been reported to reduce the number of both CD4 + and CD8 + T cells, the effect was more pronounced for the CD4 + T-cell subset (11).…”

“…Fingolimod is a sphingosine 1-phosphate (S1P) receptor modulator which prevents the egress of lymphocytes from the lymph nodes (2). Because of its mechanism of action, the risk of opportunistic infectious complication, such as varicella zoster virus infection, has been reported (3,4). Recently, three case reports of Cryptococcus infection associated with fingolimod have been documented (5-7).…”

<p>Prevention Strategies to Minimize the Infection Risk Associated with Biologic and Targeted Immunomodulators</p>

“…Sphingosine 1-phosphate receptor modulator Acyclovir/Valacyclovir prophylaxis could be considered for patients treated with corticosteroid pulse beyond 3-5 days and fingolimod. 63 Bruton Tyrosine kinase inhibitors PCP prophylaxis is recommended in CLL patients treated with ibrutinib in the presence of additional risk factors, including concomitant fludarabine or high dose corticosteroid therapy. 9,87 Phosphatidylinositol-3-kinase inhibitors PCP prophylaxis is recommended in CLL patients who are candidates for idelalisib therapy up to 2-6 months after discontinuation.…”