title: Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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).
  
  
  METHODS
  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
  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.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Arvin
authors.affiliation: Department of Neurology, The University of Texas Health Science Center at Houston.
authors.forename: Jerry S
authors.initials: JS
authors.lastname: Wolinsky
authors.affiliation: Department of Neurology, University Hospital Basel, Basel, Switzerland.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.affiliation: Department of Infectious Diseases, University of Miami, Miami, Florida.
authors.forename: Michele I
authors.initials: MI
authors.lastname: Morris
authors.affiliation: Department of Neurology, University of Chicago Medical Center, Chicago, Illinois.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Reder
authors.affiliation: Department of Neurology, MedStar Georgetown University Hospital, Washington, DC.
authors.forename: Carlo
authors.initials: C
authors.lastname: Tornatore
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York.
authors.forename: Anne
authors.initials: A
authors.lastname: Gershon
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York.
authors.forename: Michael
authors.initials: M
authors.lastname: Gershon
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora.
authors.forename: Myron J
authors.initials: MJ
authors.lastname: Levin
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Mauritz
authors.initials: M
authors.lastname: Bezuidenhoudt
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Norman
authors.initials: N
authors.lastname: Putzki
mesh_terms: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D004305:Dose-Response Relationship, Drug; D005260:Female; D000068876:Fingolimod Hydrochloride; D006562:Herpes Zoster / Q000188:drug therapy*; D014645:Herpesvirus 3, Human / Q000472:pathogenicity*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015994:Incidence; D008297:Male; D059065:Medication Reconciliation / Q000592:standards*; D008875:Middle Aged; D011358:Product Surveillance, Postmarketing; D011409:Propylene Glycols / Q000627:therapeutic use*; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine