title: Efficacy and Safety of Direct Acting Antivirals for the Treatment of Mixed Cryoglobulinemia.
abstract: OBJECTIVE
  Mixed cryoglobulinemia is strongly associated with hepatitis C virus (HCV) infection and ranges from being asymptomatic to causing life-threatening vasculitis. In those with symptoms, treatment with pegylated interferon (pegIFN) and ribavirin (RBV) reduces mortality. However, few data are available on the safety and efficacy of antiviral therapy with direct acting antivirals (DAAs) in the treatment of HCV-related cryoglobulinemia.
  
  
  METHODS
  Patients treated for HCV-related cryoglobulinemia with DAA±pegIFN were retrospectively evaluated at a tertiary care center. Primary outcomes were virological, immunological, and clinical response. Complete (normalization), partial (>50% reduction), or non-response (<50% reduction) were used to describe change in cryocrit or vasculitic manifestations at week 12 post treatment. Side effects, hospitalizations, and decompensating events were recorded.
  
  
  RESULTS
  Eighteen symptomatic and 65 asymptomatic patients were reviewed (61% male, median age 58 years) including 10 with severe/life-threatening vasculitis. Sixty-six (79.5%) patients received pegIFN-free therapy. Sustained virological response (SVR) was attained in 16 (88.9%) symptomatic and 59 (90.8%) asymptomatic patients. Cryoglobulins disappeared in 5 (29.4%) symptomatic and 27 (52.9%) asymptomatic patients. Of symptomatic patients with SVR, clinical response was complete in 7 (38.8%) and partial response in 4 (22.2%). Of the 5 viral relapsers, 1 had a complete response during therapy with no symptomatic recurrence, while the other patients had no clinical response. Among 7 with severe vasculitis, 6 achieved SVR but only 1 had a complete clinical response, with 3 showing a partial response and 2 showing no improvement. All four with life-threatening vasculitis required plasmapheresis and three received rituximab. All achieved SVR leading to partial clinical response in two, but no response in two. Skin manifestations (39% reduction) were most likely to completely resolve with lower responses seen in renal (11.2% reduction) and neurological symptoms (11.1%). Eighty-two (98.8%) patients completed therapy, with 19 (22.8%) reporting adverse events. Hospitalization for decompensation or worsening vasculitis occurred in five (6.0%) and four (22.2) patients respectively.
  
  
  CONCLUSIONS
  DAAs resulted in high rates of SVR in patients with cryoglobulinemia. Safety and tolerability were excellent; however, most patients did not have a complete clinical or immunological response, suggesting a delay to clinical response particularly in those with severe/life-threatening vasculitis. Further follow-up will be required to determine if clinical improvement continues after viral clearance.
authors.affiliation: Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Emery
authors.affiliation: Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kuczynski
authors.affiliation: Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Danie
authors.initials: D
authors.lastname: La
authors.affiliation: Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Saeed
authors.initials: S
authors.lastname: Almarzooqi
authors.affiliation: Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada.|Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Kowgier
authors.affiliation: Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Hemant
authors.initials: H
authors.lastname: Shah
authors.affiliation: Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Wong
authors.affiliation: Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Harry L A
authors.initials: HLA
authors.lastname: Janssen
authors.affiliation: Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Feld
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003449:Cryoglobulinemia / Q000150:complications / Q000188:drug therapy*; D005260:Female; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D008103:Liver Cirrhosis / Q000150:complications; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012008:Recurrence; D012189:Retrospective Studies; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a