title: Antiviral therapy of symptomatic HCV-associated mixed cryoglobulinemia: meta-analysis of clinical studies.
abstract: Hepatitis C virus (HCV) infection may be associated with extra-hepatic illness including mixed cryoglobulinemia. Evidence on HCV-related mixed cryoglobulinemia in the non-transplantation setting exists even if its appropriate management remains unclear. The cornerstone of treatment for symptomatic HCV-associated mixed cryoglobulinemia is antiviral therapy but little is known about its activity. A systematic review of the literature with a meta-analysis of clinical studies was performed in order to assess efficacy and safety of combination antiviral therapy for symptomatic HCV-associated mixed cryoglobulinemia in non-immunosuppressed individuals. The random effects model of DerSimonian and Laird was used, with heterogeneity and sensitivity analyses. The primary outcome was sustained virological response (as a measure of efficacy), and the secondary outcome was the rate of patients stopping (or dose reducing) antiviral agents (as a measure of tolerability). Ten clinical studies (300 unique patients) were identified; the rate of baseline kidney involvement ranged between 4% and 39%. The summary estimate of frequency of sustained viral response was 0.42 with a 95% confidence interval (CI) of 0.31; 0.54 (random effects model). Significant heterogeneity occurred (P = 0.00001; I(2) = 77.6%). Stratified analysis showed higher efficacy in those studies using combination therapy with pegylated-than conventional IFN; the summary estimate of sustained viral response being 0.52 (95% CI, 0.40; 0.63) and 0.32 (95% CI, 0.15; 0.49), respectively. There was good association between viral and clinical response, weighted K 0.634 (95% CI, 0.455; 0.814), by a meta-analysis at individual level on a subset of reports (n = 3; 74 unique patients). The summary estimate of frequency of patients stopping (or dose reducing) antiviral agents was 0.15 (95% CI, 0.08; 0.21); no heterogeneity occurred (P = 0.05; I(2) = 51%). In summary, combination antiviral therapy (pegylated IFN plus ribavirin) gives satisfactory response in more than the half of patients with symptomatic mixed cryoglobulinemia associated with HCV. HCV-related mixed cryoglobulinemia is uncommon in developed countries and this clearly hampers randomized controlled clinical trials aimed to evaluate efficacy and safety of antiviral therapy in non-immunosuppressed individuals.
authors.affiliation: Division of Nephrology, Maggiore Hospital, IRCCS Foundation, Milan, Italy. fabrizi@policlinico.mi.it
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Fabrizi
authors.forename: Vivek
authors.initials: V
authors.lastname: Dixit
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Messa
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D003449:Cryoglobulinemia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology / Q000821:virology; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000187:drug effects; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a