Treatment for cryoglobulinemic and non-cryoglobulinemic peripheral neuropathy associated with hepatitis C virus infection

Cochrane Database Syst Rev. 2014 Dec 20;(12):CD010404. doi: 10.1002/14651858.CD010404.pub2.


Background: Peripheral neuropathy is the most common neurologic complication of hepatitis C virus (HCV) infection. The pathophysiology of the neuropathy associated with HCV is not definitively known; however, proposed mechanisms include cryoglobulin deposition in the vasa nervorum and HCV-mediated vasculitis. The optimal treatment for HCV-related peripheral neuropathy has not been established.

Objectives: To assess the effects of interventions (including interferon alfa, interferon alfa plus ribavirin, corticosteroids, cyclophosphamide, plasma exchange, and rituximab) for cryoglobulinemic or non-cryoglobulinemic peripheral neuropathy associated with HCV infection.

Search methods: On 26 August 2014, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, and EMBASE. We also searched two trials registers, the Networked Digital Library of Theses and Dissertations (NDLTD) (October 2014), and three other databases. We checked references in identified trials and requested information from trial authors to identify any additional published or unpublished data.

Selection criteria: We included all randomized controlled trials (RCTs) and quasi-RCTs involving participants with cryoglobulinemic or non-cryoglobulinemic peripheral neuropathy associated with HCV infection. We considered any intervention (including interferon alfa, interferon alfa plus ribavirin, corticosteroids, cyclophosphamide, plasma exchange, and rituximab) alone or in combination versus placebo or another intervention ('head-to-head' comparison study design) evaluated after a minimum interval to follow-up of at least six months.

Data collection and analysis: We used standard methodological procedures expected by The Cochrane Collaboration. The planned primary outcome was change in sensory impairment (using any validated sensory neuropathy scale or quantitative sensory testing) at the end of the follow-up period. Other planned outcomes were: change in impairment (any validated combined sensory and motor neuropathy scale), change in disability (any validated disability scale), electrodiagnostic measures, number of participants with improved symptoms of neuropathy (global impression of change), and severe adverse events.

Main results: Four trials of HCV-related cryoglobulinemia fulfiled selection criteria and the review authors included three in quantitative synthesis. All studies were at high risk of bias. No trial addressed the primary outcome of change in sensory impairment. No trial addressed secondary outcomes of change in combined sensory and motor impairment, disability, or electrodiagnostic measures. A single trial of HCV-related mixed cryoglobulinemia treated with pegylated interferon alfa (peginterferon alfa), ribavirin, and rituximab versus peginterferon alfa and ribavirin did not show a significant difference in the number of participants with improvement in neuropathy at 36 months post treatment (risk ratio (RR) 4.00, 95% confidence interval (CI) 0.27 to 59.31, n = 9). One study of interferon alfa (n = 22) and two studies of rituximab (n = 61) provided adverse event data. Severe adverse events were no more common with interferon alfa (RR 7.00, 95% CI 0.38 to 128.02) or rituximab (RR 3.00, 95% CI 0.13 to 67.06) compared to the control group.

Authors' conclusions: There is a lack of RCTs and quasi-RCTs addressing the effects of interventions for peripheral neuropathy associated with HCV infection. At present, there is insufficient evidence from RCTs and quasi-RCTs to make evidence-based decisions about treatment.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Adrenal Cortex Hormones / therapeutic use
  • Antibodies, Monoclonal, Murine-Derived / therapeutic use
  • Antiviral Agents / adverse effects
  • Antiviral Agents / therapeutic use*
  • Cryoglobulinemia / complications*
  • Cryoglobulinemia / drug therapy
  • Cyclophosphamide / therapeutic use
  • Hepacivirus
  • Hepatitis C / complications*
  • Hepatitis C / drug therapy
  • Humans
  • Immunologic Factors / therapeutic use*
  • Interferon-alpha / adverse effects
  • Interferon-alpha / therapeutic use
  • Peripheral Nervous System Diseases / drug therapy*
  • Peripheral Nervous System Diseases / etiology
  • Randomized Controlled Trials as Topic
  • Ribavirin / adverse effects
  • Ribavirin / therapeutic use
  • Rituximab


  • Adrenal Cortex Hormones
  • Antibodies, Monoclonal, Murine-Derived
  • Antiviral Agents
  • Immunologic Factors
  • Interferon-alpha
  • Ribavirin
  • Rituximab
  • Cyclophosphamide