Abstract
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references in identified trials and requested information from trial authors to identify any additional published or unpublished data.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.
Plain language summary
Treatment for peripheral neuropathy associated with hepatitis C virus infection
Review question: We wanted to assess the effects of any treatment for nerve damage that occurs in hepatitis C virus (HCV) infection. We planned to use the evidence from randomized controlled trials (RCTs).
Background: Peripheral neuropathy is damage to nerves outside the spinal cord. This may cause symptoms of altered sensation or weakness. Peripheral neuropathy is the most common nervous system complication of HCV infection. It is unclear how HCV-related neuropathy arises. Sometimes HCV infection is associated with proteins in the blood called cryoglobulins. Cryoglobulins are proteins of the immune system that precipitate (become a solid) when the temperature of a blood sample is cooled below 37°C. Cryoglobulins can be measured in the blood of about 44% of people with HCV infection. The features of HCV neuropathy may differ in the presence versus the absence of cryoglobulins in the blood (called cryoglobulinemia). Treatment of HCV-related neuropathy may differ depending upon how the nerve damage occurred, such as whether or not there is cryoglobulinemia. The best way to treat HCV-related neuropathy has not been established.
Study characteristics: We found only four trials from this search of the literature. All four trials in this review included participants with peripheral neuropathy and HCV-related cryoglobulinemia. There were no studies of HCV-related non-cryoglobulinemic peripheral neuropathy. Only one trial, in which there were results for 37 participants, reported effects on neuropathy. This study compared 48 weeks of rituximab and antiviral therapy versus antiviral therapy alone. Three trials, two of rituximab and one of interferon alfa (83 participants in total), reported adverse events.
Key results and quality of the evidence: One trial of HCV-related cryoglobulinemia treated with rituximab and antiviral therapy versus antiviral therapy alone did not demonstrate any significant difference in the number of participants with improvement in neuropathy at 36 months post treatment. Two studies of rituximab (61 participants) and one of interferon alfa (22 participants) provided information on adverse events. Severe adverse events were no more common with interferon alfa or rituximab compared to the control group. All four trials had problems with their design or implementation that could have affected the results.
High-quality studies of HCV-related peripheral neuropathy treatment are lacking. There is not enough evidence to make evidence-based decisions about treatment based on the results of this review.
The evidence is current to August 2014.
