Peripheral Neuropathy After Viral Eradication With Direct-acting Antivirals in Chronic HCV Hepatitis

A Prospective Study

Maria M. Zanone; Claudia Marinucci; Alessia Ciancio; Dario Cocito; Federica Zardo; Emanuela Spagone; Bruno Ferrero; Cristina Cerruti; Lorena Charrier; Franco Cavallo; Giorgio M. Saracco; Massimo Porta


Liver International. 2021;44(11):2611-2621. 

In This Article

Abstract and Introduction


Background: HCV-related extra-hepatic complications include peripheral neuropathies, with important prevalence and impact. A recent metanalysis of previous intervention trials concluded for insufficient data to support evidence-based treatments for this complication. In this longitudinal study, we assessed for the first time prevalence and outcome of neuropathy in a cohort of patients with chronic HCV, before and after direct-acting antiviral agent (DAA) treatment.

Method: Ninety-four patients (mean age 58.5 ± 9.9, infection duration 22.2 ± 6.3 years) without systemic and metabolic diseases, underwent neurological examination and electroneurography studies before (T0) and 10.4 ± 1.7 months after the end of DAA therapy (T1), and cryoglobulins (CG) assessment. Muscle strength was evaluated by Medical Research Council (MRC) score; neuropathic pain, sensory function, disability, quality of life were assessed by validated questionnaires (DN4, NPSI, SSS, INCAT and Euro-QoL).

Results: At T0, sensory-motor neuropathy was detected in 22 patients (23%), reflexes were depressed in 32 (34%) with no association with infection duration, viral load, age, CG. Neuropathic pain (DN4 ≥4) was present in 37 patients (39%). At T1, out of the 22 patients with altered electroneurography, 3 had died or developed HCC, 4 showed normal electroneurography, and nerve amplitude parameters tended to improve in the whole group. Only 11 patients (12%) had depressed reflexes and 10 (11%) DN4 ≥4 (P < .05 compared to T0). Scores for MRC, questionnaires and Euro-QoL improved significantly (P < .05).

Conclusion: Our study confirms the high prevalence of clinical and subclinical peripheral sensory-motor neuropathy in patients with HCV infection and indicates improvement after eradication by DAA. These results support the need for larger intervention studies.


Hepatitis C virus (HCV) infection is a major cause of morbidity and mortality, with a strong socio-economic impact. The WHO estimates that 1.1% of the global population has HCV, with wide geographic distribution and potential underestimation as silent infections progress asymptomatically for years. An estimated 1.4% of the population in the US and an estimated 1.25%-1.75% in Italy has HCV, reaching 20% in people above 70 years of age[1] in some areas. HCV infection is associated with several extrahepatic manifestations that increase morbidity and mortality, decrease quality of life[2,3] and may contraindicate antiviral therapy, especially with interferon α (IFN-α). On the other hand, successful eradication of HCV with IFN- α and ribavirin was accompanied by improvement of some of these manifestations, with possible resolution in case of sustained virological response, as in the case of mixed cryoglobulinemia.[4,5]

Extrahepatic comorbidities of chronic HCV infection include neurological complications, involving both the central (fatigue, cognitive impairment) and the peripheral nervous system.[6–8] Peripheral neuropathies, cryoglobulinemic or non-cryoglobulinemic are the most common neurological complications, with a prevalence of up to 86% of infected patients with, and 43.5% of those without, cryoglobulinemia. Prevalence, however, varies depending on the study population, the definition and method of assessment of neuropathy, including electrophysiological studies and standard questionnaires.[4,8,9] For instance, standard electrophysiological studies detected peripheral neuropathy in 15.3% of patients, subclinical in approximately one-third of them.[9] Prevalence rises to 90% when considering only subjective symptoms, such as paraesthesias, among patient with mixed cryoglobulinemia.[10]

There is, at present, insufficient evidence to support treatment of HCV-related neuropathy and therapeutic approaches may differ, depending on the presence of cryoglobulinemia and the different potential pathogenetic mechanisms underlying nerve damage.[11,12] A recent metanalysis of all intervention trials, including treatments with IFN-α, ribavirin, corticosteroids, cyclophosphamide, plasma exchange, and rituximab, alone or in combination, failed to show improvement of HCV-associated peripheral neuropathy up to 36 months post-treatment, while demonstrating potential adverse events.[13] Furthermore, there are no reliable studies evaluating treatment of non-cryoglobulinemic neuropathy associated with HCV infection.

A new era started in 2013 with the introduction of direct-acting antiviral agents (DAAs), achieving HCV eradication rates of approximately 95% with reduced side effects compared to previous classical treatments.[14] Recent studies report favourable outcomes for extrahepatic HCV-related complications,[5] including insulin resistance, glycaemic control[15] or endothelial function and cardiovascular morbidity.[16,17] However, the impact of HCV eradication achieved by DAAs on HCV-related neuropathies has not been explored systematically, and some data are available only in the context of cryoglobulinemic vasculitis.[5] Two case reports of greatly improved neuropathy after diagnosis and eradication of hitherto ignored HCV infection are suggestive of favourable outcomes of DAA therapy on this complication.[18,19]

In the present study, we aimed to assess the prevalence of peripheral neuropathy associated with HCV-infection with and without cryoglobulinemia, and to evaluate prospectively the effects of HCV eradication by DAAs, using a global assessment by standard nerve conduction studies, neurological examination, together with validated questionnaires exploring neurological motor and sensory symptoms, disability and quality of life.