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

Disclosures

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

In This Article

Discussion

Extrahepatic manifestations are responsible for a portion of the morbidity and mortality related to HCV infections, and have even been regarded as contraindications to treatment in the era of IFN-based therapies, or a matter of concern for drug-drug interactions. Moreover, studies exploring the effects of successful antiviral therapies on these comorbidities are lacking. In the present prospective study, we document for the first time an improvement of motor and sensory neurological functions in a cohort of HCV-positive patients after viral eradication with DAAs. A global assessment of neurological function and impairment was carried out, combining validated sensory and motor neuropathy scales, disability, together with CMAP and SNAP amplitudes, motor and sensory conduction velocities by standard nerve conduction studies. This is to our knowledge the largest systematic study assessing the effects of any anti-viral therapy on HCV-associated neuropathy, and the only one reporting on both CG- and CG+patients.[5,13] A recent metanalysis of all 4 eligible trials, the largest of which run in 59 patients randomized to rituximab versus conventional therapy,[33] included only patients with HCV-related cryoglobulinemia and none reported on a global neuropathy assessment with pre- and post-treatment measurements. Furthermore, there are at present no reliable studies evaluating the treatment of non-cryoglobulinemic neuropathies associated with HCV infection.

In our study, at recruitment, gold standard electrophysiological analyses together with clinical examination disclosed a predominant symmetrical sensori-motor neuropathy, consistent with axonal damage, in approximately one fourth of HCV+patients and neuropathic pain in almost 40% of them, while 16% complained of moderate to severe sensory impairment (SSS), possibly reflecting associated small fibre neuropathy. Furthermore, one fourth of the patients had severe impairment of muscle strength. Prevalence values were higher, though not significantly so, in the presence of cryoglobulinemia, a worsening component in all neurological findings.[29] CG+patients were slightly older than CG- patients, possibly in line with the well-established development of immune senescence and autoimmunity with aging.[34]

In line with previous reports,[35] severity of liver fibrosis, viral genotype and viral load were not associated with neurological findings. However, a greater neurological functional impairment was associated with a worse hepatological prognostic index in 4 patients, suggesting an added component related to hepatic involvement, as for kidney disease or cardiovascular complications.[16,17,36]

A new era in the natural history of HCV infection started in 2013 with the introduction of DAA, achieving approximately 95% viral eradication rate with reduced side effects compared to previous treatments.[14,37] In our study, approximately 1 year after recruitment, DAA-induced viral eradication significantly improved all neurological scores, in terms of neuropathic pain, impairment, disability and even normalized electrophysiological alterations in 4 patients, independently of clinical and liver disease characteristics, as shown by recent studies assessing the effects of DAAs in other extrahepatic complications.[16,17,38] Moreover, a trend of increase of both motor and sensory nerve amplitudes was detected in the whole subgroup of patients with altered electroneurography at recruitment, however reaching or approaching statistical significance only for a few electroneurographic parameters. On the contrary, no increase in nerve conduction velocity was detected, possibly reflecting axonal re-growth preceding myelination. In fact, it is established that regenerated, still non myelinated fibres, have got a low conduction velocity undetectable by standard nerve conduction studies.[39,40] Notably, significant neurological improvement was detected also in GC+patients, who presented with worse sensory impairment, despite the fact that cryoglobulins are a negative predictive factor for neuropathy, associated with more severe involvement at histometrical analysis,[8] reflecting additional pathogenetic mechanisms and, possibly, inducing permanent nerve damage.[8,41]

There is a growing body of literature on the association between HCV infection and reduced quality of life, impacting all aspects of function.[3,38,42] Cognitive impairment, fatigue, depression, independently of risk behaviours, have the greatest weight. In our study, viral eradication with well tolerated DAAs, improved quality of life, possibly in relation to improved neurological function, as assessed by evaluation of mobility, self-care, usual activities, pain or discomfort, anxiety and depression.

HCV-related neuropathies include symmetrical axonal sensorimotor neuropathy, accounting for over 50% of cases, distal symmetric painful small-fibre neuropathy with predominantly sensory features, mononeuritis multiplex, pure motor polyneuropathy or, rarely, demyelinating and autonomic neuropathies.[12,43,44] Severe peripheral neuropathy, although uncommon, is also described.[8,18,43] Our study confirms the high prevalence of axonal neuropathy both in CG+and CG- HCV-positive patients, strengthen by the dimension of the cohort examined compared to previous studies.[7,8]

We do not provide evidence on mechanisms underlying neurological improvement. Indeed, pathogenic mechanisms of nerve damage are speculative and likely multifactorial. These include cryoglobulin deposition and vasculitis of epineurial, perineurial vessels and vasa nervorum, intravascular cryoglobulin deposition and vessel deposits of HCV-containing immune complexes causing ischaemia, binding of C1q protein and complement activating pathways.[44] It has also been suggested that HCV may have a direct pathogenetic role through direct, cytopathic effect[8,44,45] or by immune-mediated mechanisms such as immune complex-induced changes of the epineural vessels, inflammatory lymphocyte infiltrates of epineurium and endoneurium.[44,46] At central level, HCV replication has been demonstrated in brain microvascular endothelial cells, with release of infectious virus, conformational changes of endothelium, viral and cytokine passage across the blood-brain barrier, together with microglial activation inducing a state of neuroinflammation.[47,48] Furthermore, recent studies indicate that viral eradication with DAAs is associated with a significant improvement in endothelial function, vascular distensibility, reduction in insulin resistance and improved glycaemic control.[15–17,48,49] Improved metabolic and vascular functions could thus involve nerve microvasculature, preventing ischaemic damage, curbing endothelial activation and the local inflammatory response.[43]

According to international guidelines, from June 2018 all patients with HCV infection should be considered for treatment with DAAs, prioritizing those with symptomatic cryoglobulinemic vasculitis, extensive liver fibrosis and stage 4–5 CKD.[36,50] In line with this recommendation, our report strengthens the indications for early antiviral therapy, independently of the severity of liver disease, on the basis of the risk of developing serious extrahepatic complications, including neuropathy, with a potentially rapidly progressive course.[18]

The present study has strengths and limitations. The number of subjects examined prospectively is the largest assessed so far for neurological implications of HCV eradication, in a single centre and regardless of cryoglobulinemia. Limitations include lack of assessment of small sensory fibres, which requires more sophisticated tests as pain related-evoked potential and skin biopsy, and the lack of a control group, ethically unconceivable.

This work adds to recent reports of significant benefits after successful eradication of HCV by well tolerated DAA regimens, broadening the spectrum of patients eligible for therapy; HCV-related neuropathy should be considered a major indication for treatment even in the absence of liver disease. Long term follow-up studies exploring whether sustained virological response is associated with wider, further neurological improvement are welcome.

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