Hepatitis C Related Cognitive Impairment

Impact of Viral and Host Factors and Response to Therapy

Nir Bar; Sharon Levy; Liat Deutsch; Moshe Leshno; Liane Rabinowich; Fadi Younis; Oren Shibolet; Helena Katchman


J Viral Hepat. 2021;28(6):870-877. 

In This Article

Abstract and Introduction


Chronic hepatitis C virus (HCV) infection is associated with cognitive impairment via several suggested mechanisms including direct neurotoxicity and minimal hepatic encephalopathy. The prevalence of HCV-related cognitive impairment and whether it is reversed by anti-viral therapy is unknown. We aimed to assess predictors and reversibility of cognitive impairment of HCV-infected patients after successful treatment. Consecutive HCV patients treated during the EMERALD study (AbbVie 3D regimen for protease inhibitors failure) underwent neuropsychological (number connection test A [NCTA] and digital symbol test [DST]) and neurophysiological (critical flicker frequency [CFF]) tests at baseline and at 12 weeks post-treatment. Patient self-reported outcomes (PROs) were prospectively collected. Patients with a history of hepatic encephalopathy were excluded. Thirty-two patients underwent the cognitive tests at baseline. Seven of them had abnormal CFF test findings. Twenty-five (25/32, 78%) patients had repeated evaluations 3 months post-treatment. High viral loads were significantly associated with abnormal CFF across fibrosis levels (area under the ROC curve 0.817). CFF results significantly improved following viral eradication, from 40.9 (interquartile range 38.6–42.9) at baseline to 41.5 (39.8–44), p = .042, at follow-up. Both NCTA and DST results improved, but not significantly. There was improvement in the PROs of general health perception and vitality. The NCTA and DST results were more significantly associated with PROs than CFF. This prospective interventional study showed greater cognitive impairment in HCV patients with high viral load and demonstrated partial reversibility of HCV neurotoxicity and subsequent improvement in PROs following treatment.


Chronic hepatitis C virus (HCV) infection is prevalent worldwide and affects millions of carriers.[1,2] Even in the age of direct-acting antiviral (DAA), HCV is still a leading cause for cirrhosis, hepatocellular carcinoma and liver transplantation.[3] In addition to HCV's direct hepatotoxicity, chronic infection with the virus is associated with cryoglobulinaemia, B-cell lymphoma and neurologic involvement among others.[4] Cognitive impairment was found in as many as 50% of patients with HCV without other comorbidities, and its extent was correlated to the level of fibrosis.[5] Deficits in concentration, attention, working memory speed and other higher executive functions are frequently reported in chronic HCV infection. Cognitive impairment was suggested to be caused by direct neurotoxicity and inflammation[6,7] and also by hepatic encephalopathy (HE) in patients with cirrhosis.[5,7]

Minimal hepatic encephalopathy (MHE) is a subclinical stage of HE, which is diagnosed only by psychometric and neurophysiological tests in the absence of any clinical symptoms.[8] MHE patients experience a decline in health-related quality of life and decreased ability to perform complex tasks.[9] The psychometric hepatic encephalopathy score (PHES) is a gold standard for the diagnosis of MHE, but its results are influenced by age and level of education and require population-specific age and education-adjusted norms.[8,10,11] The critical flicker frequency (CFF) test is an extensively validated neurophysiological evaluation of visual discrimination and general arousal. Its results are influenced by retinal microglial oedema, a process that takes place not only in MHE but may also be present in the other forms of neuroinflammation and neurotoxicity.

The reversibility of HCV-related cognitive changes after anti-viral treatment is still debated. Data on the influence of new DAAs on HCV neurotoxicity improvement are scarce. In this study, we aimed to assess the cognitive impairment of HCV-infected patients and its predictors, and determine whether it is reversible after successful DAA treatment.