Although the care of patients with hepatitis C virus (HCV) infection has radically improved since the US Food and Drug Administration approved the first direct-acting antiviral medication for HCV treatment in 2013, the burden associated with the disease remains high, and the opioid epidemic has led to a surge in new cases.1 Chronic HCV infection is estimated to affect 3.5 million people in the United States and 71 million people worldwide.1,2 In this population, health outcomes and quality of life are greatly affected by a range of common comorbidities, including various types of psychological and cognitive disorders.3,4

Studies have shown that approximately one-third of patients with chronic HCV infection experience depression and anxiety, whereas other findings indicate that neuropsychiatric dysfunction occurs in up to 50% of patients.5 Symptoms of fatigue and “brain fog” are also commonly reported by individuals with chronic HCV infection.5 “Neurocognitive impairment, one of the most common extrahepatic manifestations of HCV, can lead to subtle changes in processing speed, memory, attention, fatigue, and cognitive performance,” according to a review published January 9, 2019, in Frontiers in Psychology.4

In earlier research, approximately 20% of noncirrhotic patients with HCV demonstrated cognitive deficits pertaining to attention and concentration, psychomotor speed, mental flexibility, and visual scanning and tracking, whereas roughly one-half of patients required an excessive amount of time to complete the given task and nearly 30% of patients made a significant number of errors.4 This cognitive impairment observed in patients with HCV may be similar to that seen in patients with other chronic diseases such as HIV.

Subsequent studies have also shown neuropsychiatric and cognitive deficits in patients with chronic HCV infection, and these often occurred “at stages characterized as having a lack of significant liver fibrosis and cirrhosis. These alterations typically occur independently of HCV genotype and in the absence of structural brain damage or signal abnormalities on conventional brain magnetic resonance imaging,” according to Monaco et al in a 2015 review.6 These deficits were observed in the absence of HIV co-infection, substance abuse, or depression.4

Such manifestations have been shown to be independent of the stage of liver disease and the presence of hepatic encephalopathy. Although the underlying mechanisms have yet to be elucidated, the “brain is a suitable site for HCV replication, where the virus may directly exert neurotoxicity,” as stated in a 2015 article published in the World Journal of Gastroenterology.5 Other potential mechanisms that may “explain the pathogenesis of neuropsychiatric disorders in chronic HCV infection include derangement of metabolic pathways of infected cells, alterations in neurotransmitter circuits, autoimmune disorders, and cerebral or systemic inflammation.” 5

In addition to increased rates of psychiatric illness and cognitive impairment, the authors of the 2019 review noted that psychosocial stressors, including uncertainty regarding disease course and treatment, limited social support, and a lack of coping skills affected the mental and overall health of patients with HCV.4 Stigma associated with the disease may further contribute to anxiety, decreased intimacy, social isolation, discrimination, and reduced treatment seeking and adherence.

Whether HCV-associated neurocognitive deficits improve after HCV eradication remains unclear. After HCV clearance, some studies have reported significant improvement in attention and working memory, but other findings showed no improvement in neurocognitive performance.4

In a study published in 2017, a subgroup of patients with sustained virologic response (SVR) after treatment with pegylated alfa interferon and ribavirin showed significant improvement in cognitive function.7 Based on neuroimaging data, these changes were linked to improvements in white matter integrity in the posterior corona radiata and the superior longitudinal fasciculus. “Future research should examine whether any additional improvements in neurocognition and white matter integrity among SVRs occur with longer follow-up periods,” the investigators wrote.7

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However, interferon-based therapies have been associated with high rates of mental and cognitive dysfunction and related disability.8 Emerging results of studies focused on direct-acting antivirals may provide a clearer picture of the effects of HCV eradication on these outcomes. A recent double-blind placebo-controlled trial, involving 750 patients with HCV, compared outcomes among those treated with sofosbuvir/velpatasvir vs patients receiving placebo. Patients in the active treatment group demonstrated improvements in general health, emotional well-being, and fatigue at 4 weeks and at the end of treatment.8

“The pre-vs.-post treatment neurocognitive changes that may occur among SVR patients require further research to understand the impact of neuroanatomical and functional changes in HCV patients before, over the course of treatment, and after successful clearance of the virus,” wrote the authors of the 2019 review.4 In addition, they emphasize the importance of an integrated medical and psychological approach to HCV treatment, as this model is associated with greater adherence and response to treatment.

References

1. Latt NL. Update on the management of hepatitis C virus infection in the setting of chronic kidney disease and kidney transplantation. Gastroenterol Hepatol (NY). 2018;14(12):687-705.

2. Hepatitis C. World Health Organization website. https://www.who.int/news-room/fact-sheets/detail/hepatitis-c. July 9, 2019. Accessed January 9, 2020.

3. Louie KS, St Laurent S, Forssen UM, Mundy LM, Pimenta JM. The high comorbidity burden of the hepatitis C virus infected population in the United States. BMC Infect Dis. 2012;12:86.

4. Barreira DP, Marinho RT, Bicho M, Fialho R, Ouakinin SRS. Psychosocial and neurocognitive factors associated with hepatitis C – Implications for future health and wellbeing. Front Psychol. 2019;9:2666.

5. Adinolfi LE, Nevola R, Lus G, et al. Chronic hepatitis C virus infection and neurological and psychiatric disorders: an overview. World J Gastroenterol. 2015;21(8):2269-2280.

6. Monaco S, Mariotto S, Ferrari S, et al. Hepatitis C virus-associated neurocognitive and neuropsychiatric disorders: advances in 2015. World J Gastroenterol. 2015;21(42):11974-11983.

7. Kuhn T, Sayegh P, Jones JD, et al. Improvements in brain and behavior following eradication of hepatitis C. J Neurovirol. 2017;23(4):593-602.

8. Huckans M, Fuller B, Wheaton V, et al. A longitudinal study evaluating the effects of interferon-alpha therapy on cognitive and psychiatric function in adults with chronic hepatitis C. J Psychosom Res. 2015;78(2):184-192.