Cognitive Impairment in Hepatitis C Patients on Antiviral Therapy

Chronic hepatitis C virus (HCV) is a major cause of liver-related morbidity and mortality.¹ Successful antiviral therapy with sustained viral clearance is associated with improved quality of life^2,3 and reduced risk of liver complications such as cirrhosis and hepatocellular carcinoma.^4,5 Terefore, it is recommended that every individual with chronic HCV infection be considered for antiviral therapy.⁶ However, there are relative and absolute contraindications to the use of pegylated interferon (IFN) and ribavirin, and treatment-related side effects are frequent and occasionally severe and irreversible. Consequently, the decision to pursue treatment requires a careful weighing of risks and benefits for each HCV-infected individual.

Neuropsychiatric symptoms are prevalent in persons with chronic HCV.^7–9 Cognitive dysfunction, characterized by forgetfulness, attention and concentration difficulties, poor word recall, and delayed reaction times, has been documented in 13–50% of individuals with chronic HCV infection using comprehensive neuropsychological test panels.^9,10 Although cognitive abnormalities are more common in individuals with advanced fibrosis and medical comorbidities, they are present even in the absence of advanced fibrosis and significant psychiatric and medical comorbidities.^8,10 Neurophysiologic studies reveal metabolic abnormalities on proton magnetic resonance spec-troscopy in the frontal white matter and basal ganglia,^10–12 and abnormal electrophysiologic event–related potentials in untreated patients with chronic HCV infection.¹³ The abnormalities noted are suggestive of frontal-subcorti-cal pathway involvement, similar to the involvement described in HIV infection.¹⁴

The mechanism underlying these cognitive abnormalities is unclear. HCV may directly infect the central nervous system. HCV RNA has been detected in postmortem brain tissue and cerebral spinal fluid.^15,16 The HCV identified in the central nervous system has been found to be more closely related to the virus present in the lymphoid system rather than in the circulation, suggesting a compartmentalization of infection. As HCV has the ability to replicate in extrahepatic sites, including peripheral blood mononuclear cells,^17,18 it has been theorized that infected monocytes enter the central nervous system via the normal turnover cycle of resident microg-lia, which are replaced by circulating monocytes.^16,19 Alternatively, the chronic inflammatory response induced by HCV may be responsible for the cognitive changes. Specific cytokines may affect cognition via alterations in neuroendocrine and neurochemical pathways.²⁰ Both the systemic cytokine response and the local cytokines produced by astrocytes and microglial cells could be involved. Indeed, the neuropsychiatric side effects of the cytokine, IFN, are supportive of the association between cytokines and cognitive abnormalities.²¹ As cognitive abnormalities are not seen in all HCV-infected patients, additional genetic, viral, or immunologic conditions predisposing to development of this “extrahepatic” complication must be present.

IFN-related neuropsychiatric side effects have been well recognized in the literature. Depressive symptoms have been reported by 20–35% of patients treated with pegylated IFN and ribavirin,^22,23 and higher rates have been noted with the utilization of standardized questionnaires.²⁴ Clear differences have not been seen in the frequency of neuropsychiatric symptoms between pegylated IFN-alfa and standard IFN-alfa,^25,26 but IFN in combination with ribavirin has appeared to increase the rate of depression.²⁷ Resolution of neuropsychiatric side effects has been seen within 6 months of treatment discontinuation in the majority of patients,^9,25 though anecdotal reports of symptoms lasting up to 24 months have been reported in the literature.^27,28 The mechanism of IFN therapy causing cognitive side effects is unknown. Reductions of regional cerebral blood flow to specific areas of the brain associated with memory and language function have been described.²⁹ Inhibitions of neurotransmit-ter synthesis, uptake and release,³⁰ and reduced central dopamine activity³¹ have also been noted.

In general, the cognitive complications of pegylated IFN and ribavirin have not been studied as systematically as the psychiatric side effects. Confusion, delirium, inattention, short-term memory loss, deficits in executive functions, as well as extrapyramidal effects, have been reported, primarily in the non-HCV literature. In two studies of patients with various malignancies receiving IFN-alfa, neuropsychologic testing identified fronto-subcortical deficits.^27,32 Reversible electroencephalogram abnormalities have also been identified.^33–36

Among HCV-infected patients, IFN-based therapy has been associated with cognitive changes in some but not all studies. In the largest study to date, Fontana and colleagues used a battery of 10 neuropsychologic tests to evaluate cognitive function in 177 patients with chronic HCV undergoing re-treatment with pegylated IFN and ribavirin for 24 weeks and 57 patients treated for 48 weeks.⁹ A global deficit score was calculated at baseline, at Weeks 24 and 48 of treatment, and at 24 weeks posttreat-ment. Prior to treatment, 32% of patients had evidence of cognitive impairment. Patients reported increases in difficulty concentrating, emotional distress, and symptoms of depression during treatment, but there was no significant change in cognitive function overall during therapy. In contrast, Lieb and colleagues studied 38 patients with chronic HCV and hepatitis B virus and found a significant decrease of immediate recall in the Auditory-Verbal Learning Test and a significant reduction of words recited in the Controlled Oral Word Association Test after 12 weeks of low-dose IFN therapy.²⁹ These apparently conflicting results may reflect differences in the populations studied (and their propensity to develop cognitive dysfunction), frequency of retesting, and specific measures of cognition utilized. The cognitive changes did not significantly correlate with depressive symptoms or anxiety.^9,27,37

The case reported by Ruffner-Statzer and Bernstein describes a patient experiencing a decline in cognitive function during HCV treatment without recovery post-treatment.³⁸ The absence of baseline neuropsychiatric testing and a concurrent diagnosis of depression complicate interpretation of the post-treatment outcome. Prior reports of irreversible cognitive impairment in association with IFN therapy have been infrequent,^28,37 suggesting that it is a rare event. Nonetheless, irreversible cognitive impairment is a devastating outcome for any patient, and this report highlights the relative paucity of data on the possible long-term cognitive effects of IFN therapy in patients with chronic HCV infection. As cognitive impairment is frequent in patients with chronic HCV (~30%), there may be a subgroup of patients at risk for the worsening of cognition-related side effects with treatment. Pretreatment comorbidities and age may be important cofactors.

For the clinician caring for patients with chronic HCV infection, attention to the presence of cognitive difficulties is important, and the growing literature regarding these complications suggests that increased use of neuropsychiatric testing may be warranted. In terms of treatment-related cognitive changes, larger-scale studies are needed to determine the consequences of cognitive dysfunction on quality of life and adherence to therapy, and to confirm or refute the role of IFN exposure in irreversible cognitive changes.