Earlier studies have suggested neurocognitive impairment in patients with chronic hepatitis C virus (HCV) infection even before liver cirrhosis has developed. Since these deficits might be reversible after successful antiviral therapy, we analyzed the long-term course of neurocognitive parameters in HCV patients with and without successful virus elimination by an interferon-based antiviral treatment. In a multicenter study including 168 HCV patients receiving antiviral therapy (peginterferon alpha-2b and ribavirin) we performed a long-term follow-up of neurocognitive performance before and after treatment. Neurocognitive function was psychometrically assessed using the computer-aided TAP (Test Battery of Attentional Performance). When tested at least 12 months after termination of antiviral treatment, patients with sustained virologic response (SVR) had improved significantly as compared to their pretreatment performance in three of five TAP subtasks (vigilance, P < 0.001; shared attention: optical task, P < 0.001; working memory, P < 0.001). Patients who failed to eradicate the virus, however, showed no significant long-term changes in neurocognitive performance in all five subtasks assessed (0.194 < P < 0.804). In the posttreatment evaluation, neurocognitive function was significantly better in responders to the antiviral therapy as compared to nonresponders. Conclusion: Successful eradication of HCV leads to a significant improvement of relevant aspects of attentional and neurocognitive performance, indicating that the neurocognitive impairment caused by chronic HCV infection is potentially reversible. This therefore suggests an added therapeutic benefit of antiviral treatment in HCV infection. Improvement of neurocognitive function may be an additional treatment indication in patients with HCV. (HEPATOLOGY 2013;58:497–504)
An estimated 170 to 180 million people worldwide are chronically infected with the hepatitis C virus (HCV).[1, 2] Chronic hepatitis C may lead to progressive hepatic injury and eventually to liver cirrhosis and endstage liver disease.[3, 4] HCV infection is a leading cause of cirrhosis and hepatocellular carcinoma and a major indication for liver transplantation in the Western world. The burden of chronic HCV infection remains substantial because of the high number of individuals infected before the identification of the virus.[8, 9] Until recently, the standard treatment for chronic HCV infection was peginterferon alpha combined with ribavirin administered for 24 (HCV genotype 2 or 3) or 48 weeks (genotype 1, representing the most prevalent genotype in North America and Europe). This treatment leads to a sustained virologic response (SVR) in ∼50% of HCV patients.
Impairments of attention, concentration, and memory are frequent complaints among hepatitis C patients, and an aggravation of these symptoms is reported during antiviral therapy with peginterferon alpha and ribavirin. A decline in neurocognitive function in these patients resulting from antiviral therapy has been described in the recent literature.[10, 11] However, little research has been performed to address the question of whether the chronic HCV infection and/or the concomitant hepatic inflammation per se lead to neurocognitive impairment, and whether such impairment may be reversible after successful interferon (IFN)/ribavirin therapy. The studies that have been published thus far are characterized by only small to moderate sample sizes and provide inconsistent results concerning the aspect of potential reversibility of morphological changes as documented by magnetic resonance spectroscopy.[12, 13]
Therefore, we designed a longitudinal multicenter study to assess the long-term course of neurocognitive function in HCV patients treated with antiviral therapy, and to investigate the potential impact of SVR on neurocognitive performance.
Among the well-documented neurological and psychiatric side effects of interferon, an impairment of cognitive function by this drug during antiviral treatment for chronic hepatitis C has been well documented by us and others.[10, 11, 22] However, evidence from smaller studies suggests that the brain may be affected in patients with chronic HCV infection and noncirrhotic liver disease even before an antiviral treatment has been initiated. These studies have mainly focused on cerebral magnetic resonance imaging (MRI) and functional single photon emission tomography (SPECT) neuroimaging in infected patients in comparison with healthy controls. From their results it remains unclear whether the hepatitis C virus per se has a direct effect on cerebral function, or whether the impairment is caused by the chronic inflammation in the liver.
Quantitative data on functional impairment are less frequent,[27, 28] and only few data are available describing the potential reversibility of cognitive disturbances associated with chronic HCV infection.
Therefore, this study examined pretreatment and posttreatment cognitive functions in patients with chronic HCV infection. We used a computerized test battery to quantify even small effects of permanent virus elimination on neurocognitive performance. The TAP battery measures the patients' reaction with a simple motor response to simple and easily distinguishable stimuli. It has been shown that the test is not influenced by a significant learning effect[19, 20] and is therefore applicable for longitudinal comparisons in a repeated-measures design. This was again confirmed in a subgroup of patients in this study, in whom we demonstrated the stability of performance without a relevant learning effect, even when the test was repeated after only 1 week (Table 2). In a previous study on antiviral therapy in HCV-infected patients, we used the TAP test battery to assess and quantify the negative but fully reversible effects of interferon-based therapy on neurocognitive performance.
In our study, we identified a comparatively high rate of sustained responders (116 of 168 patients, SVR 69%). This might be explained to some extent by the fact that due to the study design no dropouts during the treatment phase were included (i.e., these represent per protocol rather than intention-to-treat data). In addition, our response rate corresponds well to published data for well-motivated and treatment-adherent patient groups. McHutchison et al. published an SVR of 63% for a group (majority genotype 1) that received at least 80% of their medications over at least 80% of the time.
We observed a significant improvement of neurocognitive function measured at least 1 year after the completion of a successful antiviral therapy. However, in nonresponders or in patients that relapsed after treatment with interferon/ribavirin, there was no significant change of performance in any of the TAP subtasks. From this, it can be concluded that the cognitive impairment in patients with active HCV infection is potentially reversible. This result is further supported by the fact that we were able to exclude the exact duration of the follow-up period as a possible confounding factor. Remarkably, the posttreatment improvement consisted of only the more complex and demanding TAP subtests. The task “divided attention: optic” requires continuous visual scanning of the computer screen for predefined patterns, while in the task “divided attention: acoustic,” where no posttreatment improvement was noted, the (acoustic) signals are more readily available to the sensorium. Equally, the subtask “vigilance” is characterized by the presentation of monotonous signals over 15 minutes, and the performance is therefore sensitive to a condition with an increased fatigability, as has been described for chronic hepatitis C.[30, 31] Similarly, the subtask “working memory” requires the continuous concentration of the subjects on a sequence of numbers that is presented optically. While the pretreatment performance in all tests was identical in both patient groups, the patients after successful antiviral therapy had significantly better results in the above-mentioned subtasks “vigilance” and “working memory” in a cross-sectional comparison performed at least 1 year after treatment.
The study design chosen does not allow for an in-depth investigation of the possible underlying mechanisms. Plausible explanations for the SVR-associated neurocognitive improvement refer to either direct neurotoxicity of the HCV or indirect mechanisms mediated by HCV-triggered or inflammation-triggered induction of cytokine cascades. In an earlier study we demonstrated that a similar pattern of neurocognitive impairment, although considerably more pronounced than in the present investigation, occurs in HCV patients during high-dose IFN therapy. However, it is controversial whether endogenous IFN production is induced during chronic hepatitis C infection. While it has been demonstrated in vitro that IFN production may be impaired by HCV, another study found elevated IFN serum titers in approximately half of infected patients. Therefore, it remains unclear whether IFN or other proinflammatory cytokines confer a cognitive impairment in chronic HCV infection.
Finally, it cannot be excluded that parenchymal recovery following HCV eradication might be responsible for the observed effects because comparative pretreatment and posttreatment liver biopsies were not taken.
Our findings are consistent with previously published results from smaller studies suggesting that HCV-associated neurocognitive decline may be reversible after viral clearance: For example, Forton et al. were able to demonstrate that the ability to concentrate and the speed of memory processes were significantly impaired in patients with chronic HCV infection compared to healthy controls. In contrast, the authors found no difference in neurocognitive performance between healthy controls and former HCV patients who had cleared the virus. However, the study had a small sample size (27 viremic HCV patients and 16 patients after virus clearance) and represented a cross-sectional study approach.
Interestingly, there are also reports suggesting that chronic fatigue and cognitive dysfunction may persist in several patients even after successful clearance of the HCV virus.[13, 26] The question whether a cognitive deficit persisted even in our group of successfully treated patients compared to individuals who had never been infected cannot be answered. For this, a representative and well-matched control group would have been necessary.
In conclusion, our data confirm previous reports that in patients with chronic HCV infection, neuropsychological performance is affected not only by high-dose interferon alpha-2b therapy,[10, 34] but also by the infection per se; furthermore, this latter impairment is potentially reversible after successful virus eradication. Thus far, the prevention of liver cirrhosis and its consequences have been the main goal of antiviral therapy in patients with chronic HCV infection. We suggest that the potential benefit of a successful therapy for chronic hepatitis C with respect to the patients' neurocognitive function should be considered as an additional treatment indication in this disease.
The aim of further studies would be to clarify the exact mechanisms that link HCV infection and neurocognitive function.
The authors thank Mrs. Judy Peng, Ph.D., for critical reading of the article.