Background
Hepatitis C virus (HCV) infection is a global public health problem. It is estimated that between 130 and 185 million people are infected worldwide [
1]. Roughly 85% of patients infected go on to develop chronic hepatitis and 20 to 40% develop end-stage liver disease (i.e. cirrhosis) within 10 to 20 years [
2]. In addition to liver disease, HCV is related to a series of extrahepatic manifestations, with a negative impact on the physical and mental health of infected individuals [
3]. Patients with advanced cirrhosis commonly display hepatic encephalopathy, with characteristic neuropsychological, behavioral and neurological changes. However, in recent years a number of studies have established that up to a third of patients without cirrhosis also develop a neuropsychiatric syndrome characterized by impairment of cognitive function and symptoms related to depression [
4‐
6]. These abnormalities were shown by neuropsychological tests, magnetic resonance spectroscopy and other neuroimaging modalities and various inventories of depression [
4,
7,
8]. The main cognitive abnormalities include impairment of attention span, concentration and psychomotor skills. Depressive symptoms are found in roughly 40% of patients and reach a prevalence of 20% to 40% during antiviral treatment, particularly with interferon, with detrimental effects on both quality of life and compliance with treatment [
4,
9].
Various lines of evidence suggest the cognitive dysfunction and depressive symptoms are related to the release of pro-inflammatory cytokines caused by infection of the central nervous system by HCV. HCV replicates itself in mononuclear peripheral blood cells and in bone marrow, which are precursors to the microglial cells in the brain. It is in this way HCV is introduced to the central nervous system via a “Trojan horse” mechanism [
4,
10,
11]. However, no clear correlation between HCV viral load and cognitive impairment could be demonstrated [
12]. Despite HCV infection itself within the brain causing local inflammation and neurocognitive disturbances, another hypothesis suggest these disturbances, including depression, could be in part a result of elevated systemic cytokine levels due to chronic HCV activation of the immune system [
13‐
15]. Putative inflammatory cytokines are interleukin-1, 4, and 6, tumor necrosis factor-α and interferon-α, that can cross the blood-brain barrier and impact brain functioning [
14,
15].
Despite various rigorous studies having demonstrated that HCV infection is associated with a decline in neurocognitive function and depressive symptoms, data are scarce as to whether or not these changes are irreversible in patients who have eliminated HCV after successful treatment [
4,
6,
8]. Therefore, we conducted the present study with the aim of evaluating the impact of sustained virological response (SVR), i.e. viral clearance, in improving neurocognitive function and mood disorders in patients infected with HCV.
Discussion
In this study, the neuropsychological performance and the frequency of major depression and depressive symptoms of patients infected with HCV were compared before the beginning of treatment, right after half of the expected treatment has been reached and 6 months after the end of treatment. We observed that patients that attained viral clearance (SVR) improved significantly in the neurocognitive domains of immediate and delayed verbal episodic memory compared to patients without.
Since the seminal report by Forton et al. [
32] describing an elevated choline/creatinine ratio by proton magnetic resonance spectroscopy in the frontal white matter and basal ganglia of HCV-infected patients, several studies have suggested that the brain may be affected in chronic HCV infection. Subsequent reports have documented that up to one third of HCV infected patients may have neuropsychological impairment [
7,
11,
12,
33‐
35]. These changes are seen even in the absence of cirrhosis, decompensated liver disease, hepatic encephalopathy or previous history of abuse of psychoactive substances, suggesting an effect of the viral infection on the central nervous system. HCV locally induced inflammation and the passage of systemic pro-inflammatory cytokine through the blood-brain barrier could also impair neurologic functioning [
14,
15]. The neurocognitive disturbances may be documented long before the beginning of interferon-based antiviral therapy, which is a well-known cause of neurocognitive, mood and psychiatric dysfunction.
Most studies were based on the comparison of the brain of infected versus non-infected patients by magnetic resonance imaging and functional single photon emission tomography [
7,
12,
33‐
35]. Despite the high degree of heterogeneity of these studies, it is indisputable that chronic HCV infection is associated with impairment of attention, executive function, verbal abilities and memory. In this regard, it is noteworthy that few studies used a structured and validated neuropsychological battery of tests for diagnosing this neurocognitive dysfunction.
In contrast with a number of papers that show neuropsychological impairment in HCV infected patients, few data are available describing the potential reversibility of the cognitive disturbances after successful antiviral treatment. Byrnes et al. [
36] performed
1H magnetic resonance spectroscopy and a battery of neuropsychological tests before, during and after antiviral treatment with interferon and ribavirin in 15 HCV-infected patients. They concluded that HCV eradication had a beneficial effect on cerebral metabolism and improved verbal learning and visual and spatial memory. However, the sample size was limited and post-treatment assessment was carried out 12 weeks after the discontinuation of interferon, not enough to fulfill the definition of SVR. In a recent paper, Kraus et al. [
37] performed a multicenter study including 168 HCV patients receiving antiviral therapy with interferon and ribavirin. Twelve months after the termination of antiviral treatment, patients with SVR had significant improvement in 3 out 5 domains (vigilance, shared attention: optical task and working memory). Our findings confirm previous few observations that HCV-associated neurocognitive impairment may be reversible after viral eradication. However, our study differs from the paper of Byrnes et al. [
36] because we demonstrated that neurocognitive improvement persist long after the withdrawal of the therapy in patients with SVR, as defined by the inability to detect HCV RNA 24 weeks after completion of treatment. Despite the improvement in HVLT immediate and delay recall from baseline in those attaining SVR in our study, it is noteworthy that subjects are still performing in the impaired range. Persistent neurocognitive impairment in patients treated with interferon and ribavirin was described by Cattie et al., specifically within the domains of working memory, learning, and executive functions, even after HCV viral load undetectability [
38]. Our study has also some difference with the paper of Kraus et al. [
37]. We used a stringent protocol that included clinical assessment, exclusion of potential confounding variables such as unrelated conditions (severe anemia, fatigue, untreated hypothyroidism, and dementia), substance abuse and heavy alcohol intake. Cognitive function disturbances were assessed by a more comprehensive battery of neuropsychological tests, which included 11 domains of interest in HCV-infected patients. Mood was assessed with two different instruments. Furthermore, socio-demographical variables which could influence the performance of the patients were taken into account.
Our study observed that depression and depressive symptoms are common in untreated hepatitis C patients and they increase significantly during interferon based treatment. However, SVR did not lead to a significant decline in the frequency of these symptoms. It is worth restating that the majority of patients displayed a related condition. In fact, the illness, regardless of its cause, can influence the presence of mood disorders. It is possible that the frequency of major depression and related symptoms observed before antiviral treatment reflect, at least in part, the clinical background of the patients. It is well documented in the literature that the frequency of depression and depressive symptoms increases over the course of interferon based treatment [
39‐
41], but returns to baseline levels after the cessation of treatment, indicating the reversibility of these symptoms, observations confirmed by this study. Recently Huckans et al. also reported increased symptoms of depression during interferon therapy in a cohort of 33 HCV infected patients, which decreased or remitted following treatment discontinuation [
42]. Eccles et al. have demonstrated that hypothalamic-pituitary-adrenal axis hyperactivity prior to interferon based therapy evaluated through measurement of the waking salivary cortisol response was associated to depression during treatment [
43]. Whale et al. showed recently that younger age, previous history of major depression disorder, higher baseline psychomotor retardation and somatic symptoms item scores using the Hamilton Depression Rating Scale and HCV genotype 2 were implicated in depression during IFN treatment [
44]. In the present study we excluded patients with major depression diagnosis at baseline and we could not find predictive factors for depression during IFN treatment, maybe due to small sample evaluated. The exogenous administration of IFN in addition to the HCV chronic activation of the immune and elevated systemic cytokine levels could induce sickness behavior and depression [
13]. Interestingly, depression and / or the severity of depressive symptoms related to IFN treatment seem higher in HCV mono-infected patients when compared to HIV/HCV co-infected patients and in those with chronic hepatitis B [
45,
46]. It is notable that hemolytic anemia induced by ribavirin is common during antiviral treatment, contributing to the somatic effects of depression. An American study with 32 patients concluded that interferon exacerbates somatic depressive symptoms [
39]. However, the major limitation of this study pertains to the fact that the data were not controlled for anemia, and only US war veterans were included in the study, which is possibly not a representative sample of the population infected with HCV. Our data were rigorously controlled for hemoglobin levels throughout the course of treatment.
The frequent impairment of attention, concentration and psychomotor skills suggests a relation with the fronto-cortical systems, which would be affected by chronic HCV infection. Chronic HCV infection, independently of viral load genotype, triggers activation of inflammatory cytokines and immune response. This response is directed towards the 5-HT receptor, which plays an important role in the pathophysiology of depression and produces changes in cognitive function and mood [
4,
32,
33]. Indeed, major depression may be associated with cognitive impairments, such as executive functions and memory alterations secondary to attention deficit [
47]. In our study, however, despite an increase in depression and depressive symptoms during treatment, patients experienced improvement in the domains of immediate verbal episodic memory, delayed verbal episodic memory, selective attention and phonemic verbal fluency. Besides this, depression and depressive symptoms frequencies returned to baseline while immediate verbal episodic memory and delayed verbal episodic memory improved in those attaining SVR.
HCV therapy has experienced a revolution in recent years, with interferon free regimens directed at specific steps of viral replication (direct acting antivirals, i.e., DAA), leading to highly effective, shorter and safer treatments. To date, there are limited data regarding the impact of DAA induced viral clearance on cognition and depressive symptoms. Kleefeld et al. reported in an HCV / HIV population 12 patients who achieved viral clearance with DAA [
48]. Improvement in the domains visual memory, attention, processing speed and executive functioning were reported, however, the limited number of patients and practice effects may hamper firm conclusions. Another study with sofosbuvir and lepipasvir associated HCV viral suppression with normalization of cerebral N-acetyl aspartate evaluated by magnetic resonance spectroscopy [
49].
A limitation of our study is the lack of an untreated HCV control group to rule out some confounders, such as practice effect on the neurocognitive domains tested. Regarding the Trail Making Test A and B, we used it exclusively to evaluate the domain of sustained and alternated attention, but additional information about processing speed components could have been obtained. Another relative weakness of our study is the small number of patients, in particular those non-responders at the end of the follow-up.