HCV SVR Improves Quality of Life & Brain Function
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"The issue of whether the hepatitis C virus (HCV) affects brain function continues to arouse interest, investigation, and debate. Symptoms such as fatigue, poor memory, and concentration ("brain fog") are commonplace and an effect of this infection on mental health related quality of life, which is independent of liver fibrosis, is well established this study provides a substantial link between HCV and cerebral dysfunction by demonstrating a reduction in spectroscopic markers of cerebral inflammation and an improvement in cognition, following HCV eradication. While further larger-scale studies are required to confirm these findings, the cerebral benefit of HCV clearance should be recognized and considered an integral part of any anti-viral therapy dialog. SVRs demonstrated significant improvements in verbal learning, memory, and visuo-spatial memory..... This appears to be the first demonstration of improved cerebral inflammation and healthier neurocognitive function in SVRs and is directly attributable to the successful eradication of the virus......This study is important because it is the first to demonstrate that successful clearance of HCV infection can result in changes in cerebral metabolism that may underlie improvements in neurocognitive performance. The obvious weakness in this paper, which limits the conclusions that can be drawn at this time, is the small sample size"
SVR Improved Quality of Life & Sexual Function in Patients with Advanced Fibrosis in HALT-C Study - (02/20/07)
common co-morbidities found in patients with chronic hepatitis C, such as depression, diabetes, heart disease and obesity, are likely to contribute to the overall poor quality of life......disease stage is the major determinant of the effect of chronic hepatitis on HRQOL.....Patients with SVR had statistically significant improvements in physical and mental scores compared to baseline......these effects occurred even in patients with advanced fibrosis and cirrhosis In comparison to patients who responded and then relapsed, patients with SVR had statistically significant improvements in physical and sexual scores
Quality of life considerations for patients with chronic hepatitis C ...
Without treatment, however, patients with chronic HCV infection will be ... as well as brain imaging and evoked potential analyses have demonstrated that mild
Various novel agents, including telaprevir, boceprevir and longer-acting interferons such as albinterferon alfa-2b, appear to offer improved SVR rates and/or more convenient administration options compared with current therapies, potentially leading to improvements in HRQoL in patients with chronic hepatitis C.""
"Various studies have shown that HRQoL improves after SVR has been achieved [14,15,17-19]. A recent study of HRQoL in 29 patients receiving PEG-IFN-α showed that the 13 patients who achieved SVR after 12 weeks of treatment had significantly improved mental health summary scores on the SF-36 . A recent analysis of data from the Hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial showed that SVR significantly improved scores in the role physical, general health, vitality, and role emotional domains of the SF-36. All patients in this trial had been previous nonresponders to antiviral therapy."
Article in Press
Hepatitis C treatment - Clearing the mind
Jnl of Hepatology Jan 2012
Daniel M. Forton
Department of Gastroenterology and Hepatology, St. George's Hospital, University of London, London, UK
"SVRs demonstrated significant improvements in verbal learning, memory and visuospatial memory, which were not seen in the non-responders......What we found instead were improvements in the spectroscopic markers of cerebral inflammation (reductions in Cho and MI) in addition to improvements in selective cognitive domains, in patients who cleared virus following treatment with PIFN/R, an effect that was not observed in those who failed to respond to therapy. This appears to be the first demonstration of improved cerebral inflammation and healthier neurocognitive function in SVRs and is directly attributable to the successful eradication of the virus."
The issue of whether the hepatitis C virus (HCV) affects brain function continues to arouse interest, investigation, and debate. Symptoms such as fatigue, poor memory, and concentration ("brain fog") are commonplace and an effect of this infection on mental health related quality of life, which is independent of liver fibrosis, is well established . However, despite convergent lines of evidence pointing to a biological effect of HCV within the CNS and some hypothesised mechanisms, there remains, as yet, a lack of incontrovertible evidence to definitively prove the fact. Parallels with HIV infection are commonly drawn, where AIDS related dementia is now rare with highly active anti-retroviral therapy (HAART) but milder neurocognitive impairments can persist despite immune reconstitution and viral suppression . A degenerative brain process is not seen in HCV monoinfection and there remains doubt in the hepatology community as to whether HCV is a virus that can trigger neurological dysfunction. Furthermore, there does not appear to be a clinical consensus as to whether the relatively mild neurocognitive symptoms in HCV infection represent a significant or important element of the disease.
The possibility of a cerebral effect of HCV was raised ten years ago with the publication of proton magnetic resonance spectroscopy (MRS) and neuropsychological data, which showed evidence of altered cerebral metabolism and cognitive impairment in patients without advanced liver disease , , . A number of further imaging studies, using MRS , , positron emission tomography (PET) and single-photon emission computed tomography (SPECT)  in patients without cirrhosis have demonstrated metabolic and neurochemical brain abnormalities, which differ to those described in hepatic encephalopathy. Rather, the findings suggest an inflammatory state within the brain with altered serotonergic and dopaminergic neurotransmission. In particular, elevated basal ganglia and white matter choline (Cho) and myo-inositol (mI), measured with proton MRS and often reported relative to creatine (Cr), are consistent with glial cell activation and proliferation and parallel changes observed in cerebral HIV infection , . Reduced N-acetylaspartate (NAA) has also been reported in HIV and HCV monoinfections , .
A greater number of reports have documented mild but measureable cognitive deficits in patients with HCV infection, which are not readily accounted for by the severity of liver disease, associated recreational drug use or other potential confounding factors . Although the studies have varied with respect to the degree to which confounders were excluded or controlled for and in terms of their cognitive assessment methodology, there is a reported pattern of deficits in attention, working memory, and learning ability with increased reaction times and relatively preserved accuracy. The prevalence of depression and anxiety was high in these reports but there do not appear to be clear associations between affective symptoms and cognitive function. However, fatigue, perhaps the commonest symptom in HCV infection, was reported to be associated with worse cognitive performance .
Despite the increasing body of descriptive literature, there are very few longitudinal reports of the effect of treatment and, in particular, of the effect of successful viral clearance on brain metabolism . It is in this context that the small pilot study from Byrnes and colleagues, published in the current issue, is welcome . Large treatment studies have demonstrated an improvement in HRQL and fatigue after a sustained virological response (SVR) to pegylated interferon and ribavirin but these studies have not generally blinded their subjects to treatment outcome and the knowledge of a "cure" is highly likely to skew results . If the hypothesis to be tested were that a cerebral abnormality is due to HCV itself, objective demonstration of an improvement of that abnormality after SVR would be highly supportive of the hypothesis. Byrnes and colleagues report their findings in a small patient cohort which was studied with proton MRS and cognitive assessment before, during and after standard antiviral treatment with pegylated interferon and ribavirin. A second group of untreated patients was also studied at two time points. Overall, there were no significant changes in cerebral MRS during and after antiviral treatment. However, a sub-group analysis of viral responders and non-responders showed significant metabolic changes over time in the responder group only, consistent with normalisation of the metabolites, previously reported as elevated in HCV infection , . Significant reductions were observed in basal ganglia Cho/Cr and mI/Cr ratios in SVRs (n=8) but not in non-responders or relapsers (n=6). The authors interpret this as an improvement in cerebral immune activation in those who cleared the virus. Patients in the treated and untreated groups tended to show an improvement in cognitive function over time, which was ascribed to a practice effect on the cognitive battery. However, when responders and non-responders were compared again, SVRs demonstrated significant improvements in verbal learning, memory and visuospatial memory, which were not seen in the non-responders.
This study is important because it is the first to demonstrate that successful clearance of HCV infection can result in changes in cerebral metabolism that may underlie improvements in neurocognitive performance. The obvious weakness in this paper, which limits the conclusions that can be drawn at this time, is the small sample size. The significant findings are only seen in a sub-group analysis, with very small groups. It is possible that a treatment effect was not seen in the non-responders because of a type II error. Furthermore, the absence of a healthy control group prevents conclusions about the importance of the observed changes. In a study published this year, Pattullo and colleagues also used MRS to assess the effect of SVR on brain metabolism . In a larger study of 40 patients (31 SVRs and 9 non-responders) significant increases in globus pallidus Cho/Cr and NAA/Cr were seen in SVRs after treatment compared to baseline. These changes were not associated with cognitive measures, which did not improve with viral eradication. The opposite effect of viral eradication on Cho/Cr in the report from Byrne and colleagues is not readily explained but may be related to different patient characteristics, voxel position and acquisition parameters. Pattullo does however report reductions in globus pallidus NAA/Cr at baseline compared to controls, which increased significantly in the SVRs. Despite this, the authors concluded that when all other causes for cerebral dysfunction are excluded, viral clearance does not contribute to significant changes in brain function or biochemistry.
There are a number of strands of evidence, in addition to clinical data, that support a biological effect of HCV on the brain. Positive and negative strand HCV genetic sequences have been amplified from RNA extracted from human post-mortem brain samples and quasispecies analyses suggest replication within the CNS, albeit at a low level , . Immunohistochemical staining for HCV non-structural protein 3 (NS3) in brain tissue suggests that astrocytes and microglia might be the host cell for HCV infection . Gene expression analysis in laser dissected microglia, which stained with antibodies against HCV NS3, revealed up-regulation of proinflammatory genes such as TNF alpha and IL-1b that was not seen in NS3-ve microglia or in cells from HCV-ve individuals . There are emerging in vitro data to support neuroimmune activation by HCV  and a recent report demonstrated that a human neuroepithelioma cell line expressed HCV entry receptors and allowed productive infection by the JFH-1 HCV strain, being the first non-hepatocyte line to do so .
These studies lead to the hypothesis that certain HCV variants or strains may gain entry to the CNS in susceptible individuals, to replicate at low but sufficient levels to cause immune activation of resident microglia, triggering established pathways that result in neuronal dysfunction . In this hypothesis, successful viral eradication might reverse or attenuate the process, as suggested by the preliminary data from Byrnes and colleagues. If this is the case, it will be of interest to discover whether the evolving interferon-free regimes of direct acting anti-virals have the same effect or whether neurocognitive impairments could persist as in the case of HAART for HIV infection. Alternatively, one might consider that eradication of HCV from the liver results in normalisation of a chronic low-level inflammatory state, with concomitant improvements in brain function and metabolism secondary to a reduction of abnormal signalling, possibly by cytokines, from the periphery across the blood brain barrier.
The pilot study from Byrnes and colleagues is small but it serves to re-energise the debate as to whether there is a virological effect of HCV on brain function. A better knowledge of this is important for our understanding of the natural history of this infection and the symptoms it causes and for our ability to design appropriate therapeutic regimes. Further large studies are now indicated to determine whether successful antiviral treatment is definitively associated with improvements in brain biochemistry and function.
Article in Press
Effects of anti-viral therapy and HCV clearance on cerebral metabolism and cognition
Jnl of Hepatology
Valerie Byrnes1, Anne Miller2, Damien Lowry4, Erin Hill2, Cheryl Weinstein2, David Alsop3,Robert Lenkinski3, Nezam H. Afdhal1,
1Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States; 2Department
of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States; 3Department of Radiology, Beth
Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States; 4Liver Centre, Mater Misericordiae University
Hospital, Dublin 7, Ireland
Background & Aims
Chronic hepatitis C virus (HCV) infection is associated with altered cerebral metabolism and cognitive dysfunction. We aimed to evaluate the effect of pegylated interferon/ribavirin (PIFN/R) and HCV clearance on cerebral metabolism, and neuropsychological performance.
Fifteen non-cirrhotic HCV positive subjects underwent 1H MR spectroscopy (MRS) before, during, and after treatment with PIFN/R. The metabolites of interest namely, N-acetylaspartate (NAA), choline (Cho), myo-inositol (MI), and the control metabolite creatine (Cr), were acquired from 3 different brain regions; left basal ganglia, left frontal cortex, and left dorso-lateral pre-frontal cortex. Coinciding with this, subjects also underwent a battery of neuropsychological tests to evaluate the domains of verbal learning, memory, attention, language, executive functioning, and motor skills. Seven HCV positive controls (not receiving anti-viral therapy) underwent MRS and neuropsychological testing at two time points, 12weeks apart, to examine for variation in cerebral metabolites over time and the practice effect of repeat neuropsychological testing.
Significant reductions in basal ganglia Cho/Cr (p=0.03) and basal ganglia MI/Cr (p=0.03) were observed in sustained virological responders (SVRs, n=8), but not non-responders/relapsers (NR/R, n=6), indicative of reduced cerebral infection and/or immune activation in those who cleared virus. SVRs demonstrated significant improvements in verbal learning, memory, and visuo-spatial memory. A small but significant improvement in neurocognitive function secondary to the practice effect was seen in both HCV controls and HCV subjects during treatment.
HCV eradication has a beneficial effect on cerebral metabolism and selective aspects of neurocognitive function and is an important factor when contemplating anti-viral therapy in HCV, especially in those with mild disease.
Until recently HCV related neurocognitive dysfunction was believed to be a consequence of cirrhosis associated hepatic encephalopathy . Several studies subsequently demonstrated cognitive dysfunction in non-cirrhotic HCV patients, when compared to age- and education-matched controls , , , , , , . Selective impairments in the neurocognitive domains of attention, concentration, and working memory appear to predominate across studies , , . While it has been contended that poorer neuropsychological test performance may in fact be attributable to the many confounding factors associated with the heterogeneity of hepatitis C patient populations , , , there is a growing body of evidence supporting the hypothesis that the hepatitis C virus may adversely affect cognition through direct central nervous system (CNS) involvement , , , .
HCV sequences have been demonstrated in CSF and brain tissue (at autopsy) in chronically infected individuals, suggesting that HCV may cross the blood-brain-barrier , , . There is also evidence that HCV replicates within certain cell populations in the brain, namely macrophages and microglial cells . Studies using proton MR spectroscopy have demonstrated altered cerebral metabolism in HCV, even in patients with mild liver disease , , , . Elevated choline (Cho) and myoinositol (MI) ratios have been found in the basal ganglia, central, and frontal white matter of HCV-infected patients , , . These findings are reflective of glial cell inflammation or proliferation. In addition, decreased levels of n-acetyl aspartate (NAA) have been observed in the central white matter of HCV-infected patients, suggestive of reduced neuronal integrity or neuronal 'drop-out' , . Of particular interest is a recent finding by Forton et al. of increased MI/Cr ratios in the frontal white matter of HCV-infected patients that negatively correlated with working memory performance . This was the first demonstration of a significant relationship between the observed metabolite abnormality, and a neurocognitive correlate, suggesting that a metabolite disturbance might in fact underlie a functional property of the brain. Another study demonstrated improved neurocognitive function following successful anti-viral treatment for HCV . However, longitudinal studies on the effect of anti-viral therapy and viral clearance in HCV subjects are lacking.
This investigation sought to examine the cerebral effects of anti-viral therapy and HCV clearance in patients with mild HCV-related liver disease. We hypothesized that eradication of HCV would be associated with improved neurocognitive function as determined by MRS and neurocognitive testing, but that this may be offset by the adverse effects of PIFN/R. Demonstration of improvements in cerebral metabolism and cognition following viral eradication would strengthen the biologic link between HCV and cerebral dysfunction and may influence the criteria for patient selection for antiviral therapy in the future.
Clinical characteristics during longitudinal follow-up
Twenty-two patients were enrolled in the study, 15 treatment candidates and 7 HCV controls. Patient characteristics are presented in Table 1. Mode of HCV acquisition in the treatment group was as follows; blood transfusion (n=5), injection drug use (n=5), occupational (n=1), tattoos (n=1), cocaine snorting (n=1), and unknown (n=2). Genotype 1 was the predominant genotype in 12/15 patients while the remaining 3/15 had genotype 3.
One patient could not complete the MRI component of the study due to undiagnosed claustrophobia and another could not complete the neuropsychological assessment accurately due to non-proficiency in the English language. Another stopped PIFN due to intolerable side effects, dropped out of the study after 12weeks, and was lost to follow up. Thus, complete MRS data was available on 14/15 subjects at time 1 and 2, but 13/15 subjects for all 3 time points. Similarly, complete neuropsychological assessment was available for 13/15 at all 3 time points. All controls completed both MRI/MRS and neuropsychological testing at the 2 time points.
Of the 15 treated patients, 13 had undetectable HCV RNA by quantitative testing (<600IU/ml) at week 12 of treatment (Time 2). One patient had a reduction in HCV RNA from 395,000 to 5500IU/ml, and the remaining patient had no change in HCV RNA level and discontinued PIFN after a total of 24-week treatment. By Time 3, 8/13 patients were persistently HCV RNA negative and proved to be SVRs. The remaining 5 tested HCV RNA positive.
Table 2 provides a breakdown of cerebral metabolite ratios (NAA/Cr, Cho/Cr, MI/Cr) in the basal ganglia, frontal cortex, and dorso-lateral pre-frontal cortex (DLPFC), for all study subjects. There was no significant difference in baseline measurements of cerebral metabolites between HCV treated patients and controls. In addition, cerebral metabolite levels remained constant in the control group, indicating a lack of significant change over time.
A significant reduction was observed in Cho/Cr in the basal ganglia of SVRs at Time 3 when compared to baseline (-32%, p=0.03), this effect was not seen in NR/R (-11%, p=0.8) (Fig. 2). Likewise, a significant reduction in MI/Cr was observed in the basal ganglia of SVRs at Time 3 when compared to baseline (-11%, p=0.03), whereas basal ganglia MI/Cr slightly increased in NR/R (+2%, p=0.7) (Fig. 3). Non-significant reductions were also noted in Cho/Cr ratio measured from the DLPFC in SVRs (-24%, p=0.3) and NR/R (-5%, p=0.6) at Time 3 when compared to baseline Table 3. Interestingly, the significant decrease in basal ganglia Cho/Cr from baseline was observed as early as Time 2 (i.e., 12weeks on treatment) in subjects who subsequently achieved and SVR, although the decline did not reach significance, there was a trend towards significance (-32%, p=0.06). No differences in NAA/Cr were observed between any of the time points examined.
Minor differences were observed between HCV controls and HCV treatment candidates at baseline on select measures of working memory (Letter number sequencing; U=14.0, z=-2.21, p=0.03) in addition to immediate visuo-spatial planning and memory (ROCF copy, U=15.0, z=-2.57, p=0.01; sROCF copy, U=8.5, z=-3.0, p=0.002 respectively), indicating poorer performance in the HCV control group Table 4. It must be noted that while differences appear between groups, case summary analysis reveals no HCV candidate scored within a clinically impaired range on letter number sequencing whereas 2 (both HCV controls) exhibited impaired scores on the ROCF copy.
At the time of last follow up (Time 3), SVRs had significant improvements in total verbal learning recall (z=-2.02, p=0.04), verbal memory recognition (z=-2.21, p=0.03) and visuo-spatial memory (z=-1.99, p=0.04) when compared to baseline. This trend was not matched in non-responders/relapsers. Moreover, while improvements across verbal recognition and visuo-spatial memory domains were within a 'healthy' normative range, the median scores for total verbal learning recall were 2 SDs below the normative mean in the case of HCV controls and 1.4 SDs below in the case of HCV treatment recipients. Case summary analyses revealed between 50% and 71% of all HCV study participants exhibited impaired scores on verbal learning domains at baseline. Additionally, retrospective analysis showed that little difference in cognition existed between SVRs and NR/R at baseline with NR/Rs performing worse relative to SVR counterparts only on a measure of visuo-spatial memory (U=6.5, z=-2.143, p=0.035, r=0.59).
Furthermore, significant improvements among HCV controls were observed across 6 neurocognitive test subsections from baseline to Time 2. These include improvements in total verbal learning (z=-2.19, p=0.03), delayed verbal recall (z=-2.04, p=0.04), visuomotor construction (z=-2.19, p=0.03), visuo-spatial immediate and delayed memory (z=-2.37, p=0.02; z=-2.12, p=0.03) in addition to cognitive flexibility (z=-2.06, p=0.04) likely due to the practice effect of repeat neuropsychological testing. When all HCV participants undergoing PIFN treatment were grouped together, they were also seen to improve in four areas from baseline to Time 2, namely verbal recognition (z=-2.59, p=0.01), visuo-spatial immediate and delayed memory (z=-2.85, p=0.004) as well as working memory (z=-2.00, p=0.04) further suggesting the effect of practice from Time 1 to Time 2.
Subjective health questionnaires
Depression scores increased in subjects following 12weeks of PIFN therapy when compared to baseline (z=-2.28, p=0.02). Median scores increased from 6 at baseline to 14.5 on treatment reflecting clinically significant levels. Analyses also revealed significant reductions on treatment in composite score estimates of physical and mental functioning (z=-1.96, p=0.05; z=-2.52, p=0.01). Restored 'healthy' levels of reported depressive symptomatology, physical, and mental health functioning were observed following the cessation of treatment, (Time 3).
This study sought to investigate the cerebral effects of anti viral therapy in patients with mild chronic HCV. Our findings failed to demonstrate adverse effects of PIFN on cerebral metabolism or cognition. What we found instead were improvements in the spectroscopic markers of cerebral inflammation (reductions in Cho and MI) in addition to improvements in selective cognitive domains, in patients who cleared virus following treatment with PIFN/R, an effect that was not observed in those who failed to respond to therapy. This appears to be the first demonstration of improved cerebral inflammation and healthier neurocognitive function in SVRs and is directly attributable to the successful eradication of the virus.
Cho and MI are putative markers for glial cell inflammation and activation. Elevated levels of Cho in HCV positive subjects is believed to reflect cellular proliferation due to infection or inflammation , . MI is found only in glial cells and is also a constituent of membrane lipids . Increased levels are believed to reflect glial cell activation and increased cell membrane turnover , , . While the exact pathogenesis of glial activation in HCV is unclear, HCV RNA has been found in brain tissue and within the CSF of HCV infected individuals supporting direct infection of the central nervous system , , , , . One hypothesis is that HCV may be introduced to the CNS via infected monocytes ('Trojan Horse' mechanism) and can infect brain microglial cells, which are essentially tissue resident macrophages of blood monocytic origin . Alternatively, glial activation and inflammation in HCV may occur indirectly due to the mediation of peripherally derived pro-inflammatory cytokines such as 1L-6, IL8, IL12, and TNF-α , , , . Our finding of statistically significant reductions in Cho/Cr and MI/Cr in the basal ganglia following HCV eradication is suggestive of reduced glial cell inflammation ('gliosis') and adds support to the biologic link between HCV and cerebral metabolism as suggested by numerous other studies , , , . Trends towards significance exist in relation to the decline in basal ganglia Cho/Cr following 12weeks of PIFN/R in both SVRs and the HCV patient group as a whole. The latter observation is likely due to the high proportion of patients who were serum HCV RNA negative at this time point. Interestingly, significant reductions in basal ganglia MI and non-significant reductions in basal ganglia Cho have also been reported in HIV positive subjects following initiation of aggressive anti-retroviral therapy . We did not observe increased cerebral NAA following HCV eradication. Two studies have shown reduced NAA in HCV positive subjects when compared to HCV-negative controls, suggestive of reduced neuronal viability , . No observed 'restoration' of NAA in the current study may be due to voxel positioning, which did not include the occipital grey matter, a site of reduced NAA in prior studies. Moreover, in spite of the etiology of neuronal loss, neuronal regeneration, as indicated by increased levels of NAA, is an unlikely expected occurrence over the time frame of this study if it at all .
Coinciding with a reduction in the markers of cerebral inflammation, we found statistically significant improvements in neurocognitive performance among SVRs at the time of last follow up when compared to baseline, a trend not observed among NR/R. Areas of improvement fall particularly within verbal memory domains but also visuo-spatial abilities. It is likely that these improvements are attributable to the successful eradication of virus as NR/R exposed to the same testing procedures did not exhibit such improvements, although it is conceded that larger group sizes would strengthen such conclusions.
It must be noted that significant improvements in test performances were observed across a number of cognitive domains among both HCV controls and treatment recipients at Time 2 compared to baseline. While HCV treatment recipients reported significant deterioration in mood and HRQoL functioning, it was not associated with any deleterious effect on cognition, contrary to our working hypothesis at the outset. In fact, the opposite proved true with a number of significantly improved performances following 12weeks of PIFN/R treatment. It would appear improvements at this juncture were likely to result from a practice effect as demonstrated by concomitant improvements in the HCV control group. These findings signal caution around interpreting data from repeat neuropsychological testing of patients using short interim periods. Validity of neurocognitive test outcomes can be optimized when test sittings occur after a minimum of 6months.
This study is not without its limitations. Firstly, its small sample size may have precluded the finding of a treatment effect in the NR arm. Secondly, we also employed the use of multiple comparisons, increasing the likelihood of type I errors. We felt that the use of a Bonferroni correction for such a pilot study would have been too conservative increasing the risk of incorrectly failing to find a treatment effect. In spite of these limitations and the preliminary nature of this study, the improvements in the variables examined were consistent across the SVR group and absent from the NR/R group, but larger studies are required to validate this.
In conclusion, this study provides a substantial link between HCV and cerebral dysfunction by demonstrating a reduction in spectroscopic markers of cerebral inflammation and an improvement in cognition, following HCV eradication. While further larger-scale studies are required to confirm these findings, the cerebral benefit of HCV clearance should be recognized and considered an integral part of any anti-viral therapy dialog.