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Objective: Reduced performance in several cognitive domains has been repeatedly related to hepatitis C virus (HCV). Nevertheless, there is no consensus about the severity or cognitive profile. Moreover, other possible influential variables are scarcely controlled. The aim of this study is to define the specific cognitive profile in HCV after controlling for confounding variables., Methods: Forty-two HCV patients were distributed in 2groups according to the presence of co-infection with human immunodeficiency virus; a third group with 22 healthy controls was also included. The neuropsychological assessment included tests that assess processing speed, executive functioning, verbal memory, visual memory and working memory. Measures of depression (BDI), anxiety (HAM-A), fatigue (MAF), anhedonia (PAS), insomnia (ISI), quality of life (SF-36) and history of drug abuse (DAST-20) were taken in order to explore differences among groups and to control for their possible influence on cognitive performance., Results: HCV patients (including human immunodeficiency virus-coinfection) performed significantly worse in all cognitive measures. However, when the effect of BDI, HAM-A, MAF, ISI, SF-36 & DAST-20 was controlled, only verbal memory of HCV patients differed among groups. Coinfected patients performed worse in verbal memory., Conclusions: According to previous studies verbal memory is the unique cognitive domain related to the effect of HCV. The present study does not support that the neurovirulence effect of HCV is decreasing cognitive performance in HCV patients. Nevertheless, the present study cannot relate the fronto-striatal disruption with the cognitive performance in HCV patients., (Copyright © 2018 SEP y SEPB. Publicado por Elsevier España, S.L.U. All rights reserved.)

Since its identification in 1989, hepatitis C virus (HCV) has emerged as a worldwide health problem with roughly 185 million chronic infections, representing individuals at high risk of developing cirrhosis and liver cancer. In addition to being a frequent cause of morbidity and mortality due to liver disease, HCV has emerged as an important trigger of lymphoproliferative disorders, owing to its lymphotropism, and of a wide spectrum of extra-hepatic manifestations (HCV-EHMs) affecting different organ systems. The most frequently observed HCV-EHMs include mixed cryoglobulinemia and cryoglobulinemic vasculitis, B-cell non-Hodgkin's lymphoma, nephropathies, thyreopathies, type 2 diabetes mellitus, cardiovascular diseases, and several neurological conditions. In addition, neuropsychiatric disorders and neurocognitive dysfunction are reported in nearly 50% of patients with chronic HCV infection, which are independent of the severity of liver disease or HCV replication rates. Fatigue, sleep disturbance, depression and reduced quality of life are commonly associated with neurocognitive alterations in patients with non-cirrhotic chronic HCV infection, regardless of the stage of liver fibrosis and the infecting genotype. These manifestations, which are the topic of this review, typically occur in the absence of structural brain damage or signal abnormalities on conventional brain magnetic resonance imaging (MRI), although metabolic and microstructural changes can be detected by in vivo proton magnetic resonance spectroscopy, perfusion-weighted and diffusion tensor MRI, and neurophysiological tests of cognitive processing. Several lines of evidence, including comparative and longitudinal neuropsychological assessments in patients achieving spontaneous or treatment-induced viral clearance, support a major pathogenic role for HCV in neuropsychiatric and neurocognitive disorders.

Purpose: Our aim was to explore the interplay between human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections in the expression of cognitive disorders., Methods: We performed a multi-centre cross-sectional study, enrolling three groups of asymptomatic outpatients matched for age and education: (1) HIV mono-infected; (2) HCV mono-infected; (3) HIV-HCV co-infected. All subjects were subjected to the Zung depression scale and a comprehensive neuropsychological battery., Results: A total of 50 patients for each group were enrolled. Patients in the three groups did not significantly differ in the main common demographic and clinical characteristics, except for a lower proportion of past injecting drug use (IDU) in group 1 (4 %) in comparison to groups 2 (38 %, p < 0.001) and 3 (78 %, p < 0.001), a longer duration of HIV infection in group 3 in comparison to group 1 (p < 0.001) and a longer duration of HCV infection in group 3 in comparison to group 2 (p = 0.028). Overall, 39.3 % of patients showed minor cognitive impairment, with a higher proportion in group 3 (54 %) when compared to groups 1 (28 %, p = 0.015) or 2 (36 %, p = 0.108). Patients in group 3 [odds ratio (OR) 3.35, p = 0.038 when compared to group 1] and those with higher depression scores (OR 1.05, p = 0.017) showed an increased risk of cognitive impairment after adjusting for education and past injection drug use. In particular, group 3 showed worse performance in psychomotor speed tasks when compared to group 1 (p = 0.033)., Conclusions: A worse cognitive performance in HIV-HCV co-infected patients was observed, suggesting an additive role of the two viruses in the pathogenesis of cognitive disorders.

The purpose of this preliminary study was to examine cognitive functioning in inmates with the hepatitis C virus (HCV) and to investigate relationships among performance on the Repeatable Battery for the Assessment of Neuropsychological Status-Form A (RBANS; Randolph, 1998). Data from 43 HCV+ inmates were reviewed retrospectively and compared with a sample of HCV- inmates. Significant differences were found on two of five indices (Attention: U = 537.5, p = .003; r = -.32; Total: U = 643.0, p = .048; r = -.22) and four subtests: Coding (U = 326.0, p <.001, r = -.53), Digit Span (U = 634.0, p = .038, r = -.22), Story Memory (U = 625.5, p = .032, r = -.24), and Story Recall (U = 548.5, p = .004, r = -.31), with the HCV group scoring lower on all significant measures. In this study the RBANS proved to be an efficient measure with clinical utility among an HCV population. Within this incarcerated population patterns of performance were "typical" of current literature, with impaired attention appearing earlier in the disease process, and the study invites further exploration into proposed cognitive deficits among this population where HCV is highly prevalent.

Objective: To compare neuropsychological scores in women infected with HIV, women infected with both HIV and hepatitis C, and uninfected subjects., Background: Some, but not all, studies have demonstrated that dual infection with Hepatitis C virus (HCV) and HIV has worse effects on cognition than infection with HIV alone., Design/methods: The Women's Interagency HIV Study is an ongoing prospective study of the natural history of HIV in women where participants are reevaluated every 6 months. In a cross-sectional analysis, we evaluated the effects of active HIV and HCV infections on scores on symbol-digit modalities test, the Stroop interference test, and trails A and B after controlling for age, ethnicity, education, depression, liver disease, and current or past substance abuse., Results: Data were available for 1338 women-17.8 % had detectable hepatitis C virus and 67% were HIV seropositive. In fully adjusted general linear models, HCV viremia was not associated with scores on any of the cognitive tests., Conclusions: In this large sample of women, active HCV infection was not associated with scores on a small battery of neuropsychological tests.

Objective: Fatigue, mood disturbances and cognitive dysfunction are frequent in patients infected with hepatitis C virus (HCV) who have mild liver disease. The reason is still unclear. The present study aims to gain more insight into the pathomechanism by combining an extensive neuropsychological examination with magnetic resonance spectroscopy in four different brain regions in a patient group covering the whole spectrum of neuropsychiatric findings in patients afflicted with HCV who have only mild liver disease., Methods: 53 HCV-positive patients with only mild liver disease and differing degrees of neuropsychiatric symptoms were studied with single-voxel MRS of the parietal white matter, occipital grey matter, basal ganglia and pons. Brain metabolite concentrations were quantitatively analysed by using LCmodel. MRS data were compared to those of 23 healthy controls adjusted for age, and analysed for relationships with the extent of neuropsychiatric symptoms., Results: Choline (p=0.02), creatine (p=0.047) and N-acetyl-aspartate plus N-acetyl-aspartyl-glutamate (NN, p=0.02) concentrations in the basal ganglia and choline concentrations in the white matter (p=0.045) were significantly higher in the patients than in controls. Interestingly, the difference was most evident for the patients with low fatigue scores (eg, white matter: choline: p=0.001, creatine: p=0.003, NN: p=0.031). Myo-inositol differed significantly between groups in the white (p=0.001) and grey matter (p=0.003). Fatigue correlated negatively with white matter NN, choline and creatine and myo-inositol levels in white and grey matter and basal ganglia (p<0.01)., Conclusion: As the increase of choline, creatine and myo-inositol are usually interpreted to indicate glial activation and macrophage infiltration in chronic inflammation and slow virus infections of the brain the present data endorse the hypothesis, that HCV infection may induce neuroinflammation and brain dysfunction. The concomitant increase of NN and the negative correlation to the extent of fatigue suggest a cerebral compensatory process after HCV infection.

Background: Hepatitis C virus (HCV) is a frequent copathogen with HIV. Both viruses appear to replicate in the brain and both are implicated in neurocognitive and peripheral neuropathy syndromes. Interaction of the viruses is likely to be complicated and better understanding of the contributions of each virus will be necessary to make evidence-based therapeutic decisions., Methods: This study was designed to determine if active HCV infection, identified by quantitative HCV RNA determination, is associated with increased neurocognitive deficits or excess development of distal sensory peripheral neuropathy in HIV coinfected patients with stable HIV viral suppression. The AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT) study was the source of subjects with known HIV treatment status, neurocognitive and neuropathy evaluations, and HCV status. Subjects were selected based on HCV antibody status (249 positive; 310 negative)., Results: HCV RNA viral loads were detectable in 172 participants with controlled HIV infection and available neurologic evaluations in the ALLRT. These participants were compared with 345 participants with undetectable HCV viral load and the same inclusion criteria from the same cohort. Neurocognitive performance measured by Trail-Making A or B and digit symbol testing was not dissimilar between the 2 groups. In addition, there was no significant association between active HCV replication and distal sensory neuropathy., Conclusion: Clinically significant neurocognitive dysfunction and peripheral neuropathy were not exacerbated by active hepatitis C virus infection in the setting of optimally treated HIV infection.

Substance abuse and co-infection with hepatitis C (HCV) are two highly relevant determinants of neurocognitive and neuroimaging abnormalities associated with HIV. Substance abuse and HCV are common in the HIV population and there is increasing evidence that the CNS is directly compromised by these comorbid conditions via additive or synergistic processes. In this article we review the current literature regarding mechanisms of neuronal injury as well as the neuropsychological and neuroimaging signatures associated with substance abuse and HCV status among HIV patients. We discuss specific methodological challenges and threats to validity associated with studies of HIV and comorbid substance use disorders or HCV and review potential strategies for minimizing their confounding effects. Efforts to understand the interactions between HIV, substance abuse and HCV co-infection will lead to more complete models of neuropathogenesis of HIV and a greater understanding of the variability in neuropsychological expression of HIV Associated Neurocognitive Disorder.

Research increasingly supports the neurovirulence of chronic infection with the hepatitis C virus (HCV). For example, HCV infection has been associated with neuropsychological impairment in several ability areas, including psychomotor skills. This study aimed to examine whether HCV-associated neuropsychological impairment is predictive of declines in the independent performance of physical (PADLs) and instrumental (IADLs) activities of daily living. A total of 106 volunteers with HCV infection completed a comprehensive neuropsychological, medical, and psychiatric research evaluation. As compared to 30 HCV-seronegative comparison participants, the HCV-infected group reported significantly greater declines in both PADLs and IADLs. Within the HCV cohort, individuals with impaired speed of information processing reported significantly greater IADL declines, whereas impaired fine-motor coordination was associated with declines in both IADLs and PADLs. In a series of regression analyses, impaired speed of information processing and depressive symptoms (as measured by the Beck Depression Inventory) were the only independent predictors of IADL declines, whereas general affective distress (as measured by the Profile of Mood States), sex, and fine-motor coordination impairment were predictive of declines in PADLs. Although the clinical assessment of HCV typically emphasizes both affective (e.g., depression) and physical factors, findings from the present study suggest that cognitive impairment is an important contributor to everyday functioning in persons living with HCV infection and therefore warrants consideration in clinical and research evaluations.

Background: Hepatitis C virus (HCV) infection is a common and chronic disorder with numerous extrahepatic manifestations. We review the neurologic complications in this article., Review Summary: Neurologic complications can involve the peripheral or the central nervous system. The most frequently reported complication is a subacute, distal, symmetric, sensorimotor polyneuropathy in the presence of mixed cryoglobulinemia (MC). HCV infection is the most common cause of MC. In HCV-infected patients without MC, mononeuropathy or mononeuropathy multiplex is more common. Both ischemic and hemorrhagic strokes, probably related to MC and vasculitis, have been described. More recently, transverse myelopathy and cognitive impairment have been linked to HCV infection, but the association is less certain and needs to be confirmed in larger studies. HCV has also been reported as a possible cause of encephalomyelitis in some cases. Although there are no definite treatment guidelines, immunomodulating agents and antiviral therapy are most often used with favorable outcomes., Conclusions: HCV infection should be considered in the differential diagnosis of a variety of neurologic disorders. Further studies are necessary to establish the full spectrum of the neurologic complications, identify specific pathophysiologic mechanisms, and provide clear guidelines for management.

Hepatitis C virus (HCV) has been detected in the brain tissues of 10 individuals reported to date; it is unclear what clinical factors are associated with this, and with what frequency it occurs. Accordingly, a pilot analysis utilizing reverse transcriptase-polymerase chain reaction (RT- PCR) to detect and sequence HCV in premortem plasma and postmortem brain and liver from 20 human immunodeficiency virus (HIV)-infected and 10 HIV-naive individuals was undertaken. RNA encoding the first 126 amino acids of the HCV E1 envelope protein and the majority of the E1 signal sequence was analyzed in parallel with an 80-base-long segment of the 5' untranslated region (UTR). Liver HCV was detected only in subjects with premortem HCV viremia (10 HIV-infected and 3 HIV-naive). Brain HCV was detected in 6/10 HCV/HIV-coinfected and 1/3 HCV-monoinfected subjects. In the setting of HIV, the magnitude of plasma HCV load did not correlate with the presence of brain HCV. However, coinfected patients with brain HCV were more often off antiretroviral therapy and tended to have higher plasma HIV loads than those with HCV restricted to liver. Furthermore, premortem cerebrospinal fluid (CSF) analysis revealed that HCV/HIV-coinfected patients with brain HCV had detectable CSF HIV, whereas those without brain HCV had undetectable CSF HIV loads (P = .0205). Neuropsychologic tests showed a trend for hierarchical impairment of abstraction/executive functioning in HIV/HCV coinfection, with mean T scores for HIV monoinfected patients 43.2 (7.3), for liver-only HCV 39.5 (9.0), and for those with HCV in brain and liver 33.2 (5.1) (P = .0927). Predominant brain HCV sequences did not match those of the plasma or liver in 4 of the 6 coinfected patients analyzed. We conclude that in the setting of HIV/HCV coinfection, brain HCV is a common phenomenon unrelated to the magnitude of HCV viremia, but related to active HIV disease and detectable CSF HIV. Furthermore, there is sequence evidence of brain compartmentalization. Differences in abstraction/executive function of HCV/HIV coinfected patients compared to HIV monoinfected warrant further studies to determine if neuropsychiatric effects are predicated upon brain infection.

This study evaluated the influence of cognitive reserve on neuropsychological test performance in 198 patients infected with the hepatitis C virus. IQ scores, educational level, and occupational rating were combined to calculate a Cognitive Reserve Score (CRS) for each patient. Similar to studies of infection with the human immunodeficiency virus, there was a significantly increased risk of impairment in neuropsychological test performance in individuals with lower CRSs. It is important to account for CRS when assessing cognitive findings in large-scale clinical trials.

Objective: To evaluate the neurocognitive function in 220 women enrolled in the Women's Interagency HIV Study (WIHS), a study of disease progression in women living with HIV/AIDS and in HIV-negative controls., Methods: We evaluated the prevalence of abnormal neuropsychological (NP) results in hepatitis C virus (HCV)-positive compared with HCV-negative women in combination with HIV serostatus., Results: NP impairment was significantly higher for HCV-positive women in comparison with HCV-negative women [odds ratio (OR), 2.03; 95% confidence interval (CI), 1.17-3.51]. Women co-infected with HCV and HIV demonstrated greater abnormal NP performance than those not infected with either, particularly if there was evidence of CD4 T-lymphocyte immunosuppression [> 200 x 10(6) CD4 cells/l (OR, 3.48; 95% CI, 1.49-8.15) and < or = 200 x 10(6) CD4 cells/l (OR, 5.38; 95% CI, 1.46-19.84)]. Women who were HCV-positive/HIV-positive and not taking antiretroviral therapy (ART) were more likely (OR, 7.03; 95% CI, 2.63-18.82) to demonstrate NP impairment than those who were HCV-negative/HIV-negative. In analyses controlling separately for education, intelligence quotient, depression, sedating drug use, head injury, ethnicity, and history of substance use, HCV continued to significantly predict NP impairment. The HCV effect did not reach significance when controlling for age in bivariate or multivariate analyses although the odds ratio for NP abnormalities in HCV-infected patients was only slightly reduced (ORs above 1.9). After testing for an interaction between age and infection status, we conducted age-stratified analysis and showed a significant effect of infection status for those aged under 40 years., Conclusions: The effect of aging on co-infected populations will require further study. This study has demonstrated the association of HCV with the risk of neurocognitive impairment in women living with HIV/AIDS and suggests that co-infection has an additive effect.

Objective: To determine the effects of hepatitis C virus (HCV) infection on neuropsychological (NP) performance., Design: Cross-sectional analysis of a prospectively enrolled cohort., Methods: A total of 239 HIV-seropositive and 287 HIV-seronegative subjects enrolled in prospective cohort studies at a single center. Subjects underwent standardized assessments, including comprehensive neuropsychological testing, substance use inventory neuromedical examination, venipuncture, and lumbar puncture. HCV antibody was measured in serum. In seropositive individuals, HCV RNA was measured in plasma and cerebrospinal fluid (CSF)., Results: HCV-seropositive subjects performed worse on neuropsychological testing and were almost twice as likely to be diagnosed as globally impaired, compared with those who were HCV seronegative. In a multivariate analysis, HCV, HIV, and methamphetamine dependence were independently associated with worse performance, even after adjusting for Centers for Disease Control stage and antiretroviral use. HCV-RNA levels in plasma were higher in those with memory, but not global, impairment. In cerebrospinal fluid, HCV RNA was below 100 copies/ml in all specimens. In HIV-infected subjects, HCV was associated with higher levels of HIV RNA in CSF, but not in plasma. HCV was also associated with higher levels of monocyte chemotactic protein 1, TNF-alpha, and soluble TNF receptor II. HCV-seropositive subjects did not appear to have advanced liver disease., Conclusions: HIV, HCV, and methamphetamine independently injure the central nervous system, leading to global neuropsychological impairment. HCV may injure the brain by viral or immune-mediated mechanisms. HCV-associated brain injury may be preventable or reversible because HCV infection is potentially curable.

Objectives: Hepatitis C virus (HCV) infection is often associated with cognitive dysfunction, fatigue and depression. The current study was undertaken to determine whether HCV infection affects gene expression in brain tissue., Design: We analysed the gene expression pattern in brain tissue in a group of HCV-infected patients compared with HCV-negative controls., Methods: Brain tissue samples were obtained at autopsy from three HCV-positive patients and three HCV-negative control patients. The analysis of gene expression was conducted using differential display and reverse Northern hybridization. Only those genes that were up or downregulated more than 1.8 times were considered to be differentially expressed., Results: Altogether, 29 differentially expressed genes were identified by differential display and subsequently confirmed by reverse Northern hybridization. A prominent finding was the downregulation of mitochondrial oxidative phosphorylation genes in HCV-infected patients. The impairment of brain oxidative/energy metabolism has previously been suggested to be the proximate cause of many disorders that impair mentation. Another finding was the downregulation of some ribosomal protein genes and several genes involved in transcription regulation, perhaps reflecting reduced metabolic activities., Conclusion: Our findings suggest for the first time that there may be a biological basis for the neuropsychiatric symptoms and cognitive impairment associated with HCV infection.

Infection with hepatitis C virus (HCV) is commonly seen in persons with human immunodeficiency virus (HIV) infection, because the viruses share risk factors for transmission; coinfection is a leading cause of morbidity and mortality among HIV-infected persons. Neuropsychological consequences of HIV infection are well established, and studies of HCV-infected persons have revealed neuropsychiatric dysfunction in this population as well. Investigators now are focusing on neuropsychological sequelae of coinfection with HIV and HCV, and preliminary results suggest that coinfection has a possible deleterious effect on global cognitive functioning consistent with frontal-subcortical dysfunction. Data on neuropsychiatric symptoms in coinfected persons are inconclusive at this time and are complicated by important differences in study populations (e.g., injection drug use and disease severity). This review summarizes what is known about neuropsychological aspects of monoinfection with HIV and HCV, as well as coinfection, discusses implications of these findings, and suggests future directions for this research area.

Objective: To examine the contribution of hepatitis C virus (HCV) infection to neurocognitive dysfunction in individuals with comorbid HIV infection or methamphetamine (METH) dependence., Methods: Neurocognitive functioning was examined in 430 study participants who were either normal controls or had HCV infection, HIV infection, history of METH dependence, or combinations of these factors as risks for cognitive deficits., Results: Rates of global and domain-specific neuropsychological (NP) impairment increased with the number of risk factors. HCV serostatus was a significant predictor of NP performance both globally and in the areas of learning, abstraction, and motor skills, with trends in speeded information processing and delayed recall. HCV serostatus did not predict scores in attention/working memory or verbal fluency., Conclusion: Hepatitis C virus infection contributes to the neuropsychological deficits observed among HIV-infected and stimulant-dependent populations.

Objective: Involvement of the central nervous system (CNS) in patients with hepatitis C virus (HCV) mixed cryoglobulinemia (MC) is rare. The mechanism by which brain lesions are produced is unclear. We investigated these phenomena by clinical evaluation (neuropsychological tests) and cerebral magnetic resonance imaging (MRI) studies in patients with HCV-MC vasculitis., Methods: This prospective study included 40 patients with MC vasculitis and chronic active HCV infection (HCV RNA+), 11 HCV controls without MC, and 36 healthy controls, matched for sex and age. A battery of 10 standardized neuropsychological tests was administered by one experienced neuropsychiatrist. All patients underwent cerebral MRI investigation., Results: Twenty-four of the 27 (89%) evaluated patients with HCV-MC had a deficiency in one or more of the 10 cognitive domains examined. The most commonly involved domains were those of attention (70%), executive functions (44%), visual construction (37%), and visual spatial functions (33%). The number of impaired cognitive functions was significantly higher in patients with MC vasculitis than in HCV controls (2.18 +/- 1.84 vs 0.87 +/- 3.1; p < 0.05). MRI analysis showed that HCV-MC patients had a higher mean number of total (7.03 +/- 9.9 vs 0.90 +/- 1.81 and 2.03 +/- 3.1; p < 0.05) and periventricular (2.4 +/- 3.0 vs 0.38 +/- 0.5 and 0.8 +/- 1.4; p < 0.05) white matter high intensity signals than HCV controls and healthy controls, respectively., Conclusion: The high frequency of impaired cognitive function and the extent of MRI brain abnormalities in patients with HCV-associated mixed cryoglobulinemia vasculitis strongly suggest specific inflammatory involvement of the CNS.

Hepatic encephalopathy is the most obvious neurological consequence of chronic hepatitis C virus (HCV) infection. There are also case reports of HCV-associated cerebral vasculitis. This review is concerned with the possibility of an effect of HCV on cerebral dysfunction, occurring at an early stage of chronic infection, prior to the development of cirrhosis and unrelated to vasculitis. There is emerging evidence of mild, but significant neurocognitive impairment in HCV infection, which cannot be attributed to substance abuse, coexistent depression, or hepatic encephalopathy. In vivo magnetic resonance spectroscopy and neurophysiological studies have suggested that a biological mechanism may underlie these cognitive findings. The recent detection of HCV genetic sequences in postmortem brain tissue raises the intriguing possibility that HCV infection of the central nervous system may be related to the reported neuropsychological symptoms and cognitive impairment.