• follow‐up
• hepatitis C virus
• neuropsychiatric symptoms
• treatment

• Humans
• Male
• Female
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/psychology
• Antiviral Agents/therapeutic use
• Middle Aged
• Sustained Virologic Response
• Follow-Up Studies
• Adult
• Quality of Life
• Interferons/therapeutic use
• Neuropsychological Tests
• Treatment Outcome
• Aged
• Surveys and Questionnaires
• Hepacivirus/drug effects
• Hepacivirus/genetics

• MD was funded by the Ellen-Schmidt-Scholarship of Hannover Medical School

• Cognitive
• Direct-acting antivirals
• HIV
• HIV/HCV coinfection
• Hepatitis C
• PWH
• SVR

• Humans
• Male
• HIV Infections/drug therapy
• HIV Infections/complications
• Thailand/epidemiology
• Adult
• Antiviral Agents/therapeutic use
• Female
• Hepatitis C/drug therapy
• Hepatitis C/complications
• Sustained Virologic Response
• Middle Aged
• Coinfection/drug therapy
• Coinfection/virology
• Cohort Studies
• Neuropsychological Tests
• Hepacivirus/drug effects
• CD4 Lymphocyte Count
• Treatment Outcome

• extra-hepatic manifestations
• hepatitis C
• oral cavity
• oral mucosa

• HIV
• HIV/HCV coinfection
• PWH
• SVR
• cognitive
• direct-acting antivirals
• hepatitis C

• AAI20052001 NIAID NIH HHS
• R01 MH113560 NIMH NIH HHS

• comparative effectiveness
• direct acting antiviral
• instrument
• patient-reported outcomes
• survey
• sustained virological response

Hepatitis C virus (HCV) is a common cause of liver disease and is associated with various extrahepatic manifestations (EHMs). This mini-review outlines the currently available treatments for HCV infection and their prognostic effect on hepatic manifestations and EHMs. Direct-acting antiviral (DAA) regimens are considered pan-genotypic as they achieve a sustained virological response (SVR) > 85% after 12 wk through all the major HCV genotypes, with high percentages of SVR even in advanced fibrosis and cirrhosis. The risk factors for DAA failure include old males, cirrhosis, and the presence of resistance-associated substitutions (RAS) in the region targeted by the received DAAs. The effectiveness of DAA regimens is reduced in HCV genotype 3 with baseline RAS like A30K, Y93H, and P53del. Moreover, the European Association for the Study of the Liver recommended the identification of baseline RAS for HCV genotype 1a. The higher rate of hepatocellular carcinoma (HCC) after DAA therapy may be related to the fact that DAA regimens are offered to patients with advanced liver fibrosis and cirrhosis, where interferon was contraindicated to those patients. The change in the growth of pre-existing subclinical, undetectable HCC upon DAA treatment might be also a cause. Furthermore, after DAA therapy, the T cell-dependent immune response is much weaker upon HCV clearance, and the down-regulation of TNF-α or the elevated neutrophil to lymphocyte ratio might increase the risk of HCC. DAAs can result in reactivation of hepatitis B virus (HBV) in HCV co-infected patients. DAAs are effective in treating HCV-associated mixed cryoglobulinemia, with clinical and immunological responses, and have rapid and high effectiveness in thrombocytopenia. DAAs improve insulin resistance in 90% of patients, increase glomerular filtration rate, and decrease proteinuria, hematuria and articular manifestations. HCV clearance by DAAs allows a significant improvement in atherosclerosis and metabolic and immunological conditions, with a reduction of major cardiovascular events. They also improve physical function, fatigue, cognitive impairment, and quality of life. Early therapeutic approach with DAAs is recommended as it cure many of the EHMs that are still in a reversible stage and can prevent others that can develop due to delayed treatment.

• Hepatitis C virus
• Hepatic
• Extrahepatic
• Direct-acting antivirals
• Impact

• CD8+ T cells
• Cellular senescence
• Immune senescence
• Inclusion body myositis
• Pathophysiology

• Aged
• CD8-Positive T-Lymphocytes
• Humans
• Inflammation/pathology
• Muscle, Skeletal/pathology
• Myositis/pathology
• Myositis, Inclusion Body/pathology

• Deutsche Forschungsgemeinschaft
• Else Kröner-Fresenius-Stiftung
• Federeal Ministry of Education and Research
• Deutsche Gesellschaft für Muskelerkrankte
• Deutsche Gesellschaft für Muskelerkrankte e.V.
• Charité - Universitätsmedizin Berlin (3093)

• cognition
• depression
• hepatitis C
• minimal hepatic encephalopathy
• viral hepatitis

• Adult
• Antiviral Agents/therapeutic use
• Anxiety
• Anxiety Disorders/chemically induced
• Anxiety Disorders/complications
• Anxiety Disorders/drug therapy
• Cohort Studies
• Depression
• Female
• Hepacivirus/genetics
• Hepatitis C/drug therapy
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/drug therapy
• Humans
• Liver Cirrhosis
• Male
• Middle Aged
• Quality of Life
• Sustained Virologic Response
• Treatment Outcome

• Hepatitis C
• cognition
• direct-acting antiviral

Hepatitis C virus (HCV) infection is widespread and affects 71 million people worldwide. Although hepatic manifestations are the most frequent, ranging from chronic hepatitis to cirrhosis and hepatocellular carcinoma, it is also associated with several extrahepatic manifestations. Infected patients may present non-specific neurological symptoms, regardless of the presence of liver cirrhosis. Several pathogenetic mechanisms underlying neurological symptoms have been hypothesized: neuroinvasion, immune-mediated damage, neurotransmitter alterations and cryoglobulinemia. Alterations of the central nervous system include cerebral vasculopathy, acute or subacute encephalopathy and inflammatory disorders. HCV infection may be responsible for neuropathies, of which the most frequent form is symmetrical axonal sensory or sensory-motor polyneuropathy which causes loss of leg sensitivity and weakness. Up to 50% of patients with HCV infection may experience cognitive decline and psychological disorders, such as depression and fatigue. HCV associated neurocognitive disorder is independent of the presence of liver cirrhosis and affects different domains than in patients with hepatic encephalopathy. It can be studied using specific tests that mainly explore executive functions, verbal learning and verbal recall. These disorders significantly reduce the quality of life. The new antiviral therapies improve the extrahepatic symptoms of HCV infection and their success depends on the achievement of sustained virological response. However, the effect of therapy may differ depending on the type of organ involved; neurological symptoms can be irreversible if there is organic liver damage. The aim of this review is to provide a critical overview of physiopathological mechanisms, diagnostic and therapeutic strategies of the neurological and psychiatric effects of HCV infection.

• Hepatitis C virus
• Neurological disorders
• Psychiatric disorders
• Antiviral therapy
• Quality of life
• Hepatic encephalopathy

• Antiviral Agents/therapeutic use
• Hepacivirus
• Hepatitis C/complications
• Hepatitis C/drug therapy
• Hepatitis C, Chronic/drug therapy
• Humans
• Liver Neoplasms/drug therapy
• Quality of Life

• antiviral agents
• hepatitis c
• patient-reported outcomes
• people who inject drugs
• quality of life

• cognitive dysfunction
• direct-acting antiviral
• hepatitis C virus
• minimal hepatic encephalopathy
• patient-reported outcomes measures

• DAA therapy
• HCV
• HIV
• exosomes
• microRNA

Hepatitis C virus (HCV) frequently co-occurs with symptoms of depression, which are aggravated on interferon-based regimens. However, it is unknown whether HCV treatment with direct-acting antivirals (DAAs) has effects on depressive symptoms among people who inject drugs (PWID). In this study, we examined changes in depressive symptoms during and after HCV treatment among PWID on opioid agonist therapies (OATs).

Participants were 141 PWID who achieved sustained viral response after on-site HCV treatment at 3 OAT programs.

Depressive symptoms were assessed using the Beck Depression Inventory–II (BDI-II) at baseline, every 4 weeks during treatment, and 12 and 24 weeks after treatment completion. Current diagnosis of depression or other psychiatric diagnoses were obtained through chart review. Use of illicit drugs was measured by urine toxicology screening. Alcohol use was measured using the Addiction Severity Index–Lite.

Of the 141 PWID infected with HCV, 24.1% had severe, 9.9% had moderate, 15.6% had mild, and 50.4% had minimal levels of depression as per BDI-II scores at baseline. HCV treatment was significantly associated with reductions in depressive symptoms that persisted long term, regardless of symptom severity (P < .001) or presence of depression (P ≤ .01) or other psychiatric diagnoses (P ≤ .01) at baseline. Concurrent drug use (P ≤ .001) or hazardous alcohol drinking (P ≤ .001) did not interfere with reductions in depressive symptoms.

Depressive symptoms are highly prevalent among HCV-infected PWID. HCV treatment was associated with sustained reductions in depressive symptoms. HCV therapy with DAAs may have important implications for PWID that go beyond HCV cure.

• DAAs
• HCV
• PWID
• depression
• mental health

The impact of clinical and sociodemographic factors on fatigue remains unknown among patients with substance use disorders (SUD). This study aims to evaluate fatigue among patients with SUD using a nine-item fatigue severity scale (FSS-9) and identify the impact that clinical and sociodemographic factors – such as injecting substance use, chronic infectious diseases, liver fibrosis, opioid agonist therapy (OAT), debt difficulties, and housing situation – have on fatigue.

We used data from a cohort of patients with SUD in Norway with annual health assessments surveying FSS-9 and some clinical and sociodemographic factors. A total of 915 FSS-9 measurements were collected from 654 patients during the period 2016–2020. We defined baseline as the first annual health assessment when the health assessments were listed chronologically. Time was defined as years from baseline. We used a linear mixed model to analyse whether the clinical and sociodemographic factors affected the FSS-9 sum score, presented with beta coefficients (β) with 95% confidence intervals (CI).

The mean sum score of the FSS-9 was 43 (standard deviation: 16) at baseline. Females compared with males (adjusted mean difference of FSS-9 sum score: 4.1, 95% CI: 1.3–7.0), having debt difficulties compared with having no debt difficulties (2.9;0.4–5.3), and frequent use of benzodiazepines (5.7;3.0–8.4) or amphetamines (-5.0;-8.0– -2.0) compared to less frequent or no use of these substances changed the FSS-9 baseline sum score. The other clinical and sociodemographic factors did not predict any clinically relevant change in the FSS-9 sum score from baseline to the following health assessments.

Patients with SUD suffer from high levels of fatigue. Female patients, patients with debt difficulties, and those with extensive use of benzodiazepines are at particular risk of being fatigued. This should be taken into consideration when planning health services.

The online version contains supplementary material available at 10.1186/s13011-020-00334-x.

• Comorbidities
• Fatigue
• Fatigue severity scale
• HIV
• Illicit drugs
• Kidney disease
• Quality of life
• Substance-related disorders
• Viral human hepatitis

• chronic hepatitis C
• clinical research
• comparative effectiveness research
• direct-acting antivirals
• drug safety
• mental disorders

• Humans
• Antiviral Agents/therapeutic use
• Antiviral Agents/adverse effects
• Mental Disorders/drug therapy
• Mental Disorders/complications
• Male
• Female
• Middle Aged
• Sustained Virologic Response
• Prospective Studies
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/complications
• Adult
• Treatment Outcome
• Drug Interactions
• Aged
• Medication Adherence
• Drug-Related Side Effects and Adverse Reactions/epidemiology

• Cognitive rehabilitation
• HIV
• HIV-associated neurocognitive disorders
• Neuro-rehabilitation

• Central Nervous System/pathology
• Central Nervous System/virology
• Cognition/physiology
• Cognitive Dysfunction/psychology
• Cognitive Dysfunction/rehabilitation
• Cognitive Remediation/methods
• Comorbidity
• Exercise/physiology
• HIV Infections/pathology
• HIV Infections/psychology
• Humans
• Neurological Rehabilitation/methods
• Transcutaneous Electric Nerve Stimulation/methods

• Queen Mary University of London

Die chronische Hepatitis-C-Virus(HCV)-Infektion ist eine hochprävalente Systemerkrankung, die verschiedene neurologische Komplikationen verursachen kann. Es lassen sich HCV-assoziierte Symptome im zentralen und peripheren Nervensystem sowie der Muskulatur unterscheiden. Wichtige Pathomechanismen sind die HCV-assoziierte Autoimmunität (z. B. gemischte Kryoglobulinämie mit Polyneuropathie) und direkte Neurotoxizität (z. B. bei HCV-assoziierten kognitiven Defiziten). Die häufigsten neurologischen Komplikationen sind distal-symmetrische Polyneuropathien, Small-fiber-Neuropathien und kognitive Defizite. Die HCV-Infektion stellt außerdem einen Risikofaktor für ischämische und hämorrhagische Schlaganfälle sowie den Morbus Parkinson dar. Die frühe Identifikation und antivirale Behandlung HCV-positiver Patienten steht im Zentrum der Behandlung. Durch neue antivirale Therapien können >90 % der Patienten dauerhaft von der HCV-Infektion geheilt werden.

• Cognitive deficits
• Cryoglobulinemia
• Hepatitis C
• Polyneuropathy
• Small fiber neuropathy

• Antiviral Agents/therapeutic use
• Cryoglobulinemia/drug therapy
• Hepacivirus
• Hepatitis C/complications
• Hepatitis C/diagnosis
• Hepatitis C/drug therapy
• Hepatitis C, Chronic/drug therapy
• Humans

• Charité (3093)

Cognition was assessed in hepatitis C virus (HCV) patients, who did not meet the criteria for a minimal hepatic encephalopathy. Their liver function was compensated. We then disentangled potential cognitive changes associated with a sustained virologic response at 12 weeks (SVR-12), following treatment with direct antiviral agents (DAAs). We studied 23 selected HCV patients with a battery of standard neuropsychological tests, and with recordings of the P300 wave, a cerebral potential of “cognitive” significance. There was a baseline evaluation (T0) and a second one 6 months later (T1). We had 2 control groups of comparable age and sex, i.e., 15 patients suffering from non-alcoholic fatty liver disease (NAFLD) and 15 healthy subjects. At T0, we detected a significant (p < 0.05) cognitive impairment in the HCV group, which involved episodic and working memory, attention, visuospatial and verbal abilities, executive functions, and logic reasoning. The P300 latency was significantly (p < 0.05) delayed in the group. At T1, we observed some significant (p < 0.05) HCV recovery in given test domains, e.g., memory, executive functions, and reasoning. Accordingly, the P300 latency shortened significantly (p < 0.05). HCV patients exhibited subtle cognitive defects, somehow independent of their liver condition, possibly linked to direct or indirect brain involvement by the virus. These defects partly recovered following the SVR-12, as achieved through DAAs. The P300 wave was a valid neurophysiologic counterpart of these changes. DAAs can have a role in the early preservation of cognition in HCVs.

• Cognitive impairment
• Direct antiviral agents
• Hepatitis C
• Neuropsychology
• P300 wave

Chronic hepatitis C virus (HCV) infection is commonly associated with neurocognitive dysfunction, altered neuropsychological performance and neuropsychiatric symptoms. Quantifiable neuropsychological changes in sustained attention, working memory, executive function, verbal learning and recall are the hallmark of HCV-associated neurocognitive disorder (HCV-AND). This constellation is at variance with the neuropsychological complex that is seen in minimal hepatic encephalopathy, which is typified by an array of alterations in psychomotor speed, selective attention and visuo-constructive function. Noncognitive symptoms, including sleep disturbances, depression, anxiety and fatigue, which are less easily quantifiable, are frequently encountered and can dominate the clinical picture and the clinical course of patients with chronic HCV infection. More recently, an increased vulnerability to Parkinson’s disease among HCV-infected patients has also been reported. The degree to which neurocognitive and neuropsychiatric changes are due to HCV replication within brain tissues or HCV-triggered peripheral immune activation remain to be determined. Without absolute evidence that clearly exonerates or indicts HCV, our understanding of the so-called “HCV brain syndrome”, relies primarily on clinical and neuropsychological assessments, although other comorbidities and substance abuse may impact on neurocognitive function, thus confounding an appropriate recognition. In recent years, a number of functional and structural brain imaging studies have been of help in recognizing possible biological markers of HCV-AND, thus providing a rationale for guiding and justifying antiviral therapy in selected cases. Here, we review clinical, neuroradiological, and therapeutic responses to interferon-based and interferon-free regimens in HCV-related cognitive and neuropsychiatric disorder.

• MR spectroscopy
• PET-CT
• SPECT
• diffusion tractography
• functional MRI
• hepatitis C
• neurocognitive disorders

• Hepatitis C virus
• cognition
• functional magnetic resonance imaging
• magnetic resonance spectroscopy
• neuroimaging

• hepatitis C
• interferon-free direct-acting antiviral agents
• radiology/imaging
• viral hepatitis

• Antiviral Agents/therapeutic use
• Cost of Illness
• Global Health
• Hepatitis C/drug therapy
• Hepatitis C, Chronic/drug therapy
• Humans
• Patient Reported Outcome Measures