[Does a "hepatitis C" besides hepatitis B play an important part in blood transfusion disorders?].
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Adolescent↗
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Results for “hepatitis C”
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Contact tracing for hepatitis C: perspectives of people with experience of substance use and hepatitis C on intervention acceptability.
INTRODUCTION: Chronic hepatitis C (HCV) is a major cause of cirrhosis and hepatocellular carcinoma. In the UK, the principal risk factor for HCV is injecting drug use. The introduction of direct acting anti-virals (DAA's) have transformed HCV care, with cure rates of over 95%. However, HCV is often asymptomatic, and reinfection is a concern. Modelling and real-life studies demonstrate the potential effectiveness of a contact tracing approach for finding people who have acquired HCV through injecting drug use. However, it is not used routinely in the UK. This qualitative study was undertaken to assess the acceptability of a contact tracing approach to identify people who have injected drugs with an index patient recently diagnosed with HCV. METHODS: Twelve people with lived or living experience of injecting drug use and an HCV diagnosis were interviewed using semi-structured interview topic guides. Participants were purposefully selected according to the inclusion criteria and to ensure there was an even spread of male and female participants. Sekhon's Theoretical Framework of Acceptability, incorporating seven components (affective attitude, burden, ethicality, intervention coherence, opportunity cost, perceived effectiveness, and self-efficacy) was used to analyse data from interview transcripts. RESULTS: A sample of 12 people who inject drugs in the UK indicated that a contact tracing approach was acceptable across two components of Sekhon's acceptability framework: affective attitude and ethicality. Participants broadly found the idea of tracing people who may be at risk of contracting HCV acceptable, and the approach aligned with their value systems. A contact tracing approach would help alleviate concerns about putting other people's lives at risk through HCV transmission and was seen as a 'sensible' way of finding people at risk. However, there were caveats to this acceptability. Contact tracing approaches delivered by mainstream health, or governmental organisations increased burden, opportunity costs and perceived effectiveness of a contact tracing approach for HCV, particularly within contexts of exclusion and criminalisation of people who inject drugs. Burden and opportunity costs were also affected by individual experiences and risks of violence, sexual violence and abuse. There was a lack of knowledge of contact tracing approaches amongst respondents, leading to a lack of intervention coherence and misunderstandings of what contact tracing was and how it would work. Trusted relationships with NGOs and HCV specialist nurses reduced burden and increased confidence and ability (self-efficacy) to engage with a contact tracing approach. CONCLUSION: People who inject drugs broadly perceive contact tracing as an acceptable method of finding people who are at risk of HCV. However, this acceptability is based on specific modes of delivery through trusted organisations. Findings further highlight the importance of naming and describing contact tracing approaches appropriately, as well as assessing and mitigating against potential risk to index patients, to increase self-efficacy and capacity to engage. Considering these findings, the potential for expanding existing contact tracing approaches should be explored to ensure the UK reaches and maintains its elimination targets.
Humans↗
Differential Proteomic Profiling of Responders and Non-responders to Direct-Acting Antivirals Treatment in Chronic Hepatitis C Virus Infection.
Hepatitis C Virus (HCV), particularly genotype 3 (GT-3), is highly prevalent in India and is associated with faster progression to cirrhosis, hepatocellular carcinoma, and higher treatment failure rates. Although Direct-Acting Antivirals (DAAs) have revolutionized HCV therapy, 5-10% of patients fail to achieve sustained virological response (SVR). This proteomic study aimed to identify changes in the proteomic profile before and after treatment of both responders and non-responders to HCV treatment. Paired plasma samples from HCV GT-3 infected patients were collected before and 12 weeks after initiating DAAs treatment, along with healthy controls. Quantitative proteomic analysis was performed on the paired samples. Differentially expressed proteins (DEPs) were identified and subjected to functional analysis including gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) network analysis. GSEA revealed enrichment in extracellular matrix organization and innate immune pathways. Expression patterns of candidate proteins selected based on fold change and false discovery rate (FDR) criteria were further evaluated in an independent cohort. Western blot confirmed key expression trends of candidate proteins. Proteins linked to extracellular matrix remodeling and angiogenesis showed differential expression patterns. Successful validation of these candidate proteins in large independent cohorts holds potential to predict therapeutic outcomes.
Humans↗
Hepatitis "C" antigen in non-A, non-B post-transfusion hepatitis.
Evidence for a new hepatitis-specific antigen has been obtained from double immunodiffusion assays between acute and convalescent sera obtained from patients with non-A, non-B post-transfusion hepatitis. The designation hepatitis C (HC) antigen is proposed. HC was found in the acute-phase sera of all 13 non-A, non-B post-transfusion hepatitis patients with longer incubation and duration periods (type 2) tested, but only transiently in 4 out of 10 acutephase sera obtained from patients with type 1 non-A, non-B hepatitis, with shorter incubation and duration periods. The antigen was also detected in 2 out of 16 single specimens obtained during the acute phase from acute hepatitis patients who had not received a blood-transfusion. This suggests presence of a carrier state. No patients with alcoholic hepatitis and no healthy blood-donor carried HC antigen. The antigen seems distinct from those of hepatitis A and B (surface and core). It migrated in the serum beta-globulin region and had a buoyant density of 1.30 and a molecular weight between 100 000 and 300 000. Antibodies against HC antigen were found in only 30% of the type-2 non-A, non-B post-transfusion hepatitis patients and did not persist for long. However, these antibodies were directed specifically against HC antigen and moved in a manner similar to 7S globulin on rate-zonal centrifugation.
Acute Disease↗
Inhibition of the protein kinase PKR by the internal ribosome entry site of hepatitis C virus genomic RNA.
Translation of the hepatitis C genome is mediated by internal ribosome entry on the structurally complex 5' untranslated region of the large viral RNA. Initiation of protein synthesis by this mechanism is independent of the cap-binding factor eIF4E, but activity of the initiator Met-tRNA(f)-binding factor eIF2 is still required. HCV protein synthesis is thus potentially sensitive to the inhibition of eIF2 activity that can result from the phosphorylation of the latter by the interferon-inducible, double-stranded RNA-activated protein kinase PKR. Two virally encoded proteins, NS5A and E2, have been shown to reduce this inhibitory effect of PKR by impairing the activation of the kinase. Here we present evidence for a third viral strategy for PKR inhibition. A region of the viral RNA comprising part of the internal ribosome entry site (IRES) is able to bind to PKR in competition with double-stranded RNA and can prevent autophosphorylation and activation of the kinase in vitro. The HCV IRES itself has no PKR-activating ability. Consistent with these findings, cotransfection experiments employing a bicistronic reporter construct and wild-type PKR indicate that expression of the protein kinase is less inhibitory towards HCV IRES-driven protein synthesis than towards cap-dependent protein synthesis. These data suggest a dual function for the viral IRES, with both a structural role in promoting initiation complex formation and a regulatory role in preventing inhibition of initiation by PKR.
Animals↗
[Hepatitis C--a new discovered kind of hepatitis].
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Blood Transfusion↗
Hepatitis C Virus Enhances Lysosome-Associated Membrane Protein 2 A Transcription Through Nuclear Factor Erythroid 2-Related Factor 2 to Support Viral Replication.
Hepatitis C virus (HCV) establishes persistent infection by rewiring host stress-response pathways. Chaperone-mediated autophagy (CMA) contributes to HCV replication, but it remains unclear whether HCV regulates lysosome-associated membrane protein 2 A (LAMP-2A), the rate-limiting receptor for CMA. Here, we examined LAMP-2A regulation in HCV-infected Huh-7.5 cells. HCV infection increased LAMP-2A promoter activity, mRNA, and protein abundance, indicating transcriptional upregulation. Among candidate stress-responsive transcription factors, nuclear factor erythroid 2-related factor 2 (NRF2), hypoxia-inducible factor 1α (HIF-1α), and nuclear factor of activated T cells 1 (NFAT1) were elevated in infected cells. However, promoter mutagenesis identified NRF2 as the principal direct regulator. Mutation of the NRF2-responsive antioxidant response element markedly reduced basal and HCV-induced LAMP-2A promoter activity. Chromatin immunoprecipitation assays revealed NRF2 association with the LAMP-2A promoter, and HCV infection increased nuclear accumulation and Ser40 phosphorylation of NRF2. Functionally, shRNA-mediated knockdown of LAMP-2A reduced intracellular HCV RNA and protein levels. These findings identify an NRF2-LAMP-2A regulatory axis engaged during HCV infection and support a model in which HCV upregulates LAMP-2A to establish a cellular environment favorable for viral replication.
Hepacivirus↗
Whole genome sequencing of unusual Hepatitis C virus subtypes and drug resistance analysis during direct-acting antiviral therapy in India.
INTRODUCTION AND OBJECTIVES: Pangenotypic direct-acting antivirals (DAA) are effective against highly prevalent Hepatitis C virus (HCV) subtypes, but have been clinically validated almost exclusively in high-income countries. Unusual HCV subtypes may carry natural polymorphisms, potentially impacting DAA susceptibility. We conducted full-genome characterization and resistance analysis of unusual HCV subtypes in patients receiving DAA treatment. PATIENTS AND METHODS: In this prospective hospital-based study, eligible patients were screened for anti-HCV antibodies and active infection was confirmed by diagnostic 5'NCR-based HCV RNA detection. Genotyping was performed by core region sequencing, and viral load quantified by real-time PCR. For whole genome sequencing, multiplex primers were designed using alignments of global reference sequences. Sequencing was carried out using the Oxford Nanopore Technology platform. Phylogenetic analysis used multiple sequence alignment and the HCV-GLUE resource for resistance-associated substitution (RAS) analysis. RESULTS: Predominant genotype was genotype 3 in 64.3% (n = 45); genotype 6 in 21.4% (n = 15); and genotype 1 in 14.2% (n = 10). Unusual HCV subtype 6xa was detected in two patients and showed no NS5A resistance mutations. One genotype 3b patient relapsed at 24 weeks post-DAA treatment completion and carried NS5A resistance-associated substitutions 30 K and 31 M both at baseline and at relapse, conferring high-level resistance to NS5A inhibitors. CONCLUSION: This is the first report from India of whole genome sequencing of HCV subtype 6xa. The identification of NS5A resistance mutations in the 3b relapse case underscores challenges for global HCV elimination strategies.
Humans↗
Genetically distinct within-host subpopulations of hepatitis C virus persist after Direct-Acting Antiviral treatment failure.
Analysis of viral genetic data has previously revealed distinct within-host population structures in both untreated and interferon-treated chronic hepatitis C virus (HCV) infections. While multiple subpopulations persisted during the infection, each subpopulation was observed only intermittently. However, it was unknown whether similar patterns were also present after Direct-Acting Antiviral (DAA) treatment, where viral populations were often assumed to go through narrow bottlenecks. Here we tested for the maintenance of population structure after DAA treatment failure, and whether there were different evolutionary rates along distinct lineages where they were observed. We analysed whole-genome next-generation sequencing data generated from a randomised study using DAAs (the BOSON study). We focused on samples collected from patients (N=84) who did not achieve sustained virological response (i.e., treatment failure) and had sequenced virus from multiple timepoints. Given the short-read nature of the data, we used a number of methods to identify distinct within-host lineages including tracking concordance in intra-host nucleotide variant (iSNV) frequencies, applying sequenced-based and tree-based clustering algorithms to sliding windows along the genome, and haplotype reconstruction. Distinct viral subpopulations were maintained among a high proportion of individuals post DAA treatment failure. Using maximum likelihood modelling and model comparison, we found an overdispersion of viral evolutionary rates among individuals, and significant differences in evolutionary rates between lineages within individuals. These results suggest the virus is compartmentalised within individuals, with the varying evolutionary rates due to different viral replication rates and/or different selection pressures. We endorse lineage awareness in future analyses of HCV evolution and infections to avoid conflating patterns from distinct lineages, and to recognise the likely existence of unsampled subpopulations.
Humans↗
A novel dimerization site in non-structural protein 5A of hepatitis C virus regulates viral replication fitness.
We previously found that high genome replication fitness of the hepatitis C virus (HCV) was associated with severe disease in immunocompromised patients. Elevated replication fitness was mediated by accumulation of mutations in the replication enhancing domain (ReED) within domain (D) 2 of non-structural protein (NS) 5A. NS5A is a partially unstructured phosphoprotein lacking enzymatic activity but fulfilling a key role in HCV replication due to interacting with various cellular and viral proteins. It can exist in a variety of dimeric and oligomeric conformations mediated by NS5A D1 with clinically approved NS5A inhibitors proposed to exert their antiviral function by fixing these dimers in distinct conformations. In this study, we aimed at elucidating the ReED's mode of action. AlphaFold modelling indicated a so far unrecognized NS5A dimerization site in the ReED. Indeed, split nano luciferase assays revealed a significantly stronger NS5A dimerization of high replicator ReED variants, suggesting that high replication fitness is mediated by enforcement of NS5A self-interaction. This hypothesis was supported by the effect of low dose (1 pM) NS5A inhibitor treatment, increasing replication fitness and phenocopying the effects of ReED mutations. Furthermore, we found that HCV isolate JFH1, replicating with very high efficiency, is completely resistant to the regulatory function of the ReED. Chimeric replicons composed of ReED resistant JFH1 and the ReED sensitive isolate J6 identified NS3 helicase and NS5B polymerase as critical genetic elements mediating ReED sensitivity/resistance. Our data overall suggest that the ReED in NS5A is a negative regulator of HCV replication fitness with dimerization releasing the inhibitory interaction with helicase and/or polymerase, thereby likely facilitating initiation of RNA synthesis.
Viral Nonstructural Proteins↗
A G-Quadruplex-Activated Near-Infrared Chemiluminescent Probe for In Situ Hepatic Imaging of the Hepatitis C Virus Genome.
Real-time monitoring of viral replication is essential for infectious disease diagnosis and antiviral drug development. The G-quadruplex (G4), a conserved regulatory element within viral genomes, represents a significant endogenous biomarker for tracking viral activity. However, imaging viral G4s in deep tissues remains a challenge for current optical technologies due to severe photon attenuation and autofluorescence. Herein, we report Lumin680, the first near-infrared (NIR) chemiluminescent probe directly activated by conserved viral G4 conformations. Its chemiluminescence was triggered by parallel G4, emitting in the NIR optical window (680 nm) with a 104.6-fold signal enhancement. Notably, the luminescence of Lumin680 could penetrate up to 1.2 cm of biological tissue, outperforming traditional G4 fluorescent probe. In vivo, Lumin680 enabled the rapid visualization of orthotopic hepatitis C virus (HCV) genome RNA-presenting mini-organ within 5 min post-intravenous administration. Furthermore, the chemiluminescent intensity of Lumin680 quantitatively mapped the therapeutic efficacy of clinical direct-acting antivirals (DAAs) at both the cellular and whole-animal levels, exhibiting high concordance with the gold-standard quantitative RT-PCR (qPCR). This study not only provides a powerful G4 specific chemiluminescent tool but also establishes a novel paradigm for the non-invasive, in situ diagnosis and precise therapeutic monitoring of viral infections.
G-Quadruplexes↗
Variations in the viral hepatitis C prevalence and treatment status by material hardship and cumulative risk among people who inject drugs.
People who inject drugs (PWID) are disproportionately impacted by viral hepatitis C (HCV). Among PWID, homelessness, poverty, and material insecurity elevate infectious disease risk. We hypothesized a positive association between material hardship (difficulty accessing basic needs) and lifetime diagnosis of HCV, and a negative association between cumulative risk (material hardship and years since first injection) and HCV treatment. From 2021-22, we conducted a survey among community-recruited PWID that included items on HCV outcomes, material hardship (a sum score of usually (4) to never (1) having difficulty finding food, clothing, shelter, restrooms, and showers in the past 3 months), and years since injection drug use initiation. We developed a latent variable, cumulative risk, by combining individual scores of material hardship indicators and years since first injection drug use. Among our sample of PWID (n = 471), 246 (53%) participants reported lifetime HCV diagnosis and 27% of those who tested positive for HCV reported ever or current treatment (n = 67). In modified-Poisson regression, a one-unit increase in material hardship score was associated with a 3% (OR: 1.03, 95% CI: 1.01%, 1.05%) increase in odds of HCV diagnosis. In latent modeling, among PWID testing positive for HCV, a one-unit increase in cumulative risk score was associated with a 0.28 (OR: -0.28, 95% CI: -0.50, -0.06), decrease in the Z-score odds of receiving HCV treatment. Findings emphasize structural interventions to strengthen material security and co-delivering basic needs with health services to improve HCV-related outcomes among PWID.
HCV↗
Intranuclear virus-like particles in HBsAG- and IHxAG-negative acute hepatitis (type C?) (Preliminary report).
Virus-like particles, acute hepatitis, hepatitis type C. Intranuclear virus-like particles were found by electron microscopy in liver cells of a woman suffering from mild HBsAG- and IHxAG negative acute hepatitis. The particles encountered were morphologically different from those found in hepatitis B and hepatitis A respectively. Futher studies are required to clarify whether the structures represent an incidental finding of a new human (passenger) virus or they may be related to the aetiological agent of the supposed hepatitis type C.
Adult↗
Hepatitis in marmosets.
Some species of marmosets are susceptible, not only by parenteral inoculation but also by oral exposure, to human hepatitis A virus present in sera or feces. The stools of animals inoculated parenterally or orally contained fecal antigen during certain times of the incubation period and the early, acute phase of the disease; viruslike particles were present in feces of orally infected animals and such feces were infectious when inoculated into marmosets. The fecal antigen crossreacted both with the fecal virus particles and the immune-adherence antigen (see also papers by Purcell et al and Hilleman et al). The MS-1 and CR-326 strains of hepatitis A appeared antigenically similar or identical whereas the GB strain was antigenically different and may be associated with the recently defined type of hepatitis termed hepatitis C or hepatitis non-A/non-B. On repeated challenge hyperegic responses with diffuse liver cell necrosis occurred in some immune animals and this phenomenon must be taken into account in any future vaccination studies.
Animals↗
Mendelian Randomization Using a Japanese GWAS Identifies an HLA-Linked Causal Effect of Chronic Hepatitis B on Cholangiocarcinoma Risk.
BACKGROUND: Cholangiocarcinoma (CCA) is a highly malignant cancer that develops in the bile ducts. Its incidence is particularly high in East Asian populations, but the underlying genetic factors remain unclear. To investigate potential risk factors for CCA, we conducted a Mendelian randomization study to infer causality. METHODS: Using large-scale genome-wide association study data from the BioBank Japan resource, we systematically investigated the causal effects of genetic predisposition to seven conditions, chronic hepatitis B (CHB), chronic hepatitis C, autoimmune hepatitis, type 1 diabetes, type 2 diabetes, chronic gastritis, and chronic pancreatitis, on CCA risk. RESULTS: Our analysis reveals a significant association between genetic susceptibility to CHB with a 24% higher likelihood of developing CCA than non-susceptible individuals (Inverse-Variance Weighted Odds Ratio = 1.24, 95% Confidence Interval: 1.08-1.42; p = 0.002). This genetic association is significantly driven by instrumental variables enriched in the immune-regulatory HLA class II region (6p21), suggesting a plausible biological mechanism. For the primary outcome (CCA), statistical significance was assessed across seven exposures at a Bonferroni-corrected threshold (two-sided p<0.0071). Notably, the CHB-CCA association remains significant after correction. This primary finding is strongly supported by comprehensive sensitivity analyses that showed no evidence of confounding by horizontal pleiotropy or heterogeneity. Conversely, no significant causal effects on CCA were identified for the other six conditions. CONCLUSIONS: Our MR analysis supports a causal role of HBV infection in CCA development, highlighting the importance of targeted HBV screening and surveillance.
Female↗
Multi-Target HCC Blood Test Demonstrates Consistent Performance Across Subgroups of Patients with Chronic Liver Disease.
BACKGROUND: Early detection of hepatocellular carcinoma (HCC) is critical for improving patient outcomes; however, ultrasound-based surveillance has limited sensitivity and variable performance across patient populations. We evaluated the performance of a multitarget HCC blood test (mt-HBT), incorporating methylated DNA markers, alpha-fetoprotein (AFP), and patient sex, across clinically relevant subgroups. METHODS: We performed a subgroup analysis of a multicenter, prospective case-control study that included 159 patients with early-stage HCC (Barcelona Clinic Liver Cancer Stage 0/A) and 649 control patients with cirrhosis or chronic hepatitis B without HCC. The mt-HBT combined methylated HOXA1, TSPYL5, and B3GALT6 markers with AFP and sex. Sensitivity and specificity were evaluated overall and according to age, sex, obesity, liver disease etiology, Child Pugh class, and tumor size. Performance was compared with AFP and GALAD. RESULTS: Overall sensitivity and specificity of mt-HBT for early-stage HCC detection were 76.7% (95% CI, 69.6-82.6) and 87.5% (95% CI, 84.8-89.8), respectively. Sensitivity was significantly higher than that of AFP (35.2%, p < 0.001) and comparable to that of GALAD (78.6%, p = 0.56), whereas specificity was lower than that of AFP (98.5%, p < 0.001) but higher than that of GALAD (76.9%, p < 0.001). Sensitivity was maintained across key subgroups, including patients with obesity (68.9%), Child Pugh B cirrhosis (75.0%), hepatitis C (80.0%), hepatitis B (72.2%), alcohol-associated liver disease (80.5%), and metabolic dysfunction-associated steatotic disease (69.0%) (all p > 0.05 between subgroups). Specificity exceeded 80% in all examined populations and was significantly higher in women than in men (92.5% vs. 83.9%, p < 0.001). Sensitivity increased with tumor size, ranging from 60.0% for tumors < 2 cm to 100% for tumors > 5 cm. CONCLUSIONS: The mt-HBT demonstrated robust, consistent performance for early-stage HCC detection across diverse patient populations, including subgroups in which ultrasound surveillance commonly underperforms. These findings support the prospective validation of mt-HBT as a blood-based surveillance strategy for HCC.
liver cancer↗
Epidemiology and mode of transmission of viral hepatitis A and B.
Viral hepatitis is now subdivided into three forms: hepatitis A (HA), epidemic or short-incubation-period hepatitis; hepatitis B (HB), homologous serum or posttransfusion hepatitis; and a third form, for which the term "hepatitis C" (HC) or "non-A-non-B hepatitis" has been proposed. Hepatitis A is usually transmitted by the anal-oral route and occurs endemically and epidemically; hepatitis B is transmitted by direct inoculation but probably almost as frequently by nonparenteral routes and is usually endemic; hepatitis C occurs after transfusion and may account for more cases of posttransfusion hepatitis than HA and HB together. Both HA and HB can be diagnosed accurately by their respective antigens and corresponding antibodies; in contrast, little is known yet about the characteristics of HC.
Adolescent↗
A Case of Persistent Human Pegivirus Infection in Two Separate Pregnancies of a Woman.
Human pegivirus (HPgV) is best known for persistent, presumably non-pathogenic, infection and a propensity to co-infect with human immunodeficiency virus or hepatitis C virus. However, unique attributes, such as the increased risk of malignancy or immune modulation, have been recently recognized for HPgV. We have identified a unique case of a woman with high levels HPgV infection in two pregnancies, which occurred 4 years apart and without evidence of human immunodeficiency virus or hepatitis C virus infection. The second pregnancy was complicated by congenital heart disease. A high level of HPgV infection was detected in the maternal blood from different trimesters by RT-PCR and identified as HPgV type 1 genotype 2 in both pregnancies. In the second pregnancy, the decidua and intervillous tissue of the placenta were positive for HPgV by PCR but not the chorion or cord blood (from both pregnancies), suggesting no vertical transmission despite high levels of viremia. The HPgV genome sequence was remarkably conserved over the 4 years. Using VirScan, sera antibodies for HPgV were detected in the first trimester of both pregnancies. We observed the same anti-HPgV antibodies against the non-structural NS5 protein in both pregnancies, suggesting a similar non-E2 protein humoral immune response over time. To the best of our knowledge, this is the first report of persistent HPgV infection involving placental tissues with no clear indication of vertical transmission. Our results reveal a more elaborate viral-host interaction than previously reported, expand our knowledge about tropism, and opens avenues for exploring the replication sites of this virus.
GBV-C↗