Search Results (1,259)

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection remain a world health problem leading to fibrosis and cirrhosis. Liver damage is primarily mediated by the innate and adaptive immune responses since HBV and HCV are not directly cytotoxic. Kupffer cells and liver-recruited macrophages are heavily implicated in both viral elimination and progression of the disease. HBV and HCV proteins polarize macrophages into either an M1 pro-inflammatory phenotype, promoting hepatocyte damage or into an M2 immunosuppressive phenotype, leading to viral persistence and fibrogenesis via cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β). In this review a brief overview of the heterogeneity of liver macrophages in health and during chronic viral infection is presented. Recognition of viruses by macrophages and the modulation of macrophages by viral proteins in the pathogenesis of liver inflammation and injury are discussed in detail. Most importantly, the mechanisms that HBV and HCV are using to manipulate macrophages and escape elimination are also presented. The role of macrophages in the evolution of acute-on-chronic liver failure is analyzed. Finally, a concise presentation of the emerging, but not yet clinically used, therapeutic strategies targeting macrophages to control chronic HBV infection and restore the dysregulated immune response is discussed. In conclusion, this integrated review of liver macrophage implication summarizes the pathophysiology and pathogenesis of HBV and HCV including acute-on-chronic- liver failure and viral cirrhosis. Full article

Background: Patients with liver cirrhosis remain at a persistent risk of developing hepatocellular carcinoma (HCC) and liver decompensation even after hepatitis C virus (HCV) eradication. Objectives: We aimed to assess survival, the occurrence of recompensation and de novo decompensation events, and hepatic and extrahepatic malignancies in patients with liver cirrhosis during long-term observation (LTO) after direct-acting antiviral (DAA) treatment. Methods: The study population consisted of 326 consecutive HCV-infected patients with liver cirrhosis treated with DAAs between 1 July 2015 and 30 June 2025 at a single tertiary hepatology center, of whom we followed 298 individuals for a median (IQR) of 4.4 (2.4–8.1) years after treatment completion. Results: Men predominated in the study population, with a median age of 60 (48–69) years. The vast majority of patients had at least one comorbid condition. Fifty of them (16.8%) developed malignancies during LTO, including 33 cases of HCC and 17 with extrahepatic malignancies. New cases of HCC were documented as late as 9 years after DAA therapy. Overall, 103 patients (34.6%) died during LTO; 51 deaths occurred in patients with malignancies. Liver recompensation was observed in 27.8% of patients, while 9.9% experienced de novo decompensation events during LTO. The survival curve showed a gradual decline in survival probability from 0.96 at 1–2 years to 0.70 at 5 years and 0.51 at 10 years. Conclusions: Patients with cirrhosis should remain under long-term hepatological monitoring after antiviral treatment, as they are still at risk of liver decompensation and the development of de novo HCC. Full article

Background: Abnormalities in energy and amino acid metabolism are potentially involved in hepatocellular carcinoma (HCC) development. This study aimed to identify serum metabolites predictive of HCC following sustained virological response (SVR) with hepatitis C virus (HCV) treatment. Methods: Comparative metabolomics was conducted using time-course serum samples from patients who failed interferon-based therapy but subsequently achieved SVR with direct-acting antivirals (DAAs), minimizing inter-individual variability. Predictive biomarkers for post-SVR HCC were extracted from the results and validated by comparing 29 patients who developed post-SVR HCC with 58 age-matched patients who remained HCC-free during follow-up. Results: Metabolite concentrations changed more markedly after treatment in SVR cases than in non-SVR cases. Significant changes in methionine (Met), methionine sulfoxide (MetO), and ornithine (Orn) levels before and after treatment (Pre- and Post-Tx) were found only in the non-HCC group. Regression and survival analyses identified high levels of Pre- and Post-Tx Orn, Pre-Tx Met, and Post-Tx MetO as predictors of post-SVR HCC and enabled risk stratification. The integration of these metabolites with the fibrosis-4 (FIB-4) index and alpha-fetoprotein (AFP) facilitated risk stratification and discriminated between high- and low-risk patients. The Pre-Tx FIB-4/Met model and the Post-Tx AFP/MetO/Orn model identified low- and high-risk groups with 3-year HCC incidence rates of 6.4% and 81.8%, respectively. Conclusions: Serum Met, MetO, and Orn were identified as candidate biomarkers associated with post-SVR HCC development, which remains a concern in the fight against hepatitis C. Combining these metabolites with established clinical markers may improve post-SVR HCC risk stratification. Full article

Background: Systematic infectious screening is recommended before initiation of biologic therapies in chronic inflammatory rheumatic diseases (CIRDs), yet the clinical impact of this strategy in low-prevalence settings remains insufficiently characterized. This study aimed to evaluate the proportion of abnormal findings and their impact on treatment management. Methods: We conducted a retrospective single-center study including adult patients with CIRDs who underwent systematic pre-biologic infectious screening between January 2019 and June 2025. Screening included HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), interferon-γ release assay (IGRA), and chest radiography. The primary outcome was the proportion of abnormal results and their impact on biologic initiation. Results: A total of 418 patients was included (mean age 48.2 ± 14.6 years; 69.1% female). No active HIV, HBV, or HCV infections were detected. Past HBV infection markers were identified in 2.6% of patients, and anti-HCV antibodies in 0.7%, all without detectable viremia. None of these findings required modification of biologic therapy. IGRA positivity was observed in 4.3% of patients and indeterminate results were seen in 3.1%. Preventive antituberculous therapy was initiated in most newly identified IGRA-positive cases, leading to delayed biologic initiation in several patients. Chest radiography yielded limited additional diagnostic value. Conclusions: In this population, systematic pre-biologic infectious screening identified few clinically actionable viral infections, whereas latent tuberculosis screening represented the main determinant of therapeutic modification. These findings support continued emphasis on tuberculosis risk assessment and warrant further prospective studies to evaluate optimized and potentially targeted screening strategies incorporating cost-effectiveness analyses. Full article

Background/Objectives: Reliable quality control (QC) materials are essential for maintaining the analytical performance of hepatitis C virus (HCV) screening assays. Rapid diagnostic tests (RDTs) are widely used for point-of-care HCV screening; however, standardized plasma-based internal quality control (IQC) materials compatible with both rapid tests and automated immunoassays remain limited. This study aimed to develop and evaluate plasma-based QC materials applicable to multiple anti-HCV RDTs and automated immunoassays. Methods: QC materials were prepared from pooled HCV-positive plasma at strong-positive, weak-positive, and negative levels in liquid and lyophilized formats. Lyophilized preparations were produced with and without trehalose, while liquid samples were prepared with and without a stabilizer. Performance was evaluated using five anti-HCV RDT kits and the Elecsys Anti-HCV II automated immunoassay platform. Stability was assessed under accelerated temperature conditions (45 °C for 28 days) and long-term storage (2–8 °C and 20–30 °C for six months). Signal trends were analyzed using linear regression (p > 0.05), and homogeneity was evaluated using one-way analysis of variance and Cochran’s C test. Results: All QC formulations demonstrated consistent qualitative reactivity across the evaluated RDT kits and stable responses on the automated immunoassay platform. Lyophilized plasma containing trehalose maintained stable cut-off index (COI) values during accelerated and long-term storage, with no significant time-dependent trends (p > 0.05). Conclusions: Trehalose-stabilized lyophilized materials demonstrated enhanced stability and acceptable homogeneity, supporting practical applicability under the tested storage conditions across the evaluated rapid tests, and within the evaluated moderate-to-high positive analytical ranges on the automated anti-HCV immunoassay platform. Full article

Chronic infection with the hepatitis C virus (HCV) is the most significant risk factor for the development of hepatocellular carcinoma (HCC). It has been shown that the progression of HCV-related liver disease is mediated by both viral and host-specific factors. The HCV replication cycle is a host-dependent process that relies on intracellular signalling pathways within target cells. Thus, intracellular signal transduction plays a pivotal role in the modification of interactions between the host and HCV. These pathways are key regulators of liver diseases, including cirrhosis and HCC. In addition, HCV induces epigenetic modifications in the host genome that inhibit the expression of various tumour-suppressor genes. Some of these changes persist even after successful antiviral treatment and represent a continued risk for HCC development. Despite significant progress in the management of chronic HCV infection, this challenge remains unresolved. In this narrative review, we summarise the mechanisms of HCV-induced disease progression, focusing on the host immune response, the regulatory roles of viral and cellular proteins, and viral survival strategies during chronic infection. We also discuss HCV-induced epigenetic alterations that contribute to hepatocarcinogenesis both during infection and after viral clearance. These insights are important for identifying novel, reliable molecular biomarkers for patient surveillance and for designing new therapeutic approaches. Full article

Hepatitis E virus (HEV) infection is generally self-limiting in immunocompetent individuals but may progress to chronic infection in immunocompromised patients, underscoring the need for effective antiviral therapies. Although ribavirin is currently used off-label for HEV treatment, its associated adverse effects highlight the need for safer alternatives. In this study, we screened an anti-viral compound library comprising 800 compounds using three HEV reporter systems designed to target distinct stages of the viral life cycle. Candidate compounds were further evaluated in PLC/PRF/5 cells using both acute and chronic infection models with wild-type genotype 3 HEV (HEV-3). Antiviral activity was assessed by measuring HEV RNA levels in culture supernatants. Elbasvir, a known inhibitor of hepatitis C virus (HCV) non-structural protein 5A (NS5A), was identified as the most potent candidate. Although multiple compounds showed inhibitory effects in reporter assays, only elbasvir achieved sustained suppression of HEV growth in long-term culture, reducing HEV RNA levels to below the limit of detection. In a chronic infection co-culture model, elbasvir maintained antiviral activity at non-cytotoxic concentrations. Time-of-addition analysis demonstrated that elbasvir inhibits an early step in the viral life cycle, specifically viral internalization. Furthermore, combination with ribavirin enhanced antiviral efficacy, resulting in sustained viral suppression without detectable cytotoxicity and exhibiting an additive interaction. Collectively, these findings identify elbasvir as a promising candidate for repurposing as an anti-HEV drug and support a combination strategy targeting distinct steps of the viral life cycle. Full article

Therapeutic vaccines are a key strategy to achieve the goal of “functional cure” of chronic viral infections, including hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), human papillomavirus (HPV), and Epstein–Barr virus (EBV). Various platforms (such as viral vectors, nucleic acid vaccines, recombinant proteins, etc.) have successfully induced strong virus-specific T-cell responses in early trials, but their clinical efficacy is still limited by the immunosuppressive environment formed by the host. The core bottlenecks are severe T-cell exhaustion, viral immune escape, and various forms of local immune tolerance. Therefore, the field is moving toward combination therapies, including reduction of viral load, targeting of immune activation, and inhibition of inhibitory signaling pathways. This article summarizes the preclinical and clinical progress of therapeutic vaccines in the past decade, analyzes the major challenges in vaccine development, and discusses the future development directions in this field. Full article

Direct-acting antivirals (DAAs) have revolutionized hepatitis C virus (HCV) therapy, yet resistance-associated substitutions (RASs) remain a concern in specific clinical contexts. Here, we present a database-derived global overview of HCV RASs by analyzing 19,449 publicly available sequences across multiple genotypes and subtypes, encompassing both untreated and previously treated infections, in the NS3, NS5A, and NS5B genomic regions. We demonstrate a markedly heterogeneous distribution of RASs shaped by viral genotype, geographic origin, and treatment era. Importantly, RASs against pan-genotypic NS3 protease inhibitors (glecaprevir and voxilaprevir) were rare (generally <1% across genotypes). In contrast, NS5A inhibitors showed greater vulnerability, with the Y93H substitution detected at notable frequencies in major genotypes (3.2–7.0%) and near-universal resistance-associated substitutions (e.g., 100% Q30S) observed in the rare genotype 8. The NS5B nucleotide analogue sofosbuvir retained a high genetic barrier, with the canonical S282T substitution detected only sporadically (2.1% of genotype 4 sequences). At the population level, geographic heterogeneity was evident, with higher RAS frequencies observed in specific regions, alongside pronounced data gaps in high-prevalence areas of Africa. Temporal analyses revealed an increase in NS3 and NS5A RASs following the introduction of first-generation DAAs, with NS5A substitutions persisting into the current interferon-free era, whereas NS5B resistance remained consistently rare across all treatment periods. Together, these findings provide a global, population-level overview of resistance-associated HCV diversity and reinforce the durability of high-barrier regimens while highlighting persistent genotype-specific vulnerabilities with implications for antiviral resistance surveillance and HCV elimination efforts. Full article

The hepatitis B (HBV), C (HCV), and D (HDV) viruses remain a major public health burden. Occult HBV infection (OBI) represents a hidden reservoir with clinical and epidemiological significance, yet its prevalence in Northwest Russia is unknown. We aimed to comprehensively assess the serological and molecular epidemiology of HBV, HCV, and HDV in St. Petersburg and the Leningrad region. Methods. In this cross-sectional study, 6773 apparently healthy volunteers were enrolled. Plasma samples were tested for hepatitis B surface antigen (HBsAg), antibodies to HBV core antigen (anti-HBc), antibodies to HBsAg (anti-HBs), antibodies to HCV (anti-HCV), and antibodies to HDV (anti-HDV) by ELISA. All anti-HCV- and anti-HDV-positive samples were tested for HCV RNA and HDV RNA by real-time PCR. All samples were tested for HBV DNA using a highly sensitive in-house nested real-time PCR assay (detection limit: 5 IU/mL). All “HBV DNA-positive, HBsAg-negative” cases confirmed by two independent extractions were classified as OBI. Vaccination status, self-reported history, and iatrogenic interventions were recorded. Results. Overall seroprevalence values were: HBsAg 1.7%; anti-HBc 11.3%; anti-HBs 43.0%; anti-HCV 1.9%; and anti-HDV 0.6%. Anti-HBc increased sharply with age (3.1% in children to 26.4% in the elderly, p < 0.0001), while anti-HBs declined (69.9% to 29.8%, p < 0.0001). HBV DNA was detected in 118 participants (1.7%). Of these, only 73 individuals (1.1%) were HBsAg-positive, while the remaining 45 participants (0.7%) had undetectable HBsAg, meeting the criteria for OBI. OBI was detected across all age groups, including children. Serological profiling of OBI cases revealed that 57.8% lacked both anti-HBc and anti-HBs, 35.6% had isolated anti-HBs, 2.2% had isolated anti-HBc, and 4.4% had both antibodies. HCV RNA was detected in 15.0% of anti-HCV-positive individuals (all adults). No HDV RNA was detected. Self-reported history underestimated true infection rates: 1.4% of those denying HBV infection were HBsAg-positive and 10.6% were anti-HBc-positive. Among those denying HCV infection, 1.4% were anti-HCV-positive. Vaccination coverage was 70.8%, declining from 90.9% in children to 39.0% in the elderly (p < 0.0001). Among vaccinated individuals, 48.0% lacked protective anti-HBs (<10.0 mIU/mL). Conclusions. This comprehensive serological and molecular study in Northwest Russia is the first to combine population-level serology with molecular detection of HBV, HCV, and HDV, including OBI in this region, and reveals that OBI accounts for a substantial proportion (38%) of all active HBV infections and is strongly associated with a history of iatrogenic interventions. The presence of OBI across all age groups, including children, shows that HBsAg screening alone substantially underestimates the true HBV burden. High rates of unrecognized infection and waning vaccine-induced immunity, highlight critical gaps in current surveillance. These findings provide an evidence-based rationale for integrating molecular testing into screening algorithms and for considering booster vaccination strategies to achieve viral hepatitis elimination goals. Full article

Background: The immunological factors associated with long-term hepatitis C virus (HCV)-specific humoral immunity after cure remain uncharacterized, particularly in people with HIV (PWH). This study investigated T-cell immunophenotypes and plasma biomarkers associated with anti-E2 binding (HCV-E2Abs) and neutralizing antibody (HCV-nAbs) titers 5 years after achieving sustained virologic response (SVR). Methods: This cross-sectional study analyzed 64 PWH with cured HCV and prior advanced fibrosis. We quantified plasma antibody titers against 5 HCV genotypes, T-cell phenotypes (n = 58), and plasma biomarkers (n = 50). Associations were assessed using Generalized Linear Models (gamma distribution, log-link function) adjusted for clinical confounders, reporting adjusted Arithmetic Mean Ratios (aAMRs) and false discovery rate (FDR)-corrected q-values. Results: Higher frequencies of CD4⁺ T-cell activation (CD38⁺; aAMR = 1.58; q = 0.028) and soluble CD27 levels (aAMR = 1.46; q = 0.038) were associated with higher HCV-E2Abs titers. In contrast, memory T-cell activation across CD4⁺ and CD8⁺ compartments (HLA-DR⁺ and CD38+; all q < 0.10) and elevated soluble immune checkpoints (sCD28, sPD-L2, sLAG-3, sCTLA-4; all q < 0.10) were associated with preserved HCV-nAbs titers. Conversely, a higher frequency of naïve CD8⁺ T-cells was associated with lower neutralization capacity (aAMR = 0.41; q = 0.042). Regarding inflammatory markers, soluble TNF-RI was positively associated with neutralizing titers (aAMR = 1.44; q = 0.019), whereas IL-18 was inversely associated (aAMR = 0.53; q = 0.019). Conclusions: Specific activated T-cell subsets, checkpoint shedding, and selective inflammatory signals were associated with higher long-term HCV-nAbs titers in PWH. In contrast, higher frequencies of naïve CD8⁺ T-cells and elevated IL-18 levels were associated with reduced neutralizing capacity. Full article

Background: Chronic hepatitis C virus (HCV) infection is increasingly recognized as a systemic inflammatory condition associated with accelerated atherosclerosis and adverse cardiovascular outcomes. However, its relationship with coronary anatomical complexity in patients presenting with ST-segment elevation myocardial infarction (STEMI) remains insufficiently defined. Aims: This study aimed to evaluate the association between chronic HCV infection and coronary artery disease complexity assessed by the SYNTAX score in STEMI patients undergoing primary percutaneous coronary intervention (pPCI) and to investigate its relationship with in-hospital mortality. Methods: In this retrospective single-center cohort study, 1647 STEMI patients treated with pPCI between January 2021 and December 2025 were analyzed; 106 (6.4%) were HCV-positive. Propensity score matching based on baseline demographic and cardiovascular risk factors yielded 105 matched pairs. The primary endpoint was the SYNTAX score, while the secondary endpoint was in-hospital all-cause mortality. Results: HCV-positive patients demonstrated significantly higher SYNTAX scores than HCV-negative patients before (19.5 ± 8.5 vs. 15.8 ± 9.6; p < 0.001) and after propensity score matching (19.4 ± 8.5 vs. 15.6 ± 9.2; p = 0.002). Coronary artery bypass grafting referral was more frequent among HCV-positive patients both before (11.3% vs. 5.3%; p = 0.010) and after matching (11.4% vs. 2.9%; p = 0.016). Notably, HCV-positive patients exhibited higher coronary anatomical complexity despite lower total and LDL cholesterol levels. In multivariable analyses, HCV positivity remained independently associated with higher SYNTAX scores in both unmatched and matched cohorts. In-hospital mortality rates were comparable between groups, and HCV positivity was not independently associated with mortality. Conclusions: Chronic HCV infection was independently associated with increased coronary anatomical complexity in STEMI patients undergoing pPCI, suggesting a relationship with a more diffuse and structurally complex atherosclerotic phenotype rather than short-term in-hospital outcomes. These findings support the concept of HCV infection as a non-traditional cardiovascular risk factor associated with adverse coronary vascular remodeling. Full article

Hepatitis C virus (HCV) infection remains a major global health burden, and no vaccine preventing chronic infection is available. The envelope glycoproteins, E1 and E2, form a complex essential for viral entry; however, the mechanisms governing E1/E2 assembly and stability remain incompletely defined. Here, we investigated the role of the E1/E2 transmembrane (TM) regions in HCV infectivity using chimeras of JFH1-based recombinants with isolate-specific Core-NS2 sequences in which the C-terminal TM domains of E1 (TME1), E2 (TME2), or both (TME1E2) from the H77 isolate (genotype 1a) replaced those of isolates representing genotypes 1–6. We further introduced the TM domains of S52 (genotype 3a) or J6 (genotype 2a) into H77 and included reciprocal swaps between J6 and S52. Most TM-swap chimeras displayed impaired infectivity; however, serial passaging led to partial recovery associated with adaptive mutations in E1/E2 mapping not only to the C-terminal TM regions but also to the E1 stem and the internal E1 TM region (iTME1). Extending the TME1 swap to include upstream α-helical segments improved infectivity in selected chimeras, whereas inclusion of iTME1 abolished infectivity. These findings support functional interactions between membrane-associated regions of E1/E2 and their ectodomains and highlight their relevance for E1/E2-based HCV vaccine design. Full article

Background: Hepatitis C virus (HCV) remains a major cause of preventable liver-related mortality in the United States despite highly effective direct-acting antivirals (DAAs). Contemporary assessment of mortality trends and disparities is essential for elimination efforts. Methods: Using CDC WONDER multiple cause-of-death data (1999–2023), we identified HCV-related deaths using ICD-10 codes for acute and chronic HCV (B17.1, B18.2) and calculated age-adjusted mortality rates (AAMRs) per 100,000 (2000 US standard). Rates were stratified by sex, race/ethnicity, census region, and 2013 NCHS urban–rural classification. Joinpoint regression quantified temporal inflection points and annual percent changes (APCs). Results: Overall HCV-related AAMR increased from 1.8 (1999) to a peak of 5.0 (2014), then declined to 2.3 (2023), with a marked post-2014 decrease (APC −8.2%). Mortality was consistently higher in males than females (2023 rate ratio 2.57). In 2023, American Indian/Alaska Native individuals had the highest mortality (AAMR 8.7; rate ratio 3.48 vs. non-Hispanic White), followed by non-Hispanic Black individuals (AAMR 6.2; rate ratio 2.48). Mortality remained highest in the West and was higher in non-metropolitan than metropolitan counties (AAMR 2.8 vs. 2.3; rate ratio 1.22), with a slower post-2014 decline in non-metropolitan areas. Conclusions: Our findings indicate that while the DAA era has been associated with a substantial reduction in HCV-related mortality at the national level, this progress has not been uniform across all populations. Persistent excess mortality among Native American and non-Hispanic Black individuals may reflect inequities in the HCV care cascade, including screening, confirmatory testing, linkage to specialty care, insurance-related restrictions, and the high cost of antiviral therapy. These results highlight the need for policies and public health strategies that improve equitable and affordable access to curative HCV treatment. Full article

Hepatitis C virus (HCV) infection is still a major worldwide health concern. It is distinguished by a high degree of genetic variation that affects the course of the illness and the effectiveness of treatment. The epidemiological profile of HCV is prone to rapid change in areas where there is significant human migration, like Turkey. The purpose of this study was to evaluate the impact of long-term migration on local viral diversity by analyzing the distribution and temporal trends of HCV genotypes among Turkish citizens and asylum seekers in Kayseri, Turkey, over an eight-year period. From January 2014 to December 2021. 1173 HCV RNA-positive patients at Kayseri City Training and Research Hospital were the subject of a retrospective analysis. Genotypes were determined using the Abbott RealTime HCV Genotype II assay and Montania 4896 assay (Anatolia Geneworks, Türkiye). The most prevalent genotypes were Genotype 1b (48.3%, 95% CI: 45.5–51.2%), Genotype 4 (25.0%, 95% CI: 22.5–27.5%), and Genotype 1a (10.3%, 95% CI: 8.6–12.1%). Turkish patients exhibited the highest prevalence of Genotype 1b (98.2%), while asylum seekers demonstrated greater relative burdens of Genotype 4 (8.5% of total GT4) and Genotype 5 (83.3% of total GT5). Genotype 3a emerged in 2018, with a predominance in males (73.9%). The Cochran–Armitage trend test revealed statistically significant increasing trends for Genotype 3 (Z = 3.572, p = 0.0004) and Genotype 3a (Z = 2.600, p = 0.009). This eight-year retrospective study demonstrates that the HCV genotype distribution in Kayseri has undergone significant changes in the context of migration and demographic shifts. The statistically significant increasing trends of Genotypes 3 and 3a, particularly among younger male populations, suggest evolving transmission dynamics. These findings underscore the necessity of demographically targeted and culturally appropriate screening and treatment strategies for both resident and migrant populations to achieve HCV elimination goals. Full article