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Background: Healthcare workers (HCWs) are at higher risk of contracting hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Currently, there is no estimate of pooled data on the prevalence of HBV and HCV infections among HCWs in the country. Thus, this review aimed to determine the pooled prevalence of hepatitis B and C infections among HCWs in Ethiopia., Materials and Methods: A comprehensive literature search was conducted using electronic databases, including PubMed, Cochrane Library, Science Direct, Hinari, and African Journals Online to identify pertinent articles from the inception to April 2024. The protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42024527940) and conducted per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were extracted independently by two authors and analyzed using STATA version 11 software. A random-effect model and Egger's test were computed to estimate the pooled prevalence and assess publication bias, respectively., Results: A total of 18 studies involving4,948 healthcare workers were included in this review to estimate the pooled prevalence of HBV and HCV infections among HCWs in Ethiopia. The overall prevalence of HBV was 5.93% (95% CI; 3.22-8.63). The sub-group analysis showed that the prevalence of HBV among medical waste handlers and health professionals was8.6% (95% CI; 3.01-14.13) and 4.98% (95% CI; 1.85-8.11), respectively. The combined prevalence of HCV was 1.12% (95% CI; -4.19-6.43). In the sub-group analysis, the prevalence of HCV among medical waste handlers and health professionals was1.44% (95% CI; -5.28-8.18) and 0.59% (95% CI; -8.09-9.27), respectively., Conclusion: In this review, we found a higher (5.93%) and moderate (1.12%) prevalence of HBV and HCV infections, respectively among Ethiopian HCWs. Therefore, to reduce the infectious burden of HBV and HCV among HCWs; there is a need to strict adherence to infection prevention and control measures. In addition, adequate HBV vaccination coverage for HCWs is mandatory to reduce the burden of HBV infection in the country., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Girmay et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The prevalence of hepatitis C virus (HCV) infection in the United States has increased over the past decade despite the development of effective direct-acting antiviral treatments. To meet the World Health Organization's (WHO) goal of eliminating HCV infection by 2030, transmission events must be reduced. Currently, infection screening relies on detection of HCV antibodies, with nucleic acid amplification testing (NAAT) used to confirm HCV viremia and monitor changes in viral load. However, the seroconversion window for detection of HCV antibodies is long, averaging 6 weeks, with delayed seroconversion common in co-infected and immunosuppressed populations. Testing for HCV core antigen, which is present approximately 5 weeks before HCV antibodies, holds promise for earlier detection of HCV infection. It may also hold promise as a cheaper, more accessible, and more rapid alternative to NAAT for infection confirmation. Here, we evaluated the agreement between a research-use HCV Core Antigen Assay and NAAT among US patients receiving clinically indicated NAAT. Among 412 specimens, the overall concordance was 97.1%, with a positive percent agreement of 95.5%. Discrepancies primarily occurred among patients with chronic HCV and low viral loads; 11/12 discrepancies showed viral loads <4,000 IU/mL. Among patients being screened for HCV infection (i.e., excluding those undergoing NAAT for serial monitoring of a previously diagnosed infection), the positive percent agreement was 97.0%. Among patients undergoing serial testing, changes in HCV Core Antigen Assay signal-to-cut-off values were generally correlated with changes in the viral load. Results suggest that the research-use HCV Core Antigen Assay studied here may reliably detect and/or confirm HCV infection., Importance: A research-use HCV Core Antigen Assay showed high concordance with nucleic acid amplification testing for the detection of current hepatitis C infection. The assay may enable more rapid and lower-cost detection and/or confirmation of hepatitis C infection., Competing Interests: The authors declare no conflict of interest.

An effective vaccine against hepatitis C virus (HCV) should elicit both humoral and cellular immune responses. Previously, we characterized a bivalent vaccine candidate against hepatitis B (HBV) and HCV using chimeric HBV-HCV virus-like particles (VLP), in which the highly conserved epitope of HCV E2 glycoprotein (residues 412-425) was inserted into the hydrophilic loop of HBV small surface antigen (sHBsAg). While sHBsAg&#95;412-425 elicited cross-neutralizing antibodies, it did not trigger a T-cell response against HCV. Thus, this study aimed to develop a vaccine candidate engaging both arms of adaptive immune response, potentially offering stronger protection against HCV. We evaluated the immunogenicity of minicircle (MC) DNA vaccines encoding sHBsAg&#95;412-425 and HCV nonstructural (NS) proteins in BALB/c mice. Co-administration of sHBsAg&#95;412-425 and NS induced a potent T-cell response, especially against NS3 and high titers of antibodies specific to HCV E2. Additionally, these antibodies recognized native HCV envelope glycoprotein heterodimers (E1E2) across multiple HCV genotypes and showed binding profiles to E1E2 alanine mutants comparable to the broadly neutralizing AP33 antibody. Overall, the findings demonstrate that MC DNA vaccine incorporating both sHBsAg&#95;412-425 and HCV NS protein sequences induces robust, T-cell and AP33-like antibody responses, highlighting its potential as pan-genotypic prophylactic vaccine against HCV., (© 2024. The Author(s).)

HCV RNA test determines current active infection and is a requirement prior to initiating HCV treatment. We investigated trends and factors associated with post-diagnosis HCV RNA testing rates prior to HCV treatment, and risk factors for first positive HCV RNA among people living with HIV (PLHIV) with HCV in the Asia-Pacific region. PLHIV with positive HCV antibody and in follow-up after 2010 were included. Patients were considered HCV-antibody positive if they ever tested positive for HCV antibody (HCVAb). Repeated measures Poisson regression model was used to analyse factors associated with post-diagnosis HCV RNA testing rates from positive HCVAb test. Factors associated with time to first positive HCV RNA from positive HCVAb test were analysed using Cox regression model. There were 767 HCVAb positive participants included (87% from LMICs) of whom 11% had HCV RNA tests. With 163 HCV RNA tests post positive HCVAb test, the overall testing rate was 5.05 per 100 person-years. Factors associated with increased testing rates included later calendar years of follow-up, HIV viral load ≥1000 copies/mL and higher income countries. Later calendar years of follow-up, ALT >5 times its upper limit of normal, and higher income countries were associated with shorter time to first positive HCV RNA test. Testing patterns indicated that uptake was predominantly in high income countries possibly due to different strategies used to determine testing in LMICs. Expanding access to HCV RNA, such as through lower-cost point of care assays, will be required to achieve elimination of HCV as a public health issue., (© 2024 John Wiley & Sons Ltd.)

Background and Aims: HCV infection continues to be a major global health burden despite effective antiviral treatments. The urgent need for a protective vaccine is hindered by the scarcity of suitable HCV-permissive animal models tractable in vaccination and challenge studies. Currently, only antibody neutralization studies in infectious cell culture systems or studies of protection by passive immunization of human liver chimeric mice offer the possibility to evaluate the effect of vaccine-induced antibodies. However, differences between culture-permissive and in vivo-permissive viruses make it a challenge to compare analyses between platforms. To address this problem, we aimed at developing genotype-specific virus variants with genetic stability both in vitro and in vivo., Approach and Results: We demonstrated infection of human liver chimeric mice with cell culture-adapted HCV JFH1-based Core-NS2 recombinants of genotype 1-6, with a panel of 10 virus strains used extensively in neutralization and receptor studies. Clonal re-engineering of mouse-selected mutations resulted in virus variants with robust replication both in Huh7.5 cells and human liver chimeric mice, with genetic stability. Furthermore, we showed that, overall, these virus variants have similar in vitro neutralization profiles as their parent strains and demonstrated their use for in vivo neutralization studies., Conclusions: These mouse-selected HCV recombinants enable the triage of new vaccine-relevant antibodies in vitro and further allow characterization of protection from infection in vivo using identical viruses in human liver chimeric mice. As such, these viruses will serve as important resources in testing novel antibodies and can thus guide strategies to develop an efficient protective vaccine against HCV infection., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: Better access to direct-acting antiviral (DAA) therapy has broadened the utilization of hepatitis C virus (HCV) nucleic acid testing (NAT) positive organs with excellent outcomes. However, DAA therapy has been associated with hepatitis B virus (HBV) reactivation., Aim: To determine the risk of HBV transmission or reactivation with utilization of HBV core antibody positive (HBcAb+) and HCV NAT positive (HCV+) organs, which presumably required DAA therapy., Methods: The number of HBcAb+ donors with delineated HCV NAT status was obtained from the Organ Procurement and Transplantation Network (OPTN) database. The number of unexpected HBV infections from transplanted organs adjudicated as "proven" or "probable" transmission was obtained from the OPTN Ad Hoc Disease Transmission Advisory Committee database. A chart review of the donors of "proven" or "probable" cases was conducted., Results: From January 1, 2016, to December 31, 2021, 7735 organs were procured from 3767 HBcAb+ donors and transplanted into 7469 recipients; 545 (14.5%) donors were also HCV+. HBV transmission or reactivation occurred in seven recipients. The rate is not significantly different between recipients of HCV+ (0.18%, 2/1115) and the HCV NAT negative (HCV-) organs (0.08%, 5/6354) (p = 0.28) or between recipients of HCV+ and HCV- livers as well as non-liver organs. HBV transmission or reactivation occurred within a median of 319 (range, 41-1117) days post-transplant in the setting of missing, inadequate, or truncated prophylaxis., Conclusion: HBV reactivation associated with DAA therapy for HBcAb+ HCV+ organs is less frequent than reported in the non-transplant population, possibly due to the common use of HBV prophylaxis in the at-risk transplant population., (© 2024 The Author(s). Transplant Infectious Disease published by Wiley Periodicals LLC.)

Pakistan harbours a large burden of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. We utilised repeat sero-surveys to assess progress achieved towards hepatitis elimination in Pakistan. Multilevel logistic regression evaluated the change in HBV infection (HBV surface antigen (HBsAg)-positive) prevalence and HCV exposure (HCV antibody (HCV-Ab)-positive) prevalence between two sero-surveys from 2007 and 2019 for Sindh province and associated risk factors. Adjusted odds ratios (aORs) were estimated and population-attributable fractions (PAF) for modifiable risk factors for HCV exposure. The 2007 and 2019 surveys included 8855 and 6672 individuals. HBsAg prevalence decreased from 2.6% (95% confidence intervals (95% CI): 2.2-2.9) in 2007 to 1.1% (95% CI: 0.8-1.3) in 2019, while HCV-Ab prevalence increased from 5.1% (95% CI: 4.6%-5.5%) to 6.2% (95% CI: 5.6%-6.8%). The age and gender-adjusted HBsAg prevalence decreased by 80% (aOR = 0.2, 95% CI: 0.1-0.4) among children and 60% (aOR = 0.4, 95% CI: 0.3-0.6) among adults over 2007-2019, while HCV-Ab prevalence decreased by 60% (aOR = 0.4, 95%CI:0.2-0.7) in children and increased by 40% (aOR = 1.4, 95% CI: 1.2-1.7) in adults. HCV-Ab prevalence was lower in adults with secondary (aOR = 0.6, 95% CI: 0.5-0.8) and higher (aOR = 0.5, 95%CI:0.3-0.8) education compared to illiterates and higher among adults reporting blood transfusion (aOR = 1.7, 95% CI: 1.2-2.4), family history of hepatitis (aOR = 2.5, 95% CI: 1.9-3.3), past year medical injection (aOR = 2.1, 95% CI: 1.6-2.7), being tattooed (aOR = 1.4, 95% CI: 1.0-1.9) and shaved by traditional barber (aOR = 1.2, 95% CI: 1.0-1.5). Modifiable risk factors accounted for 45% of HCV exposure, with medical injection(s) accounting for 38% (95%CI,25.7-48.4%). Overall HCV has increased over 2007-2019 in Sindh province, while HBV prevalence has decreased. Medical injections should be an important focus of prevention activities., (© 2024 The Author(s). Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Background & Aims: Chronic HCV infection results in abnormal immunological alterations, which are not fully normalized after viral elimination by direct-acting antiviral (DAA) treatment. Herein, we longitudinally examined phenotypic, transcriptomic, and epigenetic alterations in peripheral blood regulatory T (Treg) cells from patients with chronic HCV infection before, during, and after DAA treatment., Methods: Patients with chronic genotype 1b HCV infection who achieved sustained virologic response by DAA treatment and age-matched healthy donors were recruited. Phenotypic characteristics of Treg cells were investigated through flow cytometry analysis. Moreover, the transcriptomic and epigenetic landscapes of Treg cells were analyzed using RNA sequencing and ATAC-seq (assay for transposase-accessible chromatin with sequencing) analysis., Results: The Treg cell population - especially the activated Treg cell subpopulation - was expanded in peripheral blood during chronic HCV infection, and this expansion was sustained even after viral clearance. RNA sequencing analysis revealed that viral clearance did not abrogate the inflammatory features of these Treg cells, such as Treg activation and TNF signaling. Moreover, ATAC-seq analysis showed inflammatory imprinting in the epigenetic landscape of Treg cells from patients, which remained after treatment. These findings were further confirmed by intracellular cytokine staining, demonstrating that Treg cells exhibited inflammatory features and TNF production in chronic HCV infection that were maintained after viral clearance., Conclusions: Overall, our results showed that during chronic HCV infection, the expanded Treg cell population acquired inflammatory features at phenotypic, transcriptomic, and epigenetic levels, which were maintained even after successful viral elimination by DAA treatment. Further studies are warranted to examine the clinical significance of sustained inflammatory features in the Treg cell population after recovery from chronic HCV infection., Impact and Implications: During chronic HCV infection, several immune components are altered both quantitatively and qualitatively. The recent introduction of direct-acting antivirals has led to high cure rates. Nevertheless, we have demonstrated that inflammatory features of Treg cells are maintained at phenotypic, transcriptomic, and epigenetic levels even after successful DAA treatment. Further in-depth studies are required to investigate the long-term clinical outcomes of patients who have recovered from chronic HCV infection., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The development of effective vaccines against Hepatitis C Virus (HCV) remains a global health priority and challenge. In this study, we employed an integrative approach combining computational epitope prediction with experimental validation to identify immunogenic peptides targeting the E1 glycoprotein of HCV. In the present report, computational data from various epitope prediction algorithms such as IEDB and SYFPEITHI, followed by molecular dynamics (MD) simulations and immuno-informatics analysis is presented. Through computational screening, we identified potential epitope candidates, with QVRNSSGLY (P3) and QLFTFSPRH (P7) emerging as promising candidates. MD simulations revealed stable interactions between these epitopes and MHC molecule, further validated by free energy estimations using MMPBSA method. Immuno-informatics analysis supported these findings, showing high binding potential and immunogenicity scores for the selected peptides. Subsequent synthesis and characterization of epitope peptides confirmed their structural integrity and purity required for conducting immune activation assays. Experimental immunological assays carried out in this study involved epitope peptide induced activation of CD8 + and CD4 + T cells from healthy human subjects and HCV- recovered patients. Data from experimental validation revealed significant cytokine release upon exposure to epitope peptides, particularly TNF-a, IL-6, and GM-CSF, indicative of robust immune responses. Notably, peptides P3 and P7 exhibited the most pronounced cytokine induction profiles, underscoring their potential as vaccine candidates. Further investigations addressing the mechanism of action of these epitope peptides under preclinical and clinical settings may help in developing effective vaccine against HCV., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [All the methods involving the ethical concerns were performed in accordance with the relevant guidelines and regulations of Institutional Ethical Committee of Savitribai Phule Pune University, Pune, India]., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Identification and isolation of antigen-specific T cells for downstream transcriptomic analysis is key for various immunological studies. Traditional methods using major histocompatibility complex (MHC) multimers are limited by the number of predefined immunodominant epitopes and MHC matching of the study subjects. Activation-induced markers (AIM) enable highly sensitive detection of rare antigen-specific T cells irrespective of the availability of MHC multimers. Herein, we have developed an AIM assay for the detection, sorting and subsequent single-cell RNA sequencing (scRNA-seq) analysis of hepatitis C virus (HCV)-specific T cells. We examined different combinations of the activation markers CD69, CD40L, OX40, and 4-1BB at 6, 9, 18 and 24 h post stimulation with HCV peptide pools. AIM + CD4 T cells exhibited upregulation of CD69 and CD40L as early as 6 h post-stimulation, while OX40 and 4-1BB expression was delayed until 18 h. AIM + CD8 T cells were characterized by the coexpression of CD69 and 4-1BB at 18 h, while the expression of CD40L and OX40 remained low throughout the stimulation period. AIM + CD4 and CD8 T cells were successfully sorted and processed for scRNA-seq analysis examining gene expression and T cell receptor (TCR) usage. scRNA-seq analysis from this one subject revealed that AIM + CD4 T (CD69 + CD40L + ) cells predominantly represented Tfh, Th1, and Th17 profiles, whereas AIM + CD8 T (CD69 + 4-1BB + ) cells primarily exhibited effector and effector memory profiles. TCR analysis identified 1023 and 160 unique clonotypes within AIM + CD4 and CD8 T cells, respectively. In conclusion, this approach offers highly sensitive detection of HCV-specific T cells that can be applied for cohort studies, thus facilitating the identification of specific gene signatures associated with infection outcome and vaccination.

The Centers for Disease Control and Prevention (CDC) guidelines for hepatitis C virus (HCV) testing, although effective, may miss crucial diagnostic opportunities. The goal of this study was to assess the utility of an antibody (Ab) and antigen (Ag) combination immunoassay as an alternative to traditional HCV screening. Remnant specimens from 1,341 patients with concurrent third-generation serologic (Roche anti-HCV-II) and nucleic acid amplification testing (NAAT) were assessed using the HCV Duo Ab/Ag immunoassay (Roche). Patient demographics, risk factors, and standard of care (SOC) laboratory results from the medical records were recorded. Overall, 99.0% (197/199) of the HCV Duo Ab+/Ag+specimens accurately identified active infections as confirmed by NAAT, and 99.9% (670/671) Ab-/Ag- samples corresponded to those without HCV infections. Individually, the HCV Duo Ab component demonstrated a 95.6% positive percent agreement (PPA) (95% CI = 93.8-96.9) and 99.1% negative percent agreement (NPA) (98.8-99.6) compared with SOC anti-HCV II Ab assay. The HCV Duo Ag had a 73.5% PPA (67.9-78.4) and 99.8% NPA (99.3-100) with NAAT. Among RNA+ specimens, 73.4% (197/267) were HCV Duo Ag+, and 265/267 (99.3%) were successfully detected on the HCV Duo Ab component. Notably, 5/7 (71.4%) Ab-/RNA +specimens were detected by HCV Duo, which would have been missed by traditional algorithmic testing. Fourth generation HCV Duo Ab/Ag assay demonstrated comparable performance to SOC testing and shortens the diagnostic window but does not eliminate the need for NAAT in all patients. Ab/Ag testing identified several Ab-/RNA+ cases, a subgroup often undiagnosed by current algorithmic testing, demonstrating promise for improved diagnostic efficiency and accuracy in HCV detection.IMPORTANCEThis study highlights the potential of a combined hepatitis C virus (HCV) Duo antibody (Ab) and antigen (Ag) immunoassay to improve early detection of HCV infections. Traditional Ab-only screening methods recommended by the Centers for Disease Control and Prevention may miss early-stage infections. The HCV Duo assay showed high accuracy, detecting nearly all active infections confirmed by nucleic acid amplification testing. Dual detection of HCV Ab and Ag shortens the diagnostic window, enabling intervention and treatment in a single visit, which is crucial for improving patient outcomes and reducing HCV transmission, especially in areas with limited access to confirmatory molecular testing., Competing Interests: T.I.B. has no conflict of interest. N.W.A. has served on scientific advisory boards for Roche Diagnostics and Diasorin Molecular. C.W.F. has served on scientific advisory boards for Werfen, Abbott Laboratories, Roche Diagnostics, and Cytovale and received research funding from Beckman Coulter, Abbott Laboratories, Roche Diagnostics, Cepheid, Siemens Healthineers, and Biomerieux.

Background: A barrier to hepatitis C virus (HCV) cure is conventional testing. The aim of this study was to evaluate the effect of HCV antibody and RNA point-of-care testing (POCT) on testing rates, linkage to care, treatment, and acceptability of testing in 3 priority settings in Australia., Methods: Participants were enrolled in an interventional cohort study at a reception prison, inpatient mental health service, and inpatient alcohol and other drug unit, between October 2020 and December 2021. HCV POCT was performed using SD Bioline HCV antibody fingerstick test and a reflexive Xpert HCV Viral Load Fingerstick test using capillary blood samples. A retrospective audit of HCV testing and treatment data was performed at each site for the preceding 12-month period to generate a historical control., Results: A total of 1549 participants received a HCV antibody test with 17% (264 of 1549) receiving a positive result, of whom 21% (55 of 264) tested HCV RNA positive. Across all settings the rate of testing per year significantly increased between the historical controls and the study intervention period by 2.57 fold (rate ratio, 2.57 [95% confidence interval, 2.32-2.85]) for HCV antibody testing and 1.62 (rate ratio, 1.62 [95% confidence interval, 1.31-2.01]) for RNA testing. Treatment uptake was higher during the POCT intervention (86% [47 of 55]; P = .01) compared to the historical controls (61% [27 of 44])., Conclusions: This study demonstrated across 3 settings that the use of HCV antibody and RNA POCT increased testing rates, treatment uptake, and linkage to care. The testing model was highly acceptable for most participants., Clinical Trials Registration: ACTRN-12621001578897., Competing Interests: Potential conflicts of interest. E. M. M. reports grants paid to Royal Adelaide Hospital from the Gilead Research Fellowship. J. R. reports payments from AbbVie for education. A. W. reports Medical Research Future Fund grants for 2021–2022. V. C. reports an National Health & Medical Research Council grant partnership, serving as principal investigator for the National Australian HCV Point-of-Care Testing Program, and participation as a member of the Clinical Advisory Group for the Kirby National Australian HCV Point-of-Care Testing. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Illicitly manufactured fentanyl (IMF) increases overdose mortality, but its role in infectious disease transmission is unknown. We examined whether IMF use predicts hepatitis C virus (HCV) and human immunodeficiency virus (HIV) incidence among a cohort of people who inject drugs (PWID) in San Diego, California and Tijuana, Mexico., Methods: PWID were recruited during 2020-2022, undergoing semi-annual interviewer-administered surveys and HIV and HCV serological rapid tests through 2024. Cox regression was conducted to examine predictors of seroconversion considering self-reported IMF use as a 6-month lagged, time-dependent covariate., Results: Of 398 PWID at baseline, 67% resided in San Diego, 70% were male, median age was 43 years, 42% reported receptive needle sharing, and 25% reported using IMF. HCV incidence was 14.26 per 100 person-years (95% confidence interval [CI]: 11.49-17.02), and HIV incidence was 1.29 (95% CI: .49-2.10). IMF was associated with HCV seroconversion, with a univariable hazard ratio (HR) of 1.64 (95% CI: 1.09-2.40), and multivariable HR of 1.57 (95% CI: 1.03-2.40). The direction of the relationship with HIV was similar, albeit not significant (HR 2.39; 95% CI: .66-8.64)., Conclusions: We document a novel association between IMF and HCV seroconversion among PWID in Tijuana-San Diego. Few HIV seroconversions (n = 10) precluded our ability to assess if a similar relationship held for HIV. IMF's short half-life may destabilize PWID-increasing the need for repeat dosing and sharing smoking materials and syringes. New preventive care approaches may reduce HCV transmission in the fentanyl era., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

In hepatitis C virus (HCV) infection, CD4+ and CD8+ T cells are crucial for viral control. However, a detailed understanding of the kinetic of CD4+ T cell help and its role in the generation of different CD8+ T cell subsets during acute infection is lacking. The absence of a small HCV animal model has impeded mechanistic studies of hepatic antiviral T cell immunity and HCV vaccine development. In this study, we used a recently developed HCV-related rodent hepacivirus infection mouse model to investigate the impact of CD4+ T cell help on the hepatic CD8+ T cell response and viral clearance during hepacivirus infection in vivo. Our results revealed a specific kinetic of CD4+ T cell dependency during acute infection. Early CD4+ T cell help was essential for CD8+ T cell priming and viral clearance, while CD4+ T cells became dispensable during later stages of acute infection. Effector CD8+ T cells directly mediated timely hepacivirus clearance. An analysis of hepatic CD8+ T cells specific for two different viral epitopes revealed the induction of subsets of liver-homing CD103+CD49a+ and CD103-CD49a+ effector CD8+ T cells with elevated IFN-γ and TNF-α production. CD103+CD49a+ T cells further persisted as tissue-resident memory subsets. A lack of CD4+ T cell help and CD40L-CD40 interactions resulted in reduced effector functions and phenotypical changes in effector CD8+ T cells and a specific loss of the CD103+CD49a+ subset. In summary, our study shows that early CD4+ T cell help through CD40L signaling is essential for priming functional effector CD8+ T cell subsets, including unique liver-homing subsets, and hepacivirus clearance., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lopez-Scarim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Dried blood spot (DBS) sampling is increasingly used for hepatitis C virus (HCV) screening. HCVcAg testing offers a faster and more streamlined approach to diagnosing HCV infection. We conducted a systematic review and meta-analysis to assess the diagnostic performance of the Abbott ARCHITECT HCV Ag assay for screening active HCV infection using DBS samples. Eight studies (n = 1229) were selected among all published studies available up to October 4, 2024, in different databases with a search strategy registered (PROSPERO: CRD42022363975). The gold standard method was the HCV PCR test. Data were analyzed using the MIDAS module in STATA with a random effects model. Combined diagnostic accuracy measures were as follows: sensitivity 85%, specificity 100%, positive likelihood ratio (PLR) 233.1, negative likelihood ratio (NLR) 0.15, and summary receiver operating characteristic (SROC) 0.99. Likelihood ratios and Fagan's nomogram suggested that the HCVcAg assay with DBS samples can confirm or rule out active HCV infection with over 92% accuracy in high-prevalence settings (≥5%). However, in low-prevalence settings (≤1%), a confirmatory test must be required for positive results. The ability of the test to identify people without HCV infection was high regardless of HCV prevalence, with an error rate of less than 3%. This meta-analysis is subject to limitations, particularly due to the number of included studies and significant heterogeneity among them. HCV screening using the Abbott ARCHITECT HCV Ag assay with DBS samples showed excellent diagnostic performance, but its external validity may be limited when HCV prevalence is low (≤1%)., (© 2024 Wiley Periodicals LLC.)

Hepatitis C virus (HCV) infection is a major health problem worldwide. It can cause liver cirrhosis and hepatocellular carcinoma (HCC), making it a cause of morbidity from liver disease. Thus, there is an urgent need for a prophylactic HCV vaccine. Fortunately, modern medicine has transformed the therapy for HCV infection through development of direct-acting antiviral agents (DAAs), achieving high rates of sustained virologic response and giving significant relief from HCC and associated mortality, but unfortunately it fails to eradicate the risk of HCC, especially in HCV-cleared patients with already advanced liver disease. Additionally, DAA-cured patients do not develop sufficient antiviral immunity and are susceptible to reinfection. A comprehensive strategy to control HCV infection must include a vaccine development approach in which the host can develop humoral and cellular immunity to eradicate HCV successfully; however, this remains a challenge as HCV has developed systems to evade immune attacks from its host. This review highlights the current understanding of HCV's effect on liver disease and cancer progression, the nature of immune responses from cell populations interacting with HCV, and the current strategies for vaccine development. The information in this review will advance prophylactic intervention strategies for HCV infection, with the end goal being to prevent chronicity and subsequent liver disease leading to HCC., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Aims: Evidence assessing the role of B cells and their antibodies, or lack thereof, in the spontaneous resolution of acute HCV infection is conflicting. Utilization of a strictly hepatotropic, HCV-related rodent hepacivirus (RHV) model circumvents many of the challenges facing the field in characterizing the immunological correlates of dichotomous infection outcomes. This study seeks to elucidate the importance of B cells in the clearance of acute RHV infection., Approach and Results: µMT mice were infected i.v. with RHV and found to develop chronic infection for over a year. Wild-type (WT) mice depleted of B cells also exhibited persistent viremia that resolved only upon B cell resurgence. The persistent infection developed by B1-8i and AID cre/cre mice revealed that antigen-specific, class-switched B cells or their antibodies were crucial for viral resolution. Virus-specific CD8 + and CD4 + T cells were characterized in these mice using newly developed major histocompatibility complex class I and II tetramers and ex vivo peptide stimulation. Immunoglobulin G (IgG) was purified from the serum of RHV- or lymphocytic choriomeningitis virus Armstrong-infected mice after viral clearance and passively transferred to AID cre/cre recipients, revealing viral clearance only in αRHV IgG recipients. Further, the transfer of αRHV IgG into B cell-depleted recipients also induced viral resolution. This ability of RHV-specific IgG to induce viral clearance was found to require the concomitant presence of CD8 + T cells., Conclusions: Our findings demonstrate a cooperative interdependence between immunoglobulins and the T cell compartment that is required for RHV resolution. Thus, HCV vaccine regimens should aim to simultaneously elicit robust HCV-specific antibody and T cell responses for optimal protective efficacy., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Hepatitis B virus and hepatitis C virus remains one of the leading causes of morbidity and mortality worldwide, particularly in countries with limited resources. The two hepatotropic viruses have common mode of transmission. Hepatitis B virus and hepatitis C virus are the main causes of Cirrhosis, liver cancer and death. To determine the Seroprevalence of HBsAg and anti-HCV antibodies among clinically suspected cases of viral hepatitis visiting Guhalla Primary Hospital, Northwest Ethiopia. A hospital-based retrospective study was conducted at Guhalla Primary Hospital, Northwest Ethiopia. The study included serology registration logbook data from all patients who visited the hospital and were tested using a rapid test kit between September 1st, 2017 to August 30, 2021. Data were entered, cleaned, and analyzed using SPSS version 26 software. Bivariate analysis was computed and a multivariable analysis was conducted to provide an adjusted odds ratio (AOR). p-value < 0.05 at a 95% confidence interval was considered statistically significant. In this study, a total of 883(883 for HBV and 366 for HCV) study participants were included. The overall prevalence of HBsAg and anti-HCV were 124/883(14%) and 73/366 (19.9%), respectively. The prevalence of HBV and HCV among males from the total HBV and HCV screened was 70/410 (17.1%) and 53/366(14.4%) respectively. In this study, being female (AOR 1.53, 95% CI 1.03-2.27, p = 0.003) and age group of 31-40 years (AOR 2.85; 95% CI 1.56, 5.17, p = 0.001) were statistically significant factors to HBV infection. Similarly, being female (AOR 1.97, 95% CI 1.10-3.53, p = 0.02), age group of 21-30 years (AOR 2.71; 95% CI 1.15, 6.40, p = 0.02) and age group greater than 40 years (AOR 3.13; 95% CI 1.31, 7.44, p = 0.01) were significantly associated with HCV infection. In our study, high seroprevalence of HBV and HCV infection was detected among clinically suspected patients. Females and the age groups between 31 and 40 were more affected. Community awareness of the prevention and transmission of viral hepatitis infection should be strengthened through herd immunization and health education. The prospective study should be conducted in this area., (© 2024. The Author(s).)

Chronic hepatitis C (CHC) is a serious condition of public health importance. In Portugal, the prevalence of detectable hepatitis C virus (HCV) antibodies is approximately 0.54%, with a higher prevalence in high-risk groups. Compared with the general population, the prevalence of HCV infection is higher in individuals with psychiatric disorders. As no studies have reported the prevalence of HCV antibodies in Portuguese patients with psychiatric conditions and substance use disorders, we conducted an observational, prospective study of patients followed in the Dual Pathology Outpatient and Inpatient Unit of Coimbra Hospital and University Center (CHUC), Patients were tested for HCV antibodies. Of the 149 patients, 17.4% were positive for HCV antibodies and 7.4% had detectable HCV RNA indicating CHC. Most patients with confirmed CHC were male inpatients, aged 50 to 59 years, and reported unprotected sex with more than one concurrent partner in the past 6 months. Their most common psychiatric diagnosis was "Disorders due to use of multiple specified psychoactive substances, including medications." The prevalence of HCV antibodies and confirmed CHC were higher in patients followed in the Dual Pathology Outpatient and Inpatient Unit than in the general Portuguese population.

For the rational design of epitope-specific vaccines, identifying epitopes that can be processed and presented is essential. As algorithm-based epitope prediction is frequently discordant with actually recognized CD8 + T-cell epitopes, we developed an in vitro CD8 T-cell priming protocol to enable the identification of truly and functionally expressed HLA class I epitopes. The assay was established and validated to identify epitopes presented by hepatitis C virus (HCV)-infected cells. In vitro priming of naïve CD8 T cells was achieved by culturing unfractionated PBMCs in the presence of a specific cocktail of growth factors and cytokines, and next exposing the cells to hepatic cells expressing the NS3 protein of HCV. After a 10-day co-culture, HCV-specific T-cell responses were identified based on IFN-γ ELISpot analysis. For this, the T cells were restimulated with long synthetic peptides (SLPs) spanning the whole NS3 protein sequence allowing the identification of HCV-specificity. We demonstrated that this protocol resulted in the in vitro priming of naïve precursors to antigen-experienced T-cells specific for 11 out of 98 SLPs tested. These 11 SLPs contain 12 different HLA-A*02:01-restricted epitopes, as predicted by a combination of three epitope prediction algorithms. Furthermore, we identified responses against 3 peptides that were not predicted to contain any immunogenic HLA class I epitopes, yet showed HCV-specific responses in vitro. Separation of CD8 + and CD8 - T cells from PBMCs primed in vitro showed responses only upon restimulation with short peptides. We established an in vitro method that enables the identification of HLA class I epitopes resulting from cross-presented antigens and that can cross-prime T cells and allows the effective selection of functional immunogenic epitopes, but also less immunogenic ones, for the design of tailored therapeutic vaccines against persistent viral infections and tumor antigens., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Hepatitis C virus (HCV) infection is among the leading causes of cirrhosis and hepatocellular carcinoma. Knowledge of its prevalence and risk factors can help to effectively fight the virus. This study was the first to investigate the seroprevalence of HCV, its genotypes, and factors associated with it among the general adult population of Armenia selected countrywide via cluster sampling. Anti-HCV antibodies were detected using third-generation immunoassay. Polymerase chain reaction and genotyping was performed among anti-HCV-positive individuals. Shortly after testing, the participants underwent a telephone survey. Logistic regression models were fitted to identify factors associated with anti-HCV antibody positivity and chronic HCV infection. The prevalence of anti-HCV antibodies among 3831 tested individuals was 2% (99% CI 1.4, 2.5), and chronic HCV infection was 0.7% (99% CI 0.4, 1.0), with genotypes 3 and 2 being the most common. The risk factors for chronic HCV infection included self-reported chronic liver disease (95% CI 1.47, 15.28), having tattoos (95% CI 1.34, 10.94), ever smoking (95% CI 1.16, 9.18), and testing positive for hepatitis B virus core antibody (95% CI 1.02, 7.17). These risk factors demonstrate that there could be room for strengthening infection control measures to prevent the transmission of HCV in Armenia.

Despite remarkable progress in the treatment of hepatitis C virus (HCV) infection, it remains a significant global health burden, necessitating the development of an effective prophylactic vaccine. This review paper presents the current landscape of HCV vaccine candidates and approaches, including more traditional, based on inactivated virus, and more modern, such as subunit protein, vectored, based on nucleic acids (DNA and mRNA) and virus-like particles. The concept of the HCV vaccine is first put in the context of viral genetic diversity and adaptive responses to HCV infection, an understanding of which is crucial in guiding the development of an effective vaccine against such a complex virus. Because ethical dimensions are also significant in vaccine research, development, and potential deployment, we also address them in this paper. The road to a safe and effective vaccine to prevent HCV infection remains bumpy due to the genetic variation of HCV and its ability to evade immune responses. The progress in cell-culture systems allowed for the production of an inactivated HCV vaccine candidate, which can induce cross-neutralizing antibodies in vitro, but whether this could prevent infection in humans is unknown. Subunit protein vaccine candidates that entered clinical trials elicited HCV-specific humoral and cellular responses, though it remains to be shown whether they translate into effective prevention of HCV infection or progression of infection to a chronic state. Such responses were also induced by a clinically tested vector-based vaccine candidate, which decreased the viral HCV load but did not prevent chronic HCV infection. These disappointments were not readily predicted from preclinical animal studies. The vaccine platforms employing virus-like particles, DNA, and mRNA provide opportunities for the HCV vaccine, but their potential in this context has yet to be shown. Ensuring the designed vaccine is based on conserved epitope(s) and elicits broadly neutralizing immune responses is also essential. Given failures in developing a prophylactic HCV vaccine, it is crucial to continue supporting national strategies, including funding for screening and treatment programs. However, these actions are likely insufficient to permanently control the HCV burden, encouraging further mobilization of significant resources for HCV vaccine research as a missing element in the elimination of viral hepatitis as a global public health., (© 2024 Wiley Periodicals LLC.)

Fifty-eight million individuals worldwide are affected by chronic hepatitis C virus (HCV) infection, a primary driver of liver cancer for which no vaccine is available 1 . The HCV envelope proteins E1 and E2 form a heterodimer (E1/E2), which is the target for neutralizing antibodies 2 . However, the higher-order organization of these E1/E2 heterodimers, as well as that of any Hepacivirus envelope protein complex, remains unknown. Here we determined the cryo-electron microscopy structure of two E1/E2 heterodimers in a homodimeric arrangement. We reveal how the homodimer is established at the molecular level and provide insights into neutralizing antibody evasion and membrane fusion by HCV, as orchestrated by E2 motifs such as hypervariable region 1 and antigenic site 412, as well as the organization of the transmembrane helices, including two internal to E1. This study addresses long-standing questions on the higher-order oligomeric arrangement of Hepacivirus envelope proteins and provides a critical framework in the design of novel HCV vaccine antigens., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background & Aims: In individuals highly exposed to HCV, reinfection is common, suggesting that natural development of sterilising immunity is difficult. In those that are reinfected, some will develop a persistent infection, while a small proportion repeatedly clear the virus, suggesting natural protection is possible. The aim of this study was to characterise immune responses associated with rapid natural clearance of HCV reinfection., Methods: Broad neutralising antibodies (nAbs) and Envelope 2 (E2)-specific memory B cell (MBC) responses were examined longitudinally in 15 individuals with varied reinfection outcomes., Results: Broad nAb responses were associated with MBC recall, but not with clearance of reinfection. Strong evidence of antigen imprinting was found, and the B-cell receptor repertoire showed a high level of clonality with ongoing somatic hypermutation of many clones over subsequent reinfection events. Single-cell transcriptomic analyses showed that cleared reinfections featured an activated transcriptomic profile in HCV-specific B cells that rapidly expanded upon reinfection., Conclusions: MBC quality, but not necessarily breadth of nAb responses, is important for protection against antigenically diverse variants, which is encouraging for HCV vaccine development., Impact and Implications: HCV continues to have a major health burden globally. Limitations in the health infrastructure for diagnosis and treatment, as well as high rates of reinfection, indicate that a vaccine that can protect against chronic HCV infection will greatly complement current efforts to eliminate HCV-related disease. With alternative approaches to testing vaccines, such as controlled human inoculation trials under consideration, we desperately need to identify the correlates of immune protection. In this study, in a small but rare cohort of high-risk injecting drug users who were reinfected multiple times, breadth of neutralisation was not associated with ultimate clearance of the reinfection event. Alternatively, characteristics of the HCV-specific B-cell response associated with B-cell proliferation were. This study indicates that humoral responses are important for protection and suggests that for genetically very diverse viruses, such as HCV, it may be beneficial to look beyond just antibodies as correlates of protection., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: There is a high prevalence of hepatitis C virus (HCV) carriers in prison in several developed countries, but the situation in Japan has not been well reported. This study aimed to determine the state of HCV infection among criminals in Japan., Methods: We enrolled 533 criminals in rehabilitation facilities (354 men and 179 women) who underwent a medical check-up from April 2014 to March 2022. Their records of blood tests, medical history, and drug injection use were retrospectively analyzed., Results: The HCV-antibody positive rate was 11.1 % (59/533), with rates of 8.2 % (29/354) in men and 16.8 % (30/179 in women. Approximately half of the HCV-infected residents had a history of drug injection, and this rate did not vary by age or by sex. Although an opportunity to treat HCV infection with medical assistance from government was provided to all residents who were positive for HCV RNA, 26.5 % of them abandoned the treatment., Conclusion: In spite of the generous economical support to treat HCV infection by the government and the free access system in Japan, eliminating HCV in criminals appears to be difficult. The reason for this problem might be the criminals' negligent attitude to life., Competing Interests: Declaration of competing interest Authors declare no Conflict of Interests for this article., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: An optimal HCV vaccine requires the induction of antibodies that neutralise the infectivity of many heterogenous viral isolates. In this study, we have focused on determining the optimal recombinant envelope glycoprotein component to elicit cross-neutralising antibodies against global HCV genotypes. We compared the immunoreactivity and antigenicity of the HCV genotype 1a strain H77C-derived envelope glycoprotein heterodimer gpE1/gpE2 with that of recombinant gpE2 alone., Methods: Characterisation of the envelope glycoproteins was accomplished by determining their ability to bind to a panel of broadly cross-neutralising monoclonal antibodies. Immunogenicity was determined by testing the ability of vaccine antisera to neutralise the infectivity in vitro of a panel of pseudotyped HCV particles in which gpE1/gpE2 derived from representative isolates of the major global HCV genotypes were displayed., Results: gpE1/gpE2 binds to more diverse broadly cross-neutralising antibodies than gpE2 alone and elicits a broader profile of cross-neutralising antibodies in animals, especially against more heterologous, non-1a genotypes. While not all heterologous HCV strains can be potently inhibited in vitro by gpE1/gpE2 antisera derived from a single HCV strain, the breadth of heterologous cross-neutralisation is shown to be substantial., Conclusions: Our work supports the inclusion of gpE1/gpE2 in an HCV vaccine in order to maximise the cross-neutralisation of heterogenous HCV isolates. Our data also offers future directions in formulating a cocktail of gpE1/gpE2 antigens from a small selection of HCV genotypes to further enhance cross-neutralisation of global HCV strains and hopefully advance the development of a globally effective HCV vaccine., Impact and Implications: An HCV vaccine is urgently required to prevent the high global incidence of HCV infection and disease. Since HCV is a highly heterogeneous virus, it is desirable for a vaccine to elicit antibodies that neutralise the infectivity of most global strains. To this end, we have compared the immunoreactivity and antigenicity of recombinant H77C E1E2 heterodimer with that of H77C E2 alone and show that the former exhibits more cross-neutralising epitopes and demonstrates a broader cross-neutralisation profile in vitro. In addition, our data suggests a way to further broaden cross-neutralisation using a combination of E1E2 antigens derived from a few different HCV clades. Our work is relevant for the development of an effective global HCV vaccine., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Therapy against the Hepatitis C virus (HCV) has significantly improved with the introduction of direct-acting antiviral drugs (DAAs), achieving over 95% sustained virological response (SVR). Despite this, the development of an effective anti-HCV vaccine remains a critical challenge due to the low number of patients treated with DAAs and the occurrence of HCV reinfections in high-risk groups. Current vaccine strategies aim to stimulate either B-cell or T-cell responses. Vaccines based on E1 and E2 proteins can elicit broad cross-neutralizing antibodies against all major HCV genotypes, though with varying efficiencies and without full protection against infection. In humans, the neutralizing antibodies induced by such vaccines mainly target the AR3 region, but their levels are generally insufficient for broad neutralization. Various HCV proteins expressed through different viral vectors have been utilized to elicit T cell immune responses, showing sustained expansion of HCV-specific effector memory T cells and improved proliferation and polyfunctionality of memory T cells over time. However, despite these advancements, the frequency and effectiveness of T-cell responses remain limited.

Background: Cancer patients are prone to infections such as hepatitis B virus (HBV) and hepatitis C virus (HCV), which pose a major public health challenge, especially in developing countries. However, little is known about the magnitude of these infections among cancer patients in Ethiopia. Thus, this study determined the prevalence of HBV and HCV in cancer patients at the Oncology Treatment Center, Gondar, Northwest Ethiopia., Materials and Methods: An institutional-based cross-sectional study was conducted on 115 cancer patients from 15 April to 22 July 2023 at the Oncology Treatment Center, Gondar, Northwest Ethiopia. Sociodemographic, clinical, and other relevant data were collected using a pretested structured questionnaire. Five milliliters of venous blood were collected using a vacutainer tube, serum was harvested and tested for HBV and HCV using a one-step HBsAg and anti-HCV test strip with further confirmation through an ELISA test kit. Data were analyzed using SPSS version 20 and Fisher exact test was used to determine the association between HBV/HCV infection and associated factors., Results: Out of 115 cancer patients, the majority (62.6%) were females. The median age was 50 (IQR; 40-56) years. The overall prevalence of HBV and HCV infections was 4.3% (95% CI; 0.6-8%) and 6.1% (95% CI; 1.7-10.5%), respectively. Sex was significantly associated with the prevalence of HCV (p = 0.011) with higher anti-HCV positivity in males (14%) than in females (1.4%)., Conclusions: In this study, the prevalence of HCV was higher and the HBV prevalence was intermediate in cancer patients. To reduce the burden of HBV and HCV infections, it is crucial to provide access to HBV and HCV screening services, strengthen vaccination, and improve prompt treatment in cancer patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Atanaw et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Chronic hepatitis C (CHC) infection is a major public health problem in many low- and middle-income countries. The study aimed to find out how interleukin IL-6 and IL-8 levels in the blood affect the virological response to directacting antivirals (DAAs) and to find useful clinical or immunological markers for the response to HCV treatment., Methods: CHC patients from a real Egyptian population (n = 4,300), who were treated during the Egyptian national initiative to eliminate HCV at the Sherbin Central Hospital, Dakahlia Governorate, Ministry of Health, Egypt, were enrolled in our study. They were all patients who did not obtain a sustained virological response (SVR) (n = 75; non-responder; the response rate was 98.26%), and a total of 100 patients were randomly selected from patients who obtained SVR (responder) and were age- and gender-matched (p > 0.05) with non-responder patients. Serum levels of IL-6 and IL-8 were measured by commercial ELISA kits., Results: Non-responder patients were associated with significantly high levels of ALT, AST, ALP, and total bilirubin. Non-responders had significantly (p < 0.05) higher baseline IL-6 (16.7 ± 4.92 pg/mL) and IL-8 (37.81 ± 10.55 pg/mL) levels compared to responders (12.68 ± 2.06, 29.06 ± 5.94 pg/mL, respectively). There was a substantial (p < 0.05) association between the combination of two cytokines and a high likelihood of treatment failure, as indicated by all parameters examined, with the highest correlation values seen., Conclusions: The present study showed that increased IL-6 and IL-8 were associated with HCV treatment failure. Also, IL8 was associated with hepatic fibrosis.

CD8 + T cells recognizing their cognate antigen are typically recruited as a polyclonal population consisting of multiple clonotypes with varying T-cell receptor (TCR) affinity to the target peptide-major histocompatibility complex (pMHC) complex. Advances in single-cell sequencing have increased accessibility toward identifying TCRs with matched antigens. Here we present the discovery of a monoclonal CD8 + T-cell population with specificity for a hepatitis C virus (HCV)-derived human leukocyte antigen (HLA) class I epitope (HLA-B*07:02 GPRLGVRAT) which was isolated directly ex vivo from an individual with an episode of acutely resolved HCV infection. This population was absent before infection and underwent expansion and stable maintenance for at least 2 years after infection as measured by HLA-multimer staining. Furthermore, the monoclonal clonotype was characterized by an unusually long dissociation time (half-life = 794 s and k off  = 5.73 × 10 -4 ) for its target antigen when compared with previously published results. A comparison with related populations of HCV-specific populations derived from the same individual and a second individual suggested that high-affinity TCR-pMHC interactions may be inherent to epitope identity and shape the phenotype of responses which has implications for rational TCR selection and design in the age of personalized immunotherapies., (© 2024 The Author(s). Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of the Australian and New Zealand Society for Immunology, Inc.)

Background: The diagnosis and treatment monitoring of hepatitis C is quite challenging. The screening test, i.e. antibody assay, is unable to detect acute cases, while the gold standard hepatitis C virus (HCV) reverse transcriptase polymerase chain reaction (RTPCR) assay is not feasible in resource-limited countries such as India due to high cost and infrastructure requirement. European Association for the Study of the Liver and World Health Organization have approved a new marker, i.e. HCV core antigen (HCVcAg) assay, as an alternative to molecular assay. In this study, we have evaluated HCVcAg assay for diagnosis and treatment monitoring follow-up in Indian population infected with hepatitis C., Methods: Blood specimen of 90 clinically suspected cases of acute hepatitis C were tested simultaneously for anti-HCV antibody assay via ELISA (enzyme-linked immunoassay), HCVcAg assay by chemiluminescence immune assay (CLIA) and HCV RTPCR VL (viral load) assay. Thirty-four HCV RTPCR positive patients were further enrolled in treatment monitoring group whose blood samples were tested at the beginning of treatment, two weeks, four weeks and 12 weeks via HCV core Ag assay and HCV RTPCR Viral Load assay., Results: Considering HCV RTPCR as gold standard, diagnostic performance of HCV core Ag assay and anti-HCV antibody assay was evaluated. The sensitivity and specificity of HCV core Ag assay were higher than that of anti-HCV Antibody assay, i.e. 88.3% and 100% vs. 23.3% and 83.3%, respectively. The overall diagnostic accuracy of HCV core Ag assay was 92.20%. Among treatment follow-up group, HCV core Ag levels correlated well with HCV viral load levels, at the beginning of treatment (baseline) till 12 weeks showing highly significant Spearman rank correlation coefficient of > 0.9 with HCV viral load levels., Conclusions: HCV core Ag assay is a cost-effective, practically feasible substitute of HCV RTPCR viral load assay for diagnosis as well as long duration treatment monitoring of hepatitis C infection in resource-limited settings., (© 2024. Indian Society of Gastroenterology.)

Hepatitis C virus core antigen (HCVcAg) testing can simplify and decrease costs of HCV infection confirmation compared to molecular testing (nucleic acid testing). We piloted HCVcAg testing for the confirmation of active infection. The study was conducted during June through December 2022 among the police and the general population of Islamabad, Pakistan age 18 years and older. Initial screening for HCV antibody was conducted using a rapid diagnostic test (RDT) for all consenting participants. Those who tested positive had venous blood samples tested for HCVcAg, platelets and aspartate aminotransferase (AST). Persons with HCVcAg values ≥3 fmol/L were defined as viremic, and they were offered treatment with direct acting antiviral (DAA) medications, sofosbuvir and daclatasvir. Aspartate aminotransferase to platelet ratio index (APRI) was calculated for each HCV infected person, and those with an APRI score <1.5 received treatment for 12 weeks, while those with APRI ≥ to 1.5 received 24 weeks of treatment. A total of 15,628 persons were screened for anti-HCV using RDT and 643 (4.1%) tested positive. HCVcAg values of ≥3 fmol/L was found in 399/643 (62.1%), and all were offered and accepted treatment. Of those treated, 273/399 (68.4%) returned for a follow-up SVR and HCVcAg was not detected in 261/273, a 95.6% cure rate. The pilot study demonstrated the effectiveness of reaching and treating an urban population using RDT for screening and HCVcAg for confirmation of infection and test of cure., (© 2024 The Author(s). Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Background and Aims: Second-generation direct-acting antivirals (2G DAA) to cure HCV have led to dramatic clinical improvements. HCV-associated hepatocellular carcinoma (HCC), however, remains common. Impaired immune tumor surveillance may play a role in HCC development. Our cohort evaluated the effects of innate immune types and clinical variables on outcomes including HCC., Methods: Participants underwent full HLA class I/KIR typing and long-term HCV follow-up., Results: A total of 353 HCV+ participants were followed for a mean of 7 years. Cirrhosis: 25% at baseline, developed in 12% during follow-up. 158 participants received 2G DAA therapy. HCC developed without HCV therapy in 20 subjects, 24 HCC after HCV therapy, and 10 of these after 2G DAA. Two predictors of HCC among 2G DAA-treated patients: cirrhosis (OR, 10.0, p = 0.002) and HLA/KIR profiles predicting weak natural killer (NK) cell-mediated immunity (NK cell complementation groups 6, 9, 11, 12, OR of 5.1, p = 0.02). Without 2G DAA therapy: cirrhosis was the main clinical predictor of HCC (OR, 30.8, p < 0.0001), and weak NK-cell-mediated immunity did not predict HCC., Conclusion: Cirrhosis is the main risk state predisposing to HCC, but weak NK-cell-mediated immunity may predispose to post-2G DAA HCC more than intermediate or strong NK-cell-mediated immunity., (© ([0‐9]+) Wiley‐VCH GmbH.)

The aim of this article is to formulate and study a mathematical model describing hepatitis C virus (HCV) infection dynamics. The model includes two essential modes of infection transmission, namely, virus-to-cell and cell-to-cell. The effect of therapy and adaptive immunity are incorporated in the suggested model. The adaptive immunity is represented by its two categories, namely, the humoral and cellular immune responses. Our article begins by establishing some mathematical results through proving the model's well-posedness in terms of existence, positivity and boundedness of solutions. We present all the steady states of the problem that depend on specific reproduction numbers. It moves then to the theoretical investigation of the local and global stability analysis of the free disease equilibrium and the four disease equilibria. The local and global stability analysis of the HCV mathematical model are established via the Routh-Hurwitz criteria and Lyapunov-LaSalle invariance principle, respectively. Finally, our article presents some numerical simulations to validate the analytical study of the global stability. Numerical simulations have shown the effect of the drug therapies on the system's dynamical behavior.

Background: HIV/HCV coinfection is associated with a rapid progression to liver damage. Specifically, NK cell population dysregulation is of particular interest, as these cells have been shown to block HCV replication effectively and have an anti-fibrogenic activity. The NKp30 receptor is linked to tumor cell lysis and has a crucial role during viral infections. In the present study, we determined the subpopulations of NK cells based on CD56 and CD16 expression, NKp30 receptor expression, its isoforms A, B, and C, along with the cytotoxicity molecules in patients with HIV/HCV., Results: evidenced by the APRI and FIB-4 indices, the HCV-infected patients presented greater liver damage than the HIV and HIV/HCV groups. The HCV group presented a decreased expression of NKp30 isoform A, and NK cell frequency was not different between groups; however, CD56 brigth subpopulation, NKp30 receptor, and CD247 adaptor chain were decreased in HIV/HCV patients; further, we described increased levels of soluble IL-8, IL-10, IL-12, and IL-23 in the serum of HIV/HCV patients., Conclusions: HCV and HIV/HCV patients have multiple parameters of non-fitness status in NK cells; awareness of these dysfunctional immunological parameters in HIV/HCV and HCV patients can elucidate possible novel therapeutics directed towards the improvement of NK cell fitness status, in order to improve their function against liver damage., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Chronic HCV infection leads to a complex interplay with adaptive immune cells that may result in B cell dyscrasias like cryoglobulinemia or lymphoma. While direct-acting antiviral therapy has decreased the incidence of severe liver damage, its effect on extrahepatic HCV manifestations such as B cell dyscrasias is still unclear., Methods: We sequenced B cell receptor (BCR) repertoires in patients with chronic HCV mono-infection and patients with HCV with a sustained virological response (SVR) after direct-acting antiviral therapy. This data set was mined for highly neutralizing HCV antibodies and compared to a diffuse large B cell lymphoma data set. The TKO model was used to test the signaling strength of selected B-BCRs in vitro. Single-cell RNA sequencing of chronic HCV and HCV SVR samples was performed to analyze the transcriptome of B cells with HCV-neutralizing antigen receptors., Results: We identified a B cell fingerprint with high richness and somatic hypermutation in patients with chronic HCV and SVR. Convergence to specific immunoglobulin genes produced high-connectivity complementarity-determining region 3 networks. In addition, we observed that IGHV1-69 CDR1 and FR3 mutations characterizing highly neutralizing HCV antibodies corresponded to recurrent point mutations found in clonotypic BCRs of high-grade lymphomas. These BCRs did not show autonomous signaling but a lower activation threshold in an in vitro cell model for the assessment of BCR signaling strength. Single-cell RNA sequencing revealed that B cells carrying these point mutations showed a persisting oncogenic transcriptome signature with dysregulation in signaling nodes such as CARD11, MALT1, RelB, MAPK, and NFAT., Conclusions: We provide evidence that lymphoma-like cells derive from the anti-HCV immune response. In many patients, these cells persist for years after SVR and can be interpreted as a mechanistic basis for HCV-related B cell dyscrasias and increased lymphoma risk even beyond viral elimination., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Hepatitis B virus (HBV) and Hepatitis C Virus (HCV) infections are global issues that disproportionately affect developing countries. Pregnancy-related HBV and HCV infections are associated with a high risk of vertical transmission and complications for the mother as well as the newborn. Therefore, this study aims to determine the seroprevalence of hepatitis B virus and hepatitis C virus infection among pregnant women attending antenatal care at Guhala Primary Hospital, Northwestern Ethiopia., Methods: A hospital-based retrospective study was conducted from July to September 2022 on HBV and HCV registered books from September 1, 2017, to August 30, 2019, for a year. The presence of HBsAg and anti-HCV in serum was detected using the One Step Cassette Style HBsAg and anti-HCV antibody test kit. Data were analyzed using SPSS version 26 software., Results: In this study, a total of 2252 participants for HBsAg and 538 participants for ant-HCV rapid tests of records in the laboratory logbook were included. The mean age of the study participants was 25.6years (± 5.8SD). The overall prevalence of HBsAg and anti-HCV was 6.0% (134/2252) and 2.4% (13/538), respectively. There were 0.4% (2/538) coinfection results between HBV and HCV among pregnant women., Conclusion and Recommendation: In this study, intermediate seroprevalence of HBV and HCV infection was detected among pregnant women attending antenatal care. The Hepatitis B virus was predominantly higher among pregnant women aged between 25 and 34 years. To manage and stop the potential vertical transmission of these viral agents during the early stages of pregnancy, routine prenatal testing for HBV and HCV infections should be taken into consideration., (© 2024. The Author(s).)

Objectives: Studies showed that men who have sex with men (MSM), including those using pre-exposure prophylaxis (PrEP), are at increased risk of hepatitis C virus (HCV) infection. We evaluated HCV prevalence and incidence, along with their associated determinants, in a cohort of PrEP-using individuals in the Netherlands., Methods: In 2019, the Netherlands launched a 5-year national programme that offers subsidised PrEP to eligible individuals. We used prospectively collected data from individuals registered in this programme between 2019 and 2022. Individuals underwent annual testing for HCV antibodies and additional HCV-RNA testing when antibodies were present. We calculated the prevalence of past/current HCV infection at first visit and overall incidence rate (IR) during follow-up. Univariable logistic and Poisson regression models were used to identify determinants associated with past/current prevalent or incident HCV infection, respectively. Behavioural factors referred to those occurring in the previous 6 months., Results: A total of 10 563 (n=10 319, 97.7% MSM) were included. At first visit, 66 of 10 563 (0.6%) had a past/current HCV infection, which was associated with older age [odds ratio (OR) per 10 years=1.57, 95% confidence interval (CI)=1.31 to 1.88], the use of PrEP before first visit (OR=3.03, 95% CI=1.79 to 5.13), receptive condomless anal sex (CAS) (OR=2.73, 95% CI=1.25 to 5.98), chemsex (OR=2.44, 95% CI=1.49 to 3.99) and injecting drug use (IDU) (OR=6.61, 95% CI=2.35 to 18.61). Among 9851 individuals contributing to 17 150 person-years (PYs) of follow-up, 64 incident HCV infections (IR=0.37 per 100 PYs, 95% CI=0.29 to 0.48) were identified. Factors associated with incident HCV infection were receptive CAS [incidence rate ratio (IRR)=2.59, 95% CI=1.12 to 6.02], chemsex (IRR=1.78, 95% CI=1.06 to 2.98), sexually transmitted infection diagnosis (IRR=2.30, 95% CI=1.23 to 4.31) and IDU (IRR=6.15, 95% CI=2.20 to 17.18)., Conclusions: Past/current prevalence and incidence of HCV were low among individuals in the Dutch PrEP programme. Infections were associated with behaviour known to be associated with HCV. Instead of annual HCV testing, as stated in most PrEP care guidelines, testing frequency for HCV could be based on behaviours associated with HCV acquisition., Competing Interests: Competing interests: AB has received speaker fees from Gilead Sciences, independent from the current work. EH received unrestricted research grants from Gilead Sciences paid to her institute. MP’s institution has received speaker fees and independent scientific support from Gilead Sciences, Roche, MSD and AbbVie, unrelated to the current work. All other authors report no potential conflicts., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Guidelines recommend annual hepatitis C virus (HCV) testing for gay and bisexual men (GBM) with HIV and GBM prescribed HIV pre-exposure prophylaxis (PrEP). However, there is a limited understanding of HCV testing among GBM. We aimed to examine trends in HCV testing and positivity from 2016 to 2022., Methods: Using sentinel surveillance data, we examined the proportion of GBM with at least one test and the proportion with a positive test in each year for HCV antibody testing among GBM with no previous HCV positive test, HCV RNA testing among GBM with a positive antibody test but no previous positive RNA test (naïve RNA testing), and HCV RNA testing among people who had a previous RNA positive test and a subsequent negative test (RNA follow-up testing). Trends were examined using logistic regression from 2016 to 2019 and 2020 to 2022., Results: Among GBM with HIV, from 2016 to 2019 antibody testing was stable averaging 55% tested annually. Declines were observed for both naïve HCV RNA testing (75.4%-41.4%: p<0.001) and follow-up HCV RNA testing (70.1%-44.5%: p<0.001). Test positivity declined for HCV antibody tests (2.0%-1.3%: p=0.001), HCV RNA naïve tests (75.4%-41.4%: p<0.001) and HCV RNA follow-up tests (11.3%-3.3%: p=0.001). There were minimal or no significant trends from 2020 to 2022.Among GBM prescribed PrEP, antibody testing declined from 2016 to 2019 (79.4%-69.4%: p<0.001) and was stable from 2020 to 2022. Naïve and follow-up HCV RNA testing was stable with an average of 55% and 60% tested each year, respectively. From 2016-2019, the proportion positive from HCV RNA naïve tests declined (44.1%-27.5%: p<0.046) with no significant change thereafter. Positive follow-up HCV RNA tests fluctuated with no or one new positive test among this group in most years., Conclusion: The proportion of GBM with positive HCV tests has declined, however a substantial proportion are not tested annually. A renewed focus on HCV testing, and treatment where required, is warranted to achieve HCV elimination among GBM in Australia., Competing Interests: Competing interests: MT has received speaker’s honoraria and support to attend the 2019 Hitos en Investigación Básica y Clínica en VIH/SIDA conference from Gilead Sciences. GM has received grants from Gilead Sciences and AbbVie Inc paid to her institution and payment from Janssen for chairing a meeting. MH has received investigator-initiated funding from Gilead Sciences, Merck, AbbVie and BMS. JSD has received investigator-initiated funding from AbbVie, BMS, Gilead Sciences and Merck; consultancies from Gilead Sciences and AbbVie; and support for attending meetings and/or travel from Gilead Sciences. DKvS reports payment to her institution (Public Health Service of Amsterdam) for Liver debate, sponsored by Gilead, AbbVie and Norgine. MB reports grants paid to his institution for clinical research from Gilead Sciences, ViiV Healthcare, MSD, AbbVie, Eli Lilly, Novartis and Pfizer; has received consulting fees for attendance at medical advisory boards from Gilead Sciences, ViiV Healthcare and AbbVie; has received payment or honoraria from presentations/lectures from Gilead Sciences and AbbVie; and has received payments to attend scientific meetings or advisory boards from Gilead Sciences, ViiV Healthcare and GSK., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Pakistan bears a substantial burden of hepatitis C virus (HCV) infection, with the second-highest prevalence globally. This community-based cross-sectional study, conducted from January to December 2022 in Punjab, Pakistan, investigates the seroprevalence of HCV among the men who have sex with men (MSM) population. The study identifies demographic and behavioral risk factors associated with HCV infection within this population group. Among the 501 participants, the study found an HCV seroprevalence of 14.86%. The association between demographic characteristics and seroprevalence is assessed by calculating the percentage of positive cases, revealing notable associations with age, education level, and self-identified sexual orientation. Furthermore, the study identified several behavioral risk factors positively associated with HCV seroprevalence, including sharing personal items such as razors and toothbrushes, histories of surgery, blood transfusion, dental procedures, intravenous drug use, and therapeutic injection histories. These risk factors were identified through structured interviews, and the prevalence of HCV seropositivity among the exposed groups was calculated accordingly. Interestingly, a lower HCV positivity rate was observed among self-reported HIV-positive individuals, contradicting previous research. The findings underscore the need for comprehensive, targeted prevention strategies such as risk factor awareness campaigns and educational programs tailored for the MSM population in Pakistan. Further research is warranted to validate these findings and better understand the complex interplay of factors contributing to HCV seroprevalence in this high-risk population., (© 2024. The Author(s).)

Mixed cryoglobulinemia vasculitis (MCV) is caused in ~90% of cases by chronic hepatitis C virus (HCV pos MCV) and more rarely by hepatitis B virus (HBV) infection, or apparently noninfectious. HCV pos MCV develops in only ~5% of patients with chronic hepatitis C (CHC), but risk factors other than female gender have not been identified so far. We conducted a retrospective case control study investigating whether past active HBV infection, defined by hepatitis B surface antigen (HBsAg) seroclearance and anti-core antibody (HBcAb) positivity, could be a risk factor for developing HCV pos MCV. The prevalence of HBsAg seroclearance was 48% within 123 HCV pos MCV patients and 29% within 257 CHC patients (p=0.0003). Multiple logistic regression including as variables gender, birth year, age at HBV testing, cirrhosis, and hepatocellular carcinoma, confirmed an association of HBsAg seroclearance with HCV pos MCV [adjusted odds ratio (OR) 2.82, 95% confidence interval (95% CI) 1.73-4.59, p<0.0001]. Stratification by gender, however, showed that HBsAg seroclearance was associated with HCV pos MCV in male [OR 4.63, 95% CI 2.27-9.48, p<0.0001] and not in female patients [OR 1.85, 95% 95% CI 0.94-3.66, p=0.076]. HBsAg seroclearance, and more likely occult HBV infection, is an independent risk factor for HCV pos MCV in male CHC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Morrone, Fiorilli, Cinti, Roberto, Ferri, Visentini, Pulsoni, Spinelli, De Santis, Antonelli, Basili, Tosti, Conti and Casato.)

Background: The need to expand the pool of available organs for transplantation has meant that the use of marginal organs is increasingly widespread. The advent of antiviral therapy for hepatitis C virus (HCV) has made it possible to consider the donation of organs from HCV-positive donors and even from viremic donors., Methods: In HCV-positive to HCV-negative antibody donor transplantation, the development of antibodies to HCV is uneven, depending on the organ transplanted and with differences in the time of appearance. Whether the subsequent disappearance is attributed to the development of antibodies or the transmission of immunity between donor and recipient remains unclear. In transplantation from an HCV-infected donor to a HCV-seronegative recipient, the administration of antiviral therapy to the recipient before transplantation or a few days after transplantation achieves sustained response in almost all cases. We wanted to deepen the argument by studying the data in the literature, focusing on kidney transplantation, considering that this could be of interest, particularly for possible long-term renal damage., Results: HCV infection both ongoing and previous, as well as the presence of HCV antibodies alone, can be responsible for kidney damage., Conclusions: Direct-acting anti-HCV therapy has revolutionized the treatment of HCV disease and the therapeutic possibilities of transplantation. However, we believe it is useful to keep in mind the pathophysiology of HCV-related damage especially in patients with a long life expectancy, using all emerging strategies to minimize the risk of transmission of infection or development of viremia., Competing Interests: Declaration of competing interest All authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chronic hepatitis C Virus (HCV) infection presents a global health challenge, with significant morbidity and mortality worldwide. Despite remarkable progress in treatment options, achieving elimination targets by 2030, as set by the World Health Organization, remains elusive. Our study aimed to address this gap by integrating HCV screening into a national breast cancer screening program. Between March 2022 and March 2023, a prospective cross-sectional multicenter study was conducted in four radiology centers in Montpellier, France. We proposed HCV screening to consecutive women undergoing mammography, targeting 1,500 participants aged 50-74 years. A rapid diagnostic test (RDT) for HCV antibodies (HCV Ab) was performed on capillary whole blood, with positive cases undergoing serological and RNA confirmation. Participants also completed a questionnaire on demographic data and risk factors. Acceptance rates, HCV prevalence, and linkage to care were assessed. The acceptance rate for this integrated screening approach was 82.4%. Notably, the seroprevalence of HCV was found to be 0.65%. Linkage to care was prompt, and the cascade of care demonstrated successful treatment outcomes. Importantly, the majority of detected infections were successfully resolved. These findings underscore the feasibility and acceptability of integrating HCV screening with breast cancer screening programs providing updated prevalence data and valuable insights for refining future screening strategies., (© 2024 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

The genetic diversity of killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) genes influences the host's immune response to viral pathogens. This study aims to explore the impact of five single nucleotide polymorphisms (SNPs) in KIR3DL2 and HLA-A genes on hepatitis C virus (HCV) infection. A total of 2251 individuals were included in the case-control study. SNPs including KIR3DL2 rs11672983, rs3745902, rs1654644, and HLA-A rs3869062, rs12202296 were genotyped. By controlling various confounding factors using a modified logistic regression model, as well as incorporating stratified analysis, joint effects analysis, and multidimensional bioinformatics analysis, we analyzed the relationship between SNPs and HCV infection. The logistic regression analysis showed a correlation between KIR3DL2 rs11672983 AA, KIR3DL2 rs3745902 TT, and increased HCV susceptibility (p < 0.01). Stratified analysis indicated that KIR3DL2 rs1654644 and HLA-A rs3869062 also heightened HCV susceptibility in certain subgroups. A linear trend of rising HCV infection rates was observed when combining KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT (p trend  = 0.007). Bioinformatics analysis suggested these SNPs' regulatory potential and their role in altering messenger RNA secondary structure, implying their functional relevance in HCV susceptibility. Our findings indicate that KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT are significantly associated with increased susceptibility to HCV infection., (© 2024 Wiley Periodicals LLC.)