Hepatitis C Virus Progression Research Articles

The Role of Epigenetic Mechanisms in the Pathogenesis of Hepatitis C Infection.

Hepatitis C virus (HCV) is a hepatotropic virus that can be transmitted through unsafe medical procedures, such as injections, transfusions, and dental treatment. The infection may be self-limiting or manifest as a chronic form that induces liver fibrosis, cirrhosis, or progression into hepatocellular carcinoma (HCC). Epigenetic mechanisms are major regulators of gene expression. These mechanisms involve DNA methylation, histone modifications, and the activity of non-coding RNAs, which can enhance or suppress gene expression. Abnormal activity or the dysregulated expression of epigenetic molecules plays an important role in the pathogenesis of various pathological disorders, including inflammatory diseases and malignancies. In this review, we summarise the current evidence on epigenetic mechanisms involved in HCV infection and progression to HCC.

Understanding the relationship between HCV infection and progression of kidney disease.

Hepatitis C virus (HCV) can cause a range of kidney diseases. HCV is the primary cause of mixed cryoglobulinaemia, which leads to cryoglobulinaemic vasculitis and cryoglobulinaemic glomerulonephritis (GN). Patients with acute cryoglobulinaemic vasculitis often exhibit acute kidney disease due to HCV infection, which typically progresses to acute kidney injury (AKI). HCV also increases the risk of chronic kidney disease (CKD) and the likelihood of developing end-stage renal disease (ESRD). Currently, direct-acting antiviral agents (DAAs) can be used to treat kidney disease at different stages. This review focuses on key findings regarding HCV and kidney disease, discusses the impact of DAAs, and highlights the need for further research and treatment.

Scale-up of Direct-Acting Antiviral Treatment in Prisons Is Both Cost-effective and Key to Hepatitis C Virus Elimination.

The Surveillance and Treatment of Prisoners With Hepatitis C (SToP-C) study demonstrated that scaling up of direct-acting antiviral (DAA) treatment reduced hepatitis C virus (HCV) transmission. We evaluated the cost-effectiveness of scaling up HCV treatment in statewide prison services incorporating long-term outcomes across custodial and community settings. A dynamic model of incarceration and HCV transmission among people who inject drugs (PWID) in New South Wales, Australia, was extended to include former PWID and those with long-term HCV progression. Using Australian costing data, we estimated the cost-effectiveness of scaling up HCV treatment in prisons by 44% (as achieved by the SToP-C study) for 10 years (2021-2030) before reducing to baseline levels, compared to a status quo scenario. The mean incremental cost-effectiveness ratio (ICER) was estimated by comparing the differences in costs and quality-adjusted life-years (QALYs) between the scale-up and status quo scenarios over 40 years (2021-2060) discounted at 5% per annum. Univariate and probabilistic sensitivity analyses were performed. Scaling up HCV treatment in the statewide prison service is projected to be cost-effective with a mean ICER of A$12 968/QALY gained. The base-case scenario gains 275 QALYs over 40 years at a net incremental cost of A$3.6 million. Excluding DAA pharmaceutical costs, the mean ICER is reduced to A$6 054/QALY. At the willingness-to-pay threshold of A$50 000/QALY, 100% of simulations are cost-effective at various discount rates, time horizons, and changes of treatment levels in prison and community. Scaling up HCV testing and treatment in prisons is highly cost-effective and should be considered a priority in the national elimination strategy. NCT02064049.

Generalized cost-effectiveness analysis to assess treatment value in hepatitis C.

To estimate the comprehensive value of direct-acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) compared with peginterferon alfa and ribavirin (PEG/riba) employing a generalized cost-effectiveness analysis (GCEA). To assess the societal-level cost-effectiveness of DAA treatment for HCV, we extended a previously published discrete-time Markov simulation model of HCV transmission and progression to include market dynamics and broader elements of value. We followed a stepwise process to add novel value elements to a traditional CEA model for HCV treatments. For each additional element of value, we estimated incremental cost-effectiveness ratios (ICERs) of DAAs compared with PEG/riba. The health technology assessment (HTA)-style model yielded an ICER value of $64,512 per quality-adjusted life-year (QALY). Adding transmission dynamics resulted in an ICER value of $52,971 per QALY, whereas accounting for transmission dynamics and dynamic price and efficacy further decreased ICER values by 90% to $6406 per QALY. Incorporating genericization, productivity loss, caregiver spillover, and differential valuations of LYs vs quality of life, disease severity, and insurance value further decreased the ICER value to $4487 per QALY, a 93% reduction from the baseline HTA-style CEA to the fully realized GCEA. Our GCEA study results confirm that DAAs are a cost-effective treatment for HCV compared with PEG/riba even when using conventional cost-effectiveness approaches. Incorporating broader elements of value resulted in more than a 10-fold improvement in cost-effectiveness, emphasizing the substantive impact of a generalized approach and the importance of incorporating GCEAs into decision-making.

Mathematical modeling of HIV-HCV co-infection model: Impact of parameters on reproduction number.

Background:Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) are both classified as blood-borne viruses since they are transmitted through contact with contaminated blood. Approximately 1.3 million of the 2.75 million global HIV/HCV carriers are people who inject drugs (PWID). HIV co-infection has a harmful effect on the progression of HCV, resulting in greater rates of HCV persistence after acute infection, higher viral levels, and accelerated progression of liver fibrosis and end-stage liver disease. In this study, we developed and investigated a mathematical model for the dynamical behavior of HIV/AIDS and HCV co-infection, which includes therapy for both diseases, vertical transmission in HIV cases, unawareness and awareness of HIV infection, inefficient HIV treatment follow-up, and efficient condom use. Methods:Positivity and boundedness of the model under investigation were established using well-known theorems. The equilibria were demonstrated by bringing all differential equations to zero. The associative reproduction numbers for mono-infected and dual-infected models were calculated using the next-generation matrix approach. The local and global stabilities of the models were validated using the linearization and comparison theorem and the negative criterion techniques of bendixson and dulac, respectively. Results: The growing prevalence of HIV treatment dropout in each compartment of the HIV model led to a reduction in HIV on treatment compartments while other compartments exhibited an increase in populations . In dually infected patients, treating HCV first reduces co-infection reproduction number R ech , which reduces liver cancer risk. Conclusions:From the model's results, we infer various steps (such as: campaigns to warn individuals about the consequences of having multiple sexual partners; distributing more condoms to individuals; continuing treatment for chronic HCV and AIDS) that policymakers could take to reduce the number of mono-infected and co-infected individuals.

Mathematical modeling of HIV-HCV co-infection model: Impact of parameters on reproduction number.

Background: Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) are both as classified blood-borne viruses since they are transmitted through contact with contaminated blood. Approximately 1.3 million of the 2.75 million global HIV/HCV carriers inject drugs (PWID). HIV co-infection has a harmful effect on the progression of HCV, resulting in greater rates of HCV persistence after acute infection, higher viral levels, and accelerated progression of liver fibrosis and end-stage liver disease. In this study, we developed and investigated a mathematical model for the dynamical behavior of HIV/AIDS and HCV co-infection, which includes therapy for both diseases, vertical transmission in HIV cases, unawareness and awareness of HIV infection, inefficient HIV treatment follow-up, and efficient condom use. Methods: Positivity and boundedness of the model under investigation were established using well-known theorems. The equilibria were demonstrated by bringing all differential equations to zero. The associative reproduction numbers for mono-infected and dual-infected models were calculated using the next-generation matrix approach. The local and global stabilities of the models were validated using the linearization and comparison theorem and the negative criterion techniques of bendixson and dulac, respectively. Results: The growing prevalence of HIV treatment dropout in each compartment of the HIV model led to a reduction in HIV on treatment compartments while other compartments exhibited an increase in populations . In dually infected patients, treating HCV first reduces co-infection reproduction number R ech , which reduces liver cancer risk. Conclusions: From the model's results, we infer various steps that policymakers could take to reduce the number of mono-infected and co-infected individuals.

Hepatitis C Virus positivity prediction from serum samples using NIRS and L1-penalized classification.

The hepatitis C virus (HCV) has developed a strategy to coexist with its host resulting in varying degrees of tissue and cell damage, which generate different pathological phenotypes, such as varying degrees of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). However, there is no integrated information that can predict the evolutionary course of the infection. We propose to combine Near-infrared spectroscopy (NIRS) and machine learning techniques to provide a predictive model. In this work, we propose to discriminate HCV positivity in biobank patient serum samples. 126 serum samples from 38 HCV patients in different stages of the disease were obtained from the Biobank of Hospital Universitario Fundación Alcorcon. NIRS spectrum was captured by a FT-NIRS Spectrum 100 (Perkin Elmer) device in reflectance mode. For each patient, the HCV positivity was identified (PCR) and labeled as detectable =1 and undetectable =0. We propose an L1-penalized logistic regression model to classify each spectrum as positive (1) or negative (0) for HCV presence (x). The regularization parameter is selected using 5- fold cross-validation. The penalized model will induce sparsity in the solution so that only a few relevant wavelengths will be different from zero. L1-penalized logistic regression model provided 167 wavelengths different from zero. The accuracy on an independent test set was 0.78. We present a straightforward promising approach to detect HCV positivity from patient serum samples combining NIRS and machine learning techniques. This result is encouraging to predict HCV progression, among other applications. Clinical relevance- We presented a simple while promising approach to use machine learning and NIRS to analyze viral presence on sample serums.

Hepatitis C Virus Infection Cycle-Specific MicroRNA Profiling Reveals Stage-Specific miR-4423-3p Targets RIG-I to Facilitate Infection.

Hepatitis C virus (HCV) infection is one of the main causes of chronic liver diseases, the disorders of which involve multiple pathological processes and elements including host factors such as non-coding small RNAs. Although several genes have been reported to be correlated with HCV infection, the potential regulatory network has not been deciphered clearly. By small RNA sequencing, we clarified the expression profile of microRNAs (miRNAs) in HCV-infected Huh7 and Huh7.5.1 cells and identified 6 dysregulated miRNAs with the same expression trend and 32 dysregulated miRNAs with different expression trends during different stages of HCV life cycle. By looking into each infection stage, we found that 6 miRNAs were entry stage specific, 4 miRNAs were replication stage specific, and 1 miRNA was related to the transmission stage. Moreover, due to the fact that Huh7.5.1 cells have a retinoic acid-inducible gene 1 (RIG-I) mutation which causes reduced production of interferons (IFNs), we here focused on the miRNAs of different trends to decipher the RIG-I/IFN specific miRNAs. Among them, miR-4423-3p showed a significant promotive effect on HCV infection by suppressing RIG-I/IFN pathway through direct binding to RIG-I mRNA. Together, the results displayed novel insights into the miRNA regulatory networks in HCV infection and progression, thus providing a prosperous perspective into the establishment of novel therapeutic and diagnostic targets of the disease.

Elevated Levels of IL-33, IL-17 and IL-25 Indicate the Progression from Chronicity to Hepatocellular Carcinoma in Hepatitis C Virus Patients.

Hepatitis C virus (HCV) is one of the most epidemic viral infections in the world. Three-quarters of individuals infected with HCV become chronic. As a consequence of persistent inflammation, a considerable percentage of chronic patients progress to liver fibrosis, cirrhosis, and finally hepatocellular carcinoma. Cytokines, which are particularly produced from T-helper cells, play a crucial role in immune protection against HCV and the progression of the disease as well. In this study, the role of interleukins IL-33, IL-17, and IL-25 in HCV patients and progression of disease from chronicity to hepatocellular carcinoma will be characterized in order to use them as biomarkers of disease progression. The serum levels of the tested interleukins were measured in patients suffering from chronic hepatitis C (CHC), hepatocellular carcinoma (HCC), and healthy controls (C), and their levels were correlated to the degree of liver fibrosis, liver fibrosis markers and viral load. In contrast to the IL-25 serum level, which increased in patients suffering from HCC only, the serum levels of both IL-33 and IL-17 increased significantly in those patients suffering from CHC and HCC. In addition, IL-33 serum level was found to increase by liver fibrosis progression and viral load, in contrast to both IL-17 and IL-25. Current results indicate a significant role of IL-33 in liver inflammation and fibrosis progress in CHC, whereas IL-17 and IL-25 may be used as biomarkers for the development of hepatocellular carcinoma.

Emicizumab Prophylaxis in Persons with Hemophilia A, Aged ≥50 Years, with Comorbidities - Pooled Data from Four Phase III Studies (HAVEN 1, 3, and 4, and STASEY)

Emicizumab Prophylaxis in Persons with Hemophilia A, Aged ≥50 Years, with Comorbidities - Pooled Data from Four Phase III Studies (HAVEN 1, 3, and 4, and STASEY)

Cost-effectiveness of hepatitis C virus (HCV) elimination strategies among people who inject drugs (PWID) in Tijuana, Mexico.

In Latin America, Mexico was first to launch a hepatitis C virus (HCV) elimination strategy, where people who inject drugs (PWID) are a main risk group for transmission. In Tijuana, HCV seroprevalence among PWID is >90%, with minimal harm reduction (HR). We evaluated cost-effectiveness of strategies to achieve the incidence elimination target among PWID in Tijuana. Modeling study using a dynamic, cost-effectiveness model of HCV transmission and progression among active and former PWID in Tijuana, to assess the cost-effectiveness of incidence elimination strategies from a health-care provider perspective. The model incorporated PWID transitions between HR stages (no HR, only opioid agonist therapy, only high coverage needle-syringe programs, both). Four strategies that could achieve the incidence target (80% reduction by 2030) were compared with the status quo (no intervention). The strategies incorporated the number of direct-acting anti-viral (DAA) treatments required with: (1) no HR scale-up, (2) HR scale-up from 2019 to 20% coverage among PWID, (3) HR to 40% coverage and (4) HR to 50% coverage. Costs (2019 US$) and health outcomes [disability-adjusted life years (DALYs)] were discounted 3% per year. Mean incremental cost-effectiveness ratios (ICER, $/DALY averted) were compared with one-time per capita gross domestic product (GDP) ($9698 in 2019) and purchasing power parity-adjusted per capita GDP ($4842-13 557) willingness-to-pay (WTP) thresholds. DAAs alone were the least costly elimination strategy [$173million, 95% confidence interval (CI)=126-238million], but accrued fewer health benefits compared with strategies with HR. DAAs+50% HR coverage among PWID averted the most DALYs but cost $265million, 95% CI=210-335million). The optimal strategy was DAAs+50% HR (ICER $6743/DALY averted compared to DAAs only) under the one-time per-capita GDP WTP ($9698). A combination of high-coverage harm reduction and hepatitis C virus treatment is the optimal cost-effective strategy to achieve the HCV incidence elimination goal in Mexico.

The impact of direct acting antivirals on hepatitis C virus disease burden and associated costs in four european countries.

Background and AimsWe assessed the clinical and economic impact of direct‐acting antiviral (DAA) therapy for hepatitis C virus (HCV) in England, Italy, Romania and Spain.MethodsAn HCV progression Markov model was developed considering DAA eligibility and population data during the years 2015‐2019. The period of time to recover the investment in DAAs was calculated as the cost saved by avoiding estimated clinical events for 1000 standardized treated patients. A delayed treatment scenario because of coronavirus disease (COVID‐19) was also developed.ResultsThe estimated number of avoided hepatocellular carcinoma, decompensated cirrhosis and liver transplantations over a 20‐year time horizon was: 1,057 in England; 1,221 in Italy; 1,211 in Romania; and 1,103 in Spain for patients treated during 2015‐2016 and 640 in England; 626 in Italy; 739 in Romania; and 643 in Spain for patients treated during 2017‐2019. The cost‐savings ranged from € 45 to € 275 million. The investment needed to expand access to DAAs in 2015‐2019 is estimated to be recovered in 6.5 years in England; 5.4 years in Italy; 6.7 years in Romania; and 4.5 years in Spain. A delay in treatment because of COVID‐19 will increase liver mortality in all countries.ConclusionDirect‐acting antivirals have significant clinical benefits and can bring substantial cost‐savings over the next 20 years, reaching a Break‐even point in a short period of time. When pursuing an exit strategy from strict lockdown measures for COVID‐19, providing DAAs should remain high on the list of priorities in order to maintain HCV elimination efforts.

Metabolomics approach to understand the hepatitis C virus induced hepatocellular carcinoma using LC-ESI-MS/MS

Hepatocellular carcinoma (HCC) is a typical cancer that has region specified analysis with the incidence of hepatitis C virus (HCV) infection. This study was conducted to improve the understanding of metabolic alterations associated with HCV induced HCC which can open up new strategies to monitor the high risk of HCC. Samples of the subjects with HCV, HCV induced chronic liver disease (CLD), HCV induced HCC, and healthy controls (HS) were collected after complete blood count (CBC), hepatitis viral load, α-fetoprotein (AFP), liver function tests, and albumin. A total of 147 serum samples including HCC (n = 11), CLD (n = 24), HCV (n = 71), and HS (n = 41) were analyzed by LC-ESI-MS/MS. The 21 compounds were found to be responsible for group discrimination after the application of chemometric tools. N-fructosyl tyrosine and hydroxyindoleacetic acid showed an increase in level whereas L-aspartyl-L-phenylalanine and thyroxine showed a consistent decrease in the progression of HCV to HCC in comparison with HS indicating their importance for early detection. The biological pathways such as glycerophospholipid metabolism, phenylalanine, tyrosine, and tryptophan biosynthesis, phenylalanine metabolism and tryptophan metabolism showed alteration in some metabolites. The method was internally validated by ROC plot showing AUC value for HS, HCV, CLD, and HCC as 0.99, 1, 1, and 0.89, respectively; while 16 blind samples were also validated with 93% specificity. The untargeted metabolomics investigation of HCV, CLD, and HCC can help to understand the progression of HCV-induced HCC. It reveals significant differences in metabolites to predict prognostic and diagnostic markers.

Modulation of Memory B Cell Phenotypes and Toll-Like Receptor-7 in Chronic Hepatitis C Virus Infection During Direct-Acting Antiviral Interferon-Free Therapy: Correlation with Interleukin-7.

Hepatitis C virus (HCV) infection is a major worldwide problem with the highest incidence rates in Egypt. It affects B cells that serve as reservoirs for persistent HCV, resulting in phenotypic B cell alterations. Interleukin-7 (IL-7) is a cytokine with antiviral activity, important for B cell physiology. In addition, B cell-intrinsic toll-like receptor-7 (TLR7) signaling is required for optimal B cell responses during chronic viral infection, and the deficiency of TLR7 in B cells is sufficient to significantly impact antibody responses. Based on their known immunomodulatory effects, we hypothesized that direct-acting antiviral interferon-free therapy may affect TLR7 expression and the exhausted peripheral B cell compartment with the possibility of their restoration in patients who achieved a sustained virological response and their correlation to IL-7 level. This prospective study was accomplished on 80 Egyptian HCV patients and 75 controls. Frequencies of peripheral B cell subsets, TLR7 gene expression, TLR7 protein, and serum IL-7 levels were investigated by flow cytometry, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. B cell subpopulations were exhausted and partially restored among HCV patients after receiving treatment, but not recovered with regard to activated mature or resting memory B cells. Almost all responders to direct antiviral drugs showed upregulation of TLR7 gene expression and correlated with the frequency of memory B cell, but not with IL-7. Moreover, IL-7 was not significantly different between groups although correlated with immature transitional B cells. Results may indicate the interplay between TLR7 and B cells during remission or progression of HCV. Thus, TLR7 could be used as a promising biomarker for assessment of antiviral treatment efficacy among chronically infected HCV patients, and that targeting TLR7 may be used as a potential prophylactic and/or therapeutic agent during chronic HCV as well as immune-potentiation of memory B cells.

Estimating the Year Each State in the United States Will Achieve the World Health Organization's Elimination Targets for HepatitisC.

IntroductionAlthough hepatitis C virus (HCV) infection remains a major clinical, economic, and societal burden, the development of curative antiviral therapy may accelerate the path toward elimination. This analysis assessed the progress of United States (US) states towards achieving the World Health Organization’s (WHO) 2030 HCV elimination targets for incidence, mortality, diagnosis, and treatment.MethodsA previously published Markov model was used to simulate HCV progression over time to estimate the path to HCV elimination in each state based on prevalence, annual treatment, and diagnosis inputs from two large US laboratory datasets from January 2013 to December 2017. State-specific fibrosis stage restrictions on treatment in 2017 were included. The model estimated the year individual states would meet the WHO targets for diagnosing 90% of the HCV-infected population, treating 80% of the eligible population, reducing new HCV infections by 80%, and reducing HCV-related deaths by 65%. The minimum number of annual treatments needed between 2020 and 2030 to achieve the WHO treatment target was also calculated.ResultsOverall, the USA is projected to achieve HCV elimination by 2037, with individual targets related to mortality, diagnosis, treatment, and incidence being achieved by 2020, 2027, 2033, and 2037, respectively. Three states (Connecticut, South Carolina, and Washington) are on track to meet all four elimination targets by 2030, and 18 states are not expected to meet these targets before 2040. The estimated annual number of treatments required during 2020–2030 nationally to reach the WHO treatment target is 173,514.ConclusionWith the exception of three states, the USA is not on target to meet the WHO 2030 elimination targets and 35% are off track by 10 years or more. Strategies must be implemented to reduce overall prevalence by preventing new infections, increasing rates of screening, improving linkage to care, and implementing unfettered access to curative therapy.Electronic supplementary materialThe online version of this article (10.1007/s12325-020-01535-3) contains supplementary material, which is available to authorized users.

What is required for achieving hepatitis C virus elimination in Singapore? A modeling study.

The vast majority of hepatitis C virus (HCV) infection in Singapore is among those with a history of injecting drug use (IDU), yet harm reduction is not available and what is required to achieve the World Health Organization (WHO) HCV elimination targets (80% incidence reduction and 65% mortality reduction by 2030) is unknown. We model the intervention scale-up required to achieve WHO targets in Singapore. A dynamic model of HCV transmission and progression among those with a history of IDU was calibrated to Singapore, a setting with declining IDU and no harm reduction (~11000 people with IDU history in 2017 and 45% HCV seropositive). We projected HCV treatment scale-up from 2019 required to achieve WHO targets with varying prioritization scenarios, with/without opiate substitution therapy scale-up (to 40% among people who inject drugs [PWID]). We estimated 3855 (95% confidence interval: 2635-5446) chronically HCV-infected individuals with a history of IDU and 148 (87-284) incident HCV cases in Singapore in 2019. Reaching the HCV incidence target requires 272 (187-384) treatments in 2019, totaling 2444 (1683-3452) across 2019-2030. By prioritizing PWID or PWID and cirrhotics, 60% or 30% fewer treatments are required, respectively, whereas the target cannot be achieved with cirrhosis prioritization. Opiate substitution therapy scale-up reduces treatments required by 21-24%. Achieving both WHO targets requires treating 631 (359-1047) in 2019, totaling 3816 (2664-5423) across 2019-2030. Hepatitis C virus elimination is achievable in Singapore but even with declining IDU requires immediate treatment scale-up among PWID. Harm reduction provision reduces treatments required and provides additional benefits.

Hepatitis C virus genotypes and associated risk factors in the state of Pará, Northern Brazil

BackgroundDespite the emergence of more effective therapies, hepatitis C virus (HCV) infection remains a serious public health problem at the global level. Currently, this virus is classified into seven genotypes and 67 subgenotypes, which in turn are distributed heterogeneously in Brazil and worldwide. Studies have shown that this genetic divergence results in differences in the progression of chronic disease associated with HCV infection and its treatment. ObjectiveThe aim of this study was to report the frequency of HCV genotypes in the state of Pará, Northern Brazil, and to assess the association between genotype and different clinical and laboratory characteristics, as well as risk factors for infection. MethodData from 85 medical records of untreated patients who had chronic hepatitis C infection were analyzed; the patients were evaluated at two hospitals in Belem, Pará, Brazil. ResultsCirculation of genotypes 1 and 3 was detected, with a higher prevalence of genotype 1 (75.3%) than genotype 3 (24.7%). In addition, there was a predominance of subgenotype 1b (60.34%) compared to 1a (20.69%) and 3a (18.97%). Reuse of needles and/or glass syringes was significantly associated with infection by HCV genotype 1 than genotype 3; however, the small number of patients infected with genotype 3 may have biased the results. No associations between genotype and the evaluated clinical and laboratory characteristics were observed. ConclusionThis study reinforces the differences in the distribution of HCV genotypes in Brazil and showed no association between HCV genotype and progression of chronic hepatitis C in the studied group.

Impact of interleukin IL-6 rs-1474347 and IL-10 rs-1800896 genetic polymorphisms on the susceptibility of HCV-infected Egyptian patients to hepatocellular carcinoma.

Hepatitis C virus (HCV) is considered leading cause of cirrhosis and hepatocellular carcinoma (HCC). We aimed to examine the association of IL-6 and IL-10 single-nucleotide polymorphisms with the progression of chronic HCV (CHC) infection to cirrhosis and HCC. For comparative purposes, four groups were enrolled; chronic HCV group (CHC, n= 22), HCV-related liver cirrhosis group (HCV-LC, n= 22), HCV-related HCC group (HCV-HCC, n= 54), and an apparently healthy control group (controls, n= 48). HCC diagnosis and staging were in concordance to Barcelona Clinic Liver Cancer (BCLC) staging system. IL-6 rs-1474347 and IL-10 rs-1800896 genotyping was performed by allelic (VIC- and FAM-labeled) discrimination method using assay-on-demand TaqMan real-time PCR assays. For IL-6 rs1474347, the AA genotype was more frequent in CHC, HCV-LC, and HCV-HCC compared to controls. Also, the IL-6 rs1474347 AC genotype was favorable for the progression of HCV chronic infection to cirrhosis and HCC. On the other hand, the IL-10 rs1800896 TT genotype was found to be prominent in the HCC group. Additionally, the IL-10 rs180096 TT genotype was favorable for the progression of chronic HCV infection to cirrhosis and HCC. Furthermore, higher levels of AFP were observed in HCC patients with IL-6 rs1474347 AA genotype and HCC patients with IL-10 rs1800896 CC and TT genotypes. Screening for IL-6 rs 1474347 AC genotype and IL-10 rs180096 TT genotype as well as the determination of AFP level showed to be good markers for examining the susceptibility of HCV Egyptian patients to develop cirrhosis and HCC.

Association Between Polymorphisms in Cytokine Gene and Viral Infections in Renal and Liver Transplant Recipients: A Systematic Review.

Although transplantations are associated with an increased risk of post-transplantation infections, they greatly improve life expectancy and patients' quality of life. Cytokine genes play an important role in the success of transplants due to their immunological functions. A systematic review was conducted to evaluate cytokine gene polymorphisms and risk of cytomegalovirus (CMV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in kidney and liver transplant recipients. A systematic search was conducted using PubMed, EMBASE, Medline and Google Scholar from their inception until January 28, 2019 using appropriate key words. Review articles, case reports or series, studies conducted on non-human subjects and published in languages other than English were excluded. Data were abstracted using a standardized form. The quality of the studies included was assessed using "Risk of Bias Assessment tool for Non-randomized Studies (RoBANS)". Thirty-one studies met our inclusion criteria; populations studied were diverse with a sample ranging from 20 to 1,671. Nineteen studies evaluated Interleukin (IL)-28B polymorphism, while six studies evaluated interferon lambda (IFN-λ) gene polymorphisms and their impact on CMV, HCV, and HBV progression. Polymorphisms in IL-10 gene were investigated in six studies. Polymorphisms in IL-12B and IL-1B gene were associated with a higher risk of developing CMV infections while polymorphisms in IL-28B were associated with a lower incidence of CMV infection in renal transplant recipients. Similarly, polymorphisms in IL-28B were associated with higher liver dysfunction from HBV infection in liver transplant recipients. Studies included had low risk of bias. Cytokine gene polymorphisms IL-12B and IL-1B were found to be associated with an increased risk of infection in kidney transplants and IL-28B in liver transplant recipients. However, the small number and heterogeneity of studies limits the generalization of our results. Further research may lead to finding these associations in larger studies which perhaps improve the use of genetic testing and targeted antiviral therapy. This will further reduce the risk of viral infections associated with cytokine gene polymorphisms in post renal and liver transplant recipients.

CD81+ Exosomes Play a Pivotal Role in the Establishment of Hepatitis C Persistent Infection and Contribute Toward the Progression of Hepatocellular Carcinoma.

CD81 serves as an immune modulator, playing its role in tumor growth and metastasis of hepatitis C virus (HCV)-mediated hepatocellular carcinoma (HCC). CD81 serves as a coreceptor of viral entry and is found to be enriched in exosomes. HCV E2 protein when associated with CD81 may be responsible for B cell lymphoproliferative disorders, as extrahepatic manifestation. Studies predict that HCV association with exosomes, leads to the establishment of persistent infection, through immune evasion. Herein, we confirm the association of HCV particles with CD81+ exosomes. Breifly, exosomes were enriched from peripheral blood of chronic HCV patients who have developed HCC. Sideways, exosomes were also enriched from peripheral blood of healthy individuals, who exhibited normal liver function test profile and had no known infection. Isolation of subpopulation of CD81+ exosomes was performed through immunocapture, followed by detection using FACS. Scanning electron microscopy confirmed the physical association of a fraction of exosome with HCV. CD81+ exosomes from chronic HCV patients with HCC were more granulated and larger when compared with those enriched from a healthy individual and HCV RNA was also detected in enriched fractions of CD81+ exosomes from HCV-positive HCC patients only, through real-time quantitative polymerase chain reaction. We concluded that CD81+ exosomes carry HCV particles and the association plays a pivotal role in establishing persistent infection, through immune evasion, thus leading to HCC progression. Exosomal CD81 and its interacting proteins might, therefore, serve as a potential prognostic marker and therapeutic target in HCV progression mediated by active HCV infection.