Impact of ITPA gene polymorphism for predicting anemia and treatment outcome in HCV infected patients taking Sofosbuvir Ribavirin therapy.

BACKGROUND: Globally, 80 million people are suffering from chronic Hepatitis C virus (HCV) infection. Sofosbuvir ribavirin-based anti-HCV therapy is associated with anemia and other adverse effects. Polymorphisms of Inosine triphosphatase (ITPA) gene may cause functional impairment in the Inosine triphosphate pyrophosphatase enzyme, resulting in enhanced sustained viral response (SVR) and protection from ribavirin-associated anemia in patients on therapy. The study objective was to investigate the effect of Inosine triphosphatase gene polymorphism on SVR achievement, hemoglobin decline and ribavirin dose reduction in patients on therapy. METHODS: This prospective cohort study was of 170 hepatitis C infected patients received 6-month sofosbuvir ribavirin therapy. Patient viral load, reduction in ribavirin amount, liver function test, and complete blood count were noted monthly. Inosine triphosphatase variants rs1127354 and rs7270101 were assessed through the restriction fragment length polymorphism and confirmed using Sanger sequencing. The impact of polymorphism on cumulative reduction of ribavirin, and anti-HCV therapy outcome were studied. RESULTS: A total of 74.3% of patients had ITPA rs1127354 CC genotype, 25.7% were CA and AA 0%. The frequency of ITPA genotype rs7270101-AA was 95%, AC 5%, and CC was 0%. ITPA rs1127354-CA had a notably positive impact on SVR achievement with a zero-relapse rate. ITPA rs1127354-CA genotype was significantly (P ˂0.05) protective against ≥ 2 g/dl Hb reduction from baseline to 1st, 2nd and 6th months of therapy. During treatment, Hb reduction ≥ 10 g/dl was frequently observed in rs1127354-CC genotype and rs7270101-AA genotype patients. Ribavirin dose reduction was significantly (P ˂0.05) high in rs1127354-CC genotype as compared to genotype CA whereas no significant difference was observed in ribavirin dose reduction in rs7270101 AA and non-AA genotype. Patient baseline characteristics such as age, body mass index, rs1127354-CC genotype, and baseline Hb were significantly associated with significant Hb reduction. CONCLUSION: Pretreatment evaluation of ITPA polymorphism can be a diagnostic tool to find out patients at risk of anemia and improve treatment adherence. ITPA genotype rs1127354-CA contributes to improved compliance with ribavirin dose and protects against hemoglobin decline in HCV patients while taking ribavirin-based therapy. However, ITPA rs1127354, rs7270101 polymorphism have no significant impact on SVR achievement.

Comparative efficacy and safety of Sofosbuvir/Velpatasvir and Danoprevir for the treatment of chronic hepatitis C: the real-world data in China.

BACKGROUND: Sofosbuvir/Velpatasvir (Epclusa, ECS) is the first pan-genotype direct-acting antiviral agent (DAA) for hepatitis C virus (HCV) infection, and Danoprevir (DNV) is the first DAA developed by a Chinese local enterprise, which is suitable for combined use with other drugs to treat genotype 1b chronic hepatitis C. However, previous reports have never compared the real-world data of ECS and DNV. PATIENTS AND METHODS: 178 chronic hepatitis C patients were retrospectively recruited, and 94cases were accepted with Sofosbuvir/Velpatasvir ± Ribavirin (ECS group), and others (n = 84 treated with DNV combination therapy (DNV group). The HCV genotype, virological response, adverse effects and some laboratory biochemical indexes were contrasted between above two groups in the real world study. RESULTS: DNV group had significantly lower level of alpha-fetoprotein (AFP), lower rates of decompensated cirrhosis ( P < 0.05). ECS group possessed more 6a (31.91% vs.13.10%) while DNV group was provided with more 1b (48.81% vs. 22.34%) patients. Significantly poor liver function was detected in ECS group at 4-week treatment (ALT and AST) and 12-week follow-up (AST) (all P < 0.05). The SVR12 undetectable rates of both groups were 100%, and no serious event was observed during the treatment and follow-up in both groups. CONCLUSION: In this retrospective real-world study, the efficacy of DNV combined therapy is similar to Sofosbuvir/Velpatasvir ± Ribavirin for chronic HCV infection, and the safety is comparable. DNV based therapy is a promising regimen for chronic hepatitis C.

The Severity of Depressive Symptoms as an Independent Predictor of Sustained Virological Response During Treatment of Hepatitis C With Pegylated Interferon-α2a and Oral Ribavirin.

BACKGROUND: Sustained virological response (SVR) is the best indicator of successful therapy for hepatitis C virus (HCV) infection. Patients with chronic HCV infection treated with pegylated interferon-α and ribavirin (PEG-IFN-α/RBV) can achieve SVR 56% of the time. OBJECTIVES: This study aimed to evaluate baseline predictors of SVR in patients treated with PEG-IFN-α/RBV for HCV chronic infection. METHODS: A total of 101 patients receiving PEG-IFN-α/RBV for chronic HCV infection participated in the prospective cohort study. Symptoms of depression were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS) before the treatment. The multivariate regression analysis was applied to determine predictors of SVR. RESULTS: Of a total of 101 patients included, 99 patients reached the primary end point-24 weeks after completing treatment. After the initial analysis of probable predictive variables, the logistic analysis included age, sex, HCV genetic type, and MADRS score. The HCV genotype (odds ratio = 0.22 [confidence interval = 0.073-0.68, p = .008) and MADRS score (OR = 0.88 [confidence interval = 0.80-0.98), p = .013]) predicted an SVR outcome. CONCLUSIONS: The severity of depressive symptoms before treatment and HCV genotype are independent predictors of SVR.

Real-World Safety and Effectiveness of an 8-Week Regimen of Glecaprevir/Pibrentasvir in Patients with Hepatitis C and Cirrhosis.

INTRODUCTION: In 2019, an 8-week regimen of glecaprevir/ pibrentasvir (GLE/PIB) was FDA-approved for treatment of chronic hepatitis C (HCV) in patients with cirrhosis. We used data from the Chronic Hepatitis Cohort Study (CHeCS) to evaluate treatment response and adverse events among patients with HCV and cirrhosis under routine clinical care. METHODS: Using an intention-to-treat (ITT)/modified ITT (mITT) approach, endpoints were (1) sustained virological response (SVR) at 12 weeks (SVR12) post-treatment; and (2) adverse events (AEs)/serious AEs during treatment. Patients with cirrhosis from two CHeCS sites were included if they were prescribed GLE/PIB from August 2017 to June 2020. Detailed treatment and clinical data were collected. Patient baseline characteristics were described with mean/standard deviation (std) for continuous variables, and proportions for categorical variables. Analyses were propensity score adjusted. The final model retained variables that were significant with p value < 0.05. RESULTS: The ITT sample included 166 patients, with 43, 116, and 7 patients in the 8-week, 12-week, and > 12-week planned treatment groups. Among them, 159 had confirmed SVR (95.8%, LCL 93.2%). The mITT analysis included 160 patients after excluding 6 with unknown HCV RNA results; 159 achieved SVR (99.4%, LCL 98.3%). There were no significant differences in rates of SVR between the 8-week and 12-week regimens in either analysis, nor any association with patient characteristics. SAEs were experienced by 1 patient (2%) in the 8-week group, 7 (5%) in the 12-week group (including one death), and 2 (29%) in the > 12-week group; 4 patients (from the 12-week group) experienced serious AEs or hepatic events that were "likely attributable" to GLE/PIB treatment. CONCLUSION: An 8-week regimen of GLE/PIB is well tolerated and highly effective among US patients with HCV and cirrhosis receiving routine clinical care.

Exosomal microRNAs as biomarkers for viral replication in tofacitinib-treated rheumatoid arthritis patients with hepatitis C.

Notwithstanding recent advances in direct antiviral specialists (DAAs) for hepatitis C infection (HCV), it is yet a pervasive overall issue in patients with rheumatoid arthritis (RA). Exosomal microRNAs (miRNAs) is associated with HCV infection. However, it remains unknown how miRNAs respond following biologic disease-modifying antirheumatic drug (bDMARD) and targeted synthetic DMARD (tsDMARD) treatment in HCV patients with RA. We prospectively recruited RA patients taking anti-tumor necrosis factor-α (TNF-α) inhibitors rituximab (RTX) and tofacitinib. The serum hepatitis C viral load was measured using real-time quantitative reverse transcriptase PCR before and 6 months after bDMARD and tsDMARD therapy. HCV RNA replication activity was measured using an HCV-tricistronic replicon reporter system, and quantitative analysis of hsa-mir-122-5p and hsa-mir-155-5p in patients was performed using quantitative PCR. HCV RNA replication in hepatocytes was not affected by tofacitinib or TNF-α inhibitor treatment. Hsa-mir-155-5p and hsa-mir-122-5p were significantly expanded in RA patients with HCV as compared with those without HCV. We observed a dramatic increase in hsa-mir-122-5p and a decrease in hsa-mir-155-5p expression levels in patients taking RTX in comparison with other treatments. Finally, a reduction in hsa-mir-122-5p and an increase in hsa-mir-155-5p were observed in a time-dependent manner after tofacitinib and DAA therapy in RA-HCV patients. These results showed that hsa-mir-155-5p and hsa-mir-122-5p were significantly increased in RA-HCV patients as compared with those without HCV after taking tofacitinib. Hsa-mir-155-5p and hsa-mir-122-5p may be potential biomarkers for treatment efficacy in RA patients with HCV.

Exploration of a hypoxia-immune-related microenvironment gene signature and prediction model for hepatitis C-induced early-stage fibrosis.

BACKGROUND: Liver fibrosis contributes to significant morbidity and mortality in Western nations, primarily attributed to chronic hepatitis C virus (HCV) infection. Hypoxia and immune status have been reported to be significantly correlated with the progression of liver fibrosis. The current research aimed to investigate the gene signature related to the hypoxia-immune-related microenvironment and identify potential targets for liver fibrosis. METHOD: Sequencing data obtained from GEO were employed to assess the hypoxia and immune status of the discovery set utilizing UMAP and ESTIMATE methods. The prognostic genes were screened utilizing the LASSO model. The infiltration level of 22 types of immune cells was quantified utilizing CIBERSORT, and a prognosis-predictive model was established based on the selected genes. The model was also verified using qRT-PCR with surgical resection samples and liver failure samples RNA-sequencing data. RESULTS: Elevated hypoxia and immune status were linked to an unfavorable prognosis in HCV-induced early-stage liver fibrosis. Increased plasma and resting NK cell infiltration were identified as a risk factor for liver fibrosis progression. Additionally, CYP1A2, CBS, GSTZ1, FOXA1, WDR72 and UHMK1 were determined as hypoxia-immune-related protective genes. The combined model effectively predicted patient prognosis. Furthermore, the preliminary validation of clinical samples supported most of the conclusions drawn from this study. CONCLUSION: The prognosis-predictive model developed using six hypoxia-immune-related genes effectively predicts the prognosis and progression of liver fibrosis. The current study opens new avenues for the future prediction and treatment of liver fibrosis.

Impact of amino acid substitutions in hepatitis C virus core region on the severe oxidative stress.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, leading to liver steatosis, fibrosis, and hepatocellular carcinoma (HCC). Despite the accumulation of clinical data showing the impact of amino acid substitutions at positions 70 (R70Q/H) and/or 91 (L91M) in the HCV core protein in progressive liver diseases, including HCC, the underlying mechanisms have not been elucidated. We analyzed 72 liver biopsy specimens from patients with chronic HCV genotype 1b (HCV-1b) infection prior to antiviral treatment. Levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nuclear factor erythroid 2-related factor 2 (NRF2) in the nucleus were quantified using liver tissue immunohistochemistry. The effects of amino acid substitutions in the HCV core region on hepatocellular oxidative stress were investigated using wild-type or double-mutant (R70Q/H+L91M) HCV-1b core transfection and stable expression in human hepatoma HuH-7 cells. Overall, 24, 19, 11, and 18 patients had the wild-type, R70Q/H, L91M, and R70Q/H+L91M genotypes, respectively, in the HCV core. A significantly higher accumulation of hepatocellular 8-OHdG and a lower NRF2/8-OHdG ratio were observed in patients with R70Q/H+L91M than in those with the wild-type disease. Increased levels of intracellular superoxide and hydrogen peroxide in the cytoplasm and mitochondria, mRNA expression of enzymes generating oxidative stress, and nuclear expression of nicotinamide adenine dinucleotide phosphate oxidase 4 were augmented in cells treated with R70Q+L91M. HCV core proteins harboring either or both substitutions of R70Q/H or L91M enhanced hepatocellular oxidative stress in vivo and in vitro. These amino acid substitutions may affect HCC development by enhancing hepatic oxidative stress in patients with chronic HCV-1b infection.

Suppressor of Cytokine Signaling-3 Gene Polymorphisms and the Risk of Hepatocellular Carcinoma in Chronic Hepatitis C Patients in Egypt.

BACKGROUND: Hepatocellular carcinoma (HCC) contributes significantly to cancer mortalities worldwide. The association between a specific single nucleotide polymorphism (SNP) located within the SOCS3 gene as well as the likelihood of hepatocellular carcinoma (HCC) progression in individuals with chronic hepatitis C virus (CHC) was found to be significant. We aimed to study SOCS3 gene polymorphisms at rs4969168 and rs4969170and HCC susceptibility in individuals with CHC. METHODS: The current prospective study involved 111 subjects divided in to three groups (HCC, HCV with and with no cirrhosis, and apparently healthy individuals). Tumor staging was done using BCLC staging system. SOCS3 (rs4969168 and rs4969170) gene polymorphisms' analysis was done utilizing real-time polymerase chain reaction (RT-PCR) (via DNA extracted from all subjects). All subjects underwent a complete history, medical examination, and laboratory and radiological data collection. RESULTS: Compared to healthy controls, homozygous AA genotypes and heterozygous GA genotypes were substantially overrepresented in  HCC patients as well as those with CHCaccompanied by cirrhosis.AFP, smoking, glucose level, and AA genotype of rs4969170 might be critical significant parameters for HCC development. CONCLUSION: SOCS3 gene polymorphisms at rs4969168 and rs4969170 are associated with HCC and liver fibrosis progression in the Egyptian population with CHC infection.

Direct-acting antiviral resistance of Hepatitis C virus is promoted by epistasis.

Direct-acting antiviral agents (DAAs) provide efficacious therapeutic treatments for chronic Hepatitis C virus (HCV) infection. However, emergence of drug resistance mutations (DRMs) can greatly affect treatment outcomes and impede virological cure. While multiple DRMs have been observed for all currently used DAAs, the evolutionary determinants of such mutations are not currently well understood. Here, by considering DAAs targeting the nonstructural 3 (NS3) protein of HCV, we present results suggesting that epistasis plays an important role in the evolution of DRMs. Employing a sequence-based fitness landscape model whose predictions correlate highly with experimental data, we identify specific DRMs that are associated with strong epistatic interactions, and these are found to be enriched in multiple NS3-specific DAAs. Evolutionary modelling further supports that the identified DRMs involve compensatory mutational interactions that facilitate relatively easy escape from drug-induced selection pressures. Our results indicate that accounting for epistasis is important for designing future HCV NS3-targeting DAAs.

TLR3 Gene Polymorphism in HCV Infection in the Kazakh Population of Western Kazakhstan.

BACKGROUND AND OBJECTIVES: Hepatitis C virus (HCV) infection is a common cause of cirrhosis worldwide, leading to significant economic and social burdens. Approximately 170 million people (3% of the population) are infected with HCV, with the risk of developing complications such as cirrhosis and hepatocellular carcinoma. In the United States, HCV is the main cause of liver cirrhosis, accounting for 26% of cases. Recent studies have shown an increase in the proportion of HCV-related liver cirrhosis. MATERIALS AND METHODS: A total of 102 patients with chronic hepatitis C in the reactivation phase from the Atyrau and Aktobe regional hepatology centers, who had not previously received antiviral therapy, were examined. A control group, matched by gender and age, included 127 practically healthy individuals of Kazakh nationality. All patients underwent a comprehensive examination, which included a complete blood count, a biochemical blood analysis and PCR for HCV. Venous blood samples were taken from all subjects for molecular genetic analysis. Genotyping of TLR3 polymorphism (rs5743312, rs5743305, rs3775291, rs5743311, rs1879026) was performed using real-time PCR. Thes study is a case control study. RESULTS: In patients with cirrhosis of the liver resulting from chronic hepatitis C (HCV), the results of biochemical analysis were statistically significantly higher than in patients with HCV without liver cirrhosis: the levels of total bilirubin (p 0.017*), alkaline phosphatase (p 0.022*), and gamma-glutamyl transferase (0.041*) were elevated. The results indicated that the CC genotype of TLR3 rs1879026 was associated with the development and chronicity of HCV infection compared to practically healthy individuals (p=0.001). In the distribution of genotypes and alleles for rs5743312, rs5743305, rs3775291, and rs5743311, no significant differences were found between patients with HCV and the healthy control group. CONCLUSION: The TLR3 rs1879026 gene polymorphism plays a significant role in the predisposition to HCV infection in the Kazakh population of the Aktobe and Atyrau regions.

Cytokine profile and viral diversity in the early seronegative stage of community-acquired hepatitis C virus (HCV) infection.

Most Hepatitis C virus (HCV)-infected subjects develop chronic infection, whereas a minority clear the virus in the early phase of infection. We analyzed factors associated with outcome (chronicity vs clearance) during the preclinical seronegative phase of community-acquired HCV infection. Among 17.5 million blood donations in the years 2000-2016, 124 blood donors were found to be HCV RNA-positive/anti-HCV-negative. All were contacted after 0.5-12.7 years and 40 responded and provided blood sample. Hypervariable region 1 was analyzed by ultradeep pyrosequencing and cytokines in serum were quantified by Luminex (R&D Systems) multiplex immunoassay. Twenty-one (52.5%) donors were found to be HCV-RNA-positive, while 19 (47.5%) were HCV RNA negative (none received antiviral treatment). All but one seroconverted to anti-HCV. Donors with resolving hepatitis did not differ significantly from donors with chronic infection with respect to age, genotypes, IL28B polymorphisms, number of viral variants, nucleotide diversity per site or the overall number of nucleotide substitutions. However, the former group had significantly higher levels of IL-1beta, IL-1RA, IL-6, IFN-gamma and FGF-2 in serum. In our study of community-acquired acute hepatitis C approximately half of all subjects eliminated the virus spontaneously, and this clearance was associated with marked cytokine response in the early seronegative stage of infection.

Mitochondrial DNA copy number in Hepatitis C virus-related chronic liver disease: impact of direct-acting antiviral therapy.

Hepatitis C virus (HCV) infection can regulate the number and dynamics of mitochondria, and is associated with a prominent hepatic mitochondrial injury. Mitochondrial distress conveys oxidative damage which is implicated in liver disease progression. The present study was conducted to assess the change of mitochondrial DNA (mtDNA) copy number in patients with HCV-related chronic liver disease and the impact of direct-acting antiviral (DAA) therapy. Whole blood mtDNA copy number was measured using real-time quantitative polymerase chain reaction at baseline and 12 weeks after the end of therapy in 50 treatment-naïve HCV-infected patients who achieved sustained viral response (SVR) after DAA therapy and 20 healthy controls. Whole blood mtDNA copy number appeared significantly lower in HCV-infected patients before therapy compared to healthy subjects (P < 0.001). Post-treatment, there was significant increase of mtDNA copy number in HCV-infected patients at SVR12 compared to the pre-treatment values (P < 0.001), meanwhile it didn't differ significantly between HCV-infected patients after therapy and healthy subjects (P = 0.059). Whole blood mtDNA copy number correlated inversely to the serum bilirubin in HCV-infected patients (P = 0.013), however it didn't correlate significantly to the serum aminotransferases, viral load or fibrosis-4 score (P > 0.05). In conclusion, chronic HCV infection has been associated with a prominent mitochondrial injury which could mediate a progressive liver disease. The improved mtDNA content after DAA therapy highlights a possible potential of these drugs to alleviate mitochondrial damage in HCV-related liver disease.

Cytokine polymorphisms and genotypic susceptibility of HCV infection in ribavirin response to peg interferon.

Immune responses are largely regulated by cytokines. Genetic polymorphisms of the regulatory coding regions are recognized to impact the expression of cytokines. The abnormal cytokine levels in hepatitis C virus (HCV) infection seems to be involved in disease progression, viral survival, and therapeutic response. The current study assesses the polymorphisms associated with IL-6, IL-10, IL28B, IFN-γ, TGF-ß, and TNF-α on the genotypic susceptibility to HCV infection and Ribavirin response to Peg interferon. Droplet digital polymerase chain reaction (PCR) was used to assess the gene polymorphisms associated with IL-6 A/G (rs2069837), IL-10-1082 G/A (rs1800896)], IL28B C/T (rs12979860), IFN-γ +874 A/T (rs2430561), TGF-ß 1-509 C/T (rs1800469) and TNF-α-308 G/A promoter (rs1800629) from stored samples of 200 healthy individuals and 300 HCV infected patients. There was a significant association of AG and AA genotypes of IL28B, IFN-γ, TGF-ß1, and TNF-α over HCV susceptibility and treatment outcome. However, no association between IL-6 and IL-10 gene polymorphism to HCV susceptibility response to the treatment. The observations indicate IL28B CT, TGF-ß1 CT, TT and TNF- AG with AA genotypes influence the cytokine expression, which is related to susceptibility and resistance to HCV infection and combined antiviral therapy.

Associations of ITPA gene polymorphisms with outcomes among chronic hepatitis C patients treated with Peg-interferon/ribavirin: A 5-year follow-up study.

To investigate associations between inosine triphosphatase (ITPA) gene polymorphisms and long-term outcomes among chronic hepatitis C (CHC) patients in Northeast China treated with Peg-interferon (IFN)/ribavirin (RBV). CHC patients who received Peg-IFN-2a/RBV treatment during between 2011 and 2013 at 5 hepatitis centers in Northeast China were enrolled. ITPA single nucleotide polymorphisms rs1127354 and rs7270101 from all patients were detected and their associations with 5-year outcomes were analyzed. A total of 635 patients, including 421 infected with hepatitis C virus (HCV) genotype 1 and 214 infected with non-genotype 1 were included. No significant differences were observed in the distribution frequencies of ITPA rs1127354 variants and ITPase activity between patients with HCV genotype 1 and non-genotype 1. In patients who received more than 80% of the planned RBV dose, the 5-year virological response rate and the improvement in liver fibrosis were higher in those with ITPA rs1127354 non-CC with ITPase activity <25% compared with these outcomes in patients with ITPA rs1127354 CC with 100% ITPase activity. Multiple regression analysis revealed that HCV genotype non-1, low baseline HCV ribose nucleic acid (RNA) levels (≤4 × 105 IU/mL), interleukin-28B rs12979860 CC genotype, low baseline liver fibrosis (Fibroscan 0-2), and ITPA rs1127354 non-CC genotype were independent predictors for a high long-term virological response rate, whereas interleukin-28B rs12979860 CC genotype, ITPA rs1127354 non-CC genotype, and low baseline liver fibrosis were independent predictors for improvement of liver fibrosis. ITPA rs1127354 polymorphisms is predictors of long-term outcomes in CHC patients treated with Peg-IFN/RBV.

Polymorphisms Related to Iron Homeostasis Associate with Liver Disease in Chronic Hepatitis C.

Dysregulation of iron metabolism in chronic hepatitis C (CHC) is a significant risk factor for hepatic cirrhosis and cancer. We studied if known genetic variants related to iron homeostasis associate with liver disease progression in CHC. Retrospective analysis included 249 CHC patients qualified for antiviral therapy between 2004 and 2014. For all patients, nine SNPs within HFE, TFR2, HDAC2, HDAC3, HDAC5, TMPRSS6, and CYBRD1 genes were genotyped. Expression of selected iron-related genes, was determined with qRT-PCR in 124 liver biopsies, and mRNA expression of co-inhibitory receptors (PD-1, Tim3, CTLA4) was measured in 79 liver samples. CYBRD1 rs884409, HDAC5 rs368328, TFR2 rs7385804, and TMPRSS6 rs855791 associated with histopathological changes in liver tissue at baseline. The combination of minor allele in HDAC3 rs976552 and CYBRD1 rs884409 linked with higher prevalence of hepatocellular carcinoma (HCC) during follow up (OR 8.1 CI 2.2-29.2; p = 0.001). Minor allele in HDAC3 rs976552 associated with lower hepatic expression of CTLA4. Tested polymorphisms related to iron homeostasis associate with histopathological changes in the liver. The presence of both HDAC3 rs976552 G and CYBRD1 rs884409 G alleles correlates with HCC occurrence, especially in the group of patients with elevated AST (>129 IU/L). rs976552 in HDAC3 could impact immunological processes associated with carcinogenesis in CHC.

Prediction of response to sofosbuvir-based therapy using serum interleukin-12 and single nucleotide polymorphism of the interleukin 28B gene as predictive factors in HCV positive genotype-4 patients.

Some hepatitis-C virus patients have resistance to direct-acting-antivirals (DAAs). Genetic polymorphisms have been associated with drug resistance. This study aimed to evaluate the role of interleukin (IL)-28B gene polymorphism and IL-12 levels as predictors for a response to sofosbuvir/ribavirin (SOF/RBV) with (triple-therapy) or without (dual-therapy) Peg-alpha-interferon. 92 hepatitis C virus (HCV)/RNA (+)-patients treated with dual (n = 72) or triple (n = 20) therapy. IL28B genetic polymorphism and IL-12 level assessments. 30.4% of the patients were IL28B C/C genotype, 56.5% C/T-genotype, and 13% T/T-genotype. Mean baseline IL-12 levels were 27.5 ± 3.0 pg/mL. Rapid viral response was achieved in 86/92 patients. All patients achieved end-of-treatment virologic response. The 12- and 24-week sustained virologic responses (SVR) were achieved in 76 patients (82.6%), that is, a relapse was found in 16 patients (17.4%). 8 and 12-weeks after antiviral therapy, IL-12 levels decreased significantly, and became comparable to those of the control-group. That drop in IL-12 levels was similar across the dual- and triple-therapy patients. Finally, logistic regression analysis showed that the increase in baseline aspartate aminotransferase (AST) and T/T genotyping had an independent effect on increasing the probability a SVR failing in both dual- and triple-therapy groups (P = .0007 and P = .02, respectively). Single-nucleotide polymorphism (SNP) in IL-28B and IL-12 levels play roles as predictors in DAAs resistance.

The Influence of Single Nucleotide Polymorphisms on Vitamin D Receptor Protein Levels and Function in Chronic Liver Disease.

Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene have been associated with chronic liver disease. We investigated the role of VDR SNPs on VDR protein levels and function in patients with chronic liver disease. VDR expression levels were determined in peripheral T lymphocytes (CD3+VDR+), monocytes (CD14+VDR+), and plasma from patients (n = 66) and healthy controls (n = 38). Genotyping of SNPs and the determination of expression of VDR/vitamin D-related genes were performed by using qPCR. The effect of FokI SNP on vitamin D-binding to VDR was investigated by molecular dynamics simulations. CD14+VDR+ cells were correlated with the MELD score. The ApaI SNP was associated with decreased CD3+VDR+ levels in cirrhotic patients and with higher liver stiffness in HCV patients. The BsmI and TaqI SNPs were associated with increased VDR plasma concentrations in cirrhotic patients and decreased CD14+VDR+ levels in HCV patients. The FokI SNP was associated with increased CD3+VDR+ levels in cirrhotic patients and controls. VDR polymorphisms were significantly related to the expression of genes critical for normal hepatocyte function and immune homeostasis. VDR expression levels were related to the clinical severity of liver disease. VDR SNPs may be related to the progression of chronic liver disease by affecting VDR expression levels.

Metabolic disorders induced by PNPLA3 and TM6SF2 gene variants affect chronic kidney disease in patients infected with non-genotype 3 hepatitis C virus.

BACKGROUND: Patients with chronic hepatitis C virus (HCV) infections differ in their risk for metabolic disorders and chronic kidney disease (CKD). The aim of this study was to investigate the effect of metabolic disorders induced by genetic factors on CKD in HCV-infected patients. METHODS: Patients with chronic non-genotype 3 HCV infection with or without CKD were examined. PNPLA3 and TM6SF2 variants were determined using high-throughput sequencing. The relationships of variants and different combinations with metabolic disorders were analyzed in CKD patients. Univariate and multivariate analyses were used to identify factors associated with CKD. RESULTS: There were 1022 patients with chronic HCV infection, 226 with CKD and 796 without CKD. The CKD group had more severe metabolic disorders, and also had higher prevalences of liver steatosis, the PNPLA3 rs738409 non-CC genotype, and the TM6SF2 rs58542926 CC genotype (all P < 0.05). Relative to patients with the PNPLA3 rs738409 CC genotype, patients with the non-CC genotype had a significantly decreased eGFR and a greater prevalence of advanced CKD (CKD G4-5). Patients with the TM6SF2 rs58542926 CC genotype had a lower eGFR and a higher prevalence of CKD G4-5 than those with the non-CC genotype. Multivariable analysis indicated that multiple metabolic abnormalities, including liver steatosis and the PNPLA3 rs738409 C > G variant, increased the risk of CKD, but the TM6SF2 rs58542926 C > T variant decreased the risk of CKD. CONCLUSION: Specific PNPLA3 rs738409 and TM6SF2 rs58542926 variants are independent risk factors for CKD in patients with chronic HCV infections and are associated with the severity of renal injury.

B-cell Clonality in HCV-Induced Patients Treated with Oral Direct-Acting Antiviral Agents.

BACKGROUND: Hepatitis C virus (HCV) is a worldwide' health problem as Egypt has a very high prevalence (14.7%) that may affect the B-Lymphocytes, and in some cases leading to an expansion of monoclonal B-cell detected by immunoglobulin heavy chain (IgH) gene rearrangement. Therefore, we aimed to assess the occurrence of IgH gene rearrangement in Egyptian chronic HCV patients and studying the effect of oral direct-acting antiviral (DAAs) therapy on regression of the clonality markers. METHODS: 78 Egyptian patients with chronic HCV infection were included in this study and polymerase chain reaction (PCR) analysis was used to detect IgH rearrangement based on standardized PCR protocols of the BIOMED-2 international guidelines study. RESULTS: Clonal IgH showed a significant increase of HCV-RNA expression and correlated with increased alanine transaminase (ALT) in all patients, while a significant increase of kappa and lambda free light chain observed only in clonal IgH with lymphoproliferative disorders (LPD) patients. A total of 37.17% (29/78) IgH clonality was detected in all patients (7.69% with LPD and 29.48% without LPD). 37% of these IgH clonality disappeared with HCV eradication after DAAs regimen. CONCLUSIONS: we concluded that different DAAs regimen with or without RBV is safe and effective for the treatment of Egyptian patients, but its effect is partially and not completely in the eradication of IgH clonality. Also, using IgH rearrangement in patients with chronic HCV is helpful as indicator in patients at high risk for prediction of LPD.