Opportunities for treatment of the hepatitis C virus-infected patient with chronic kidney disease

The prevalence of hepatitis C virus(HCV) infection amongst patients with chronic kidney disease(CKD) and end-stage renal disease exceeds that of the general population. In addition to predisposing to the development of cirrhosis and hepatocellular carcinoma, infection with HCV has been associated with extra-hepatic complications including CKD, proteinuria, glomerulonephritis, cryoglobulinemia, increased cardiovascular risk, insulin resistance, and lymphoma. With these associated morbidities, infection with HCV is not unexpectedly accompanied by an increase in mortality in the general population as well as in patients with kidney disease. Advances in the understanding of the HCV genome have resulted in the development of direct-acting antiviral agents that can achieve much higher sustained virologic response rates than previous interferon-based protocols. The direct acting antivirals have either primarily hepatic or renal metabolism and excretion pathways. This information is particularly relevant when considering treatment in patients with reduced kidney function. In this context, some of these agents are not recommended for use in patients with a glomerular filtration rate < 30 m L/min per 1.73 m^2. There are now Food and Drug Administration approved direct acting antiviral agents for the treatment of patients with kidney disease and reduced function. These agents have been demonstrated to be effective with sustained viral response rates comparable to the general population with good safety profiles. A disease that was only recently considered to be very challenging to treat in patients with kidney dysfunction is now curable with these medications.

Associations of content and gene polymorphism of macrophage inhibitory factor-1 and chronic hepatitis C virus infection

BACKGROUND The expression of macrophage inhibitory factor-1(MIC-1) is increased in peripheral blood of patients with chronic hepatitis and liver cirrhosis. However, whether MIC-1 gene polymorphism is correlated with relevant diseases is not yet reported.AIM To explore the correlation between gene polymorphism in MIC-1 exon region and chronic hepatitis C virus(HCV) infection.METHODS This case-control study enrolled 178 patients with chronic hepatitis C(CHC) in the case group, and 82 healthy subjects from the same region who had passed the screening examination comprised the control group. The genotypes of rs1059369 and rs1059519 loci in the MIC-1 gene exon were detected by DNA sequencing. Also, the MIC-1 level, liver function metrics, liver fibrosis metrics, and HCV RNA load were determined. Univariate analysis was used to compare the differences and correlations between the two groups with respect to these parameters. Multivariate logistic regression was used to analyze the independent relevant factors of CHC.RESULTS The plasma MIC-1 level in the CHC group was higher than that in the control group(P < 0.05), and it was significantly positively correlated with alanine aminotransferase, aspartate aminotransferase(AST), type III procollagen N-terminal peptide(known as PIIINP), type IV collagen, and HCV RNA(P < 0.05), whereas negatively correlated with total protein and albumin(P < 0.05). The genotype and allele frequency distribution at the rs1059519 locus differed between the two groups(P < 0.05). The allele frequency maintained significant difference after Bonferroni correction(Pc < 0.05). Logistic multiple regression showed that AST, PIIINP, MIC-1, and genotype GG at the rs1059519 locus were independent relevant factors of CHC(P < 0.05). Linkage disequilibrium(LD) was found between rs1059369 and rs1059519 loci, and significant difference was detected in the distribution of haplotype A-C between the CHC and control groups(P < 0.05). Meanwhile, we found the MIC-1 level trend to increase among rs1059519 genotypes(P = 0.006) and the level of MIC-1 in GG genotype to be significantly higher than CC genotype(P = 0.009, after Bonferroni correction).CONCLUSION Plasma MIC-1 level was increased in CHC patients and correlated with liver cell damage, liver fibrosis metrics, and viral load. The polymorphism at the MIC-1 gene rs1059519 locus was correlated with HCV infection, and associated with the plasma MIC-1 level. G allele and GG genotype may be an important susceptible factor for CHC.

Comment on review article:Chronic hepatitis C virus infection cascade of care in pediatric patients

An enhanced cascade of care should include a younger population,helping to achieve the goal of the World Health Organization with a focus on elimination in the pediatric population.Furthermore,enhanced screening and awareness efforts and continued education of health care providers will improve the outcomes of chronic hepatitis C virus(HCV)infection in the pediatric population.The present work discusses and comments on the topic"cascade of care in HCV chronic pediatric patients".

Ribavirin induced hemolysis:A novel mechanism of action against chronic hepatitis C virus infection

Hepatitis C virus(HCV)is not usually cleared by our immune system,leading to the development of chronic hepatitis C infection.Chronic HCV induces the production of various cytokines,predominantly by Kupffer cells(KCs),and creates a pro-inflammatory state in the liver.The chronic dysregulated production of interferon(IFN)and other cytokines by KCs also promotes innate immune tolerance.Ribavirin(RBV)monotherapy has been shown to decrease inflammation in liver of patients with chronic hepatitis C.Sustained virological response(SVR)is significantly higher when IFN is combined with RBV in chronic HCV(c HCV)infection.However,the mechanism of their synergy remains unclear.Previous theories have attempted to explain the anti-HCV effect based on direct action of RBV alone on the virus or on the immune system;however,these theories have serious shortcomings.We propose that hemolysis,which universally occurs with RBV therapy and which is considered a limiting side effect,is precisely the mechanism by which the anti-HCV effect is exerted.Passive hemolysis results in anti-inflammatory/antiviral actions within the liver that disrupt the innate immune tolerance,leading to the synergy ofRBV with IFN-α.Ribavirin-induced hemolysis floods the hepatocytes and KCs with heme,which is metabolized and detoxified by heme oxygenase-1(HMOX1)to carbon monoxide(CO),biliverdin and free iron(which induces ferritin).These metabolites of heme possess anti-inflammatory and antioxidant properties.Thus,HMOX1 plays an extremely important anti-oxidant,anti-inflammatory and cytoprotective role,particularly in KCs and hepatocytes.HMOX1 has been noted to have anti-viral effects in hepatitis C infected cell lines.Additionally,it has been shown to enhance the response to IFN-αby restoring interferon-stimulated genes(ISGs).This mechanism can be clinically corroborated by the following observations that have been found in patients undergoing RBV/IFN combination therapy for c HCV:(1)SVR rates are higher in patients who develop anemia;(2)once anemia(due to hemolysis)occurs,the SVR rate does not depend on the treatment utilized to manage anemia;and(3)ribavirin analogs,such as taribavirin and levovirin,which increase intrahepatic ribavirin levels and which produce lesser hemolysis,are inferior to ribavirin for treating c HCV.This mechanism can also explain the observed RBV synergy with direct antiviral agents.This hypothesis is testable and may lead to newer and safer medications for treating c HCV infection.

Circulating autoantibodies to endogenous erythropoietin are associated with chronic hepatitis C virus infection-related anemia

BACKGROUND： Chronic hepatitis C virus （HCV） infection is associated with autoimmune phenomena and is often complicated by anemia. Circulating autoantibodies to endogenous erythropoietin （anti-EPO） have been detected in patients with chronic viral infections and were correlated to anemia. The present study aimed to determine anti-EPO prevalence in pa- tients with chronic HCV infection and investigate its possible association with anemia. METHODS： Ninety-three consecutive patients （62 males and 31 females） with chronic HCV infection, who had never re- ceived antiviral therapy or recombinant EPO, were enrolled in the study. Circulating anti-EPO were detected in the serum by using an ELISA assay. Quantitative determination of serum EPO levels was done by radioimmunoassay. HCV RNA viral load t and genotype sequencing were also performed. RESULTS： Circulating anti-EPO were detected in 10.8% of HCV-infected patients and the prevalence of anti-EPO was significantly higher in patients with anemia （19.4% vs 5.3%, P=0.040） compared to that in those without anemia. Compared to anti-EPO negative cases, anti-EPO positive patients had higher frequency of anemia （70.0% vs 34.9%, P=0.030）, lower EPO concentrations （median 16.35 vs 30.65 mU/mL, P=0.005）, and higher HCV RNA viral load （median 891.5x103 vs 367.5x 103 IU/mL, P=0.016）. In multivariate regression anal- ysis the presence of anti-EPO remained an independent predictor of anemia （adjusted OR： 14.303, 95% CI： 1.417-36.580, P=0.024）. EPO response to anemia was less prominent among anti-EPO positive patients （P=0.001）. CONCLUSIONS： Circulating anti-EPO are detected in a significant proportion of treatment-naive HCV-infected patients and are independently associated with anemia, suggesting a further implication of autoimmunity in the pathophysiology of HCV-related anemia.

Spleen stiffness mirrors changes in portal hypertension after successful interferon-free therapy in chronic-hepatitis C virus patients

AIM To investigate changes in spleen stiffness measurements(SSMs) and other non-invasive tests(NITs) after treatment with direct-acting antivirals(DAAs) and identify predictors of SSM change after sustainedvirological response(SVR). METHODS We retrospectively analysed 146 advanced-chronic liver disease(ACLD) patients treated with DAA with available paired SSM at baseline and SVR24. Liver stiffness(LSM), spleen diameter(SD), platelet count(PLT) and liver stiffness-spleen diameter to platelet ratio score(LSPS) were also investigated. LSM ≥ 21 k Pa was used as a cut-off to rule-in clinically significant portal hypertension(CSPH). SSM reduction > 20% from baseline was defined as significant.RESULTS SSM significantly decreased at SVR24, in both patients with and without CSPH; in 44.8% of cases, SSM reduction was > 20%. LSPS significantly improved in the entire cohort at SVR24; SD and PLT changed significantly only in patients without CSPH. LSM significantly decreased in 65.7% of patients and also in 2/3 patients in whom SSM did not decrease. The independent predictor of decreased SSM was median relative change of LSM. CSPH persisted in 54.4% patients after SVR. Delta LSM and baseline SSM were independent factors associated with CSPH persistence.CONCLUSION SSM and other NITs significantly decrease after SVR, although differently according to the patient's clinical condition. SSM faithfully reflects changes in portal hypertension and could represent a useful NIT for the follow-up of these patients.

Interaction of IFNL3 with insulin resistance,steatosis and lipid metabolism in chronic hepatitis C virus infection

Metabolic changes are inextricably linked to chronic hepatitis C(CHC).Recently polymorphisms in the IFNL3(IL28B)region have been shown to be strongly associated with spontaneous and treatment induced recovery from hepatitis C virus(HCV)infection.Further,circumstantial evidence suggests a link between IFNL3single nucleotide polymorphisms and lipid metabolism,steatosis and insulin resistance in CHC.The emerging picture suggests that the responder genotypes of IFNL3polymorphisms are associated with a higher serum lipid profile,and less frequent steatosis and insulin resistance.This review analyzes the current data regarding this interaction and its meaning for HCV pathogenesis and disease progression.

Hepatitis C virus genotypes, HLA-DRB alleles and their response to interferon-α and ribavirin in patients with chronic hepatitis C

BACKGROUND: Hepatitis C virus (HCV) is a worldwide common disease. Some predictive factors influencing the response to interferon alpha (IFN-α) therapy have been identified, but the conclusions differ in various counties and areas. The aim of this study was to study the associa- tions between HCV genotypes, HLA-DRB alleles and their response to IFN-α and ribavirin in Chinese patients with chronic hepatitis C in Northeast China. METHODS: HCV genotypes of 113 patients with HCV were investigated. Gene chips were used to analyze the fre- quency of HLA-DRB in 25 of these patients and their re- sponse to IFN-α and ribavirin. The associations of HCV genotypes, HLA-DRB alleles and their response to IFN-α and ribavirin were also studied. RESULTS: The response rates differed in several types of HCV, with HCV 2b being the highest (57.78% ), HCV 1a and 2a lower (46.15% and 47.62% ) and HCV 1b the low- est (11.76% ). The response rates to IFN-α and ribavirin in patients with DRB1 07 were higher than those with DRB1 04. Sex, HCV type and HLA-DRB were all related to the response. Most female patients with HCV 2b and HLA- DRB1 07 presented complete response, whereas male pa- tients with HCV 1b and HLA-DRB1 04 usually demon- strated no response. DRB1 07 allele and HCV 2b were the factors closely related to the response. CONCLUSIONS: The response rate of HCV 1b may be the lowest even IFN-α and ribavirin are combined in treat- ment. Not only virus but also the host plays an important role in anti-virus therapy. Thus, it is necessary to adjust the host's immune status to accelerate the clearance of HCV.

Chronic hepatitis C virus infection:Serum biomarkers inpredicting liver damage

Currently, a major clinical challenge in the management of the increasing number of hepatitis C virus(HCV) infected patients is determining the best means for evaluating liver impairment. Prognosis and treatment of chronic hepatitis C(CHC) are partly dependent on the assessment of histological activity, namely cell necrosis and inflammation, and the degree of liver fibrosis. These parameters can be provided by liver biopsy; however, in addition to the risks related to an invasive procedure, liver biopsy has been associated with sampling error mostly due to suboptimal biopsy size. To avoid these pitfalls, several markers have been proposed as non-invasive alternatives for the diagnosis of liver damage. Distinct approaches among the currently available non-invasive methods are(1) the physical ones based on imaging techniques; and(2) the biological ones based on serum biomarkers. In this review, we discuss these approaches with special focus on currently available non-invasive serum markers. We will discuss:(1) class?Ⅰ?serum biomarkers individually and as combined panels, particularly those that mirror the metabolism of liver extracellular matrix turnover and/or fibrogenic cell changes;(2) class Ⅱ biomarkers that are indirect serum markers and are based on the evaluation of common functional alterations in the liver; and(3) biomarkers of liver cell death, since hepatocyte apoptosis plays a significant role in the pathogenesis of HCV infection. We highlight in this review the evidence behind the use of these markers and assess the diagnostic accuracy as well as advantages, limitations, and application in clinical practice of each test for predicting liver damage in CHC.

Hepatocellular carcinoma in patients with chronic hepatitis C virus infection without cirrhosis

AIM:To investigate and characterise patients with chronic hepatitis C virus(HCV) infection presenting with hepatocellular carcinoma(HCC) in the absence of cirrhosis.METHODS:Patients with chronic hepatitis C infection without cirrhosis presenting with HCC over a 2-year period were identified.The clinical case notes,blood test results and histological specimens were reviewed to identify whether additional risk factors for the development of HCC were present.RESULTS:Six patients(five male,one female) with chronic hepatitis C infection without cirrhosis presented to a single centre with HCC over a 2-year period.Five patients were treated by surgical resection and one patient underwent liver transplantation.Evaluation of generous histological specimens confirmed the presence of HCC and the absence of cirrhosis in all cases.The degree of fibrosis of the background liver was staged as mild(n = 1),moderate(n = 4) or bridging fibrosis(n = 1).Review of the clinical case notes revealed that all cases had an additional risk factor for the development of HCC(four had evidence of past hepatitis B virus infection;two had a history of excessive alcohol consumption;a further patient had prolonged exposure to immune suppression).CONCLUSION:HCC does occur in patients with non-cirrhotic HCV infection who have other risk factors for hepatocarcinogenesis.

Interleukin-6-174G/C polymorphism is associated with a decreased risk of type 2 diabetes in patients with chronic hepatitis C virus

BACKGROUND Chronic hepatitis C(CHC)is associated with type 2 diabetes mellitus.Although the pathogenesis remains to be elucidated,a growing evidence has suggested a role of pro-inflammatory immune response.Increased serum concentrations of Interleukin 6(IL-6)have been associated with insulin resistance,type 2 diabetes mellitus as well as advanced forms of liver disease in chronic hepatitis C infection.AIM To investigate the frequency of IL-6-174G/C(rs1800795)single nucleotide polymorphism(SNP)in CHC patients and in healthy subjects of the same ethnicity.Associations between type 2 diabetes mellitus(dependent variable)and demographic,clinical,nutritional,virological and,IL-6 genotyping data were also investigated in CHC patients.METHODS Two hundred and forty-five patients with CHC and 179 healthy control subjects(blood donors)were prospectively included.Type 2 diabetes mellitus was diagnosed according to the criteria of the American Diabetes Association.Clinical,biochemical,histological and radiological methods were used for the diagnosis of the liver disease.IL-6 polymorphism was evaluated by Taqman SNP genotyping assay.The data were analysed by logistic regression models.RESULTS Type 2 diabetes mellitus,blood hypertension and liver cirrhosis were observed in 20.8%(51/245),40.0%(98/245)and 38.4%(94/245)of the patients,respectively.The frequency of the studied IL-6 SNP did not differ between the CHC patients and controls(P=0.81)and all alleles were in Hardy-Weinberg equilibrium(P=0.38).In the multivariate analysis,type 2 diabetes mellitus was inversely associated with GC and CC genotypes of IL-6-174(OR=0.42;95%CI=0.22-0.78;P=0.006)and positively associated with blood hypertension(OR=5.56;95%CI=2.79-11.09;P<0.001).CONCLUSION This study was the first to show that GC and CC genotypes of IL-6-174 SNP are associated with a decreased risk of type 2 diabetes mellitus in patients chronically infected with hepatitis C virus.The identification of potential inflammatory mediators involved in the crosstalk between hepatitis C virus and the axis pancreas-liver remains important issues that deserve further investigations.

Smad3 phospho-isoform signaling in hepatitis C virus-related chronic liver diseases

The risk of hepatocellular carcinoma(HCC) development increases as hepatitis virus C(HCV)-related liver diseases progress,especially in patients with active inflammation.Insight into hepatic carcinogenesis have emerged from recent detailed analyses of transforming growth factor-β and c-Jun-N-terminal kinase signaling processes directed by multiple phosphorylated(phospho)-isoforms of a Smad3 mediator.In the course of HCV-related chronic liver diseases,chronic inflammation and host genetic/epigenetic alterations additively shift the hepatocytic Smad3 phospho-isoform signaling from tumor suppression to carcinogenesis,increasing the risk of HCC.Chronic inflammation represents an early carcinogenic step that provides a nonmutagenic tumor-promoting stimulus.After undergoing successful antiviral therapy,patients with chronic hepatitis C could experience a lower risk of HCC as Smad3 phospho-isoform signaling reverses from potential carcinogenesis to tumor suppression.Even after HCV clearance,however,patients with cirrhosis could still develop HCC because of sustained,intense carcinogenic Smad3 phospho-isoform signaling that is possibly caused by genetic or epigenetic alterations.Smad3 phospho-isoforms should assist with evaluating the effectiveness of interventions aimed at reducing human HCC.

Vitamin D in addition to peg-interferon-alpha/ribavirin in chronic hepatitis C virus infection: ANRS-HC25-VITAVIC study

AIM: To investigate if correction of hypovitaminosis D before initiation of Peg-interferon-alpha/ribavirin(Peg IFN/RBV) therapy could improve the efficacy of Peg IFN/RBV in previously null-responder patients with chronic genotype 1 or 4 hepatitis C virus(HCV) infection.METHODS:Genotype 1 or 4 HCV-infected patients with null response to previous Peg IFN/RBV treatment and with hypovitaminosis D(<30 ng/m L)prospectively received cholecalciferol 100000 IU per week for 4 wk[from week-4(W-4)to W0],followed by 100000 IUper month in combination with Peg IFN/RBV for 12 mo(from W0 to W48).The primary outcome was the rate of early virological response defined by an HCV RNA<12 IU/m L after 12 wk Peg IFN/RBV treatment.RESULTS:A total of 32 patients were included,19(59%)and 13(41%)patients were HCV genotype1 and 4,respectively.The median baseline vitamin D level was 15 ng/m L(range:7-28).In modified intention-to-treat analysis,29 patients who received at least one dose of Peg IFN/RBV were included in the analysis.All patients except one normalized their vitamin D serum levels.The rate of early virologic response was 0/29(0%).The rate of HCV RNA<12IU/m L after 24 wk of Peg IFN/RBV was 1/27(4%).The safety profile was favorable.CONCLUSION:Addition of vitamin D to Peg IFN/RBV does not improve the rate of early virologic response in previously null-responders with chronic genotype 1or 4 HCV infection.

Efficacy and tolerability of low-dose interferon-α in hemodialysis patients with chronic hepatitis C virus infection

AIM:To evaluate the efficacy and tolerability of lowdose standard or pegylated interferon(PEG-IFN)in hepatitis C virus(HCV)-positive hemodialysis patients.METHODS:In total,19 patients were enrolled in this study,of which 12 received PEG-IFNα-2a 67.5μg 1time/wk(Group 1)and 7 received standard interferonα-2b subcutaneously 1.5×106 U 3 times/wk(Group2).The treatment durations were 48 wk for patients infected with HCV genotype 1 and 24 wk for patients infected with HCV genotype 2/3.All patients were prospectively followed after the completion of therapy.The efficacy and tolerability of the treatment were evaluated based on the sustained virological response(SVR)and treatment-related drop-out rate.RESULTS:In Group 1,11 of the 12 patients completed the treatment.Early virological response(EVR)and sustained virological response(SVR)rates were 83.3%and 91.7%,respectively.One patient withdrew from treatment due to an adverse event(leukopenia).The drop-out rate was 8.3%in this group.In Group 2,5 of the 7 patients completed the treatment with an EVR and SVR of 85.7%and 71.4%,respectively.Two patients withdrew due to treatment-related adverse events(nausea and depression).In this group,the drop-out rate was 28.6%.In total,16 of the patients attained EVR,and 15 of them completed the treatment.The SVR rate for the patients who attained EVR was93.7%.Anemia was the most frequent side effect and was observed in 10/19 patients(55.5%),but could be effectively managed with erythropoietin.CONCLUSION:Low-dose interferon monotherapy,either with PEG-IFNα-2a or standard interferonα-2b,is an effective treatment option for hemodialysis patients with chronic hepatitis C.

Is chronic hepatitis C virus infection a risk factor for breast cancer?

AIM:To evaluate the prevalence of breast tumors in adult females with chronic hepatitis C virus(HCV) infection.METHODS:Prospective,single-center study,based on female outpatients consulting in a liver unit,for 1 year.The study group included females with present and/or past history of chronic infection by HCV.Patients with spontaneous recovery were excluded.Chronic hepatitis had been proved by liver biopsy in the majority of cases and/or biological markers of inflammation and fibrosis.The control group included female patients with other well documented chronic liver diseases:chronic hepatitis B,alcoholic liver disease,autoimmune hepatitis,hemochromatosis,non alcoholic liver disease,chronic cholangitis.Participating patients were prospectively questioned during consultation about past breast history and follow-up by mammography.RESULTS:Breast carcinoma was recorded in 17/294 patients with HCV infection(5.8%,95% CI:3.1-8.4) vs 5/107 control patients(4.7%,95% CI:0.67-8.67).Benign tumors of the breast(mastosis,nodules,cysts) were recorded in 75/294 patients with HCV infection(25.5%,95% CI:20.5-30.5) vs 21/107(19.6%,95% CI:12.1-27.1) in the control group.No lesion was noted in 202 patients with HCV(68.7%,95% CI:63.4-74) vs 81 control patients(75.7%,95% CI:67.6-83.8).Despite a trend to an increased prevalence in the group with HCV infection,the difference was not significant compared to the control group(P=NS).In patients over 40 years,the results were,respectively,as follows:breast cancer associated with HCV:17/266 patients(6.3%,95% CI:3.4-9.3) vs 5/95 patients(5.2%,95% CI:0.7-9.7) in the control group;benign breast tumors:72/266 patients with HCV infection(27%,95% CI:21.7-32.4) vs 18/95 patients(18.9%,95% CI:11-26.8) in the control group;no breast lesion 177/266(66.5%,95% CI:60.9-72.2) in patients with HCV infection vs 72/95(75.7%,95% CI:67.1-84.4) in the control group.The differences were not significant(P=NS).CONCLUSION:These results suggest that chronic HCV infection is not a strong promoter of breast carcinoma in adult females of any age.

Anti-hepatitis C virus therapy in chronic kidney disease patients improves long-term renal and patient survivals

BACKGROUND Hepatitis C virus (HCV) infection is a documented risk factor for chronic kidney disease (CKD) and progression to end-stage renal disease (ESRD). However, to date there are no reports on the long-term hard endpoints (ESRD and death) of anti-HCV therapy [interferon-based therapy (IBT) or new direct-acting antivirals] in CKD patients. Direct-acting antivirals are not available in Taiwan’s singlepayer national health insurance database currently released for research. Therefore, we hypothesized that a retrospective analysis of the long-term outcomes of IBT in CKD patients will serve as a proxy for direct-acting antivirals to increase our understanding of progression to ESRD following HCV infection. AIM To evaluate the long-term outcomes (ESRD and death) of anti-HCV therapy, especially IBT, in HCV-infected patients with stage 1-5 CKD. METHODS We analyzed 93894 Taiwan Residents adults diagnosed with CKD and without HBV infection. Of these, 4.9% were infected with HCV. Of the 4582 HCV-infected CKD patients, 482 (10.5%) received IBT (treated cohort). They were matched 1:4 with 1928 untreated HCV-infected CKD patients (untreated cohort) by propensity scores and year, which further matched 1:2 by propensity scores with 3856 CKD patients without HCV infection (uninfected cohort). All participants were followed until the occurrence of ESRD, death, or the end of 2012. The association between HCV infection, IBT use, and risks of ESRD and death was analyzed using competing risk analysis. RESULTS Taking the uninfected cohort as a reference, the adjusted hazard ratios for ESRD, after adjusting for competing mortality, were 0.34 (0.14-0.84, P = 0.019) and 1.28 (1.03-1.60, P = 0.029) in the treated and untreated cohorts, respectively. The treated cohort had a 29%(0.54-0.92, P = 0.011) decrease in mortality compared to the untreated cohort, in which the mortality was 31%(1.18-1.45, P < 0.001) higher than in the uninfected cohort. The reduced risks of ESRD (0.14, 0.03–0.58, P = 0.007) and death (0.57, 0.41-0.79, P = 0.001) were greatest in HCV-infected CKD patients who received at least 4 mo of IBT, which accounted for 74% of the treated cohort.CONCLUSION Adequate anti-HCV therapy in CKD patients improves long-term renal and patient survival.

Efficacy and Safety of Glecaprevir/Pibrentasvir in Combination Therapy in Chronic Hemodialysis Patients with Genotype 2 Hepatitis C Virus Infection

Background: Glecaprevir (nonstructural protein 3/4A protease inhibitor) and Pibrentasvir (nonstructural protein 5A inhibitor) (G/P), a coformulated once-daily, all oral, ribavirin (RBV)-free, direct-antiviral regimen, was evaluated for safety and efficacy in chronic hemodialysis patients with genotype 2 hepatitis C virus infection. Methods: In this prospective, observational, single-center study at Masuko Memorial Hospital, between November 2017 and December 2018, a total of 8 HD patients with an HCV infection genotype 2 received G/P combination therapy. Age was an average of 67.1 (61 - 75) years and there were four men and two women. It was FIB4 INDX an average of 2.67 (1.5 - 3.34) before the start of therapy. It was quantity of HCV RNA an average of 4.43 (2.1 - 6.5). HCV RNA levels were measured by real-time RCR-based method (COBAS AmpiPrep/COBAS TaqMan HCV Test. 4 cases 12 weeks were 2 cases eight weeks for dosing period. Patients were excluded if they had evidence of hepatocellular carcinoma. This study was approved by the ethics committee of our hospital, while we obtained written consent from the participants after providing a thorough explanation of the contents and methods of this study. Results: 6 patients were available for total dose internal use. As for the HCV RNA of the fourth week, (100%) HCV RNA became negative after administration start of therapy. Rapid virologic response (RVR) achieved all cases. 5 patients achieved 12-week sustained virologic response (SVR12) and were following up the 1 patient. The itching appeared in two cases (33%), but there was symptom improvement in nalfurafine hydrochloride use treatment, and treatment continuation was possible. Conclusion: It is thought that G/P can be given to the HD patients’ safety, but we will accumulate a case in future, and it is thought to be necessary to examine utility and safety.

Impact of hepatitis C virus core mutations on the response to interferon-based treatment in chronic hepatitis C

AIM To determine whether hepatitis C virus(HCV) core substitutions play a role in the response to interferon-based treatment in Caucasian patients. METHODS One hundred eight HCV chronically infected patients initiating treatment with pegylated IFN plus ribavirin for 48 wk were tested for baseline substitutions at codons 70 and 91 of the viral core protein(Big Dye Terminator vers.3.1, Applied Biosystems,) and for genetic polymorphisms in host IL28 B gene rs12979860(Custom TaqM an 5' allelic discrimination assay; Applied Biosystems).RESULTS Of the patients, all were infected with HCV genotype 1b, 44.4% had low baseline HCV viral load, and 37.9% had mild/moderate fibrosis. Only 38.9% achieved therapeutic success, defined as sustained virological response(SVR). Eighty-eight percent of the patients presented at least one substitution at core position 70(R70Q/H) or/and position 91(L91M). The favorable IL28 B CC polymorphism was detected in only 17.6% of the patients. In the univariate analysis, young age(P < 0.001), urban residence(P = 0.004), IL28 B CC genotype(P < 0.001), absence of core mutations(P = 0.005), achievement of rapid virologic response(P < 0.001) and early virological response(P < 0.001) were significantly correlated with SVR. A multivariate analysis revealed three independent predictors of therapeutic success: young age(P < 0.001), absence of core substitutions(P = 0.04) and IL28 B CC genotype(P < 0.001); the model correctly classified 75.9% of SVR cases with a positive predictive value of 80.7%. CONCLUSION HCV core mutations can help distinguish between patients who can still benefit from the affordable IFNbased therapy from those who must be treated with DAAs to prevent the evolution towards end-stage liver disease.

Serum Level of Thyroid Hormones in Patients with Chronic Hepatitis C Virus Infection

Objective: There are clinical and laboratory associations between thyroid and liver diseases. Hepatitis C virus (HCV) is known to be responsible for both hepatic and extrahepatic diseases. The most frequent and clinically important endocrine extrahepatic diseases are thyroid disorders and type 2 diabetes mellitus. We aim to study the relationship between the serum level of thyroid hormones (THs) and the severity of liver disease in patients with chronic hepatitis C virus (CHC) infection. Methods: 60 patients with CHC infection were selected for the study. They were divided into two groups: with or without liver cirrhosis. Those with liver cirrhosis were further subdivided according to the Child-Turcotte-Pugh scoring system. Serum levels of free T3 (FT3), free T4 (FT4) and TSH were measured to all patients. Results: There was decrease in the FT3 and FT4 levels and increase in the TSH levels in patients with CHC with cirrhosis when compared to patients with CHC without cirrhosis. Conclusion: Thyroid profile abnormalities were seen in cirrhotic HCV patients when compared to non-cirrhotic patients. The abnormalities in the serum level of THs (decreased FT3, FT4, and increased TSH) are strongly associated with the severity of liver damage and advancing of the child score.

Antiviral therapies for chronic hepatitis C virus infection with cirrhosis

Patients who are infected with hepatitis C virus(HCV) and also have advanced fibrosis or cirrhosis have beenrecognized as "difficult-to-treat" patients during an era when peginterferon and ribavirin combination therapy is the standard of care. Recent guidelines have clearly stated that treatment should be prioritized in this population to prevent complications such as decompensation and hepatocellular carcinoma. Recent advances in the treatment of chronic hepatitis C have been achieved through the development of direct-acting antiviral agents(DAAs). Boceprevir and telaprevir are first-generation DAAs that inhibit the HCV NS3/4A protease. Boceprevir or telaprevir, in combination with peginterferon and ribavirin, improved the sustained virological response rates compared with peginterferon and ribavirin alone and were tolerated in patients with HCV genotype 1 infection without cirrhosis or compensated cirrhosis. However, the efficacy is lower especially in prior non-responders with or without cirrhosis. Furthermore, a high incidence of adverse events was observed in patients with advanced liver disease, including cirrhosis, in real-life settings. Current guidelines in the United States and in some European countries no longer recommend these regimens for the treatment of HCV. Next-generation DAAs include second-generation HCV NS3/4A protease inhibitors, HCV NS5 A inhibitors and HCV NS5 B inhibitors, which have a high efficacy and a lower toxicity. These drugs are used in interferon-free or in interferon-based regimens with or without ribavirin in combination with different classes of DAAs. Interferon-based regimens, such as simeprevir in combination with peginterferon and ribavirin, are well tolerated and are highly effective especially in treatmentnave patients and in patients who received treatment but who relapsed. The efficacy is less pronounced in nullresponders and in patients with cirrhosis. Interferonfree regimens in combination with ribavirin and/or two or more DAAs could be used for treatment-nave, treatment-experienced and even for interferon-ineligible or interferon-intolerant patients. Some clinical trials have demonstrated promising results, and have shown that the efficacy and safety were not different between patients with and without cirrhosis. There are also promising regimens for genotypes other than genotype 1. Interferonis contraindicated in patients with decompensated cirrhosis, and further studies are needed to establish the optimal treatment regimen for this population. In the future, interferon-free and ribavirin-free regimens with high efficacy and improved safety are expected for HCVinfected patients with advanced liver diseases.