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

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World Journal of Gastroenterology 2016年第37期22卷 8406-8413页

作者： camelia Sultana Gabriela Oprisan Monica Delia Teleman Sorin Dinu HepGen 88/2012 Project Team cristiana Oprea Mihai Voiculescu Simona Ruta Virology Discipline Carol Davila University of Medicine and Pharmacy Emergent Diseases Department Stefan S.Nicolau Institute of Virology Faculty of Pharmacy Titu Maiorescu University Molecular Epidemiology Laboratory NIRDMI Cantacuzino Department of Microbiology and Epidemiology Carol Davila University of Medicine and Pharmacy Victor Babes clinic of Infectious and Tropical Diseases Fundeni Institute

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 ce(P = 0.004), IL28 B cc genotype(P ce of core mutations(P = 0.005), achievement of rapid virologic response(P cal response(P cantly correlated with SVR. A multivariate analysis revealed three independent predictors of therapeutic success: young age(P ce of core substitutions(P = 0.04) and IL28 B cc genotype(P 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.

关键词： Chronic hepatitis C caucasian patients core substitutions IL28B polymorphism Treatment

Peginterferon alfa-2a for the treatment of Chronic hepatitis C in the era of direct-acting antivirals

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Hepatobiliary & Pancreatic Diseases International 2017年第5期16卷 470-479页

作者： Yan Huang Ming-Hui Li Min Hou Yao Xie Shanghai Roche Pharmaceuticals Ltd. Shanghai 201203 China Liver Disease center Beijing Ditan Hospital Capital Medical University Beijing 100015 China

BAcKGROUND: The availability of novel direct-acting antivirals (DAAs) represents a new era of curative hepatitis c virus (HcV) treatment, with over 95% of patients infected with HcV genotype 1 achieving sustained virological response (SVR). Nevertheless, the majority of patients globally are unable to access these treatments because of cost and infrastructure constraints and, thus, remain untreated and uncured. DATA SOURcE: Relevant articles of peginterferon (PegIFN)-based treatments in HcV and sofosbuvir-based treatments, simeprevir, daclatasvir/asunaprevir, ritonavir-boosted paritaprevir/ombitasvir/dasabuvir, and grazoprevir/elbasvir, were searched in PubMed database, including general population and special population. RESULTS: PegIFN in combination with ribavirin remains an important and relevant option for some patients, achieving SVR rates of up to 79% in genotype 1 and 89% in genotype 2 or 3 infections, which increases for patients with favorable IL28B genotypes. Triple therapy of DAA plus PegIFN/ribavirin is effective in treating difficult-to-cure patients infected with HcV genotype 3 or with resistance-associated variants. Owing to its long history in HcV management, the efficacy, tolerability and long-term outcomes associated with PegIFN alfa-2a are well established and have been validated in large-scale studies and in clinical practice for many populations. Furthermore, emerging data show that IFN-induced SVR is associated with lower incidences of hepatocellular carcinoma compared with DAAs. On the contrary, novel DAAs have yet to be studied in special populations, and long-term outcomes, particularly tumor development and recurrence in patients with cirrhosis and/or hepatocellular carcinoma, and reactivation of HBV in dually infected patients, are still unclear. cONcLUSION: In this interferon-free era, PegIFN-based regimens remain a safe and effective option for selected HcV patients.

关键词： Chronic hepatitis C direct-acting antivirals hepatitis c virus peginterferon alfa-2a ribavirin

Angiopoietin-2/angiopoietin-1 as non-invasive biomarker of cirrhosis in Chronic hepatitis C

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World Journal of Gastroenterology 2016年第44期22卷 9744-9751页

作者： ángel Hernández-Bartolomé Rosario López-Rodríguez María Jesús Borque Leticia González-Moreno Yolanda Real-Martínez Luisa García-Buey Ricardo Moreno-Otero Paloma Sanz-cameno Gastroenterology Service Instituto Investigación Sanitaria Princesa Molecular Biology Unit Instituto Investigación Sanitaria Princesa cIBERehd

AIM To evaluate the efficacy of peripheral blood concentrations of angiopoietins(Ang) as cirrhosis biomarkers of Chronic hepatitis C(cHc).METHODS Ang1 and Ang2 serum levels were measured by enzyme-linked immunosorbent assays(ELISA) in samples from 179 cirrhotic and non-cirrhotic cHc patients, classified according to the METAVIR system.Groups were compared by non-parametric MannWhitney U test. Subsequently, the association of peripheral concentrations of angiopoietins with the stage of fibrosis was analyzed using Spearman correlation test. Finally, the accuracy, sensitivity and specificity of circulating angiopoietins for cirrhosis diagnosis were determined by the study of the respective area under the curve of receiver operator characteristics(AUc-ROc).RESULTS Peripheral blood concentrations of Ang1 and Ang2 in cHc patients were significantly related to fibrosis. While Ang1 was decreased in cirrhotic subjects compared to non-cirrhotic(P cantly increased as cHc progressed to the end stage of liver disease(P consequently, Ang2/Ang1 ratio was notably amplified and significantly correlated with fibrosis(P ce of each angiopoietin for the diagnosis of cirrhosis reached notable AUc-ROc values(above 0.7, both), but the Ang2/Ang1 ratio was much better(AUc-ROc = 0.810) and displayed outstanding values of sensitivity(71%), specificity(84%) and accuracy(82.1%) at the optimal cut-off(10.33). Furthermore, Ang2/Ang1 ratio improved the performance of many other previously described biomarkers or scores of liver cirrhosis in cHc.cONcLUSION Ang2/Ang1 ratio might constitute a useful tool for monitoring the progression of chronic liver disease towards cirrhosis and play an important role as therapeutic target.

关键词： Chronic hepatitis C Area under the curve of receiver operator characteristics Liver fibrosis cirrhosis Angiopoietin-2 Angiopoietin-1 Biomarker Angiogenesis

The Role of Direct-acting Antivirals in the Treatment of children with Chronic hepatitis C

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Journal of clinical and Translational Hepatology 2017年第1期5卷 59-66页

作者： christine Hong Ting Yang Eric R.Yoo Aijaz Ahmed Division of Pediatric Gastroenterology Stanford University School of MedicineStanfordCAUSA Department of Medicine University of Illinois College of MedicineChicagoILUSA Division of Gastroenterology and Hepatology Stanford University School of MedicineStanfordCAUSA

In the United States,chronic infection with the hepatitis c virus(HcV)affects an estimated 0.1-2%of the pediatric population,who are consequently at risk for major complications,including cirrhosis,hepatocellular carcinoma,and death.The current standard of treatment for Chronic hepatitis C(cHc)in children is pegylated-interferon-alpha(PEG-IFN)in combination with ribavirin.PEG-IFN/ribavirin therapy is approved for children ages 3 and older;however,it is often held from use until adulthood because of its extensive list of potential side effects and high likelihood of causing adverse symptoms.While cHc is usually indolent in children and adolescents,immediately treating and curbing the spread of HcV before adulthood is important,as there can be transmission to other individuals via sexual activity and infected females can later vertically transmit the infection during pregnancy,the latter representing the most common means of transmission for children in the United States.The recent development of direct-acting antivirals has shown promising results in clinical trials for use in children and has dramatically increased the rates of sustained virological response in adults while improving side effect profiles as compared to interferonbased treatments.Given the usually indolent course of cHc in children,significant side effects of the currently-approved PEG-IFN/ribavirin therapy,and likely availability of all-oral interferon-free regimens for children within a few years,deferring treatment in clinically-stable children with cHc in anticipation of upcoming superior treatment modalities may be justified.

关键词： hepatitis c virus Chronic hepatitis C Pediatric children Anti-viral therapy

Decade of optimizing therapy with direct-acting antiviral drugs and the changing profile of patients with Chronic hepatitis C

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World Journal of Gastroenterology 2023年第6期29卷 949-966页

作者： MichałBrzdęk Dorota Zarębska-Michaluk Federica Invernizzi Marta cilla Krystyna Dobrowolska Robert Flisiak collegium Medicum Jan Kochanowski UniversityKielce 25-516Poland of Infectious Diseases Jan Kochanowski UniversityKielce 25-516Poland center for Liver Disease Division of Internal Medicine and HepatologyIRCCS Ospedale San RaffaeleMilan 20-132Italy Department of Infectious Diseases and Hepatology Medical University of BiałystokBiałystok 15-540Poland

chronic infection with the hepatitis c virus(HcV)remains a major health problem affecting approximately 58 million people worldwide.In the era of interferon(IFN)-based regimens,patients particularly infected with genotypes 1 and 4 achieved a low response rate.The implementation of direct-acting antivirals changed the landscape of HcV treatment.The increase in effectiveness provided us with the hope of eliminating HcV as a significant public threat by 2030.In the following years,there was an observed improvement in the treatment of HcV with genotype-specific regimens and highly effective pangenotypic options that are the most recent stage of the revolution.The optimization of therapy was accompanied by changes in the patient profile from the beginning of the IFN-free era over time.Patients treated with antiviral therapies were younger in successive periods,less burdened with comorbidities and comedications,more frequently treatment-naïve and had less advanced liver disease.Before the IFN-free era,specific subpopulations such as patients with HcV/HIV coinfection,those with a history of previous treatment,patients with renal impairment or with cirrhosis had lower chances for a virologic response.currently,these populations should no longer be considered difficult to treat.Despite the high effectiveness of HcV therapy,there is a small percentage of patients with treatment failure.However,they can be effectively retreated with pangenotypic rescue regimens.

关键词： hepatitis c virus Interferon Direct-acting antiviral Epidemiology Chronic hepatitis C

Longitudinal assessment of liver stiffness by transient elastography for Chronic hepatitis C patients

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World Journal of clinical cases 2022年第17期10卷 5566-5576页

作者： Anya Mezina Arunkumar Krishnan Tinsay A Woreta Kevin B Rubenstein Eric Watson Po-Hung chen carla Rodriguez-Watson Department of Medicine Johns Hopkins School of MedicineBaltimoreMD 21287United States Division of Gastroenterology and Hepatology Johns Hopkins School of MedicineBaltimoreMD 21231United States Mid-Atlantic Permanente Research Institute Kaiser Permanente Mid-Atlantic StatesRockville 20852United States Department of Health Policy and Management Bloomberg School of Public HealthJohns Hopkins UniversityBaltimoreMD 21287United States Innovation in Medical Evidence Development and Surveillance(IMEDS)Program Reagan-Udall Foundation for the FDAWashington20036United States

BAcKGROUND Liver fibrosis is a common pathway of liver injury and is a feature of most chronic liver diseases.Fibrosis progression varies markedly in patients with hepatitis c virus(HcV).Liver stiffness has been recommended as a parameter of fibrosis progression/regression in patients with HcV.AIM To investigate changes in liver stiffness measured by transient elastography(TE)in a large,racially diverse cohort of United States patients with Chronic hepatitis C(cHc).METHODS We evaluated the differences in liver stiffness between patients treated with direct-acting antiviral(DAA)therapy and untreated patients.Patients had≥2 TE measurements and no prior DAA exposure.We used linear regression to measure the change in liver stiffness between first and last TE in response to treatment,controlling for age,sex,race,diabetes,smoking status,human immunodeficiency virus status,baseline alanine aminotransferase,and baseline liver stiffness.Separate regression models analyzed the change in liver stiffness as measured by kPa,stratified by cirrhosis status.RESULTS Of 813 patients,419(52%)initiated DAA treatment.Baseline liver stiffness was 12 kPa in 127(16%).Median time between first and last TE was 11.7 and 12.7 mo among treated and untreated patients,respectively.There was no significant change in liver stiffness observed over time in either the group initiating DAA treatment(0.016 kPa/month;cI:-0.051,0.084)or in the untreated group(0.001 kPa/mo;cI:-0.090,0.092),controlling for covariates.A higher baseline kPa score was independently associated with decreased liver stiffness.cONcLUSION DAA treatment was not associated with a differential change in liver stiffness over time in patients with cHc compared to untreated patients.

关键词： Chronic hepatitis C Liver stiffness cirrhosis Transient elastography Direct-acting antiviral therapy

Extrahepatic manifestations of Chronic hepatitis C virus infection：297 cases from a tertiary medical center in Beijing, china

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chinese Medical Journal 2014年第7期127卷 1206-1210页

作者： cheng Zhaojing Zhou Baotong Shi Xiaochun Zhang Yao Zhang Lifan chen Limeng Liu Xiaoqing Department of Infectious Diseases Peking Union Medical College Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100730China Department of Nephrology Peking Union Medical College Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100730China

Background Chronic hepatitis C virus （HcV） infection can affect multiple organ systems and cause a variety of extrahepatic manifestations （EMs）.We sought to assess the constituent ratio of EMs in chinese patients with chronic HcV infection and identify the clinical and biological factors associated with EM.Methods The medical records of 297 patients with chronic HcV infection were analyzed and demographic and epidemiological information was collected.The diagnosis of chronic HcV infection was based on positive anti-HcV combined with a positive HcV-RNA or at least two times of elevated aminotransferases attributable to HcV infection.Patients with HBV and/or HIV coinfection,autoimmune hepatitis,and history of alcohol abuse were excluded.Results Sixty-two percent （184/297） of the patients had at least one EM,including fatigue （29.4％）,type 2 diabetes mellitus （28.2％）,renal involvement （12.5％）,lymphadenopathy （9.6％）,fever （9.4％）,thyroid dysfunction （8.1％）,and arthralgia （7.4％）.Neuropathy,sicca syndrome,B-cell lymphoma,Raynaud＇s phenomenon,and lichen planus were rare.The mean age of patients with EM was older compared with those without EM.conclusions EMs were common in chinese patients with chronic HcV infection,particularly fatigue,type 2 diabetes,renal impairment,lymphadenophy,fever,and thyroid dysfunction.Older age was associated with EMs.

关键词： Chronic hepatitis C extrahepatic manifestation thrombocytopenia cryoglobulinemia

Efficacy and factors influencing treatment with peginterferon alpha-2a and ribavirin in elderly patients with Chronic hepatitis C

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Hepatobiliary & Pancreatic Diseases International 2012年第2期11卷 185-192页

作者： Jian-Wu Yu,Li-Jie Sun,Peng Kang,Bing-Zhu Yan and Yong-Hua Zhao Department of Infectious Diseases, Second Affiliated Hospital, Harbin Medical University, Harbin 150086, china Department of Infectious Diseases，Second Affiliated Hospital，Harbin Medical University，Harbin 150086，china Yu JW，Sun LJ，Kang P，Yan BZ and Zhao YH

BAcKGROUND:In china,hepatitis c virus(HcV) infection is characterized by an increasing prevalence during aging.This study was undertaken to evaluate the efficacy of treatment with peginterferon alpha-2a and ribavirin in elderly Chronic hepatitis C(cHc) patients and study the factors related to the sustained virologic response(SVR).METHODS:The medical records of 417 patients treated with peginterferon and ribavirin were retrospectively analyzed.These patients were divided into two groups according to age:patients aged ≥65 years(n=140) and patients aged ction or discontinuation and virologic response rates of the two groups were compared.The factors influencing SVR were studied by multivariate analysis.RESULTS:Ribavirin reduction or discontinuation was more frequent in patients aged ≥65 years than patients aged cant differences in virologic response rates between the two groups for patients with genotype 2.For genotype 1,in patients aged ≥65 years,the SVR rate of females was lower than that of males(28.6%,12/42 vs 47.6%,30/63;χ 2 =8.150,P=0.004);in the high viral load group,patients aged ≥65 years had a lower SVR rate than patients aged c regression analysis,the independent factors associated with SVR in patients aged ≥65 years were sex(P=0.020),genotype(P=0.005),ribavirin reduction or discontinuation(P=0.009) and presence of rapid virologic response(RVR)(P=0.001).cONcLUSIONS:The rate of ribavirin reduction or discontinuation and relapse rate of patients aged ≥65 years with genotype 1 are high,and the SVR rate is low.Age has no impact on virologic responses rates for genotype 2.Among patients ≥65 years

关键词： Chronic hepatitis C elderly patients sustained virologic response

Metabolomics in Chronic hepatitis C:Decoding fibrosis grading and underlying pathways

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World Journal of Hepatology 2023年第11期15卷 1237-1249页

作者： Adriana camargo Ferrasi Samara Vitória Granja Lima Aline Faria Galvani Jeany Delafiori Flavia Luísa Dias-Audibert Rodrigo Ramos catharino Giovanni Faria Silva Roberta Rodrigues Praxedes Driele Bretones Santos Dayane Trevisan de Macedo Almeida Estela Oliveira Lima Department of Internal Medicine Sao Paulo State UniversityBotucatu 18618-686Brazil Innovare Biomarkers Laboratory University of CampinasCampinas 13083-877Brazil

BAcKGROUND Chronic hepatitis C(cHc)affects 71 million people globally and leads to liver issues such as fibrosis,cirrhosis,cancer,and death.A better understanding and prognosis of liver involvement are vital to reduce morbidity and mortality.The accurate identification of the fibrosis stage is crucial for making treatment decisions and predicting outcomes.Tests used to grade fibrosis include histological analysis and imaging but have limitations.Blood markers such as molecular biomarkers can offer valuable insights into fibrosis.AIM To identify potential biomarkers that might stratify these lesions and add information about the molecular mechanisms involved in the disease.METHODS Plasma samples were collected from 46 patients with hepatitis c and classified into fibrosis grades F1(n=13),F2(n=12),F3(n=6),and F4(n=15).To ensure that the identified biomarkers were exclusive to liver lesions(cHc fibrosis),healthy volunteer participants(n=50)were also included.An untargeted metabolomic technique was used to analyze the plasma metabolites using mass spectrometry and database verification.Statistical analyses were performed to identify differential biomarkers among groups.RESULTS Six differential metabolites were identified in each grade of fibrosis.This six-metabolite profile was able to establish a clustering tendency in patients with the same grade of fibrosis;thus,they showed greater efficiency in discriminating grades.cONcLUSION This study suggests that some of the observed biomarkers,once validated,have the potential to be applied as prognostic biomarkers.Furthermore,it suggests that liquid biopsy analyses of plasma metabolites are a good source of molecular biomarkers capable of stratifying patients with cHc according to fibrosis grade.

关键词： Chronic hepatitis C Fibrosis Metabolome Biomarkers Plasma Liquid biopsy