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World Journal of Gastroenterology 2018年第38期24卷 4304-4310页

作者： Ken Sato Toshio Uraoka Department of Gastroenterology and Hepatology Gunma University Graduate School of Medicine

Interferon(IFN)-based therapy for hepatitis c virus(HcV) infection has recently been replaced by IFNfree direct-acting antiviral(DAA)-based therapy, which has been established as a 1^(st) line therapy with high efficacy and tolerability due to its reasonable safety profile. Resistance-associated substitutions(RASs) have been a weakness of DAA-based therapy. For example, combination therapy with daclatasvir and asunaprevir(DcV/ASV) is less effective for HcV genotype 1-infected patients with Y93H as a nonstructural protein 5A RAS. However, the problem regarding RASs has been gradually overcome with the advent of recently developed DAAs, such as sofosbuvir-based regimens or combination therapy with glecaprevir and pibrentasvir. Despite the high efficiency of DAA-based therapy, some cases fail to achieve viral eradication. P32 deletion, an NS5A RAS, has been gradually noticed in patients with DcV/ASV failure. P32 deletion has been sporadically reported and the prevalence of this RAS has been considered to be low in patients with DcV/ASV failure. Thus, the picture of P32 deletion has not been fully evaluated. Importantly, currently-commercialized DAA-based combination therapy was not likely to be effective for patients with P32 deletion. Exploring and overcoming this RAS is essential for antiviral therapy for chronic hepatitis c.

关键词： chronic hepatitis c Direct-acting antivirals Resistant-associated substitution P32 deletion Nonstructural protein 5A

Hepatitis c virus related cirrhosis decreased as indication to liver transplantation since the introduction of direct-acting antivirals: A single-center study

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World Journal of Gastroenterology 2018年第38期24卷 4403-4411页

作者： Alberto Ferrarese Giacomo Germani Martina Gambato Francesco Paolo Russo Marco Senzolo Alberto Zanetto Sarah Shalaby Umberto cillo Giacomo Zanus Paolo Angeli Patrizia Burra Multivisceral Transplant Unit Department of Surgery Oncology and Gastroenterology Padua University Hospital Hepatobiliary Surgery and Liver Transplant Unit Department of Surgery Oncology and Gastroenterology Padua University Hospital Internal Medicine Department of Medicine Padua University Hospital

AIM To evaluate waiting list(WL) registration and liver transplantation(LT) rates in patients with hepatitis c virus(HcV)-related cirrhosis since the introduction of direct-acting antivirals(DAAs).METHODS All adult patients with cirrhosis listed for LT at Padua University Hospital between 2006-2017 were retrospectively collected using a prospectivelyupdated database; patients with HcV-related cirrhosis were divided by indication for LT [dec-HcV vs HcV/hepatocellular carcinoma(Hcc)] and into two interval times(2006-2013 and 2014-2017) according to the introduction of DAAs. For each patient, indications to LT, severity of liver dysfunction and the outcome in the WL were assessed and compared between the two different time periods. For patients receiving DAA-based regimens, the achievement of viral eradication and the outcome were also evaluated. RESULTS One thousand one hundred and ninty-four [male(M)/female(F): 925/269] patients were included. considering the whole cohort, HcV-related cirrhosis was the main etiology at the time of WL registration(490/1194 patients, 41%). HcV-related cirrhosis significantly decreased as indication to WL registration after DAA introduction(from 43.3% in 2006-2013 to 37.2% in 2014-2017, P = 0.05), especially amongst decHcV(from 24.2% in 2006-2013 to 15.9% in 2014-2017, P = 0.007). Even HcV remained the most common indication to LT over time(289/666, 43.4%), there was a trend towards a decrease after DAAs introduction(from 46.3% in 2006-2013 to 39% in 2014-2017, P = 0.06). HcV patients(M/F: 43/11, mean age: 57.7 ± 8 years) who achieved viral eradication in the WL had better transplant-free survival(log-rank test P = 0.02) and delisting rate(P = 0.002) than untreated HcV patients. cONcLUSION Introduction of DAAs significantly reduced WL registrations for HcV related cirrhosis, especially in the setting of decompensated cirrhosis.

关键词： Liver transplantation Hepatitis c cirrhosis Sustained virological response

Impact of new treatment options for hepatitis c virus infection in liver transplantation

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World Journal of Gastroenterology 2015年第38期21卷 10760-10775页

作者： Elda Righi Angela Londero Alessia carnelutti Umberto Baccarani Matteo Bassetti Infectious Diseases Division Santa Maria della Misericordia University Hospital Liver Transplant Unit Santa Maria della Misericordia University Hospital

Liver transplant candidates and recipients with hepatitis c virus(HcV)-related liver disease greatly benefit from an effective antiviral therapy. The achievement of a sustained virological response before transplantation can prevent the recurrence of post-transplant HcV disease that occurs universally and correlates with enhanced progression to graft cirrhosis. Previous standard-of-care regimens(e.g.,pegylated-interferon plus ribavirin with or without first generation protease inhibitors,boceprevir and telaprevir) displayed suboptimal results and poor tolerance in liver transplant recipients. A new class of potent direct-acting antiviral agents(DAA) characterized by all-oral regimens with minimal side effects has been approved and included in the recent guidelines for the treatment of liver transplant recipients with recurrent HcV disease. Association of sofosbuvir with ribavirin and/or ledipasvir is recommended in liver transplant recipients and patients with decompensated cirrhosis. Other regimens include simeprevir,daclatasvir,and combination of other DAA. Possible interactions should be monitored,especially in coinfected human immunodeficiency virus/HcV patients receiving antiretrovirals.

关键词： Hepatitis c virus Direct antiviral agents Liver tr

changes of shear-wave velocity by interferon-based therapy in chronic hepatitis c

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World Journal of Gastroenterology 2015年第35期21卷 10215-10223页

作者： Keisuke Osakabe Naohiro Ichino Toru Nishikawa Hiroko Sugiyama Miho Kato Ai Shibata Wakana Asada Naoto Kawabe Senju Hashimoto Michihito Murao Takuji Nakano Hiroaki Shimazaki Toshiki Kan Kazunori Nakaoka Yuka Takagawa Masashi Ohki Takamitsu Kurashita Tomoki Takamura Kentaro Yoshioka Faculty of Medical Technology School of Health SciencesFujita Health University center of Ultrasound Diagnosis Fujita Health University Hospital Department of Liver Biliary Tract and Pancreas DiseasesFujita Health University

AIM: To evaluate the changes of shear-wave velocity(Vs) by acoustic radiation force impulse after treatment in chronic hepatitis ***: Eighty-seven patients with chronic hepatitis c were consecutively treated with combinations of interferon(IFN) plus ribavirin(RBV). Vs value(m/s) was measured with acoustic radiation force impulse before treatment, at end of treatment(EOT), 1 year after EOT, and 2 years after ***: In patients with a sustained virological response(SVR)(n = 41), Vs significantly decreased at EOT [1.19(1.07-1.37), P = 0.0004], 1 year after EOT [1.10(1.00-1.22), P = 0.0001], and 2 years after EOT [1.05(0.95-1.16), P compared with baseline [1.27(1.11-1.49)]. In patients with a relapse(n = 26), Vs did not significantly decrease at EOT [1.23(1.12-1.55)], 1 year after EOT [1.20(1.12-1.80)], and 2 years after EOT [1.41(1.08-2.01)] compared with baseline [1.39(1.15-1.57)]. In patients with a nonvirological response(n = 20), Vs did not significantly decrease at EOT [1.64(1.43-2.06)], 1 year after EOT [1.66(1.30-1.95)], and 2 years after EOT [1.61(1.36-2.37)] compared with baseline [1.80(1.54-2.01)]. Among genotype 1 patients, baseline Vs was significantly lower in SVR patients [1.28(1.04-1.40)] than in non-SVR patients [1.56(1.20-1.83)](P = 0.0142).cONcLUSION: Reduction of Vs values was shown in SVR patients after IFN-plus-RBV therapy by acoustic radiation force impulse.

关键词： Hepatitis c virus Fibrosis Interferon and ribaviri

clinical impact of hepatitis B and c virus envelope glycoproteins

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World Journal of Gastroenterology 2013年第5期19卷 654-664页

作者： Hélène Jeulin Aurélie Velay John Murray Evelyne Schvoerer Virology Laboratory Centre Hospitalier Universitaire de NancyVandoeuvre-lès-NancyF-54511France EA RHEM 4369 Universitéde LorraineF-54000 NancyFrance School of Mathematics and Statistics University of New South WalesSydneyNSW 2052Australia The Kirby Institute University of New South WalesSydneyNSW 2052Australia

chronic infection by either hepatitis B virus(HBV)or hepatitis c virus(HcV)share epidemiological characteristics with risks for development of severe complications such as liver cirrhosis and hepatocellular *** and HcV also share a high genetic variability. Among highly variable regions,viral genes encoding surface proteins(hepatitis B surface antigen,E1/E2 HcV glycoproteins)play key roles in the stimulation of the host-related immune response and viral entry into *** segments of HBV envelope proteins(preS1,"a"determinant)are crucial in the entry process into permissive *** entry is a complex multistep process involving multiple cell cofactors (glycosaminoglycans,low density lipoprotein receptor, SR-B1,cD81,claudin-1,occludin,EGFR,EphA2)in the interaction with HcV E1/E2 envelope *** vitro both viruses can be controlled by antibody-me-diated neutralization targeting viral envelope,also essential in preventing HBV infection in vivo as observed through successful vaccination using HBs *** preventive vaccination and/or therapeutic pressure can influence HBV and HcV *** HBV,the patterns of antiviral drug resistance in chronic hepatitis are complex and the original pol/S gene overlap has to be taken into ***-induced HBV mutations in pol could indeed generate S mutants with subsequent modified antigenicity or increased cancer *** of HBV and HcV envelope proteins combining high exposure to selective pressures and crucial functional roles require investigation in the context of diagnostic,vaccination and treatment *** this editorial a synthesis is performed of HBV and HcV envelope properties at the entry step and as antigenic proteins,and the subsequent clinical impact.

关键词： Hepatitis B Hepatitis c Viral envelope glycoproteins clinical outcome

Effects of dual sofosbuvir/daclatasvir therapy on, chronic hepatitis c infected, survivors of childhood malignancy

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World Journal of clinical cases 2019年第16期7卷 2247-2255页

作者： Mortada HF El-Shabrawi Laila M Sherief Mostafa Yakoot Naglaa M Kamal Mohamed A Almalky Manal M AbdElgawad Aml A Mahfouz Sherine Helmy Enas M Kamal Dina Attia Hisham R El-Khayat Paediatric Hepatology Department Cairo Faculty of MedicineCairo 11559Egypt Paediatric Hematology-Oncology Department Zagazig Faculty of MedicineZagazig 21121Egypt Internal medicine Pediatrics and HepatologyGreen Clinic and Research CenterAlexandria UniversityAlexandria 21121Egypt Paediatric Hepatology Department Alexandria Faculty of medicineAlexandria 21121Egypt Innovations & Research Pharco CorporationAlexandria 21121Egypt Endemic medicine and Hepatology Department Minia UniversityMinia 22233Egypt Endemic medicine and Hepatology Department Beni-suef UniversityBeni-suef 62511Egypt Gastroenterology and Endemic Medicine Department Theodore Research InstituteCairo 23323Egypt

BAcKGROUND childhood cancer survivors are potentially at a higher risk of infection with hepatitis c virus (HcV).The effects of all-oral direct-acting antiviral therapy (DAA) on both the HcV infection as well as the state of cancer remission have not been well investigated in this *** To test the effects of dual sofosbuvir/daclatasvir (SOF/DcV) therapy in the treatment of chronic HcV in survivors of hematologic malignancy in pediatric age *** We conducted a prospective,uncontrolled,open-label multicenter study.A total of 20 eligible,chronic HcV,genotype-4,infected children who had been in continuous complete remission from hematologic cancer (leukemia/lymphoma) for at least one year were included in the *** patients were treated with combined SOF/DcV for 12 *** were monitored throughout the study till 12 wk after end of treatment for safety and efficacy outcomes including the sustained virologic response 12 (SVR12) rate,hematological indices,liver and kidney *** The intent-to-treat SVR12 rate was 20 of 20 (100%;95%cI: 84%-100%).All patients showed normalized liver enzymes from *** hematological indices,liver and kidney functions were kept normal throughout the *** fatalities or treatment-emergent serious or severe adverse events were reported throughout the *** SOF/DcV combined therapy could be used safely and effectively in the treatment of chronic HcV genotype-4 infection in leukemia/lymphoma treated *** relapses were detected during treatment and throughout the follow up period for either the original malignant disease or the HcV infection.

关键词： chronic hepatitis c Survivors of childhood cancer Sofosbuvir Daclatasvir Efficacy

Burden of pediatric hepatitis c

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World Journal of Gastroenterology 2013年第44期19卷 7880-7888页

作者： Mortada Hassan El-Shabrawi Naglaa Mohamed Kamal Alanani Pediatrics and Pediatric Hepatology Faculty of MedicineCairo University Giza 12411 Egypt

Hepatitis c virus(HcV)is a major health burden infecting 170-210 million people *** 3-4millions are newly-infected *** of pediatric infection varies from 0.05%-0.36%in the United States and Europe;up to 1.8%-5.8%in some developing *** highest prevalence occurs in Egypt,sub-Saharan Africa,Amazon basin and *** has been present in some populations for several centuries,notably genotypes 1 and 2 in West *** anti-schistosomal therapy practiced in the 1960s until the early 1980s had spread HcV infection throughout *** acquisition of HcV remains a major route for infection among Egyptian *** screening of transfusions,unsterilized injection equipment and re-used needles and syringes continue to be major routes of HcV transmission in developing countries,whereas vertical transmission and adolescent high-risk behaviors(e.g.,injection drug abuse)are the major routes in developed *** risk of vertical transmission from an infected mother to her unborn/newborn infant is approximately 5%.Early stages of HcV infection in children do not lead to marked impairment in the quality of life nor to cognitive,behavioral or emotional dysfunction;however,caregiver stress and family system strain may *** slowly progresses to serious complications as cirrhosis(1%-2%)and hepatocellular carcinoma(Hcc)especially in the presence of risk factors as hemolytic anemias,obesity,treated malignancy,and concomitant human immune deficiency and/or hepatitis B virus *** vaccine remains elusive to *** the immune mechanisms in patients who successfully cleared the infection is essential for vaccine *** pediatric standard of care treatment consists of pegylated interferon-α2a or b plus ribavirin for 24-48 *** new oral direct acting antivirals,approved for adults,need further evaluation in *** virologic response varies depending on the viral lo

关键词： Hepatitis c virus Burden Genotypes cost Pediatrics

Modulation of host lipid metabolism by hepatitis c virus: role of new therapies

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World Journal of Gastroenterology 2015年第38期21卷 10776-10782页

作者： José A Del campo Manuel Romero-Gómez Digestive Diseases and cIBERehd Valme University Hospital

It is well established that hepatitis c virus(HcV) infection and replication relies on host lipid metabolism. HcV proteins interact and associate with lipid droplets to facilitate virion assembly and production. Besides,circulating infective particles are associated with verylow-density lipoprotein. On the other hand,higher serum lipid levels have been associated with sustained viral response to pegylated interferon and ribavirin therapy in chronic HcV infection,suggesting a relevant role in viral clearance for host proteins. Host and viral genetic factors play an essential role in chronic infection. Lipid metabolism is hijacked by viral infection and could determine the success of viral replication. Recently development of direct acting antiviral agents has shown a very high efficacy(> 90%) in sustained viral response rates even for cirrhotic patients and most of the viral genotypes. HcV RNA clearance induced by Sofosbuvir has been associated with an increased concentration and size of the low-density lipoprotein particles. In this review,host genetic factors,viral factors and the interaction between them will be depicted to clarify the major issues involved in viral infection and lipid metabolism.

关键词： Hepatitis c virus Lipid metabolism Direct acting a

MicroRNAs as possible biomarkers for diagnosis and prognosis of hepatitis b- and c-related-hepatocellularcarcinoma

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World Journal of Gastroenterology 2016年第15期22卷 3907-3936页

作者： Sirio Fiorino Maria Letizia Bacchi-Reggiani Michela Visani Giorgia Acquaviva Adele Fornelli Michele Masetti Andrea Tura Fabio Grizzi Matteo Zanello Laura Mastrangelo Raffaele Lombardi Luca Di Tommaso Arrigo Bondi Sergio Sabbatani Andrea Domanico carlo Fabbri Paolo Leandri Annalisa Pession Elio Jovine Dario de Biase Unita Operativa di Medicina c Ospedale Maggiore 40133 Bologna Italy Dipartimento di Medicina Sperimentale Istituto di Cardiologia Policlinico S. Orsola-Malpighi Universita degli Studi di Bologna 40138 BolognaItaly Dipartimento di Farmacia e Biotecnologie Universita di Bologna 40139 Bologna Italy Dipartimento di Medicina Sperimentale Universita di Bologna Ospedale Bellaria 40139 Bologna Italy Servizio di Anatomia Patologica Ospedale Maggiore 40133 Bologna Italy Unita Operativa di chirurgia A Ospedale Maggiore 40133 Bologna Italy cNR Institute of Neuroscience Padova Italy 35121 Padova Italy Humanitas clinical and Research center 20089 Rozzano Milano Italy Istituto di Malattie Infettive Policlinico S. Orsola-Malpighi Universita degli Studi di Bologna 40138 Bologna Italy Unita Operativa di Medicina Interna A Ospedale Maggiore 40133 Bologna Italy Unita Operativa di Endoscopia Digestiva Ospedale Maggiore 40133 Bologna Italy

Aim of the present review is to summarize the current knowledge about the potential relationship between mi RNAs and hepatitis B virus(HBV)-hepatitis c virus(HcV) related liver diseases. A systematic computerbased search of published articles, according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis Statement, was performed to identify relevant studies on usefulness of serum/plasma/urine mi RNAs, as noninvasive biomarkers for early detection of HBV and HcV-induced hepatocellular carcinoma(Hcc) development, as well as for its prognostic evaluation. The used Medical Subject Headings terms and keywords were: "HBV", "HcV", "hepatocellular carcinoma", "micro RNAs", "mi RNAs", "diagnosis", "prognosis", "therapy", "treatment". Some serum/plasma mi RNAs, including mi R-21, mi R-122, mi-125a/b, mi R-199a/b, mi R-221, mi R-222, mi R-223, mi R-224 might serve as biomarkers for early diagnosis/prognosis of Hcc, but, to date, not definitive results or well-defined panels of mi RNAs have been obtained. More well-designed studies, focusing on populations of different geographical areas and involving larger series of patients, should be carried out to improve our knowledge on the potential role of mi RNAs for Hcc early detection and prognosis.

关键词： Hepatitis B virus Hepatitis c virus Hepatocellular carcinomas Liver diseases MicroRNAs Review

Retreatment with peginterferon and ribavirin in chronic hepatitis c

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World Journal of Gastroenterology 2015年第6期21卷 1994-1999页

作者： Yong Min Jo Sung Wook Lee Sang Young Han Yang Hyun Baek Soo Young Kim Woo Jae Kim Ji Hye Ahn Ji Young Lee Department of Internal Medicine Dong-A University School of Medicine

The development of boceprevir and telaprevir was a major step forward in the treatment of chronic hepatitis *** addition,the treatment of these infections has been recently revolutionized by the approval of sofosbuvir and ***,there are several challenges associated with the application of noveldrugs,such as new and more frequent adverse events,new drug interactions,and excessively high treatment *** additional concern is viral *** considerations highlight the fact that direct-acting antiviral agents are not a panacea and may not be the best option for all patients who are in need of *** retrospective study revealed that the sustained virologic response was not significantly reduced following peginterferon and ribavirin retreatment compared with the new *** suggest that patients who experience relapse shortly after completing treatment with peginterferon and ribavirin have a reasonable chance of achieving a sustained virologic response when retreated with these drugs alone.

关键词： chronic hepatitis c Direct-acting antiviral agents