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Amjed S, Saleem HGM, Ullah S, Latif S, Shabana, Jafar J, Waqar AB. Impact of ITPA gene polymorphism for predicting anemia and treatment outcome in HCV infected patients taking Sofosbuvir Ribavirin therapy. BMC Infect Dis 2024; 24:301. [PMID: 38468199 PMCID: PMC10926675 DOI: 10.1186/s12879-024-09188-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 03/03/2024] [Indexed: 03/13/2024] Open
Abstract
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.
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Affiliation(s)
- Sameen Amjed
- University Institute of Medical Laboratory Technology, Faculty of Allied Health Sciences, The University of Lahore, Raiwind Road Campus, Lahore, Pakistan.
- Medical Laboratory Technology Department, Faculty of Rehabilitation and Allied Health Sciences, RIPHAH International University, Gulberg Campus, Lahore, Pakistan.
| | - Hafiz Ghulam Murtaza Saleem
- University Institute of Medical Laboratory Technology, Faculty of Allied Health Sciences, The University of Lahore, Raiwind Road Campus, Lahore, Pakistan
- Medical Laboratory Technology Department, Faculty of Rehabilitation and Allied Health Sciences, RIPHAH International University, Gulberg Campus, Lahore, Pakistan
| | - Sajjad Ullah
- University Institute of Medical Laboratory Technology, Faculty of Allied Health Sciences, The University of Lahore, Raiwind Road Campus, Lahore, Pakistan
| | - Shahzad Latif
- Gastroenterology Department, Akthar Saeed Medical and Dental College, Lahore, Pakistan
| | - Shabana
- Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan
| | - Junaid Jafar
- Specilized Health Care and Medical Education Department, Lahore, Punjab, Pakistan
| | - Ahmad Bilal Waqar
- University Institute of Medical Laboratory Technology, Faculty of Allied Health Sciences, The University of Lahore, Raiwind Road Campus, Lahore, Pakistan
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Tao XM, Zeng MH, Zhao YF, Han JX, Mi YQ, Xu L. Direct-acting antivirals failed to reduce the incidence of hepatocellular carcinoma occurrence in hepatitis C virus associated cirrhosis: A real-world study. World J Hepatol 2024; 16:41-53. [PMID: 38313240 PMCID: PMC10835484 DOI: 10.4254/wjh.v16.i1.41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/18/2023] [Accepted: 01/09/2024] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Direct-acting antivirals (DAAs) revolutionized the treatment of chronic hepatitis C virus (HCV)-associated disease achieving high rates of sustained virological response (SVR). However, whether DAAs can reduce the occurrence of hepatocellular carcinoma (HCC) in patients with HCV-associated cirrhosis who are at high risk have not been concluded. AIM To investigate the effect of DAAs on the occurrence of HCC in patients with HCV-associated cirrhosis after achieving SVR. METHODS Of 427 inpatients with HCV-associated cirrhosis were enrolled in Tianjin Second People's Hospital from January 2014 to April 2020. 118 patients weren't received antiviral treatment with any reasons named non-antiviral treatment group, and 236 patients obtained from the 309 DAAs treatment patients according to the propensity score matching named DAAs treatment group. Demographic information and laboratory data were collected from baseline and the following up. Kaplan-Meier curve and Log-Rank test were used to compare the incidence and cumulative incidence of HCC between the two groups. Cox proportional risk regression was used to re-evaluate the risk factors for HCC. RESULTS HCC incidence was 4.68/100PY (95%CI, 3.09-6.81) in the DAAs treatment group, while it was 3.00/100PY (95%CI, 1.50-5.37) in the non-antiviral treatment group, and the relative risk was 1.82 (95%CI, 0.93-3.53, P > 0.05). The incidence of HCC at 12, 24, 36 and 48 months was 3.39%, 6.36%, 8.47% and 10.17% in the DAAs treatment group, and it was 0%, 0%, 3.39% and 9.32% in the non-antiviral treatment group, respectively. Age > 58 [hazard ratio (HR) = 1.089; 95%CI, 1.033-1.147; P = 0.002] and liver stiffness measurement > 27.85 kPa (HR = 1.043; 95%CI, 1.022-1.065; P = 0.000) were risk factors for HCC in all patients (n = 427), and DAAs treatment didn't show protective efficacy. CONCLUSION DAAs treatment seems failed to reduce the incidence of HCC occurrence in HCV-associated cirrhosis in 48 months, and even increased the incidence of HCC in 36 months.
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Affiliation(s)
- Xue-Mei Tao
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China
| | - Ming-Hui Zeng
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China
| | - You-Fei Zhao
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China
| | - Jia-Xin Han
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China
| | - Yu-Qiang Mi
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China
| | - Liang Xu
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China
- Department of Hepatology, Tianjin Research Institute of Liver Diseases, Tianjin 300192, China.
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Yoon JH, Kim SE, Cho SH, Kim GA, Park Y, Park JW, Kang SH, Lee YS, Kim JH. Prognosis of Patients with Chronic Hepatitis C Genotype 1b Infection Treated Using Daclatasvir/Asunaprevir after Sustained Virologic Response: A 6-Year Multicenter Prospective Observational Study. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1436. [PMID: 37629725 PMCID: PMC10456703 DOI: 10.3390/medicina59081436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 08/01/2023] [Accepted: 08/06/2023] [Indexed: 08/27/2023]
Abstract
Aim and Objectives: Direct-acting antiviral (DAA) therapy can cure chronic hepatitis C (CHC), and daclatasvir (DCV)/asunaprevir (ASV) was the first interferon-free DAA therapy introduced in Korea. Patients who achieve sustained virologic response (SVR) after DAA treatment are expected to have good prognoses. Therefore, in this study, we aimed to investigate the prognosis of these patients. Materials and Methods: This multicenter prospective observational study included patients with CHC who achieved SVR after DCV/ASV treatment. The primary endpoint was hepatocellular carcinoma (HCC) occurrence, which was reviewed annually. Results: We included 302 patients (median follow-up duration: 38 [16.5-60.0] months; median age: 58 [49-67] years) in the study. Cirrhosis was observed in 103 patients (34.1%), and the median Child-Pugh score was 5.0. HCC occurred in 16 patients (5.3%) within six years post-SVR; these patients were older and had higher cirrhosis prevalence, alpha-fetoprotein levels, and fibrosis-4 index scores than did those without HCC development. Cox proportional hazards analysis revealed that age > 71 years (p = 0.005) and cirrhosis (p = 0.035) were significant risk factors for HCC occurrence. Conclusions: Although the prognoses of patients who achieved SVR with DCV/ASV therapy were generally good, the risk for HCC was present, especially in older patients and in those with cirrhosis. Hence, early treatment at younger ages and regular follow-up surveillance after achieving SVR are warranted.
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Affiliation(s)
- Jae-Hyun Yoon
- Department of Internal Medicine, School of Medicine, Chonnam National University Hospital, Gwangju 61469, Republic of Korea; (J.-H.Y.); (S.-H.C.)
| | - Sung-Eun Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Anyang 14068, Republic of Korea; (S.-E.K.); (J.-W.P.)
| | - Su-Hyeon Cho
- Department of Internal Medicine, School of Medicine, Chonnam National University Hospital, Gwangju 61469, Republic of Korea; (J.-H.Y.); (S.-H.C.)
| | - Gi-Ae Kim
- Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (G.-A.K.); (Y.P.)
| | - Yewan Park
- Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (G.-A.K.); (Y.P.)
| | - Ji-Won Park
- Department of Internal Medicine, College of Medicine, Hallym University, Anyang 14068, Republic of Korea; (S.-E.K.); (J.-W.P.)
| | - Seong-Hee Kang
- Department of Internal Medicine, Inje University Sanggye Paik Hospital, Seoul 01757, Republic of Korea;
| | - Young-Sun Lee
- Department of Internal Medicine, Korea University Medical Center, Seoul 08308, Republic of Korea;
| | - Jeong-Han Kim
- Department of Internal Medicine, School of Medicine, Konkuk University, Seoul 05030, Republic of Korea
- Research Institute of Medical Science, School of Medicine, Konkuk University, Seoul 05030, Republic of Korea
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Shrivastava-Ranjan P, Jain S, Chatterjee P, Montgomery JM, Flint M, Albariño C, Spiropoulou CF. Development of a novel minigenome and recombinant VSV expressing Seoul hantavirus glycoprotein-based assays to identify anti-hantavirus therapeutics. Antiviral Res 2023; 214:105619. [PMID: 37142192 DOI: 10.1016/j.antiviral.2023.105619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 04/24/2023] [Accepted: 04/27/2023] [Indexed: 05/06/2023]
Abstract
Seoul virus (SEOV) is an emerging global health threat that can cause hemorrhagic fever with renal syndrome (HFRS), which results in case fatality rates of ∼2%. There are no approved treatments for SEOV infections. We developed a cell-based assay system to identify potential antiviral compounds for SEOV and generated additional assays to characterize the mode of action of any promising antivirals. To test if candidate antivirals targeted SEOV glycoprotein-mediated entry, we developed a recombinant reporter vesicular stomatitis virus expressing SEOV glycoproteins. To facilitate the identification of candidate antiviral compounds targeting viral transcription/replication, we successfully generated the first reported minigenome system for SEOV. This SEOV minigenome (SEOV-MG) screening assay will also serve as a prototype assay for discovery of small molecules inhibiting replication of other hantaviruses, including Andes and Sin Nombre viruses. Ours is a proof-of-concept study in which we tested several compounds previously reported to have activity against other negative-strand RNA viruses using our newly developed hantavirus antiviral screening systems. These systems can be used under lower biocontainment conditions than those needed for infectious viruses, and identified several compounds with robust anti-SEOV activity. Our findings have important implications for the development of anti-hantavirus therapeutics.
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Affiliation(s)
- Punya Shrivastava-Ranjan
- Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA, USA.
| | - Shilpi Jain
- Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Payel Chatterjee
- Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Joel M Montgomery
- Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Mike Flint
- Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - César Albariño
- Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Christina F Spiropoulou
- Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA, USA.
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Kamal AM, Dumitrescu F, Mită A, Săbiescu DM, Alexandru DO, Gheorghe CE, Filip MM, Ionescu-Ciocâlteu A, Maria DT, Kamal D, Kamal CK. Liver Function Tests and FIB-4 Score as Predictors of Severity in COVID-19 Patients from the South-West of Romania. LIFE (BASEL, SWITZERLAND) 2022; 12:life12070934. [PMID: 35888026 PMCID: PMC9318778 DOI: 10.3390/life12070934] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/19/2022] [Accepted: 06/20/2022] [Indexed: 01/08/2023]
Abstract
Background: The coronavirus disease 2019 pandemic (COVID-19) is the most important global health crisis to date. In this study, we performed an analysis to find the association between liver damage, FIB-4 score and the severity of COVID-19 disease. Methods: We included a total of 580 patients that tested positive for SARS-CoV-2 infection and were hospitalized. No patient included had any known history of liver disease. Liver function tests were performed, and FIB-4 score was calculated in order to assess their involvement in the disease progression. Results: More than half of the patients had elevated liver function tests. Age, high body mass index, associated heart disease and diabetes were associated with poor outcome. Corticosteroids, antibiotics, and anticoagulants strongly correlated with liver injuries. Liver impairment and injury, as well as a FIB-4 score higher than 3.5, also correlated with higher degrees of disease severity. Conclusion: Liver injury and elevated FIB-4 score were associated with poor clinical outcome and disease severity, as well as being a valuable tool to predict COVID-19-related mortality.
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Affiliation(s)
- Adina M. Kamal
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
- Correspondence: ; Tel.: +40-742-030-978
| | - Florentina Dumitrescu
- Department of Infectious Disease, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (F.D.); (D.M.S.)
| | - Adrian Mită
- Department of Clinical Semiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Denisa M. Săbiescu
- Department of Infectious Disease, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (F.D.); (D.M.S.)
| | - Dragoș O. Alexandru
- Department of Informatics and Biostatistics, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Codruța E. Gheorghe
- Department of Family Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (C.E.G.); (C.K.K.)
| | - Monalisa M. Filip
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (M.M.F.); (A.I.-C.)
| | - Adriana Ionescu-Ciocâlteu
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (M.M.F.); (A.I.-C.)
| | - Daniela T. Maria
- Department of Nephrology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Diana Kamal
- Department of Physical and Rehabilitation Medicine, Filantropia Municipal Hospital Craiova, 200516 Craiova, Romania;
| | - Constantin K. Kamal
- Department of Family Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (C.E.G.); (C.K.K.)
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Fujii H, Kimura H, Hasebe C, Akahane T, Satou T, Kusakabe A, Kojima Y, Kondo M, Marusawa H, Kobashi H, Tsuji K, Ogawa C, Uchida Y, Joko K, Mitsuda A, Kurosaki M, Izumi N. Real‐world long‐term analysis of daclatasvir plus asunaprevir in patients with hepatitis C virus infection. JGH Open 2022; 6:344-352. [PMID: 35601120 PMCID: PMC9120887 DOI: 10.1002/jgh3.12749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/30/2022] [Accepted: 04/23/2022] [Indexed: 11/10/2022]
Abstract
Background and Aim Methods Results Conclusions
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Affiliation(s)
- Hideki Fujii
- Department of Gastroenterology Japanese Red Cross Kyoto Daiichi Hospital Kyoto Japan
| | - Hiroyuki Kimura
- Department of Gastroenterology Japanese Red Cross Kyoto Daiichi Hospital Kyoto Japan
| | - Chitomi Hasebe
- Department of Gastroenterology Asahikawa Red Cross Hospital Asahikawa Japan
| | - Takehiro Akahane
- Department of Gastroenterology Japanese Red Cross Ishinomaki Hospital Ishinomaki Japan
| | - Takashi Satou
- Department of Gastroenterology Nasu Red Cross Hospital Otawara Japan
| | - Atsunori Kusakabe
- Department of Gastroenterology Nagoya Daini Red Cross Hospital Nagoya Japan
| | - Yuji Kojima
- Department of Gastroenterology and Hepatology Ise Red Cross Hospital Ise Japan
| | - Masahiko Kondo
- Department of Gastroenterology Otsu Red Cross Hospital Siga Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology Osaka Red Cross Hospital Osaka Japan
| | - Haruhiko Kobashi
- Department of Hepatology Japanese Red Cross Okayama Hospital Okayama Japan
| | - Keiji Tsuji
- Department of Gastroenterology Hiroshima Red Cross Hospital and Atomic‐Bomb Survivors Hospital Hiroshima Japan
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology Takamatsu Red Cross Hospital Takamatsu Japan
| | - Yasushi Uchida
- Department of Gastroenterology Matsue Red Cross Hospital Matsue Japan
| | - Kouji Joko
- Center for Liver and Biliary Diseases Matsuyama Red Cross Hospital Ehime Japan
| | - Akeri Mitsuda
- Department of Gastroenterology Japanese Red Cross Tottori Hospital Tottori Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology Musashino Red Cross Hospital Musashino Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology Musashino Red Cross Hospital Musashino Japan
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Owusu Sekyere S, Port K, Deterding K, Cornberg M, Wedemeyer H. Inflammatory patterns in plasma associate with hepatocellular carcinoma development in cured hepatitis C cirrhotic patients. United European Gastroenterol J 2021; 9:486-496. [PMID: 33349201 PMCID: PMC8259286 DOI: 10.1177/2050640620976991] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 10/31/2020] [Indexed: 01/10/2023] Open
Abstract
Introduction The risk of hepatocellular carcinoma persists in some patients despite achieving sustained virologic response with current interferon‐free direct‐acting antiviral therapy for hepatitis C. The subject of an even higher carcinoma risk in this context has been reported and is currently being debated. The quest for understanding this paradox relative to the dynamics of inflammatory biomarkers in cirrhosis patients receiving antiviral therapy thus remains a subject of importance. Objective Here, we aimed at evaluating the effects of direct‐acting antiviral therapy‐induced hepatitis C cure on plasmatic markers of systemic inflammation measured before, during and after treatment. Specifically, soluble immune mediator phenotype associations that impact the odds of hepatocellular carcinoma development and the related changes that arise upon direct‐acting antiviral‐mediated hepatitis C clearance in cirrhosis patients was investigated. Methods Employing multiplex technology that measured up to 91 circulating biomarker proteins, we profiled the plasma soluble immune mediator concentrations of cirrhosis patients who developed posttreatment hepatocellular carcinoma and their respective negative controls, before and after direct‐acting antiviral treatment. Results Elevated pretherapy concentrations of specific soluble immune mediators including MCP‐3, GDNF, CDCP1, IL‐17C, IL‐17A, signalling lymphocytic activation family 1, CCL11, FGF‐5, LIF‐R, interleukin 10 (IL‐10), IL‐10RA, IL‐15RA, beta NGF, CCL28, CCL25 and NT‐3 distinguished patients who developed posttreatment hepatocellular carcinoma relative to those that did not. Particularly, GDNF, FGF‐5 and IL‐15RA displayed independent predictive biomarker attributes for delineating carcinoma emergence regardless of de novo or recurrence groupings. Upon successful therapy, the elevated pretherapy soluble immune mediator establishment of the patients who eventually developed hepatocellular carcinoma stayed largely unperturbed whereas a panel of some 38 soluble immune mediators in the posttherapy carcinoma‐free patients experienced significant ameliorations. Conclusions These results have considerable implications for delineating potential hepatocellular carcinoma emergence before initiating direct‐acting antiviral therapy for hepatitis C in cirrhosis patients. They provide preliminary contribution to unravelling cases where the benefit of direct‐acting antiviral therapies would be superior to the risk of developing carcinoma.
Established knowledge on this subject
Current interferon (IFN)‐free direct‐acting antivirals (DAAs) are effective at eliminating hepatitis C virus (HCV), but risks of residual liver disease and development of hepatocellular carcinoma persists. The hepatic inflammation that occurs during chronic hepatitis C causes systemic changes in blood soluble immune mediators (SIMs) that impact carcinogenetic processes involved in the growth, invasion and metastasis of hepatocellular carcinoma (HCC). DAA‐induced HCV cure does not lead to a complete immunological restitution of the altered soluble inflammatory compartment in chronic hepatitis C.
Significant and/or new findings of this study
An elevated pre‐therapy plasma profile of an extended repertoire of SIMs in cirrhosis was associated with HCC development post‐DAA therapy. Successful DAA therapy did not alter the baseline elevated plasma SIM profile of cirrhosis patients that developed post‐therapy HCC contrary to its effect in those that remained HCC‐free.
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Affiliation(s)
- Solomon Owusu Sekyere
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen, Germany
| | - Kerstin Port
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Katja Deterding
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner-site Hannover-Braunschweig, Braunschweig, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany.,German Center for Infection Research (DZIF), Partner-site Hannover-Braunschweig, Braunschweig, Germany.,Integrated Research and Treatment Centre Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
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McDonald SA, Pollock KG, Barclay ST, Goldberg DJ, Bathgate A, Bramley P, Dillon JF, Fraser A, Innes HA, Kennedy N, Morris J, Went A, Hayes PC, Hutchinson SJ. Real-world impact following initiation of interferon-free hepatitis C regimens on liver-related outcomes and all-cause mortality among patients with compensated cirrhosis. J Viral Hepat 2020; 27:270-280. [PMID: 31696575 DOI: 10.1111/jvh.13232] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 09/27/2019] [Accepted: 10/31/2019] [Indexed: 02/06/2023]
Abstract
Few studies have investigated clinical outcomes among patients with cirrhosis who were treated with interferon (IFN)-free direct-acting antiviral (DAA). We aimed to quantify treatment impact on first decompensated cirrhosis hospital admission, first hepatocellular carcinoma (HCC) admission, liver-related mortality and all-cause mortality among a national cohort of cirrhotic patients. Through record linkage between Scotland's HCV Clinical Database and inpatient/day-case hospitalization and deaths records, a study population comprising chronic HCV-infected patients with compensated cirrhosis and initiated on IFN-free DAA between 1 March 2013 and 31 March 2018 was analysed. Cox regression evaluated the association of each clinical outcome with time-dependent treatment status (on treatment, responder, nonresponder or noncompliant), adjusting for patient factors including Child-Pugh class. Among the study population (n = 1073) involving 1809 years of follow-up, 75 (7.0%) died (39 from liver-related causes), 47 progressed to decompensated cirrhosis, and 28 developed HCC. Compared with nonresponders, treatment response (96% among those attending their 12 weeks post-treatment SVR test) was associated with a reduced relative risk of decompensated cirrhosis (hazard ratio [HR] = 0.14; 95% CI: 0.05-0.39), HCC (HR = 0.17; 95% CI: 0.04-0.79), liver-related death (HR = 0.13; 95% CI: 0.05-0.34) and all-cause mortality (HR = 0.30; 95% CI: 0.12-0.76). Compared with responders, noncompliant patients had an increased risk of liver-related (HR = 6.73; 95% CI: 2.99-15.1) and all-cause (HR = 5.45; 95% CI: 3.07-9.68) mortality. For HCV patients with cirrhosis, a treatment response was associated with a lower risk of severe liver complications and improved survival. Our findings suggest additional effort is warranted to address the higher mortality among the minority of cirrhotic patients who do not comply with DAA treatment or associated RNA testing.
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Affiliation(s)
- Scott A McDonald
- School of Health and Life Sciences, Glasgow Caledonian University and Health Protection Scotland, Glasgow, UK
| | - Kevin G Pollock
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
| | | | - David J Goldberg
- School of Health and Life Sciences, Glasgow Caledonian University and Health Protection Scotland, Glasgow, UK
| | | | | | - John F Dillon
- School of Medicine, University of Dundee, Dundee, UK
| | | | - Hamish A Innes
- School of Health and Life Sciences, Glasgow Caledonian University and Health Protection Scotland, Glasgow, UK
| | | | | | | | | | - Sharon J Hutchinson
- School of Health and Life Sciences, Glasgow Caledonian University and Health Protection Scotland, Glasgow, UK
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Baseline Amino Acid Substitutions in the NS5A ISDR and PKR Binding Domain of Hepatitis C and Different Fibrosis Levels and Levels of Development of Hepatocellular Carcinoma in Patients Treated with DAAs. Viruses 2020; 12:v12030255. [PMID: 32106574 PMCID: PMC7150791 DOI: 10.3390/v12030255] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 02/17/2020] [Accepted: 02/22/2020] [Indexed: 02/07/2023] Open
Abstract
Variations in the interferon sensitivity-determining region (ISDR) within the NS5A region were related to the development of hepatocellular carcinoma (HCC) in patients infected with hepatitis C virus (HCV). The aim of the study was to investigate a relationship between ISDR/PKR substitutions and their association with liver fibrosis or HCC development. A total of 316 patients infected with HCV and treated with DAAs were evaluated. HCV RNA was quantified and sequenced before treatment. The liver fibrosis stage was assessed by transient elastography and equalized to METAVIR scores. Multivariate analysis showed that ≥3 substitutions in ISDR and ≥6 in PKR-bd were significantly associated with advanced fibrosis. Advanced fibrosis was observed in patients with higher substitutions in ISDR and PKR-bd. A higher correlation between advanced fibrosis and a high frequency of ≥3 substitutions in ISDR and ≥6 in PKR-bd was observed in patients infected with genotype 2c. In addition, in a higher proportion of HCC patients, advanced fibrosis (40.4% vs. 88.2%; p < 0.001) and ≥6 substitutions in PKR-bd (15.4% vs. 41.2%; p = 0.01) was observed. In conclusion, a higher number of substitutions in ISDR and PKR-bd were associated with advanced liver fibrosis, suggesting a use of like predictors for progression in the liver damage. A significantly higher number of PKR-bd substitutions was observed in HCC patients; in particular, in patients infected with HCV genotype 2c.
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10
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Interferon- and ribavirin-free therapy with new direct acting antivirals (DAA) for chronic hepatitis C improves vascular endothelial function. Int J Cardiol 2018; 271:296-300. [DOI: 10.1016/j.ijcard.2018.04.058] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 03/25/2018] [Accepted: 04/13/2018] [Indexed: 12/15/2022]
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Calvaruso V, Cabibbo G, Cacciola I, Petta S, Madonia S, Bellia A, Tinè F, Distefano M, Licata A, Giannitrapani L, Prestileo T, Mazzola G, Di Rosolini MA, Larocca L, Bertino G, Digiacomo A, Benanti F, Guarneri L, Averna A, Iacobello C, Magro A, Scalisi I, Cartabellotta F, Savalli F, Barbara M, Davì A, Russello M, Scifo G, Squadrito G, Cammà C, Raimondo G, Craxì A, Di Marco V. Incidence of Hepatocellular Carcinoma in Patients With HCV-Associated Cirrhosis Treated With Direct-Acting Antiviral Agents. Gastroenterology 2018; 155:411-421.e4. [PMID: 29655836 DOI: 10.1053/j.gastro.2018.04.008] [Citation(s) in RCA: 257] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 03/13/2018] [Accepted: 04/08/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Studies have produced conflicting results of the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus-associated cirrhosis treated with direct-acting antivirals (DAAs). Data from clinics are needed to accurately assess the occurrence rate of HCC in patients with cirrhosis in the real world. METHODS We collected data from a large prospective study of 2,249 consecutive patients (mean age = 65.4 years, 56.9% male) with hepatitis C virus-associated cirrhosis (90.5% with Child-Pugh class A and 9.5% with Child-Pugh class B) treated with DAAs from March 2015 through July 2016 at 22 academic and community liver centers in Sicily, Italy. HCC occurrence was evaluated by Kaplan-Meier curves. Cox regression analysis was used to identify variables associated with HCC development. RESULTS A sustained virologic response (SVR) was achieved by 2,140 patients (total = 95.2%; 95.9% with Child Pugh class A and 88.3% with Child Pugh class B; P < .001). Seventy-eight patients (3.5%) developed HCC during a mean follow-up of 14 months (range = 6-24 months). At 1 year after exposure to DAAs, HCC developed in 2.1% of patients with Child-Pugh class A with an SVR and 6.6% of patients with no SVR and in 7.8% of patients with Child-Pugh class B with an SVR and 12.4% of patients with no SVR (P < .001 by log-rank test). Albumin level below 3.5 g/dL (hazard ratio = 1.77, 95% confidence interval = 1.12-2.82, P = .015), platelet count below 120 × 109/L (hazard ratio = 3.89, 95% confidence interval = 2.11-7.15, P < .001), and absence of an SVR (hazard ratio = 3.40, 95% confidence interval = 1.89-6.12, P < .001) were independently associated increased risk for HCC. The mean interval from exposure to DAAs to an HCC diagnosis was 9.8 months (range = 2-22 months) and did not differ significantly between patients with (n = 64, 9.2 months) and without (n = 14, 12.0 months) an SVR (P = .11). A larger proportion of patients with an SVR had a single HCC lesion (78% vs 50% without an SVR; P = .009) or an HCC lesion smaller than 3 cm (58% vs 28% without an SVR; P = .07). CONCLUSIONS In an analysis of data from a large prospective study of patients with hepatitis C virus-associated compensated or decompensated cirrhosis, we found that the SVR to DAA treatment decreased the incidence of HCC over a mean follow-up of 14 months.
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Affiliation(s)
- Vincenza Calvaruso
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S.), University of Palermo, Palermo, Italy
| | - Giuseppe Cabibbo
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S.), University of Palermo, Palermo, Italy
| | - Irene Cacciola
- UOC Epatologia Clinica e Biomolecolare and AOUP G Martino, Dipartimento di Medicina Interna e Sperimentale, University of Messina, Messina, Italy
| | - Salvatore Petta
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S.), University of Palermo, Palermo, Italy
| | | | | | - Fabio Tinè
- UOC Gastroenterologia, AO Villa Sofia-Cervello, Palermo, Italy
| | - Marco Distefano
- UOC Malattie Infettive, Ospedale Vittorio Emanuele di Siracusa, ASP Siracusa, Siracusa, Italy
| | - Anna Licata
- UOC Medicina Interna, AOUP Paolo Giaccone, Palermo, Italy
| | | | - Tullio Prestileo
- UOC Malattie Infettive, ARNAS Civico-Di Cristina-Benefratelli, Palermo, Italy
| | - Giovanni Mazzola
- UOC Malattie Infettive, Azienda Ospedaliera Universitaria Paolo Giaccone, Palermo, Italy
| | | | - Licia Larocca
- UOC Malattie infettive, AOUP G Rodolico, Catania, Italy
| | | | | | | | - Luigi Guarneri
- UOC Malattie Infettive, Ospedale di Enna, ASP Enna, Enna, Italy
| | - Alfonso Averna
- UOC Malattie Infettive, Ospedale di Caltanissetta, ASP Caltanissetta, Caltanissetta, Italy
| | | | - Antonio Magro
- UOC Medicina Interna, Ospedale di Agrigento, ASP Agrigento, Agrigento, Italy
| | - Ignazio Scalisi
- UOC Medicina Interna, Ospedale di Mazzara del Vallo, ASP, Trapani, Italy
| | | | - Francesca Savalli
- UOC Malattie Infettive, Ospedale di Trapani, ASP Trapani, Trapani, Italy
| | - Marco Barbara
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S.), University of Palermo, Palermo, Italy
| | - Antonio Davì
- UOC Malattie Infettive, Ospedale di Modica, ASP Ragusa, Ragusa, Italy
| | | | - Gaetano Scifo
- UOC Malattie Infettive, Ospedale Vittorio Emanuele di Siracusa, ASP Siracusa, Siracusa, Italy
| | - Giovanni Squadrito
- UOC Epatologia Clinica e Biomolecolare and AOUP G Martino, Dipartimento di Medicina Interna e Sperimentale, University of Messina, Messina, Italy
| | - Calogero Cammà
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S.), University of Palermo, Palermo, Italy
| | - Giovanni Raimondo
- UOC Epatologia Clinica e Biomolecolare and AOUP G Martino, Dipartimento di Medicina Interna e Sperimentale, University of Messina, Messina, Italy
| | - Antonio Craxì
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S.), University of Palermo, Palermo, Italy
| | - Vito Di Marco
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S.), University of Palermo, Palermo, Italy.
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Koretz RL, Jakobsen JC, Djurisic S, Poropat G, Hauser G, Bjelakovic M, Bjelakovic G, Gluud C. Who is wrong? Responses to Kwo et al. Am J Gastroenterol 2018; 113:779-780. [PMID: 29487409 DOI: 10.1038/s41395-018-0029-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Accepted: 01/05/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Ronald L Koretz
- Granada Hills, Los Angeles, CA, USA. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia. Medical Faculty, University of Nis, Nis, Serbia. Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
| | - Janus Christian Jakobsen
- Granada Hills, Los Angeles, CA, USA. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia. Medical Faculty, University of Nis, Nis, Serbia. Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia.,Granada Hills, Los Angeles, CA, USA. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia. Medical Faculty, University of Nis, Nis, Serbia. Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
| | - Snezana Djurisic
- Granada Hills, Los Angeles, CA, USA. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia. Medical Faculty, University of Nis, Nis, Serbia. Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
| | - Goran Poropat
- Granada Hills, Los Angeles, CA, USA. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia. Medical Faculty, University of Nis, Nis, Serbia. Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
| | - Goran Hauser
- Granada Hills, Los Angeles, CA, USA. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia. Medical Faculty, University of Nis, Nis, Serbia. Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
| | - Milica Bjelakovic
- Granada Hills, Los Angeles, CA, USA. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia. Medical Faculty, University of Nis, Nis, Serbia. Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
| | - Goran Bjelakovic
- Granada Hills, Los Angeles, CA, USA. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia. Medical Faculty, University of Nis, Nis, Serbia. Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
| | - Christian Gluud
- Granada Hills, Los Angeles, CA, USA. The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia. Medical Faculty, University of Nis, Nis, Serbia. Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
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13
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Ultrasound-Based Liver Stiffness Surveillance in Patients Treated for Chronic Hepatitis B or C. APPLIED SCIENCES-BASEL 2018. [DOI: 10.3390/app8040626] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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14
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15
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Wedemeyer H, Reimer J, Sandow P, Hueppe D, Lutz T, Gruengreiff K, Goelz J, Christensen S, Pfeiffer-Vornkahl H, Alshuth U, Manns MP. Long-term outcome of chronic hepatitis C virus infection in a real-world setting: The German LOTOS study. Liver Int 2017; 37:1468-1475. [PMID: 28247572 DOI: 10.1111/liv.13399] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 02/11/2017] [Indexed: 01/08/2023]
Abstract
BACKGROUND & AIMS There are few large-scale, prospective studies comparing liver-associated events in treated and untreated patients with CHC managed in routine clinical practice. METHODS Patients with CHC were prospectively enrolled in a non-interventional study. Data from patients with available documentation who had either achieved a sustained virological response, or were non-responders, relapsers, or had virological breakthrough following treatment with peginterferon alfa-2a±ribavirin, or who had been diagnosed but never treated at least 3 years previously, and who remained under medical observation were analyzed. Primary endpoint was liver-associated events (composite of decompensation/liver failure, ascites, hepatocellular carcinoma, or liver transplant/placement on a transplant list). RESULTS In all, 1444 eligible patients were identified. Mean follow-up was 4.7 (standard deviation; SD 1.1) years. Patients with sustained virological response had a lower incidence of liver-associated events vs non-responders, relapsers, or virological breakthrough and never treated patients (1.7% vs 4.7% and 4.7% respectively). The proportion of patients with cirrhosis increased from baseline in the non-responders, relapsers, or virological breakthrough (6.8%-10.5%) and never treated group (3.7%-8.4%), with an associated increase in severity, but was unchanged in the sustained virological response group (2.1%). Event-free survival was significantly higher in sustained virological response patients (P=.0082). CONCLUSIONS In this "real-world" cohort, the achievement of sustained virological response almost eliminated liver-related morbidity and mortality compared with patients who failed to achieve sustained virological response and those who were untreated. Overall, the LOTOS cohort highlights the importance of timely and effective treatment for patients with CHC.
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Affiliation(s)
- Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Jens Reimer
- Centre for Interdisciplinary Addiction Research, University of Hamburg, Hamburg, Germany
| | | | | | | | | | | | | | | | | | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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16
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Nitsche B, Miller SC, Giorgio M, Berry CA, Muir A. Improving Hepatitis C Identification: Technology Alone Is Not the Answer. Health Promot Pract 2017; 19:506-512. [PMID: 28893101 DOI: 10.1177/1524839917725501] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
An estimated 3 to 5 million Americans are chronically infected with hepatitis C virus (HCV), and approximately 75% of those persons were born between 1945 and 1965 (the so-called baby boomer generation). Because of the largely asymptomatic nature of HCV, up to 50% of those infected are unaware of their disease. Risk-based testing has been largely ineffective. Based on prevalence data, the Centers for Disease Control and Prevention and other organizations recommend a onetime HCV antibody test for all baby boomers. However, uptake of this recommendation requires significant changes in clinical practice for already busy primary care clinicians. We studied the effectiveness of a quality improvement initiative based on continuous audit and feedback combined with education for improving testing in alignment with guidelines; the control group was a cohort of clinicians whose only reminder was an institution-wide electronic health record prompt. Our data show improved testing rates among all clinician groups, but more significant improvement occurred among providers who received continuous feedback about their clinical performance coupled with education.
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17
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Wranke A, Serrano BC, Heidrich B, Kirschner J, Bremer B, Lehmann P, Hardtke S, Deterding K, Port K, Westphal M, Manns MP, Cornberg M, Wedemeyer H. Antiviral treatment and liver-related complications in hepatitis delta. Hepatology 2017; 65:414-425. [PMID: 27770553 DOI: 10.1002/hep.28876] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 09/22/2016] [Indexed: 12/14/2022]
Abstract
UNLABELLED Hepatitis delta virus (HDV) is the most severe form of viral hepatitis. Pegylated interferon alfa (PEG-IFNα) is effective in only 25%-30% of patients and is associated with frequent side effects. The aim of this study was to analyze the clinical long-term outcome of hepatitis delta in relation to different antiviral treatment strategies. We studied 136 anti-HDV-positive patients who were followed for at least 6 months in a retrospective single-center cohort (mean time of follow-up, 5.2 years; range, 0.6-18.8). Liver cirrhosis was already present in 62 patients at first presentation. Twenty-nine percent of patients did not receive any antiviral treatment, 38% were treated with interferon alfa (IFNα)-based therapies, and 33% received nucleos(t)ide analogues (NAs) only. Clinical endpoints defined as hepatic decompensation (ascites, encephalopathy, and variceal bleeding), hepatocellular carcinoma, liver transplantation, and liver-related death developed in 55 patients (40%). Patients who received IFNα-based therapies developed clinical endpoints less frequently than those treated with NA (P = 0.02; HR, 4.0) or untreated patients (P = 0.05; HR, 2.2; 17%, 64%, and 44%), respectively, which was significant in both chi-square and Kaplan-Meier analysis. In addition, considering various clinical and virological parameters, IFNα therapy was independently associated with a more benign clinical long-term outcome in multivariate logistic regression analysis (P = 0.04; odds ratio, 0.25; 95% confidence interval, 0.07-0.9). Loss of HDV RNA during follow-up was more frequent in IFNα-treated patients and strongly linked with a lower likelihood to experience liver-related complications. CONCLUSION IFNα-based antiviral therapy of hepatitis delta was independently associated with a lower likelihood for clinical disease progression. Durable undetectability of HDV RNA is a valid surrogate endpoint in the treatment of hepatitis delta. (Hepatology 2017;65:414-425).
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Affiliation(s)
- Anika Wranke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Beatriz Calle Serrano
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Benjamin Heidrich
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Side Hannover Medical School, Hannover, Germany
| | - Janina Kirschner
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Patrick Lehmann
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Svenja Hardtke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Side Hannover Medical School, Hannover, Germany
| | - Katja Deterding
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Kerstin Port
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Max Westphal
- Institute for Biometry, Hannover Medical School, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Side Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Center Transplantation, Hannover Medical School, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Side Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Side Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Center Transplantation, Hannover Medical School, Germany
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Wilson EM, Rosenthal ES, Kattakuzhy S, Tang L, Kottilil S. Clinical Laboratory Testing in the Era of Directly Acting Antiviral Therapies for Hepatitis C. Clin Microbiol Rev 2017; 30:23-42. [PMID: 27795306 PMCID: PMC5217793 DOI: 10.1128/cmr.00037-16] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Directly acting antiviral (DAA) combination therapies for chronic hepatitis C virus (HCV) infection are highly effective, but treatment decisions remain complex. Laboratory testing is important to evaluate a range of viral, host, and pharmacological factors when considering HCV treatment, and patients must be monitored during and after therapy for safety and to assess the viral response. In this review, we discuss the laboratory tests relevant for the treatment of HCV infection in the era of DAA therapy, grouped according to viral and host factors.
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Affiliation(s)
- Eleanor M Wilson
- Institute of Human Virology, University of Maryland School of Medicine, University of Maryland, Baltimore, Maryland, USA
- Critical Care Medicine Department of the NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Elana S Rosenthal
- Critical Care Medicine Department of the NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Sarah Kattakuzhy
- Institute of Human Virology, University of Maryland School of Medicine, University of Maryland, Baltimore, Maryland, USA
- Critical Care Medicine Department of the NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Lydia Tang
- Institute of Human Virology, University of Maryland School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Shyam Kottilil
- Institute of Human Virology, University of Maryland School of Medicine, University of Maryland, Baltimore, Maryland, USA
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Wranke A, Wedemeyer H. Antiviral therapy of hepatitis delta virus infection - progress and challenges towards cure. Curr Opin Virol 2016; 20:112-118. [PMID: 27792905 DOI: 10.1016/j.coviro.2016.10.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 10/03/2016] [Accepted: 10/10/2016] [Indexed: 12/14/2022]
Abstract
Hepatitis B-/D-virus co-infection causes the most severe form of viral hepatitis, frequently leading to liver cirrhosis, hepatic decompensation and consecutive liver-related mortality. Treatment options for hepatitis delta are limited. The only recommended therapy is pegylated interferon alpha which leads to virological responses in about 25-30% of patients. However, interferon therapy is associated with frequent side-effects and late HDV RNA relapses have been described during long-term follow even in patients who were HDV RNA negative 24 weeks after the end of therapy. Thus, alternative treatment options are urgently needed. Clinical studies have been performed exploring prenylation inhibitors, viral entry inhibitors and nucleic acid polymers to block particle release. We here summarize the progress and challenges towards cure of HDV infection.
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Affiliation(s)
- Anika Wranke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Partner Side HepNet Study-House, Hannover, Germany; HepNet Study-House, Hannover, Germany; Integrated Research and Treatment Center Transplantation, Hannover Medical School, Germany.
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Liu CY, Chu JY, Chiang JH, Yen HR, Hsu CH. Utilization and prescription patterns of traditional Chinese medicine for patients with hepatitis C in Taiwan: a population-based study. Altern Ther Health Med 2016; 16:397. [PMID: 27769222 PMCID: PMC5073439 DOI: 10.1186/s12906-016-1379-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 10/08/2016] [Indexed: 12/15/2022]
Abstract
BACKGROUND To characterize the utilization of Traditional Chinese Medicine (TCM) among patients with hepatitis C (HC). METHODS This study examined datasets from the National Health Insurance Research Database in Taiwan. One cohort, including one million patients randomly sampled from the beneficiaries of the National Health Insurance Programme from January 1 to December 31 in 2010, was chosen for this analysis. People who had at least three outpatient or inpatient records and had been diagnosed with hepatitis C virus infection from 2000 to 2010 were defined as patients with HC. Patients with HC who had at least one TCM outpatient clinical record from 2000 to 2010 were defined as TCM users (N = 5,691), whereas patients with no TCM outpatient records were defined as non-TCM users (N = 2,876). The demographic data, treatment modalities and disease distributions of TCM users were analysed. RESULTS Overall, 66.4 % of the patients with HC had used TCM from 2000 to 2010. Of the TCM users, 54.1 % were female. The utilization rate of TCM increased with age and peaked in the age group of those 40 - 64 years old. Herbal remedies (52.4 %) were the most commonly used agents, followed by combination therapy (46.4 %) and acupuncture alone (1.2 %). Patients who had more extrahepatic diseases and were taking more antiviral agents tended to visit TCM clinics. Jia-Wei-Xiao-Yao-San and Dan-Shen (Salvia miltiorrhiza) were the most commonly used formula and single herb, with 88,124 person-days and 59,252 person-days, respectively. CONCLUSIONS Our nationwide population-based study revealed a high prevalence and specific usage patterns of TCM in patients with HC in Taiwan.
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van der Meer AJ, Berenguer M. Reversion of disease manifestations after HCV eradication. J Hepatol 2016; 65:S95-S108. [PMID: 27641991 DOI: 10.1016/j.jhep.2016.07.039] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Revised: 07/29/2016] [Accepted: 07/29/2016] [Indexed: 12/13/2022]
Abstract
Chronic infection with the hepatitis C virus (HCV) may lead to hepatic fibrosis and eventually cirrhosis, at which stage, patients have a substantial risk of liver failure, hepatocellular carcinoma (HCC) and liver-related death. Moreover, HCV infection is associated with several extrahepatic manifestations which impact the quality of life and increase the non-liver-related mortality rate. For patients with compensated liver disease, interferon (IFN)-based antiviral therapy has been a treatment option for over two decades. Long-term follow-up studies indicated that among those with sustained virological response (SVR) the extend of hepatic fibrosis can regress and that their risk of cirrhosis-related complications (including HCC) is reduced, also in case of cirrhosis. Recent population-based studies extended these observations for solid extrahepatic outcomes, such as end-stage renal failure and cardiovascular events. Most importantly, SVR has been associated with prolonged overall survival. These results highlight the importance of the development of new direct-acting antivirals (DAAs), by which almost all patients are able to eradicate HCV in a comfortable manner. Based on the excellent first experiences with the DAAs, physicians gained confidence to use these drugs among patients with decompensated cirrhosis on a more regular basis as well. This was not possible with interferon therapy. Also in this high risk population the DAAs show high SVR rates with improvements in biochemical parameters of liver function shortly after therapy, especially in case of SVR. In fact, some patients could actually be removed from the liver transplantation waiting list due to clinical improvement following DAA therapy. How these short-term results translate into a prolonged (long-term) survival has yet to be determined, as well as which patients with decompensated liver disease are likely or not to benefit from viral eradication. Here we review the current data regarding the beneficial clinical outcome with antiviral therapy as well the remaining uncertainties in this field, both for patients with compensated liver disease and patients with decompensated liver disease.
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Affiliation(s)
- Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
| | - Marina Berenguer
- Hepatology and Liver Transplant Unit and Ciberehd, La Fe Univ. Hospital and Univ. Valencia, Spain
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Affiliation(s)
- Raoel Maan
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
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Komatsu T, Virdee S. ICBS and ECBS Chemical Biology Meeting 2015 - Let Them Come to Berlin! ACS Chem Biol 2016; 11:1159-66. [PMID: 27198933 DOI: 10.1021/acschembio.6b00268] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Toru Komatsu
- Graduate
School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
- JST PRESTO, Tokyo, Japan
| | - Satpal Virdee
- MRC
Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, United Kingdom
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Álvaro-Meca A, Jiménez-Sousa MA, Boyer A, Medrano J, Reulen H, Kneib T, Resino S. Impact of chronic hepatitis C on mortality in cirrhotic patients admitted to intensive-care unit. BMC Infect Dis 2016; 16:122. [PMID: 26979964 PMCID: PMC4793506 DOI: 10.1186/s12879-016-1448-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 02/29/2016] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Cirrhosis and severe sepsis are factors associated with increased mortality in intensive care unit (ICU), but chronic hepatitis C (CHC) has been less studied in ICU. The aim of this study was to analyze the impact of CHC on the mortality of cirrhotic patients admitted to ICU according to severe sepsis and decompensated cirrhosis. METHODS We carried out a retrospective study based on CHC-cirrhotic patients (CHC-group) admitted to ICU (n = 1138) and recorded in the Spanish Minimum Basic Data Set (2005-2010). A control-group (randomly selected cirrhotic patients without HIV, HBV, or HCV infections) was also included (n = 4127). The primary outcome variable was ICU mortality. The cumulative mortality rate on days 7, 30, and 90 in patients admitted to the ICUs was calculated by dividing the number of deaths by the number of patients admitted to the ICU. The adjusted hazard ratio (aHR) for death in the ICU was estimated through a semi-parametric Bayesian model of competing risk. RESULTS The CHC-group had a higher cumulative incidence of severe sepsis than the control-group in compensated cirrhosis (37.4 vs. 31.1%; p = 0.024), but no differences between the CHC-group and the control-group in decompensated cirrhosis were found. Moreover, a higher cumulative incidence of severe sepsis was associated with decompensated cirrhosis compared to compensated cirrhosis in the control-group (40.1 vs. 31.1%; p < 0.001) whereas this was not observed in the CHC group (38.1 vs. 37.4%; p = 0.872). The CHC-group had higher cumulative mortality than the control-group by days 7 (47 vs. 41.3%; p < 0.001), 30 (78.5 vs. 73.5%; p < 0.001), and 90 (96.3 vs. 95.9%; p < 0.001). In a competitive risk model, the CHC-group had a higher risk of dying if the ICU course was complicated by severe sepsis (adjusted hazard ratio (aHR) = 1.19; p = 0.003), but no significant values in patients with absence of severe sepsis were found (aHR = 1.09; p= 0.068). When patients were stratified by cirrhosis stage and severe sepsis, CHC patients with compensated cirrhosis had the higher risk of death if they had severe sepsis (aHR = 1.35; p = 0.002). Moreover, the survival was low in patients with decompensated cirrhosis and severe sepsis but we did not find significant differences between CHC-group and control-group. CONCLUSIONS CHC was associated with an increased risk of death in cirrhotic patients admitted to ICUs, particularly in patients with compensated cirrhosis and severe sepsis.
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Affiliation(s)
- Alejandro Álvaro-Meca
- Departamento de Medicina Preventiva y Salud Pública, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain
| | - María A Jiménez-Sousa
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Alexandre Boyer
- Université de Bordeaux, INSERM U657, Pharmaco-épidémiologie et évaluation de l'impact des produits de santé sur les populations, F-33000, Bordeaux cedex, France
| | - José Medrano
- Departamento de Medicina, Universidad del País Vasco UPV/EHU, Vitoria-Gasteiz, Spain.,Servicio de Urgencias, Hospital Universitario de Araba, Vitoria-Gasteiz, Spain
| | - Holger Reulen
- Chair of Statistics, University of Goettingen, 37073, Göttingen, Germany
| | - Thomas Kneib
- Chair of Statistics, University of Goettingen, 37073, Göttingen, Germany
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain. .,Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda- Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
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Janczewska E, Flisiak R, Zarebska-Michaluk D, Kozielewicz D, Berak H, Dobracka B, Librant-Suska M, Lojewski W, Jurczyk K, Musialik J, Postawa-Klosińska B, Wroblewski J, Augustyniak K, Dudziak M, Olszok I, Ruszala A, Pisula A, Lapinski T, Kryczka W, Horban A, Dobracki W. Effect of Peginterferon or Ribavirin Dosing on Efficacy of Therapy With Telaprevir in Treatment-Experienced Patients With Chronic Hepatitis C and Advanced Liver Fibrosis: A Multicenter Cohort Study. Medicine (Baltimore) 2015; 94:e1411. [PMID: 26402801 PMCID: PMC4635741 DOI: 10.1097/md.0000000000001411] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
We investigated the safety, efficacy, and impact of ribavirin and peginterferon dose reduction on complete early virologic response and sustained virologic response (SVR) to triple therapy with telaprevir in treatment-experienced patients with advanced liver fibrosis.Treatment was initiated for 211 patients who failed treatment with peginterferon and ribavirin, with bridging fibrosis (F3, n = 68) or cirrhosis (F4, n = 143), including 103 (49%) null-responders (NR), 30 (14%) partial responders (PR), and 78 (37%) relapsers (REL). Impaired liver function (ILF) platelets <100,000/mm or albumin <35 g/L were present in 40 patients. The distribution of hepatitis C virus subtypes was: 1a, 1b, or 1, with undetermined subtype for 10 (5%), 187 (89%), and 14 (6%) patients, respectively. Treatment was started with peginterferon alpha-2a or alpha-2b, ribavirin, and telaprevir at standard doses.The overall SVR24 rate was 56% and was lower in cirrhotic patients (NR: 35%, PR: 40%, and REL: 63%, respectively) than in patients with bridging fibrosis (NR: 50%, PR: 75%, and REL: 75%, respectively). The lowest probability of SVR24 was in NRs with ILF (26%). The SVR24 rate significantly decreased in NRs receiving <60% vs >60% of the total ribavirin dose (23% vs 44%, respectively) or <80% vs >80% of the total ribavirin dose (33% vs 48%, respectively). A significant SVR24 decrease was noted subsequent to a total peginterferon dose reduction, both when comparing patients who received <60% vs >60% of the total dose (NR: 0% vs 44%; REL: 33% vs 68%) and patients who received <80% vs >80% of the total dose (NR: 17% vs 50%; REL: 46% vs 71%).Serious adverse events were observed in 31 patients (15%). Deaths occurred in 4 patients. All of the deceased subjects were cirrhotic members of the ILF (baseline serum albumin level <35 g/L and/or platelet count <100,000/mm) group.Ribavirin dose reduction did not affect efficacy in REL but did in NR. Peginterferon dose reduction decreased the SVR24 rate for all groups, particularly in prior NR. ILF increased the risk of fatal complications with a low probability to achieve SVR24. One solution might be to provide wide and early access to novel, efficient, and safe interferon-free combinations to treatment-experienced patients, particularly those with liver cirrhosis.
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Affiliation(s)
- Ewa Janczewska
- From the ID Clinic, Myslowice, Poland (EJ, AP); Klinika Chorob Zakaznych i Hepatologii, Uniwersytet Medyczny, Białystok, Poland (RF, TL); Uniwersytet J. Kochanowskiego i Wojewodzki Szpital Zespolony, Kielce, Poland (DZ-M, WK); Department of Infectious Diseases and Hepatology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland (DK); Hospital of Infectious Diseases, Warsaw, Poland (HB); Infectious Diseases Clinic, Wroclaw, Poland (BD, WD); Poradnia Wirusowych Zapalen Watroby SU, Kraków, Poland (ML-S); NZOZ Poradnia Chorob Watroby, Zielona Gora, Poland (WL); Department of Infectious Diseases, Hepatology, and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland (KJ); Department of Gastroenterology and Hepatology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland (JM); Department of Basic Biomedical Science, School of Pharmacy, Division of Laboratory, Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland (JM); Oddzial Obserwacyjno-Zakazny, Szpital im. Zeromskiego, Kraków, Poland (BP-K); Oddzial Obserwacyjno-Zakazny, Szpital Wojewodzki, Koszalin, Poland (JW); Oddzial Chorób Zakaznych, Walbrzych, Poland (KA); Klinika Chorob Infekcyjnych i Alergologii WIM, Warsaw, Poland (MD); Oddzial Obserwacyjno-Zakazny, Szpital Rejonowy, Raciborz, Poland (IO); Ośrodek Leczenia WZW, Centrum Medyczne, Lancut, Poland (AR); Warsaw Medical University and Hospital of Infectious Diseases, Warsaw, Poland (AH); and Faculty of Health Science, Medical University, Wroclaw, Poland (WD)
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Maan R, van der Meer AJ, Hansen BE, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, Manns MP, Zeuzem S, Janssen HLA, de Knegt RJ, Veldt BJ. Risk of infections during interferon-based treatment in patients with chronic hepatitis C virus infection and advanced hepatic fibrosis. J Gastroenterol Hepatol 2015; 30:1057-64. [PMID: 25682797 DOI: 10.1111/jgh.12929] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/16/2015] [Indexed: 01/16/2023]
Abstract
BACKGROUND & AIM Pegylated interferon-based treatment is still the backbone of current hepatitis C therapy and is associated with bone marrow suppression and an increased risk of infections. The aim of this retrospective cohort study was to assess the risk of infections during interferon-based treatment among patients with chronic hepatitis C virus (HCV) infection and advanced hepatic fibrosis and its relation to treatment-induced neutropenia. METHODS This cohort study included all consecutive patients with chronic HCV infection and biopsy-proven bridging fibrosis or cirrhosis (Ishak 4-6) who started treatment between 1990 and 2003 in five large hepatology units in Europe and Canada. Neutrophil counts between 500-749/μL and below 500/μL were considered as moderate and severe neutropenia, respectively. RESULTS This study included 723 interferon-based treatments, administered to 490 patients. In total, 113 infections were reported during 88 (12%) treatments, of which 24 (21%) were considered severe. Only one patient was found to have moderate neutropenia and three patients were found to have severe neutropenia at the visit before the infection. Three hundred and twelve (99.7%) visits with moderate neutropenia and 44 (93.6%) visits with severe neutropenia were not followed by an infection. Multivariable analysis showed that cirrhosis (odds ratio [OR] 2.85, 95% confidence interval [CI] 1.38-5.90, P=0.005) and severe neutropenia at the previous visit (OR 5.42, 95% CI 1.34-22.0, P=0.018) were associated with the occurrence of infection, while moderate neutropenia was not. Among a subgroup of patients treated with pegylated interferon, severe neutropenia was not significantly associated (OR 1.63, 95% CI 0.19-14.2, P=0.660). CONCLUSIONS In this large cohort of patients with bridging fibrosis and cirrhosis, infections during interferon-based therapy were generally mild. Severe interferon-induced neutropenia rarely occurred, but was associated with on-treatment infection. Moderate neutropenia was not associated with infection, suggesting that current dose reduction guidelines might be too strict.
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Affiliation(s)
- Raoel Maan
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
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Simmons B, Saleem J, Heath K, Cooke GS, Hill A. Long-Term Treatment Outcomes of Patients Infected With Hepatitis C Virus: A Systematic Review and Meta-analysis of the Survival Benefit of Achieving a Sustained Virological Response. Clin Infect Dis 2015; 61:730-40. [PMID: 25987643 PMCID: PMC4530725 DOI: 10.1093/cid/civ396] [Citation(s) in RCA: 207] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Accepted: 05/09/2015] [Indexed: 02/06/2023] Open
Abstract
The results of this meta-analysis suggest that there is a significant survival benefit of achieving an sustained virologic response compared with unsuccessful treatment in the general hepatitis C virus-infected population. This benefit is held in patients with cirrhosis and those coinfected with human immunodeficiency virus. Background. Achievement of a sustained virologic response (SVR) after treatment for Hepatitis C infection is associated with improved outcomes. This meta-analysis aimed to determine the impact of SVR on long-term mortality risk compared with nonresponders in a range of populations. Methods. An electronic search identified all studies assessing all-cause mortality in SVR and non-SVR patients. Eligible articles were stratified into general, cirrhotic, and populations coinfected with human immunodeficiency virus. The adjusted hazard ratio (95% confidence interval [CI]) for mortality in patients achieving SVR vs non-SVR, and pooled estimates for the 5-year mortality in each group were calculated. Results. 31 studies (n = 33 360) were identified as suitable for inclusion. Median follow-up time was 5.4 years (interquartile range, 4.9–7.5) across all studies. The adjusted hazard ratio of mortality for patients achieving SVR vs non-SVR was 0.50 (95% CI, .37–.67) in the general population, 0.26 (95% CI, .18–.74) in the cirrhotic group, and 0.21 (.10–.45) in the coinfected group. The pooled 5-year mortality rates were significantly lower for patients achieving SVR compared with non-SVR in all 3 populations. Conclusions. The results suggest that there is a significant survival benefit of achieving an SVR compared with unsuccessful treatment in a range of populations infected with hepatitis C virus.
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Affiliation(s)
| | | | | | | | - Andrew Hill
- Pharmacology and Therapeutics, Liverpool University, United Kingdom
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van der Meer AJ. Achieving sustained virological response: what's the impact on further hepatitis C virus-related disease? Expert Rev Gastroenterol Hepatol 2015; 9:559-66. [PMID: 25579804 DOI: 10.1586/17474124.2015.1001366] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Continuous hepatic inflammation as a result of chronic infection with the hepatitis C virus may lead to the development of fibrosis and eventually cirrhosis. At the stage of cirrhosis, patients are at elevated risk of liver failure and hepatocellular carcinoma, two complications that shorten their life expectancy. Survival may be further impaired by the extra-hepatic manifestations of chronic hepatitis C virus infection, such as diabetes mellitus and lymphoma. Sustained virological response (SVR) following antiviral therapy has been associated with regression of hepatic fibrosis as well as with a reduction in portal pressure, both important markers of liver disease severity. Long-term follow-up studies indicated that SVR was related not only to a reduced occurrence of solid clinical end points, including liver failure and hepatocellular carcinoma, but also cardiovascular events and malignant lymphomas. Together, these findings may explain the recently observed improved overall survival among patients who attained SVR, even in the case of advanced liver disease.
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Affiliation(s)
- Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, 's Gravendijkwal 230, Room Ha 206, 3015 CE Rotterdam, The Netherlands
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van der Meer AJ. Association between antiviral treatment and extrahepatic outcomes in patients with hepatitis C virus infection. Gut 2015; 64:364-6. [PMID: 25601636 DOI: 10.1136/gutjnl-2014-308745] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
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Zornitzki T, Malnick S, Lysyy L, Knobler H. Interferon therapy in hepatitis C leading to chronic type 1 diabetes. World J Gastroenterol 2015; 21:233-239. [PMID: 25574096 PMCID: PMC4284340 DOI: 10.3748/wjg.v21.i1.233] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Revised: 07/20/2014] [Accepted: 07/25/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To review the prevalence, clinical data and course of interferon- associated type 1 diabetes in chronic hepatitis C virus (HCV) infection.
METHODS: Search of all interferon (INF)-related type 1 diabetes mellitus (T1DM) cases published in the English literature from 1992 to December 2013 according to the key words: chronic hepatitis C infection, diabetes mellitus type 1, insulin dependent diabetes mellitus, and interferon treatment. We found 107 cases and analyzed their clinical and laboratory data and long-term follow-up. Due to the predominance of cases described in Japanese literature, we analyzed separately cases of Caucasian and Japanese origin. In addition we describe a representative case with HCV who developed INF-related T1DM.
RESULTS: Our data show that INF treatment increases the risk of developing T1DM by 10-18 fold compared with the corresponding general population and the median age of onset was 43 years (range: 24-66 years) in Caucasians and 52 years (range: 45-63 years) in Japanese. Most patients developed T1DM during INF treatment, after a median time-period of 4.2 and 5.7 mo in Caucasian and Japanese groups, respectively. The clinical course was characterized by a fulminant course with abrupt severe hyperglycemia or ketoacidosis, a high titer of anti-islet autoantibodies and almost all patients (105/107) permanently required insulin therapy with a follow-up of up to 4 years. A substantial number of patients had evidence for other autoimmune disorders mainly thyroid diseases (25% and 31% in Caucasian and Japanese groups, respectively).
CONCLUSION: INF-associated T1DM in HCV has a fulminant course, often associated with other autoimmune diseases, and results almost inevitably in permanent insulin therapy requirement.
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Bichoupan K, Martel-Laferriere V, Sachs D, Ng M, Schonfeld EA, Pappas A, Crismale J, Stivala A, Khaitova V, Gardenier D, Linderman M, Perumalswami PV, Schiano TD, Odin JA, Liu L, Moskowitz AJ, Dieterich DT, Branch AD. Costs of telaprevir-based triple therapy for hepatitis C: $189,000 per sustained virological response. Hepatology 2014; 60:1187-95. [PMID: 25065814 PMCID: PMC4190678 DOI: 10.1002/hep.27340] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 06/11/2014] [Accepted: 07/24/2014] [Indexed: 12/15/2022]
Abstract
UNLABELLED In registration trials, triple therapy with telaprevir (TVR), pegylated interferon (Peg-IFN), and ribavirin (RBV) achieved sustained virological response (SVR) rates between 64% and 75%, but the clinical effectiveness and economic burdens of this treatment in real-world practice remain to be determined. Records of 147 patients who initiated TVR-based triple therapy at the Mount Sinai Medical Center (May-December 2011) were reviewed. Direct medical costs for pretreatment, on-treatment, and posttreatment care were calculated using data from Medicare reimbursement databases, RED Book, and the Healthcare Cost and Utilization Project database. Costs are presented in 2012 U.S. dollars. SVR (undetectable hepatitis C virus [HCV] RNA 24 weeks after the end of treatment) was determined on an intention-to-treat basis. Cost per SVR was calculated by dividing the median cost by the SVR rate. Median age of the 147 patients was 56 years (interquartile range [IQR] = 51-61), 68% were male, 19% were black, 11% had human immunodeficiency virus/HCV coinfection, 36% had advanced fibrosis/cirrhosis (FIB-4 scores ≥3.25), and 44% achieved an SVR. The total cost of care was $11.56 million. Median cost of care was $83,721 per patient (IQR = $66,652-$98,102). The median cost per SVR was $189,338 (IQR = $150,735-$221,860). Total costs were TVR (61%), IFN (24%), RBV (4%), adverse event management (8%), professional fees (2%), and laboratory tests (1%). CONCLUSIONS TVR and Peg-IFN accounted for 85% of costs. Pharmaceutical prices and the low (44%) SVR rate, in this real-world study, were major contributors to the high cost per SVR.
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Affiliation(s)
- Kian Bichoupan
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
| | | | - David Sachs
- Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Michel Ng
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
| | | | - Alexis Pappas
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
| | - James Crismale
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Alicia Stivala
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Viktoriya Khaitova
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Donald Gardenier
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Michael Linderman
- Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY
| | | | - Thomas D. Schiano
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Joseph A. Odin
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Lawrence Liu
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Alan J. Moskowitz
- Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Douglas T. Dieterich
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Andrea D. Branch
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
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Tsochatzis EA, Crossan C, Longworth L, Gurusamy K, Rodriguez-Peralvarez M, Mantzoukis K, O'Brien J, Thalassinos E, Papastergiou V, Noel-Storr A, Davidson B, Burroughs AK. Cost-effectiveness of noninvasive liver fibrosis tests for treatment decisions in patients with chronic hepatitis C. Hepatology 2014; 60:832-43. [PMID: 25043847 PMCID: PMC4265295 DOI: 10.1002/hep.27296] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Accepted: 06/27/2014] [Indexed: 12/13/2022]
Abstract
UNLABELLED The cost-effectiveness of noninvasive tests (NITs) as alternatives to liver biopsy is unknown. We compared the cost-effectiveness of using NITs to inform treatment decisions in adult patients with chronic hepatitis C (CHC). We conducted a systematic review and meta-analysis to calculate the diagnostic accuracy of various NITs using a bivariate random-effects model. We constructed a probabilistic decision analytical model to estimate health care costs and outcomes (quality-adjusted life-years; QALYs) using data from the meta-analysis, literature, and national UK data. We compared the cost-effectiveness of four treatment strategies: testing with NITs and treating patients with fibrosis stage≥F2; testing with liver biopsy and treating patients with ≥F2; treat none; and treat all irrespective of fibrosis. We compared all NITs and tested the cost-effectiveness using current triple therapy with boceprevir or telaprevir, but also modeled new, more-potent antivirals. Treating all patients without any previous NIT was the most effective strategy and had an incremental cost-effectiveness ratio (ICER) of £9,204 per additional QALY gained. The exploratory analysis of currently licensed sofosbuvir treatment regimens found that treat all was cost-effective, compared to using an NIT to decide on treatment, with an ICER of £16,028 per QALY gained. The exploratory analysis to assess the possible effect on results of new treatments, found that if SVR rates increased to >90% for genotypes 1-4, the incremental treatment cost threshold for the "treat all" strategy to remain the most cost-effective strategy would be £37,500. Above this threshold, the most cost-effective option would be noninvasive testing with magnetic resonance elastography (ICER=£9,189). CONCLUSIONS Treating all adult patients with CHC, irrespective of fibrosis stage, is the most cost-effective strategy with currently available drugs in developed countries.
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Affiliation(s)
- Emmanuel A Tsochatzis
- Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, Royal Free HospitalLondon, UK,* These two authors contributed equally to this work and are joint first auth
| | - Catriona Crossan
- Health Economics Research Group, Brunel UniversityUxbridge, UK,* These two authors contributed equally to this work and are joint first auth
| | | | | | | | - Konstantinos Mantzoukis
- Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, Royal Free HospitalLondon, UK
| | - Julia O'Brien
- Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, Royal Free HospitalLondon, UK
| | - Evangelos Thalassinos
- Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, Royal Free HospitalLondon, UK
| | - Vassilios Papastergiou
- Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, Royal Free HospitalLondon, UK
| | - Anna Noel-Storr
- Cochrane Dementia and Cognitive Improvement Group, Nuffield Department of Medicine, Oxford UniversityOxford, UK
| | | | - Andrew K Burroughs
- Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, Royal Free HospitalLondon, UK
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van der Meer AJ, Feld JJ, Zeuzem S, Janssen HLA. Reply to: 'Evidence recommending antiviral therapy in hepatitis C'. J Hepatol 2014; 60:1102-3. [PMID: 24445220 DOI: 10.1016/j.jhep.2014.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Accepted: 01/09/2014] [Indexed: 12/04/2022]
Affiliation(s)
- Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
| | - Jordan J Feld
- Liver Centre, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
| | - Stefan Zeuzem
- Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany
| | - Harry L A Janssen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands; Liver Centre, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
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Koretz RL, Gurusamy K, Davidson B, Burroughs A. Evidence recommending antiviral therapy in hepatitis C. J Hepatol 2014; 60:1101-2. [PMID: 24445221 DOI: 10.1016/j.jhep.2013.12.031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Accepted: 12/15/2013] [Indexed: 12/12/2022]
Affiliation(s)
| | - Kurinchi Gurusamy
- Royal Free Campus, University College London Medical School, London, UK
| | - Brian Davidson
- Royal Free Campus, University College London Medical School, London, UK
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