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Xavier JB, Schmillevitch J, Emori C, Uehara S, Nunes EJ, Ferraz ML. EARLY NONINVASIVE EVALUATION OF LIVER FIBROSIS AFTER HEPATITIS C TREATMENT: THE IMPACT OF INFLAMMATION. ARQUIVOS DE GASTROENTEROLOGIA 2024; 61:e24043. [PMID: 39776122 DOI: 10.1590/s0004-2803.24612024-043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 10/29/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND Liver biopsy (LB) is still the gold standard method for assessing hepatic fibrosis (HF), associated diseases, and liver inflammation. Nowadays, noninvasive techniques such as Acoustic radiation force impulse (ARFI) elastography have been introduced instead of liver biopsy. However, there are controversies about the time it should be performed after treatment for hepatitis C virus (HCV). OBJECTIVE To evaluate hepatic fibrosis using ARFI technology before and after successive treatments for chronic HCV. METHODS We prospectively included 50 adult patients with chronic HCV (genotype 1). Patients were first submitted to triple therapy with first-generation protease inhibitors (boceprevir and telaprevir) at the hepatitis division of the Gastroenterology Department of the Federal University of São Paulo. The non-responders underwent re-treatment with interferon-free direct-acting antiviral agents (DDAs - sofosbuvir associated with daclatasvir or simeprevir). Assessment of hepatic stiffness by ARFI was performed before and after the first treatment and before and after the re-treatment with DDAs. RESULTS ARFI values decreased significantly after treatments. In patients on first-generation protease inhibitor therapy and achieving sustained virological response (SVR), ARFI decreased from 2.41±0.58 pre-treatment to 2.02+/-0.58 (P<0.042) post-treatment. In patients who did not reach SVR, that is, non-responders, a significant reduction was similarly observed (2.39±0.63 to 2.03±0.54; P<0.001 before and after treatment, respectively). Before starting the re-treatment, non-responders had elevated ARFI values again, dropping after SVR following re-treatment (from 2.46±0.57 to 1.45±0.68, P<0.004). Laboratory parameters such as AST and ALT were directly correlated to ARFI elastography. CONCLUSION The evaluation of hepatic elastography by the ARFI method before and after (6 - 9 months) successive treatment of hepatitis C in responders and non-responders led to the conclusion that the reduction of elastography parameters seems to be related to a decrease in hepatic inflammation rather than a reduction in fibrosis per se.
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Affiliation(s)
| | - Joel Schmillevitch
- Faculdade de Ciências Médicas da Santa Casa de São Paulo, São Paulo, SP, Brasil
| | - Christini Emori
- Instituto de Infectologia Emílio Ribas, São Paulo, SP, Brasil
| | - Silvia Uehara
- Universidade Federal de Mato Grosso do Sul, Hospital Universitário Maria Aparecida Pedrossian, Campo Grande, MS, Brasil
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Dawood RM, El-Meguid MA, Shousha HI, Elsayed A, Nabeel MM, Yosry A, Abdelaziz A, Salum GM. Seven gene signature explores the impact of DAAs on the appearance of hepatocellular carcinoma in HCV infected patients. Heliyon 2022; 8:e10119. [PMID: 36033258 PMCID: PMC9404272 DOI: 10.1016/j.heliyon.2022.e10119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/30/2022] [Accepted: 07/25/2022] [Indexed: 11/03/2022] Open
Abstract
UNLABELLED HCV damages the hepatocytes ending with hepatocellular carcinoma (HCC). The direct-acting antivirals (DAAs) treatment has raised hopes for reducing the incidence of HCC. However, several scientific debate regarding the impact of DAAs on the occurrence of HCC in patients with cirrhosis. We aimed to study the Cirrhosis Risk Score (CRS), several clinical factors and tumor characteristics between patients who developed HCC either with or without DAAs treatment "DAA-exposed HCC patients" and "DAA-unexposed HCC patients". METHODS CRS was assessed via genotyping by allelic discrimination assays in HCV patients who developed de novo HCC (with DAAs (DAA-exposed HCC patients, n = 50), and without DAAs treatment (DAA-unexposed HCC patients, n = 40)). APRI, FIB-4 scores, and tumor characteristics were assessed. RESULTS Around 60% and 48% of DAA-exposed HCC patients and DAA-unexposed HCC patients; respectively had high CRS scores without significant difference. DAA-exposed HCC patients showed elevated Albumin, Hemoglobin and decreased ALT, AST compared with DAA-unexposed HCC patients (P = 0.002, 0.04, <0.001 and 0.006; respectively). FIB4 and APRI didn't reach the statistical difference between the studied groups. DAA-exposed HCC patients have higher overall survival (OS) than DAA-unexposed HCC patients (median: 30 & 15 months; respectively (p = 0.019)). Moreover, no significant differences were observed between the two groups in their focal lesion characteristics. CONCLUSION All studied patients are genetically predisposed to develop HCC. Moreover, DAAs significantly improved the OS and the biochemical parameters. No differences between the two groups were detected regarding their tumor characteristics. Accordingly, the appearance of HCC after treatment is attributed to the natural course of cirrhosis.
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Affiliation(s)
- Reham M. Dawood
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, 33 EL Bohouth Street Dokki, Giza, 12622, Egypt
| | - Mai Abd El-Meguid
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, 33 EL Bohouth Street Dokki, Giza, 12622, Egypt
| | - Hend Ibrahim Shousha
- Department of Endemic Medicine and Hepato-gastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Ahmed Elsayed
- Department of Endemic Medicine and Hepato-gastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Mohamed Mahmoud Nabeel
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, 33 EL Bohouth Street Dokki, Giza, 12622, Egypt
| | - Ayman Yosry
- Department of Endemic Medicine and Hepato-gastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Ashraf Abdelaziz
- Department of Endemic Medicine and Hepato-gastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Ghada M. Salum
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, 33 EL Bohouth Street Dokki, Giza, 12622, Egypt
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Salum GM, Dawood RM, Abd el-Meguid M, Ibrahim NE, Abdel Aziz AO, El Awady MK. Correlation between IL28B/TLR4 genetic variants and HCC development with/without DAAs treatment in chronic HCV patients. Genes Dis 2020; 7:392-400. [PMID: 32884993 PMCID: PMC7452484 DOI: 10.1016/j.gendis.2019.05.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 05/13/2019] [Accepted: 05/20/2019] [Indexed: 02/07/2023] Open
Abstract
In Egypt, Sofosbuvir (SOF) in combination with Dataclasvir (DCV) is the broadly used DAAs with excellent therapeutic profile. This study is designed to explore the relation between IL28B/TLR4 genetic variants and each of the followings; HCC development post SOF/DCV treatment, progression to HCC in naïve patients and SOF/DCV therapy outcome. A total of 493 blood samples were collected (controls (n = 70); HCV patients treated with SOF/DCV (n = 252) of whom 65 patients developed HCC, 187 patients didn't develop HCC (125 responders, 62 relapsers); naïve HCV patients (n = 171) had early (n = 48), late liver fibrosis (n = 21) and HCC (n = 102)). Both SNPs were genotyped using a TaqMan 5' allelic discrimination assay. At IL28B rs12979860 SNP, the C allele was significantly correlating with the response rate more than T allele (OR 1.9, 95% CI 1.29-2.9, p = 0.004), while at TLR4 rs4986791 SNP, no association was found (OR 6.5, 95% 0.57-75.28, p = 0.09). Both SNPs couldn't detect the probability for HCC emergence after treatment. In naïve patients, the protective alleles were detected in their lowest frequency in HCC patients (p = 0.1, for rs12979860 and, p = 0.001 for rs4986791). SOF/DCV combination improved SVR rates in HCV genotype 4a infected patients regardless of IL28B genotype, with the best rates in those lacking the T allele.
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Key Words
- DAAs
- DAAs, Direct acting antiviral agents
- DCV
- DCV, Dataclasvir
- HCC
- HCC, Hepatocellular carcinoma
- HCV
- HCV, hepatitis C virus
- IFNλ, Type III IFNs
- IL28B
- ISGs, interferon-stimulated genes
- JAK/STAT, Janus kinase/signal transducers and activators of transcription
- PAMPs/DAMPs, pathogen/damage associated molecular patterns
- SNP, single nucleotide polymorphism
- SOF
- SOF, Sofosbuvir
- SVR, sustained virological response
- TLR4
- TLRs, toll like receptors
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Affiliation(s)
- Ghada M. Salum
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, 33 EL Bohouth St.(former El Tahrir St.), Dokki, Giza, P.O. 12622, Egypt
| | - Reham M. Dawood
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, 33 EL Bohouth St.(former El Tahrir St.), Dokki, Giza, P.O. 12622, Egypt
| | - Mai Abd el-Meguid
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, 33 EL Bohouth St.(former El Tahrir St.), Dokki, Giza, P.O. 12622, Egypt
| | - Noha E. Ibrahim
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, 33 EL Bohouth St.(former El Tahrir St.), Dokki, Giza, P.O. 12622, Egypt
| | - Ashraf O. Abdel Aziz
- Department of Tropical Medicine, Faculty of Medicine, Cairo University, Giza, P.O. 12622, Egypt
| | - Mostafa K. El Awady
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, 33 EL Bohouth St.(former El Tahrir St.), Dokki, Giza, P.O. 12622, Egypt
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Frías M, Rivero-Juárez A, Machuca I, Camacho Á, Rivero A. The outlook for precision medicine for the treatment of chronic hepatitis C infection: challenges and opportunities. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2020. [DOI: 10.1080/23808993.2020.1764346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Mario Frías
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
| | - Antonio Rivero-Juárez
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
| | - Isabel Machuca
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
| | - Ángela Camacho
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
| | - Antonio Rivero
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
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Abdel Alem S, Elsharkawy A, El Akel W, Abdelaziz AO, Salama RM, El-Sayed MH, El Kassas M, Anees M, Shedeed M, Abdelsalam F, Ziada DH, El Shazly Y, El-Serafy M, Waked I, Esmat G, Doss W. Liver stiffness measurements and FIB-4 are predictors of response to sofosbuvir-based treatment regimens in 7256 chronic HCV patients. Expert Rev Gastroenterol Hepatol 2019; 13:1009-1016. [PMID: 31418303 DOI: 10.1080/17474124.2019.1653183] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 08/05/2019] [Indexed: 12/18/2022]
Abstract
Objectives: To assess the role of baseline liver stiffness (LS) by Transient elastography (TE) and FIB-4 in the prediction of virological response to sofosbuvir - based regimens in chronic HCV patients.Methods: A retrospective, multicenter study including 7256 chronic HCV patients who received different sofosbuvir-based regimens. Baseline demographic and laboratory data were recorded. TE was performed with FIB-4 calculation at baseline.Results: Sustained virological response at week 12 post-treatment (SVR12) was 91.4%. Pretreatment TE values and FIB-4 were significantly lower among sustained responders (17.8 ± 11.5 kPa, 2.66 ± 1.98, respectively) versus relapsers (24.5 ± 13.9 kPa, 4.02 ± 3.3, respectively). Best cutoff levels for LS by TE and FIB-4 score for prediction of failure to treatment response were 16.7 kPa and 2.4, respectively. Among different treatment protocol, patients with FIB-4 > 2.4, TE values >16.7 kPa are more prone to treatment failure except when using SOF/SIM treatment regimens.Conclusion: Baseline LS by TE and FIB-4 score may be useful for predicting treatment outcome in the new era of DAAs and could be integrated into pretreatment assessment of chronic HCV patients for better optimization of patient management.
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Affiliation(s)
- Shereen Abdel Alem
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Aisha Elsharkawy
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Wafaa El Akel
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ashraf O Abdelaziz
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Rabab Maamoun Salama
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Mohamed El Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan university, Cairo, Egypt
| | - Mahmoud Anees
- Department of Tropical Medicine & Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mahmoud Shedeed
- Department of infectious and Endemic Diseases, Faculty of medicine, Suez Canal University, Ismailia, Egypt
| | - Fatma Abdelsalam
- Department of hepatology, gastroenterology and infectious diseases, Banha University, Banh, Egypt
| | - Dina H Ziada
- Department of Tropical Medicine & Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Yehia El Shazly
- Internal Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Magdy El-Serafy
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Imam Waked
- Department of Hepatology, National Liver Institute, Menoufyia University, Menoufyia, Egypt
| | - Gamal Esmat
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Wahid Doss
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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Jain MK, Thamer M, Therapondos G, Shiffman ML, Kshirsagar O, Clark C, Wong RJ. Has Access to Hepatitis C Virus Therapy Changed for Patients With Mental Health or Substance Use Disorders in the Direct-Acting-Antiviral Period? Hepatology 2019; 69:51-63. [PMID: 30019478 DOI: 10.1002/hep.30171] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 07/05/2018] [Indexed: 12/20/2022]
Abstract
Direct-acting antivirals (DAA) for hepatitis C virus (HCV) became available in 2014, but the role of mental health or substance use disorders (MH/SUD) on access to treatment is unknown. The objective of this study was to examine the extent and predictors of HCV treatment in the pre-DAA and post-DAA periods in four large, diverse health care settings in the United States. We conducted a retrospective analysis of 29,544 adults with chronic HCV who did or did not receive treatment from January 1, 2011, to February 28, 2017. Kaplan-Meier curve was used to examine cumulative risk for receiving HCV treatment stratified by MH/SUD. Predictors of HCV treatment in the pre-DAA (January 1, 2011, to December 31, 2013) and post-DAA (January 1, 2014, to February 28, 2017) cohorts were analyzed using multivariate generalized estimating equations and a modified Poisson model. Overall, 21.7% (2,879/13,240) of those with chronic HCV post-DAA were treated compared with 3.5% (574/16,304) in the pre-DAA period. Compared with non-Hispanic whites, Hispanic whites (adjusted odds ratio [AOR] 0.36; 95% confidence interval [CI], 0.25, 0.52) were less likely to be treated in the post-DAA period. Those with concurrent nonalcoholic fatty liver disease (AOR 1.39; 95% CI, 1.05, 1.83), cirrhosis (AOR 2.00; 95% CI, 1.74, 2.31), and liver transplant (AOR 2.72; 95% CI, 1.87, 3.94) were more likely to be treated post-DAA. Those with MH/SUD were less likely to be treated both before (AOR 0.46; 95% CI, 0.36, 0.60) and after (AOR 0.63; 95% CI, 0.55, 0.71) DAA therapy was available. Overall, the cumulative risk for receiving HCV treatment from 2011 to 2017 among those with versus without MH/SUD was 13.6% versus 21.6%, respectively (P < 0.001). Conclusion: The volume of patients treated for HCV has increased in the post-DAA period, especially among those with liver-related comorbidities, but disparities in access to treatment continue among those with MH/SUD.
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Affiliation(s)
- Mamta K Jain
- Division of Infectious Diseases, University of Texas Southwestern Medical Center, Dallas, TX.,Parkland Health and Hospital System, Dallas, TX
| | - Mae Thamer
- Medical Technology and Practice Patterns Institute, Bethesda, MD
| | - George Therapondos
- Multi-Organ Transplant Institute, Ochsner Health System, New Orleans, LA
| | | | - Onkar Kshirsagar
- Medical Technology and Practice Patterns Institute, Bethesda, MD
| | | | - Robert J Wong
- Division of Gastroenterology & Hepatology, Alameda Health System - Highland Hospital, Oakland, CA
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Alqahtani SA, Sulkowski MS. The Role of Interferon for the Treatment of Chronic Hepatitis C Virus Infection. TOPICS IN MEDICINAL CHEMISTRY 2019:97-113. [DOI: 10.1007/7355_2018_59] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Hsieh MH, Yu ML. Reply to "Rescue for interferon failures in HCV genotype 1/HBV dually infection". J Formos Med Assoc 2018; 117:861-862. [PMID: 30041996 DOI: 10.1016/j.jfma.2018.06.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Accepted: 06/19/2018] [Indexed: 11/23/2022] Open
Affiliation(s)
- Meng-Hsuan Hsieh
- Health Management Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine, Graduate Institute of Clinical Medicine, College of Medicine, Lipid Science and Aging Research Center, Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Health Management Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine, Graduate Institute of Clinical Medicine, College of Medicine, Lipid Science and Aging Research Center, Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan; Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
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Wei L, Wedemeyer H, Liaw YF, Chan HLY, Piratvisuth T, Marcellin P, Jia J, Tan D, Chow WC, Brunetto MR, Diago M, Gurel S, Morozov V, He H, Zhu Y, Wat C, Surujbally B, Thompson AJ. No association between IFNL3 (IL28B) genotype and response to peginterferon alfa-2a in HBeAg-positive or -negative chronic hepatitis B. PLoS One 2018; 13:e0199198. [PMID: 30016335 PMCID: PMC6049926 DOI: 10.1371/journal.pone.0199198] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 05/22/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND & AIMS It has yet to be firmly established whether host IFNL3 (IL28B) genotype influences interferon responsiveness in patients with chronic hepatitis B. We investigated associations between single-nucleotide polymorphisms (SNPs) in the IFNL3 region and response to peginterferon alfa-2a in 701 patients enrolled in three large, randomized, international studies. METHODS Responses were defined as hepatitis B surface antigen (HBsAg) loss and/or hepatitis B e antigen (HBeAg) seroconversion plus hepatitis B virus (HBV) DNA <2000 IU/ml in HBeAg-positive patients, and HBsAg loss and/or HBV DNA <2000 IU/ml in HBeAg-negative patients (24 weeks after end of treatment). Associations between treatment response and the number of copies of the poor-response allele at three SNPs (rs8099917, rs12980275, rs12979860) were explored with logistic regression models in Asian and white patients. RESULTS The HBeAg-positive and -negative populations comprised 465 (92% Asian, 50% HBV genotype C) and 236 (79% Asian, 41% HBV genotype C) patients, respectively, and had respective response rates of 26% and 47%. The IFNL3 genotype was strongly associated with ethnicity. There was no association between IFNL3 genotype and treatment response in HBeAg-positive or -negative patients. Independent predictors of treatment response were: sex, HBV DNA level and alanine aminotransferase level in HBeAg-positive Asian patients; age in HBeAg-negative Asian patients; and HBV DNA in HBeAg-negative white patients. CONCLUSIONS This is the largest analysis to date of associations between IFNL3 genotype and peginterferon response in patients with chronic hepatitis B. The data suggest that IFNL3 polymorphism is not a major determinant of the response to peginterferon alfa-2a in either HBeAg-positive or HBeAg-negative patients.
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Affiliation(s)
- Lai Wei
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing, China
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Henry Lik-Yuen Chan
- Department of Medicine and Therapeutics, Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Prince of Songkla University, Songklanagarind Hospital, Songkhla, Thailand
| | - Patrick Marcellin
- Service d’Hépatologie and INSERM CRB3/U773, Université Paris-Diderot, Clichy, France
| | - Jidong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Deming Tan
- Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Wan-Cheng Chow
- Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore, Singapore
| | | | | | - Selim Gurel
- Department of Gastroenterology, Medical Faculty, Uludag University, Bursa, Turkey
| | | | - Hua He
- Roche Products Ltd, Welwyn, United Kingdom
| | - Yonghong Zhu
- Genentech Inc., San Francisco, California, United States of America
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Frias M, Rivero-Juárez A, López-López P, Rivero A. Pharmacogenetics and the treatment of HIV-/HCV-coinfected patients. Pharmacogenomics 2018; 19:979-995. [PMID: 29992850 DOI: 10.2217/pgs-2018-0046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
This review will summarize the role of pharmacogenetics in the natural history of hepatitis C, particularly in patients with HIV/HCV and will take the perspective of pharmacogenetics and its influence on the response to antiviral therapy and the susceptibility to develop adverse effects. This review will also devote a section to host genetics in other clinical situations, such as disease progression and acute HCV infection, which may determine whether treatment of HIV-/HCV-coinfected patients is implemented or deferred.
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Affiliation(s)
- Mario Frias
- Department of Clinical Virology & Zooneses, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba. Córdoba, 14004, Spain
| | - Antonio Rivero-Juárez
- Department of Clinical Virology & Zooneses, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba. Córdoba, 14004, Spain
| | - Pedro López-López
- Department of Clinical Virology & Zooneses, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba. Córdoba, 14004, Spain
| | - Antonio Rivero
- Department of Clinical Virology & Zooneses, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba. Córdoba, 14004, Spain
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Zia A, Ali M, Aziz H, Zia M, Shinwari ZK, Raza A. A case of a patient infected with a hepatitis C virus genotype 3a multidrug resistant variant in Pakistan. Infect Dis Poverty 2018; 7:11. [PMID: 29429413 PMCID: PMC6389057 DOI: 10.1186/s40249-018-0386-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 01/10/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Approximately 10 million people in Pakistan are infected with the hepatitis C virus (HCV). Most patients develop chronic hepatitis, with rare cases of spontaneous clearance. However, little is known about multidrug resistant viral variants in Pakistan. FINDINGS This case study describes a 47-year-old male diagnosed with chronic HCV genotype 3a infection in 2003. After an initial diagnosis of viral infection, the patient remained treatment naïve for 5 years. He received two therapy cycles of interferon (IFN) plus ribavirin (RBV) in 2007 and 2010, however, he was non-responsive to the therapy. The patient then received an additional two treatment cycles of pegylated IFN α-2b plus RBV (in 2011 and 2013); he was still non-responsive. In 2016, the patient underwent sofosbuvir plus RBV combination therapy, however, the sustained virological response was still not achieved. The host genetic factor was found to be heterozygous guanine and thymine (GT) and cytosine and thymine (CT) genotypes of rs8099917 and rs12979860 polymorphism of IL28B, respectively. Phylogenetic analysis suggests that the resistant variant belong to an out-group and may require triple therapy. CONCLUSIONS This is the first case that reports on a HCV-infected individual who was a non-responder to multiple IFN therapies in Pakistan. Further studies are needed to understand multidrug-resistant HCV variants in the Pakistani population.
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Affiliation(s)
- Asad Zia
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Muhammad Ali
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Hafsa Aziz
- Nuclear Oncology and Radiotherapy Institute (NORI), Islamabad, Pakistan
| | - Muhammad Zia
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Zabta Khan Shinwari
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Abida Raza
- National Institute of Lasers and Optronics (NILOP), Nanomedicine Research Labs, Islamabad, Pakistan
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12
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Acero Fernández D, Ferri Iglesias MJ, Buxó Pujolràs M, López Nuñez C, Serra Matamala I, Queralt Molés X, Aldeguer Manté X. Changes in the epidemiology and distribution of the hepatitis C virus genotypes in North-Eastern Spain over the last 35 years. GASTROENTEROLOGIA Y HEPATOLOGIA 2017; 41:2-11. [PMID: 29150360 DOI: 10.1016/j.gastrohep.2017.09.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Revised: 09/02/2017] [Accepted: 09/15/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND Genotypic distribution and epidemiology of HCV infection in Western Europe countries has changed over the last decades. AIM To establish the local genotypic profile and characterize the associated demographic variables. MATERIAL AND METHOD All the genotyping from 1988 to 2015 were considered. Associated demographic variables were included in logistic regression models. Genotyping was carried out with updated commercial kits. RESULTS Genotype 1b was the most prevalent (42.4%) followed by 1a (22.5%), 3 (18.6%), 4 (10.6%) and 2 (4.6%). The prevalence of 1a was higher in males, in patients younger than 45 and in intravenous drug users (IDU). 1b was more frequent in older than 45, with transfusion-associated and parenteral/nosocomial infections and in immigrants from Eastern Europe. Genotype 2 was highly prevalent in the postransfusional route (54.9%). Genotype 3 prevalence was high in males, in patients younger than 45, in IDU (69.3%) and in Asian and Eastern European immigrants. Genotype 4 was high in males, in patients younger than 45, and in IDU (63.5%). 1a, 3, 4 were the most prevalent genotypes in HIV-coinfected patients. There was a significant decline in genotype 1b and an increase in genotypes 3 and 4 over time. CONCLUSIONS There has been a decline of genotype 1b, associated with transfusion or parenteral/nosocomial infections, and increases in the prevalence of genotypes 1a, 3 and 4 associated with male gender and IDU, now the most prevalent infection route. Immigration contributed with genotype 2 infections from Africa and genotype 1b and 3 infections from Eastern Europe and Asia.
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Affiliation(s)
| | | | | | - Carmen López Nuñez
- Department of Digestive Diseases, Hospital de Girona, Doctor Josep Trueta, Girona, Spain
| | - Isabel Serra Matamala
- Department of Digestive Diseases, Hospital de Girona, Doctor Josep Trueta, Girona, Spain
| | | | - Xavier Aldeguer Manté
- Department of Digestive Diseases, Hospital de Girona, Doctor Josep Trueta, Girona, Spain; Institut de Investigacions Biomèdiques de Girona, IdIBGi, Salt, Spain
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13
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Nagaty A, Abd El-Wahab EW. Real-life results of sofosbuvir based therapy in chronic hepatitis C -naïve and -experienced patients in Egypt. PLoS One 2017; 12:e0184654. [PMID: 28981513 PMCID: PMC5628811 DOI: 10.1371/journal.pone.0184654] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 08/28/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND More than ten million Egyptians are infected with HCV. Every one of them is going to infect about three to four persons every year. Treating those patients is a matter of national security. A dramatic improvement in hepatitis C virus (HCV) infection treatment was achieved in the last five years. A new era of direct-acting antivirals is now dawning in Egypt. OBJECTIVE(S) We share in this report our clinical experience in treating chronic HCV Egyptian patients with Sofosbuvir based regimens to evaluate its safety and efficacy on real life practical ground. METHODS A total of 205 chronic HCV patients (195 naive and 15 experienced) were enrolled in the study. Patient were treated with Sofosbuvir+Ribavirin 24 weeks as standard of care. Two interferon eligible patients were treated with PEG-INF+ Sofosbuvir+Ribavirin for 12 weeks. The primary efficacy endpoint was the proportion of patients with sustained virologic response at 24 weeks after cessation of therapy. RESULTS The overall response rate was 97.1%. Sustained virological response rate did not differ among treatment-naive patients and patients with previous history of IFN-based therapy. Portal hypertension, prediabetes, and lack of early virologic response were predictors of non response. No clinically significant treatment-emergent adverse effects were noted. No treatment discontinuation was encountered. CONCLUSION In the real-life setting, Sofosbuvir based regimens for 24 weeks has established an efficacious and well tolerated treatment in naïve and experienced patients with chronic HCV genotype 4 infection; although shorter treatment durations may be possible. However, patient follow up should extent to at least 6 months post-treatment and verifying viral load on yearly basis is warranted to track any late relapse.
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Affiliation(s)
- Ahmed Nagaty
- Consultant of Hepatology and Infectious Diseases, Ministry of Health, Alexandria, Egypt
| | - Ekram W. Abd El-Wahab
- Tropical Health Department, High Institute of Public Health, Alexandria University, Alexandria, Egypt
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14
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Palenzuela Gardón D, Guillen IA, Fernández JR, Camacho H, Estevez ZC, Dueñas S, Alvares-Lajonchere L, Amador Y, Martinez-Donato G, Han J, Zhang Z, Zhang X, Gao Y, Campaña JR, Novoa LI. Assessment of IL-28: rs12979860 and rs8099917 Polymorphisms in a Cohort of Cuban Chronic HCV Genotype 1b Patients. J Biomol Tech 2017; 28:80-86. [PMID: 28058039 PMCID: PMC5159608 DOI: 10.7171/jbt.17-2801-001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Hepatitis C virus (HCV) is a significant global public health problem with >185 million infections worldwide. A series of genome-wide association studies (GWAS) has identified IL-28B polymorphisms as a predictor of sustained virologic response (SVR), as well as spontaneous clearance in chronic HCV genotype 1 patients. The objective of this work was to evaluate the prevalence of IL-28B rs12979860 and rs8099917 polymorphisms in Cuban chronic HCV patients. The study cohort included 73 chronic HCV patients treated with concomitant administration of CIGB-230 and nonpegylated IFN-α plus ribavirin (non-pegIFN-α/R) antiviral therapy. The genotype distribution of IL-28B rs12979860CC, -CT, and -TT was 29, 41, and 30%, respectively, and the distribution for rs8099917TT, -TG, and -GG was 63, 31, and 5%, respectively. The allele frequencies for rs12979860C and -T alleles were 51 and 49%, respectively, and for rs8099917G and -T alleles, the values were 21 and 79%, respectively. SVR rates were 55, 42, and 35% for rs12979860CC, -CT, and -TT, respectively, and 52, 30, and 25% for rs8099917TT, -GT, and -GG, respectively. The combined assessment of both single nucleotide polymorphisms (SNPs) resulted in 3 major genotypes (rs12979860CC/rs8099917TT, rs12979860CT/rs8099917TT, and rs12979860CT/rs8099917GG) with a frequency of 30.1, 21.9, and 20.5%, respectively. In patients with heterozygous variant rs12979860CT, the additional genotyping of rs8099917 contributed to increase the SVR rate. It is concluded that in Cuban HCV-infected patients, the responder homogeneous variant rs8099917TT is the most frequent genotype. The simultaneous genotyping of 2 IL-28B SNPs could improve the prediction of SVR contributing to better therapeutic decisions and treatment management.
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Affiliation(s)
| | | | | | - Hamlet Camacho
- Center for Genetic Engineering and Biotechnology, Havana, Cuba; and
| | | | - Santiago Dueñas
- Center for Genetic Engineering and Biotechnology, Havana, Cuba; and
| | | | - Yalena Amador
- Center for Genetic Engineering and Biotechnology, Havana, Cuba; and
| | | | - Junsong Han
- Shanghai Biochip Company Limited/National Engineering Center for Biochip at Shanghai, Shanghai, China
| | - Zhiming Zhang
- Shanghai Biochip Company Limited/National Engineering Center for Biochip at Shanghai, Shanghai, China
| | - Xiaona Zhang
- Shanghai Biochip Company Limited/National Engineering Center for Biochip at Shanghai, Shanghai, China
| | - Yang Gao
- Shanghai Biochip Company Limited/National Engineering Center for Biochip at Shanghai, Shanghai, China
| | | | - Lidia I. Novoa
- Center for Genetic Engineering and Biotechnology, Havana, Cuba; and
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15
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Waring JF, Davis JW, Dumas E, Cohen D, Idler K, Abel S, Georgantas R, Podsadecki T, Dutta S. Epigenetic analysis of the IFNλ3 gene identifies a novel marker for response to therapy in HCV-infected subjects. J Viral Hepat 2017; 24:397-403. [PMID: 27925355 DOI: 10.1111/jvh.12661] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 11/22/2016] [Indexed: 12/31/2022]
Abstract
Chronic hepatitis C virus (HCV) infection is characterized by high interindividual variability in response to pegylated interferon and ribavirin. A genetic polymorphism on chromosome 19 (rs12979860) upstream of interferon-λ3 (IFNλ3) is associated with a twofold change in sustained virologic response rate after 48 weeks of treatment with pegylated interferon/ribavirin in HCV genotype 1 (GT1) treatment-naïve patients. We conducted epigenetic analysis on the IFNλ3 promoter to investigate whether DNA methylation is associated with response to HCV therapy. DNA samples from HCV GT1-infected subjects receiving an interferon-free paritaprevir-containing combination regimen (N=540) and from HCV-uninfected, healthy controls (N=124) were analysed for IFNλ3 methylation levels. Methylation was strongly associated with rs12979860 allele status whether adjusting for HCV status (r=65.0%, 95% CI: [60.2%, 69.5%]), or not (r=64.4%), both with P<2.2×10-16 . In HCV GT1-infected subjects, C/C genotypes had significantly lower methylation levels relative to C/T or T/T genotypes (P<1×10-14 ), with each T allele resulting in a nine-unit increase in mean methylation level. Methylation levels did not correlate with response in subjects treated for 12 or 24 weeks. However, non-C/C subjects with higher methylation levels were more likely to relapse when treatment duration was 8 weeks. This analysis suggests that methylation status of the IFNλ3 promoter region may be a useful parameter that identifies patients more likely to relapse following HCV therapy; however, continuing therapy for a sufficient duration can overcome this difference. These findings may provide mechanistic insight into the role of IFNλ3 genetic variants in HCV treatment response.
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Affiliation(s)
| | | | - E Dumas
- AbbVie Inc., North Chicago, IL, USA
| | - D Cohen
- AbbVie Inc., North Chicago, IL, USA
| | - K Idler
- AbbVie Inc., North Chicago, IL, USA
| | - S Abel
- AbbVie Inc., North Chicago, IL, USA
| | | | | | - S Dutta
- AbbVie Inc., North Chicago, IL, USA
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16
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Gray E, Pasta DJ, Norris S, O'Leary A. Effectiveness of triple therapy with direct-acting antivirals for hepatitis C genotype 1 infection: application of propensity score matching in a national HCV treatment registry. BMC Health Serv Res 2017; 17:288. [PMID: 28424064 PMCID: PMC5395881 DOI: 10.1186/s12913-017-2188-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 03/24/2017] [Indexed: 11/18/2022] Open
Abstract
Background Observational studies are used to measure the effectiveness of an intervention in non-experimental, real world scenarios at the population level and are recognised as an important component of the evidence pyramid. Such data can be accrued through prospective cohort studies and a patient registry is a proven method for this type of study. The national hepatitis C (HCV) registry was established in Ireland in 2012 with the aim of monitoring the clinical and economic outcomes from new, high cost regimens for the treatment of HCV infection. A sustained virological response (SVR) 24 weeks following completion of therapy with interferon-containing regimens is considered a cure. Non-randomisation in these studies can result in confounding or selection bias. Propensity score (PS) matching is one of a number of statistical tools that can be used to mitigate the effects of confounding in observational studies. Methods We analysed the data of 309 patients who underwent triple therapy treatment with telaprevir (TPV) in combination with pegylated-interferon and ribavirin (PR) or boceprevir (BOC)/PR between June 2012 and December 2014. The decision to initiate treatment and the selection of the treatment regimen was at the discretion of the physician. To adjust for confounding, three approaches to propensity score matching were assessed Adjusted sustained-virological response rates (SVR), odds ratios, p-values and 95% confidence intervals were calculated from the three PS matched dataset. Results Prior to matching, the unadjusted sustained virological response rates 24 weeks after treatment complete (SVR24) were 74% (n = 158/215) and 61% (n = 57/94) for telaprevir/PR and boceprevir/PR, respectively. After matching, adjusted SVR24 rates were between 73–74% and 60–61% for telaprevir/PR and boceprevir/PR, respectively. Conclusion Efficacy rates were comparable with those reported in pivotal clinical trials and real world studies. After adjusting for confounding, we conclude that there was no difference in treatment effect after PS matching. The small sample size limits the conclusions that can be made about the effect of PS matching. Propensity score adjustment remains a tool that can be applied to future analysis, however, we suggest, where possible, using a larger sample size in order to reduce the uncertainty around the outcomes. Electronic supplementary material The online version of this article (doi:10.1186/s12913-017-2188-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Emma Gray
- School of Medicine, Trinity College Dublin, Dublin, Ireland.
| | | | - Suzanne Norris
- School of Medicine, Trinity College Dublin, Dublin, Ireland.,Department of Hepatology, St James' Hospital, Dublin, Ireland
| | - Aisling O'Leary
- National Centre for Pharmacoeconomics, St. James' Hospital, Dublin, Ireland.,School of Pharmacy, Royal College of Surgeons of Ireland, Dublin, Ireland
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17
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Bichoupan K, Tandon N, Martel-Laferriere V, Patel NM, Sachs D, Ng M, Schonfeld EA, Pappas A, Crismale J, Stivala A, Khaitova V, Gardenier D, Linderman M, Olson W, Perumalswami PV, Schiano TD, Odin JA, Liu LU, Dieterich DT, Branch AD. Factors associated with success of telaprevir- and boceprevir-based triple therapy for hepatitis C virus infection. World J Hepatol 2017; 9:551-561. [PMID: 28469811 PMCID: PMC5395804 DOI: 10.4254/wjh.v9.i11.551] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 03/17/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate new therapies for hepatitis C virus (HCV), data about real-world outcomes are needed.
METHODS Outcomes of 223 patients with genotype 1 HCV who started telaprevir- or boceprevir-based triple therapy (May 2011-March 2012) at the Mount Sinai Medical Center were analyzed. Human immunodeficiency virus-positive patients and patients who received a liver transplant were excluded. Factors associated with sustained virological response (SVR24) and relapse were analyzed by univariable and multivariable logistic regression as well as classification and regression trees. Fast virological response (FVR) was defined as undetectable HCV RNA at week-4 (telaprevir) or week-8 (boceprevir).
RESULTS The median age was 57 years, 18% were black, 44% had advanced fibrosis/cirrhosis (FIB-4 ≥ 3.25). Only 42% (94/223) of patients achieved SVR24 on an intention-to-treat basis. In a model that included platelets, SVR24 was associated with white race [odds ratio (OR) = 5.92, 95% confidence interval (CI): 2.34-14.96], HCV sub-genotype 1b (OR = 2.81, 95%CI: 1.45-5.44), platelet count (OR = 1.10, per x 104 cells/μL, 95%CI: 1.05-1.16), and IL28B CC genotype (OR = 3.54, 95%CI: 1.19-10.53). Platelet counts > 135 x 103/μL were the strongest predictor of SVR by classification and regression tree. Relapse occurred in 25% (27/104) of patients with an end-of-treatment response and was associated with non-FVR (OR = 4.77, 95%CI: 1.68-13.56), HCV sub-genotype 1a (OR = 5.20; 95%CI: 1.40-18.97), and FIB-4 ≥ 3.25 (OR = 2.77; 95%CI: 1.07-7.22).
CONCLUSION The SVR rate was 42% with telaprevir- or boceprevir-based triple therapy in real-world practice. Low platelets and advanced fibrosis were associated with treatment failure and relapse.
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18
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Mangia A, Foster GR, Berg CP, Curescu M, Ledinghen VD, Habersetzer F, Manolakopoulos S, Negri E, Papatheodoridis G, Ahlers S, Castillo M, Bakalos G, Mauss S. Efficacy and safety profile of boceprevir- or telaprevir-based triple therapy or dual peginterferon alfa-2a or alfa-2b plus ribavirin therapy in chronic hepatitis C: the real-world PegBase observational study. Ann Gastroenterol 2017; 30:327-343. [PMID: 28469364 PMCID: PMC5411384 DOI: 10.20524/aog.2017.0136] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 02/19/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The aim of the study was to determine the efficacy and safety of triple therapy with a first-generation protease inhibitor (PI; boceprevir, telaprevir) plus peginterferon alfa-2a or -2b plus ribavirin, and dual therapy (peginterferon alfa-2a or -2b plus ribavirin) in patients with chronic hepatitis C (CHC) in routine clinical practice. METHODS PegBase was an international, prospective, observational study in which 4441 patients with CHC were enrolled in 27 countries. This analysis focuses on results in 4100 treatment-naïve and previously treated patients treated with PI-based triple therapy or dual therapy, according to the discretion of the investigator and local standards of practice. The primary efficacy outcome was sustained virological response after 12-week follow up (SVR12). RESULTS SVR12 rates in treatment-naïve genotype (G) 1 patients were 56.6% and 62.9% for recipients of boceprevir plus peginterferon alfa-2a/ribavirin and boceprevir plus peginterferon alfa-2b/ribavirin, respectively, and 65.3% and 58.6% for recipients of telaprevir plus peginterferon alfa-2a/ribavirin and telaprevir plus peginterferon alfa-2b/ribavirin, respectively. In previously treated patients assigned to these four regimens, SVR12 rates were 43.6%, 48.3%, 60.3% and 56.1%, respectively. Among treatment-naïve patients assigned to peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin, respectively, SVR12 rates were 49.2% and 41.9% in G1 patients, 75.7% and 83.3% in G2 patients, 65.9% and 65.9% in G3 patients, and 49.7%, and 51.1% in G4 patients. The safety and tolerability of dual and triple therapy were consistent with previous reports. CONCLUSION The efficacy and safety of first-generation PI-based triple-therapy and dual-therapy regimens in this real-world cohort were broadly comparable to those of previous studies.
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Affiliation(s)
- Alessandra Mangia
- Liver Unit, IRCCS Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy
| | - Graham R Foster
- Institute of Cellular and Molecular Sciences, Queen Mary University of London, London, UK
| | - Christoph P Berg
- Department of Internal Medicine, Medizinische Universitätsklinik Tübingen, Tübingen, Germany
| | - Manuela Curescu
- Clinic of Infectious Diseases, University of Medicine and Pharmacy Timişoara, Timişoara, Romania
| | | | - François Habersetzer
- Unité Hépatologie, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Inserm 1110, Université de Strasbourg, Strasbourg, France
| | | | - Elisa Negri
- UO Malattie Infettive ed Epatologia, Azienda Ospedaliero - Universitaria di Parma, Parma, Italy
| | | | | | | | | | - Stefan Mauss
- Center for HIV and Hepatogastroenterology, Düsseldorf, Germany
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Hernández-Alvarez N, Pascasio Acevedo JM, Quintero E, Fernández Vázquez I, García-Eliz M, de la Revilla Negro J, Crespo García J, Hernández-Guerra M. Effect of season and sunlight on viral kinetics during hepatitis C virus therapy. BMJ Open Gastroenterol 2017; 4:e000115. [PMID: 28321328 PMCID: PMC5353279 DOI: 10.1136/bmjgast-2016-000115] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 10/28/2016] [Accepted: 11/28/2016] [Indexed: 02/07/2023] Open
Abstract
Background and aims Rapid viral response (RVR) during antiviral treatment for hepatitis C virus (HCV) predicts sustained viral response (SVR). Recently, vitamin D levels have been associated with SVR. As sunlight is the most important source of vitamin D and shows seasonal variation, we evaluated the effect of season on viral kinetics during peginterferon/ribavirin-based therapy for HCV. Methods Consecutive HCV patients treated with peginterferon/ribavirin and boceprevir/ telaprevir (June 2011–July 2014) were included. Patients were grouped according to season when therapy was initiated (Season A: May–October and Season B: November–April) depending on hours of daily sunlight. Multiple logistic regression analysis included factors known to influence SVR to treatment. The dependent variables were undetectable viral load (VL) or VL ≤15 UI/mL (VL ≤15) at weeks 4, 8 and 12, end of treatment and SVR. Results The study included 930 patients (66.8% men; median 54 years) treated with telaprevir (n=537) or boceprevir, without (n=481) or with lead-in therapy of peginterferon/ribavirin. Baseline characteristics of patients in Season A (45.3%, n=421) and Season B groups were similar. Overall, a higher rate of RVR (23.5% vs 16.1%, p=0.005) and VL ≤15 (51.0% vs 38.6%, p≤0.001) was observed in patients starting treatment during Season A versus Season B. By logistic regression analysis, initiating treatment in Season A proved to be an independent predictor of RVR and VL ≤15. Conclusions In our setting, seasonality affects viral kinetics in HCV genotype 1 patients treated with peginterferon/ribavirin-based therapy. Our findings support the hypothesis that vitamin D influences viral response to peginterferon/ribavirin-based therapy.
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Affiliation(s)
| | | | | | | | - María García-Eliz
- Hospital Universitari i Politècnic La Fe, CIBERehd , Valencia , Spain
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20
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Mensing S, Eckert D, Sharma S, Polepally AR, Khatri A, Podsadecki TJ, Awni WM, Menon RM, Dutta S. Population pharmacokinetics of paritaprevir, ombitasvir, dasabuvir, ritonavir and ribavirin in hepatitis C virus genotype 1 infection: analysis of six phase III trials. Br J Clin Pharmacol 2017; 83:527-539. [PMID: 27662429 PMCID: PMC5306483 DOI: 10.1111/bcp.13138] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 09/07/2016] [Accepted: 09/16/2016] [Indexed: 12/23/2022] Open
Abstract
AIM The aim of the current study was to characterize the population pharmacokinetics of a triple direct-acting antiviral (DAA) regimen (3D) (ombitasvir, paritaprevir-ritonavir and dasabuvir) and adjunctive ribavirin, and estimate covariate effects in a broad spectrum of subjects with hepatitis C virus (HCV) genotype 1 infection. METHODS Pharmacokinetic data from six phase III studies and one phase II study in subjects receiving the currently approved doses of the 3D ± ribavirin regimen for treating HCV genotype 1 infection for 12 weeks or 24 weeks were characterized using separate population pharmacokinetic models, built using each component of the regimen from nonlinear mixed-effects methodology in NONMEM 7.3. In the models, demographic and clinical covariates were tested. Models were assessed via goodness-of-fit plots, visual predictive checks and bootstrap evaluations. RESULTS The population pharmacokinetic models for each component of the 3D ± ribavirin regimen (DAAs and ritonavir, n = 2348) and ribavirin (n = 1841) adequately described their respective plasma concentration-time data. Model parameter estimates were precise and robust, and all models showed good predictive ability. Significant covariate effects associated with apparent clearance and volume of distribution included age, body weight, gender, cirrhosis, HCV subtype, opioid or antidiabetic agent use, and creatinine clearance. CONCLUSION The population pharmacokinetics of the 3D ± ribavirin regimen components in HCV-infected patients were characterized using phase II and III HCV clinical trial data. Although several statistically significant covariates were identified, their effects were modest and not clinically meaningful to necessitate dose adjustments for any component of the 3D regimen.
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Affiliation(s)
- Sven Mensing
- Clinical Pharmacology and PharmacometricsAbbVie Deutschland GmbH & Co., KGKnollstrasse 5067061Ludwigshafen am RheinGermany
| | - Doerthe Eckert
- Clinical Pharmacology and PharmacometricsAbbVie Deutschland GmbH & Co., KGKnollstrasse 5067061Ludwigshafen am RheinGermany
| | - Shringi Sharma
- Clinical Pharmacology and Pharmacometrics, Dept. R4PK, Bldg. AP31‐3AbbVie, Inc.1 North Waukegan RoadNorth ChicagoIL60064USA
- Department of Clinical PharmacologyGilead Sciences, Inc.333 Lakeside DriveFoster CityCA94404USA
| | - Akshanth R. Polepally
- Clinical Pharmacology and Pharmacometrics, Dept. R4PK, Bldg. AP31‐3AbbVie, Inc.1 North Waukegan RoadNorth ChicagoIL60064USA
| | - Amit Khatri
- Clinical Pharmacology and Pharmacometrics, Dept. R4PK, Bldg. AP31‐3AbbVie, Inc.1 North Waukegan RoadNorth ChicagoIL60064USA
| | | | - Walid M. Awni
- Clinical Pharmacology and Pharmacometrics, Dept. R4PK, Bldg. AP31‐3AbbVie, Inc.1 North Waukegan RoadNorth ChicagoIL60064USA
| | - Rajeev M. Menon
- Clinical Pharmacology and Pharmacometrics, Dept. R4PK, Bldg. AP31‐3AbbVie, Inc.1 North Waukegan RoadNorth ChicagoIL60064USA
| | - Sandeep Dutta
- Clinical Pharmacology and Pharmacometrics, Dept. R4PK, Bldg. AP31‐3AbbVie, Inc.1 North Waukegan RoadNorth ChicagoIL60064USA
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Boisvert M, Shoukry NH. Type III Interferons in Hepatitis C Virus Infection. Front Immunol 2016; 7:628. [PMID: 28066437 PMCID: PMC5179541 DOI: 10.3389/fimmu.2016.00628] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 12/08/2016] [Indexed: 12/20/2022] Open
Abstract
The interferon (IFN)-λ family of type III cytokines includes the closely related interleukin (IL)-28A (IFN-λ2), IL-28B (IFN-λ3), and IL-29 (IFN-λ1). They signal through the Janus kinases (JAK)-signal transducers and activators of transcription pathway and promote an antiviral state by the induction of expression of several interferon-stimulated genes (ISGs). Contrary to type I IFNs, the effect of IFN-λ cytokines is largely limited to epithelial cells due to the restricted pattern of expression of their specific receptor. Several genome-wide association studies have established a strong correlation between polymorphism in the region of IL-28B gene (encoding for IFN-λ3) and both spontaneous and therapeutic IFN-mediated clearance of hepatitis C virus (HCV) infection, but the mechanism(s) underlying this enhanced viral clearance are not fully understood. IFN-λ3 directly inhibits HCV replication, and in vitro studies suggest that polymorphism in the IFN-λ3 and its recently identified overlapping IFN-λ4 govern the pattern of ISGs induced upon HCV infection of hepatocytes. IFN-λ can also be produced by dendritic cells, and apart from its antiviral action on hepatocytes, it can regulate the inflammatory response of monocytes/macrophages, thus acting at the interface between innate and adaptive immunity. Here, we review the current state of knowledge about the role of IFN-λ cytokines in mediating and regulating the immune response during acute and chronic HCV infections.
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Affiliation(s)
- Maude Boisvert
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM) , Montréal, QC , Canada
| | - Naglaa H Shoukry
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada; Département de médecine, Université de Montréal, Montréal, QC, Canada
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Robaeys G, Bielen R, Azar DG, Razavi H, Nevens F. Global genotype distribution of hepatitis C viral infection among people who inject drugs. J Hepatol 2016; 65:1094-1103. [PMID: 27520879 DOI: 10.1016/j.jhep.2016.07.042] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 07/28/2016] [Accepted: 07/30/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Hepatitis C viral infection (HCV) after injection drug use is very prevalent. The kind of genotype determines the response to treatment. However, no systematic review update on the global genotype distribution of HCV in people who inject drugs (PWID) is currently available. METHODS A systematic review was performed by using the keywords: Genotype, Hepatitis C, Injection drug user/Intravenous drug user/Substance user/ PWID, Name of countries in Pubmed, Embase and PsycINFO. The results were compared with the review of Gower et al. in 2014, concerning the distribution of HCV genotypes in the general HCV population. RESULTS Using these keywords, 132 studies in 48 countries (from 1995 to 2015) were collected. After grading these results, the data of 48 studies were used to determine the distribution of genotypes in PWID. Genotype 1 is the most prevalent genotype all over the world in PWID. In Europe, genotypes 1, 3 and 4 are highly prevalent. In North and South America and in Australia genotype 1 and 3 are most prevalent. In Asia genotype 2 and 6, and Africa genotype 1a and 4 are mostly observed. Overall, the most important differences comparing with the general population are a lower prevalence of genotype 1b in the PWID population and higher prevalence of genotype 1a and 3. CONCLUSIONS There is a different prevalence of genotype distribution in PWID than in the general population. Genotype 3 is especially highly prevalent in the Western countries. LAY SUMMARY Hepatitis C viral infection after injection drug use is very prevalent. The most important genotype causing HCV infection in PWID globally is genotype 1, as is the case in the general population, but also genotype 3 is highly prevalent in PWID. Genotype 4 is most prevalent in Africa, spreading into Europe, whereas genotype 2 and 6 are more located in Asia. The most important difference comparing to the general population are generally lower prevalence of genotype 1b, and higher prevalence of genotype 1a and 3 in PWID. As the genotype nowadays still determines the treatment, and as there is a different genotype distribution than in the general population, it is important to identify the genotype also in PWID.
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Affiliation(s)
- Geert Robaeys
- Ziekenhuis Oost-Limburg, Dept. of Gastro-enterology and Hepatology, Schiepse Bos 6, 3600 Genk, Belgium; Hasselt University, Faculty of Medicine and Life Sciences, Martelarenlaan 42, 3500 Hasselt, Belgium; KULeuven, Dept. of Gastro-enterology and Hepatology, Herestraat 49, 3000 Leuven, Belgium
| | - Rob Bielen
- Ziekenhuis Oost-Limburg, Dept. of Gastro-enterology and Hepatology, Schiepse Bos 6, 3600 Genk, Belgium; Hasselt University, Faculty of Medicine and Life Sciences, Martelarenlaan 42, 3500 Hasselt, Belgium.
| | - Darush Ghezel Azar
- Ziekenhuis Oost-Limburg, Dept. of Gastro-enterology and Hepatology, Schiepse Bos 6, 3600 Genk, Belgium; KULeuven, Dept. of Gastro-enterology and Hepatology, Herestraat 49, 3000 Leuven, Belgium
| | - Homie Razavi
- Center for Disease Analysis, 1120 W South Boulder Road, Suite 102, Louisville, CO 80026, USA
| | - Frederik Nevens
- KULeuven, Dept. of Gastro-enterology and Hepatology, Herestraat 49, 3000 Leuven, Belgium
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Mangia A, De Ledinghen V, Bailly F, Brahm J, Keiss J, Valantinas J, Rasmann N, Messinger D, Tatsch F, Bakalos G, Foster GR. IL28B genotype is associated with cirrhosis or transition to cirrhosis in treatment-naive patients with chronic HCV genotype 1 infection: the international observational Gen-C study. SPRINGERPLUS 2016; 5:1990. [PMID: 27917361 PMCID: PMC5116020 DOI: 10.1186/s40064-016-3663-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 11/07/2016] [Indexed: 02/07/2023]
Abstract
Background and purpose Contradictory data exist on the association between host interleukin-28B (IL28B) rs12979860 genotype and liver fibrosis in patients with chronic hepatitis C (CHC). This large, international, observational study (NCT01675427/MV25600) investigated relationships between IL28B rs12979860 genotype and liver fibrosis stage in CHC patients. Methods A total of 3003 adult, treatment-naive CHC patients were enrolled into the study. Patients made one study visit to provide a blood sample for genotyping; other data were obtained from medical records. Results 2916 patients comprised the analysis population; the majority were enrolled in Europe (n = 2119), were Caucasian (n = 2582) and had hepatitis C virus (HCV) genotype (G)1 infection (n = 1702) (G2 = 323, G3 = 574, G4 = 260). Distribution of IL28B genotypes varied according to region of enrolment, patient ethnicity and HCV genotype. A significant association was observed between increasing number of IL28B T alleles and the prevalence of cirrhosis/transition to cirrhosis (based on biopsy or non-invasive assessments) in G1-infected patients (CC = 22.2% [111/499], CT = 27.5% [255/928], TT = 32.3% [87/269]; p = 0.0018). The association was significant in the large subgroup of European Caucasian G1 patients (n = 1245) but not in the smaller Asian (n = 25), Latin American (n = 137) or Middle Eastern (n = 289) G1 subgroups. IL28B genotype was not associated with liver fibrosis stage in patients with HCV G2, G3 or G4 infection. Conclusion This large, international study found that IL28B rs12979860 genotype is significantly associated with liver fibrosis stage in CHC patients with HCV G1 infection. This association was evident in European Caucasians but not in G1-infected patients from Asia, Latin America or the Middle East. Electronic supplementary material The online version of this article (doi:10.1186/s40064-016-3663-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Alessandra Mangia
- Liver Unit, IRCCS Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, 71013 Italy
| | | | - François Bailly
- Hepatology Unit, Groupe Hospitalier Nord, CHU Lyon, 69004 Lyon, France
| | - Javier Brahm
- Gastroenterology Department, University of Chile Clinical Hospital, Santiago, 8380456 Chile
| | - Jazeps Keiss
- Latvian Centre of Infectious Diseases, LLC Riga East University Hospital, Riga, 1006 Latvia
| | - Jonas Valantinas
- Centre of Hepatology, Gastroenterology and Dietetics, Vilnius University, 08661 Vilnius, Lithuania
| | - Nele Rasmann
- Center for Infectious Diseases, West Tallinn Central Hospital, 10617 Tallinn, Estonia
| | | | - Fernando Tatsch
- Global Medical Affairs, F. Hoffmann-La Roche Ltd, 4074 Basel, Switzerland ; AbbVie, North Chicago, IL USA
| | - Georgios Bakalos
- Global Product Development Medical Affairs, F. Hoffmann-La Roche Ltd, 4074 Basel, Switzerland
| | - Graham R Foster
- Institute of Cellular and Molecular Sciences, Queen Mary University of London, London, E1 2AT UK
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24
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Boceprevir plus pegylated interferon/ribavirin to re-treat hepatitis C virus genotype 1 in HIV-HCV co-infected patients: final results of the Spanish BOC HIV-HCV Study. Int J Infect Dis 2016; 53:46-51. [PMID: 27815225 DOI: 10.1016/j.ijid.2016.10.028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 10/13/2016] [Accepted: 10/25/2016] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION Boceprevir (BOC) was one of the first oral inhibitors of hepatitis C virus (HCV) NS3 protease to be developed. This study assessed the safety and efficacy of BOC+pegylated interferon-α2a/ribavirin (PEG-IFN/RBV) in the retreatment of HIV-HCV co-infected patients with HCV genotype 1. METHODS This was a phase III prospective trial. HIV-HCV (genotype 1) co-infected patients from 16 hospitals in Spain were included. These patients received 4 weeks of PEG-IFN/RBV (lead-in), followed by response-guided therapy with PEG-IFN/RBV plus BOC (a fixed 44 weeks was indicated in the case of cirrhosis). The primary endpoint was the sustained virological response (SVR) rate at 24 weeks post-treatment. Efficacy and safety were evaluated in all patients who received at least one dose of the study drug. RESULTS From June 2013 to April 2014, 102 patients were enrolled, 98 of whom received at least one treatment dose. Seventy-three percent were male, 34% were cirrhotic, 23% had IL28b CC, 65% had genotype 1a, and 41% were previous null responders. The overall SVR rate was 67%. Previous null-responders and cirrhotic patients had lower SVR rates (57% and 51%, respectively). Seventy-six patients (78%) completed the therapy scheme; the most common reasons for discontinuation were lack of response at week 12 (12 patients) and adverse events (six patients). CONCLUSIONS Response-guided therapy with BOC in combination with PEG-IFN/RBV led to an overall SVR rate of 67%, but an SVR rate of only 51% in patients with cirrhosis. The therapy was generally well tolerated. Although the current standards of care do not include BOC+PEG-IFN/RBV, the authors believe that this combination can be beneficial in situations where new HCV direct antiviral agent interferon-free therapies are not available yet.
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Nguyen LT, Gray E, O'Leary A, Carr M, De Gascun CF, Irish Hepatitis C Outcomes Research Network. The Role of Hepatitis C Virus Core Antigen Testing in the Era of Direct Acting Antiviral Therapies: What We Can Learn from the Protease Inhibitors. PLoS One 2016; 11:e0163900. [PMID: 27711230 PMCID: PMC5053597 DOI: 10.1371/journal.pone.0163900] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 09/18/2016] [Indexed: 12/16/2022] Open
Abstract
Direct-acting antiviral (DAA) therapies have revolutionised the treatment of hepatitis C virus (HCV). The financial cost of DAAs however is significant, and first generation protease inhibitors (PIs) also require frequent monitoring of viral RNA levels to guide treatment. In this context, we examined the relevance of HCV antigen testing to evaluate the potential role in monitoring virological response to HCV antiviral treatment with the PI-based triple therapies, telaprevir (TVR) and boceprevir (BOC). Chronic HCV-infected individuals (n = 152) enrolled in the Irish Hepatitis C Outcomes Research Network (ICORN) study were prospectively analysed for baseline markers and the early viral kinetics associated with SVR. The sustained virological response (SVR) rates in the cohort receiving TVR and BOC were 87.3% and 73.8%, respectively. Baseline factors associated with successful outcome in TVR therapy were age (P = 0.0098), IFNL3 genotype (P = 0.0330) and viral load (P = 0.0456). RNA level at week 4 (P = 0.0068) and viral antigen negativity at week 2 (P = 0.0359) were predictive of SVR for TVR-based therapy. In BOC therapy, prior interferon treatment (P = 0.0209) and IFNL3 genotype (P = 0.0410) were baseline predictors of SVR. Evidence of viraemia based either on viral RNA or antigen at week 4 predicted SVR in these patients. Our data showed that rapid decline of HCV antigen to negative level at week 2 in TVR treatment and <0.96 log fmol/l in BOC treatment after commencement of PI triple therapy were associated with SVR. HCV antigen measurement should be considered as a potential alternative for monitoring treatment response during DAA-based regimens.
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Affiliation(s)
- Linh Thuy Nguyen
- National Virus Reference Laboratory, University College Dublin, Dublin, Ireland
- School of Medicine and Medical Science, University College Dublin, Dublin, Ireland
- Ireland Vietnam Blood-Borne Virus Initiative (IVVI), Dublin, Ireland and Hanoi, Vietnam
- * E-mail:
| | - Emma Gray
- National Centre for Pharmacoeconomics in Ireland, St James’s Hospital, Dublin, Ireland
| | - Aisling O'Leary
- National Centre for Pharmacoeconomics in Ireland, St James’s Hospital, Dublin, Ireland
| | - Michael Carr
- National Virus Reference Laboratory, University College Dublin, Dublin, Ireland
| | - Cillian F. De Gascun
- National Virus Reference Laboratory, University College Dublin, Dublin, Ireland
- School of Medicine and Medical Science, University College Dublin, Dublin, Ireland
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26
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Zhao YJ, Khoo AL, Lin L, Teng M, Koh CJ, Lim SG, Lim BP, Dan YY. Cost-effectiveness of strategy-based approach to treatment of genotype 1 chronic hepatitis C. J Gastroenterol Hepatol 2016; 31:1628-37. [PMID: 26990023 DOI: 10.1111/jgh.13341] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 02/10/2016] [Accepted: 02/29/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM The high cost of chronic hepatitis C (HCV) direct-acting antivirals (DAAs) poses significant financial challenges for health payers, especially in Asia. A personalized treatment strategy based on individualized probability of virological response using oral DAAs as second-line therapy would seem practical but has not been studied. METHODS We performed a Markov model to project health outcomes and costs for patients with genotype 1 HCV through 10 treatment strategies over a lifetime period. The implication of retreatment was also incorporated to reflect real-life situation. RESULTS Using boceprevir and peginterferon/ribavirin (BOC/PR, the least costly treatment) as a base case, the all-oral therapies such as ombitasvir/paritaprevir/ritonavir-dasabuvir are cost-effective with an incremental cost-effective ratio of $US50 828. However, the all-oral DAAs would no longer be cost-effective compared with conventional therapies if retreatment were taken into account. A road map strategy using rapid virological response to guide use of BOC/PR and sofosbuvir/PR had the most favorable incremental cost-effective ratio ($US27 782) relative to BOC/PR. Nevertheless, the trade-off with the cost-effectiveness of the road map strategy is an increased number of liver-related deaths compared with all-oral DAAs (52 vs 10-20 per 10 000 patients) by incorporating retreatment. CONCLUSIONS The 12-week all-oral DAAs were cost-effective options using conventional drug-to-drug comparison. However, they cease to be cost-effective when treatment strategies incorporating DAA retreatment for interferon failures are incorporated. HCV management can be optimized by adopting individualized treatment algorithm providing a practical solution to health payers to make oral DAAs accessible to those who need them most.
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Affiliation(s)
- Ying Jiao Zhao
- Pharmacy and Therapeutics Office, Group Corporate Development, National Healthcare Group, Singapore
| | - Ai Leng Khoo
- Pharmacy and Therapeutics Office, Group Corporate Development, National Healthcare Group, Singapore
| | - Liang Lin
- Pharmacy and Therapeutics Office, Group Corporate Development, National Healthcare Group, Singapore
| | - Monica Teng
- Pharmacy and Therapeutics Office, Group Corporate Development, National Healthcare Group, Singapore
| | - Calvin J Koh
- Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, Singapore
| | - Seng Gee Lim
- Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, Singapore
| | - Boon Peng Lim
- Pharmacy and Therapeutics Office, Group Corporate Development, National Healthcare Group, Singapore
| | - Yock Young Dan
- Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, Singapore. .,Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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27
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Velosa J. Why is viral eradication so important in patients with HCV-related cirrhosis? Antivir Ther 2016; 22:1-12. [PMID: 27553973 DOI: 10.3851/imp3077] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/18/2016] [Indexed: 02/07/2023]
Abstract
Approximately one-third of patients infected with chronic HCV have cirrhosis, and this is likely to increase in the near future. The risk of complications, mainly the development of hepatocellular carcinoma, depends on the presence of cirrhosis, and a significant increase in the incidence of cirrhosis-related events, including mortality, is likely in the following years. All-oral therapy with direct-acting antivirals (DAAs) offers a safe and short treatment, with cure rates over 90% in compensated cirrhosis. Cirrhotic patients should be given high priority for treatment because viral clearance has a significant impact on the natural history of HCV infection, halting the progression of the disease and inducing the regression of fibrosis, as well as reducing the need for liver transplantation and improving survival. The benefit of DAAs is great in patients with decompensated cirrhosis, up until recently a population for whom no alternative therapy was available. The efficacy of all-oral therapy has been reported to improve liver function in about 50% of Child-Pugh class C patients. The regression of cirrhosis observed in more than half of patients achieving viral eradication on prior interferon-based regimens still has to be demonstrated in patients treated with DAAs, although there is reason to believe that this will happen. Advanced cirrhosis will eventually become the last boundary of antiviral therapy that will soon be conquered with new drugs currently pending approval.
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Affiliation(s)
- José Velosa
- Hospital de Santa Maria - Gastroenterology and Hepatology, Lisbon, Portugal
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28
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Pecoraro V, Cariani E, Villa E, Trenti T. Optimisation of triple therapy for patients with chronic hepatitis C: a systematic review. Eur J Clin Invest 2016; 46:737-48. [PMID: 27376688 DOI: 10.1111/eci.12656] [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] [Received: 05/05/2016] [Accepted: 02/11/2016] [Indexed: 12/15/2022]
Abstract
BACKGROUND Triple therapy with Pegylated-Interferon α (PEG-IFNα)/Ribavirin (RBV) and Boceprevir (Boc) or Telaprevir (Tel) significantly improved sustained virological response (SVR) rates for patients with genotype 1 HCV infection compared to PEG-IFNα/RBV alone (dual therapy). However, less is known about factors associated with rates of SVR and of adverse events (AEs). MATERIAL AND METHODS The aim of this systematic review was to evaluate the evidence regarding the factors affecting response and rate of AEs associated with triple therapy. We performed systematic electronic searches in Medline, Embase, Scopus and Central as well as a list of reference literature. We included randomised controlled trials examining triple therapy compared with dual therapy and reporting data according to patients features and about AEs. Odds ratios (OR) were pooled using either fixed or random effect model, as appropriate. RESULTS We included data from 14 studies. Treatment with triple therapy increased SVR rate compared to dual therapy especially in patients previously treated with PEG-IFNα/RBV and with increased pretreatment alanine aminotransferase (ALT) levels. Higher rate of serious AEs and treatment discontinuation due to AEs was also observed particularly in treatment-experienced patients. CONCLUSIONS The present study shows how improved results of triple therapy are mainly observed in some patients' subsets and are accompanied by increased risk of AEs compared to dual therapy. These results might be useful for optimising treatment of chronic hepatitis C when IFN-free regimens are unavailable.
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Affiliation(s)
- Valentina Pecoraro
- Clinical Pathology - Toxicology, Ospedale Civile Sant'Agostino Estense, Modena, Italy
| | - Elisabetta Cariani
- Clinical Pathology - Toxicology, Ospedale Civile Sant'Agostino Estense, Modena, Italy
| | - Erica Villa
- Division of Gastroenterology, AOU Modena, Modena, Italy
| | - Tommaso Trenti
- Clinical Pathology - Toxicology, Ospedale Civile Sant'Agostino Estense, Modena, Italy
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Benítez-Gutiérrez L, Barreiro P, Labarga P, de Mendoza C, Fernandez-Montero JV, Arias A, Peña JM, Soriano V. Prevention and management of treatment failure to new oral hepatitis C drugs. Expert Opin Pharmacother 2016; 17:1215-23. [PMID: 27149603 DOI: 10.1080/14656566.2016.1182156] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Chronic hepatitis C virus (HCV) infection has become a curable disease. Sustained virologic response rates above 90% have been achieved with recommended direct-acting antiviral (DAA) combinations in most registration trials. However, outcomes in real-world patients are lower. In patients experiencing DAA failure, resistance-associated variants (RAVs) are almost universally selected. At this time it is unclear when and how to re-treat hepatitis C in patients with prior DAA failure. AREAS COVERED The rate of DAA failure and predictors of lack of treatment response using distinct DAA combinations are analyzed. We discuss the management of HCV treatment failure and the impact of RAVs on re-treatment strategies. EXPERT OPINION Failure to DAA combinations occurs more often in chronic hepatitis C patients with baseline predictors of poor response, such as those with RAVs, genotypes 3 or 1a, advanced liver cirrhosis, elevated serum HCV-RNA and perhaps HIV coinfection. Impaired antiviral efficacy is more frequent when multiple factors are present. On-treatment predictors of DAA failure are poor drug adherence and development of side effects. Extending the length of therapy, adding ribavirin and/or using DAA from other drug families may allow successful re-treatment of most prior DAA failures.
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Affiliation(s)
- Laura Benítez-Gutiérrez
- a Department of Internal Medicine , Puerta de Hierro Research Institute & University Hospital , Majadahonda , Spain
| | - Pablo Barreiro
- b Infectious Diseases Unit , La Paz University Hospital , Madrid , Spain
| | - Pablo Labarga
- c Department of Internal Medicine , La Milagrosa Clinic , Madrid , Spain
| | - Carmen de Mendoza
- a Department of Internal Medicine , Puerta de Hierro Research Institute & University Hospital , Majadahonda , Spain
| | - José V Fernandez-Montero
- d Department of Infectious Diseases , University Hospital Crosshouse , Kilmarnock , Scotland , United Kingdom
| | - Ana Arias
- a Department of Internal Medicine , Puerta de Hierro Research Institute & University Hospital , Majadahonda , Spain
| | - José M Peña
- b Infectious Diseases Unit , La Paz University Hospital , Madrid , Spain
| | - Vicente Soriano
- b Infectious Diseases Unit , La Paz University Hospital , Madrid , Spain
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30
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Simoes P, Asaad A, Abed J, Engelson ES, Kotler DP. Effect of Gender on the Response to Hepatitis C Treatment in an Inner-City Population. Womens Health Issues 2016; 25:289-93. [PMID: 25965157 DOI: 10.1016/j.whi.2015.02.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 02/23/2015] [Accepted: 02/25/2015] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Hepatitis C virus (HCV) is the leading cause of cirrhosis, hepatocellular carcinoma, and liver transplantation in the United States. Response to treatment has improved with the addition of direct acting protease inhibitors. However, there are limited real-world data on the role of gender in achieving a sustained virologic response (SVR). METHODS We conducted a cross-sectional study in 70 patients treated for HCV, genotype 1 infection with pegylated alpha interferon, ribavirin, and either telaprevir or boceprevir at our inner-city liver clinic. RESULTS The SVR was significantly lower in women than in men (24% vs. 59%; p < .01). Statistical significance persisted after adjusting for age, race, genotype, prior treatment status, duration of therapy, and stage of fibrosis. The adjusted odds ratio for achieving SVR was significantly lower in women than in men (odds ratio [OR], 0.13; 95% CI, 0.03-0.58; p = .01). Relapse after completing treatment was more likely to occur in women (p = .02). Thirty-four patients (48%) did not complete therapy. Discontinuation because of loss to follow-up was more likely in women, whereas discontinuation owing to therapy limiting adverse drug events were more common in men. Discontinuation rates owing to failure of therapy were similar in men and women. CONCLUSIONS There was a significant difference in SVR between men and women. Both biological and nonbiological factors, the latter including access to care, adherence to therapy, and attitudes of and toward health care providers all could play a role in contributing to the observed disparity between sexes in treatment response.
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Affiliation(s)
- Priya Simoes
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, St. Luke's and Roosevelt Hospitals, New York, New York
| | - Adel Asaad
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, St. Luke's and Roosevelt Hospitals, New York, New York
| | - Jean Abed
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, St. Luke's and Roosevelt Hospitals, New York, New York
| | - Ellen S Engelson
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, St. Luke's and Roosevelt Hospitals, New York, New York; Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, St. Luke's and Roosevelt Hospitals, New York, New York
| | - Donald P Kotler
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, St. Luke's and Roosevelt Hospitals, New York, New York; Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, St. Luke's and Roosevelt Hospitals, New York, New York.
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31
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Jensen DM, Asselah T, Dieterich D, Foster GR, Sulkowski MS, Zeuzem S, Mantry P, Yoshida EM, Moreno C, Ouzan D, Wright M, Morano LE, Buynak R, Bourlière M, Hassanein T, Nishiguchi S, Kao JH, Omata M, Paik SW, Wong DK, Tam E, Kaita K, Feinman SV, Stern JO, Scherer J, Quinson AM, Voss F, Gallivan JP, Böcher WO, Ferenci P. Faldaprevir, pegylated interferon, and ribavirin for treatment-naïve HCV genotype-1: pooled analysis of two phase 3 trials. Ann Hepatol 2016; 15:333-349. [PMID: 27049487 DOI: 10.5604/16652681.1198803] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION & AIM Faldaprevir is a potent once-daily (q.d.) hepatitis C virus (HCV) NS3/4A protease inhibitor. The STARTVerso1 and STARTVerso2 phase 3 studies evaluated faldaprevir plus peginterferon alfa-2a/ribavirin (PegIFN/RBV) in treatment-naïve patients with chronic HCV genotype-1 infection. MATERIAL AND METHODS Patients were randomized 1:2:2 to receive placebo, faldaprevir 120 mg q.d. (12 or 24 weeks) or faldaprevir 240 mg q.d. (12 weeks) all with PegIFN/RBV (24-48 weeks). Faldaprevir 120 mg for 12 weeks only (STARTVerso1 only) required early treatment success (ETS, HCV RNA < 25 IU/mL at week 4 and undetected at week 8). All faldaprevir-treated patients with ETS stopped PegIFN/RBV at week 24. Primary endpoint: sustained virologic response 12 weeks post-treatment (SVR12). RESULTS SVR12 rates were significantly higher for patients treated with faldaprevir 120 or 240 mg (72% and 73%, respectively) compared with placebo (50%); estimated differences (adjusted for trial, race, and genotype-1 subtype) faldaprevir 120 mg 24% (95% CI: 17-31%, P < 0.0001), faldaprevir 240 mg 23% (95% CI: 16-30%, P < 0.0001). Subgroup analyses consistently showed higher SVR12 rates for patients receiving faldaprevir compared with placebo. The incidence of adverse events (AEs) was similar in faldaprevir 120-mg and placebo groups and slightly higher in the faldaprevir 240-mg group. Serious Aes were reported in 6%, 7%, and 8% of patients in placebo, faldaprevir 120-mg, and faldaprevir 240-mg groups, respectively. CONCLUSION Addition of faldaprevir to PegIFN/RBV increased SVR12 in patients with HCV genotype-1, and was well tolerated. Faldaprevir 120 mg is effective in the treatment of HCV genotype-1. ClinicalTrials.gov: NCT01343888 and NCT01297270.
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Affiliation(s)
| | - Tarik Asselah
- Hôpital Beaujon, APHP, University Paris-Diderot and INSERM CRB3, Clichy, France
| | - Douglas Dieterich
- Icahn School of Medicine at Mount Sinai, New York, NY, USA. 4 Queen Mary University of London, London, UK
| | | | | | | | - Parvez Mantry
- The Liver Institute at Methodist Dallas Medical Center, Dallas, TX, USA
| | | | - Christophe Moreno
- CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Denis Ouzan
- Institut Arnault Tzanck, St. Laurent du Var, France
| | - Mark Wright
- Wellcome Trust Clinical Research Facility, Southampton, UK
| | | | - Robert Buynak
- Northwest Indiana Center for Clinical Research, Valparaiso, IN, USA
| | | | | | | | | | - Masao Omata
- Yamanashi Central and Kita Hospitals, Yamanashi, Japan
| | - Seung W Paik
- Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea
| | - David K Wong
- Toronto Western Hospital Liver Center, Toronto, ON, Canada
| | | | - Kelly Kaita
- HSC University of Manitoba, Winnipeg, MB, Canada
| | - S Victor Feinman
- Hepatitis Centre, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Jerry O Stern
- Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA
| | | | | | - Florian Voss
- Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
| | | | - Wulf O Böcher
- Afiliacja Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
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Baba H, Tajiri K, Nagata K, Kawai K, Minemura M, Sugiyama T. Hyperbilirubinemia without Transaminitis during Combined Therapy with Daclatasvir and Asunaprevir. Case Rep Gastroenterol 2016; 10:352-359. [PMID: 27504082 PMCID: PMC4965544 DOI: 10.1159/000447486] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Accepted: 06/07/2016] [Indexed: 02/05/2023] Open
Abstract
Daclatasvir (DCV) and asunaprevir (ASV) are direct-acting antivirals (DAAs) used in the treatment of chronic hepatitis C virus (HCV) infection. Combined therapy with DCV and ASV shows high efficacy and safety even in patients with cirrhosis. We encountered a patient exhibiting severe hyperbilirubinemia during combined therapy, which is an unreported side effect of DCV and ASV. A 78-year-old woman with cirrhosis developed hyperbilirubinemia >10 mg/dl without transaminitis 3 weeks after starting combined therapy. We suspected DAAs-induced liver disorder and discontinued treatment, which resulted in the improvement of hyperbilirubinemia. Caution is required in the use of DAAs for patients with advanced cirrhosis.
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Affiliation(s)
- Hayato Baba
- The Third Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
- Department of Education and Clinical Training, Toyama University Hospital, Toyama, Japan
| | - Kazuto Tajiri
- The Third Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
| | - Kohei Nagata
- The Third Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
| | - Kengo Kawai
- The Third Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
| | - Masami Minemura
- The Third Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
| | - Toshiro Sugiyama
- The Third Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
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Reau N, Fried MW, Nelson DR, Brown RS, Everson GT, Gordon SC, Jacobson IM, Lim JK, Pockros PJ, Reddy KR, Sherman KE. HCV Council--critical appraisal of data: recommendations for clinical practice in a rapidly evolving therapeutic landscape. Liver Int 2016; 36:488-502. [PMID: 26509462 PMCID: PMC5063106 DOI: 10.1111/liv.12993] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 10/21/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS HCV Council 2014, like its predecessor HCV Council 2011, assembled leading clinicians and researchers in the field of hepatitis C to critically evaluate current data regarding best practices for managing patients with chronic hepatitis C virus (HCV). METHODS Clinical practice statements were developed that reflect the areas of potential controversy with high clinical impact. Faculty members were responsible for reviewing the literature to support or reject these statements. After a review and comprehensive discussion of the data, the HCV Council faculty voted on the nature of the evidence and the level of support for each statement. RESULTS The results of the detailed analysis with expert opinion are summarized in this article. CONCLUSION Numerous questions regarding optimal management of certain populations and clinical scenarios remain unanswered. The discussion in the article provides a summary of evidenced-based expert opinion that may help guide clinicians as additional information is developed.
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Affiliation(s)
- Nancy Reau
- Rush University Medical CenterChicagoILUSA
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Di Maio VC, Cento V, Di Paolo D, Aragri M, De Leonardis F, Tontodonati M, Micheli V, Bellocchi MC, Antonucci FP, Bertoli A, Lenci I, Milana M, Gianserra L, Melis M, Di Biagio A, Sarrecchia C, Sarmati L, Landonio S, Francioso S, Lambiase L, Nicolini LA, Marenco S, Nosotti L, Giannelli V, Siciliano M, Romagnoli D, Pellicelli A, Vecchiet J, Magni CF, Babudieri S, Mura MS, Taliani G, Mastroianni C, Vespasiani-Gentilucci U, Romano M, Morisco F, Gasbarrini A, Vullo V, Bruno S, Baiguera C, Pasquazzi C, Tisone G, Picciotto A, Andreoni M, Parruti G, Rizzardini G, Angelico M, Perno CF, Ceccherini-Silberstein F. HCV NS3 sequencing as a reliable and clinically useful tool for the assessment of genotype and resistance mutations for clinical samples with different HCV-RNA levels. J Antimicrob Chemother 2016; 71:739-750. [PMID: 26679249 DOI: 10.1093/jac/dkv403] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 10/29/2015] [Indexed: 01/13/2025] Open
Abstract
OBJECTIVES This study aims to evaluate the reliability and clinical utility of NS3 sequencing in hepatitis C virus (HCV) 1-infected patients who were candidates to start a PI-containing regimen. METHODS NS3 protease sequencing was performed by in-house-developed HCV-1 subtype-specific protocols. Phylogenetic analysis was used to test sequencing reliability and concordance with previous genotype/subtype assignment by commercial genotyping assays. RESULTS Five hundred and sixty-seven HCV plasma samples with quantifiable HCV-RNA from 326 HCV-infected patients were collected between 2011 and 2014. Overall, the success rate of NS3 sequencing was 88.9%. The success rate between the two subtype protocols (HCV-1a/HCV-1b) was similarly high for samples with HCV-RNA >3 log IU/mL (>92% success rate), while it was slightly lower for HCV-1a samples with HCV-RNA ≤3 log IU/mL compared with HCV-1b samples. Phylogenetic analysis confirmed the genotype/subtype given by commercial genotyping assays in 92.9% (303/326) of cases analysed. In the remaining 23 cases (7.1%), 1 was HCV-1g (previously defined as subtype 1a), 1 was HCV-4d (previously defined as genotype 1b) and 1 was HCV-1b (previously defined as genotype 2a/2c). In the other cases, NS3 sequencing precisely resolved the either previous undetermined/discordant subtype 1 or double genotype/subtype assignment by commercial genotyping assays. Resistance-associated variants (RAVs) to PI were detected in 31.0% of samples. This prevalence changed according to PI experience (17.1% in PI-naive patients versus 79.2% in boceprevir/telaprevir/simeprevir-failing patients). Among 96 patients with available virological outcome following boceprevir/telaprevir treatment, a trend of association between baseline NS3 RAVs and virological failure was observed (particularly for HCV-1a-infected patients: 3/21 failing patients versus 0/22 achieving sustained virological response; P = 0.11). CONCLUSIONS HCV-NS3 sequencing provides reliable results and at the same time gives two clinically relevant pieces of information: a correct subtype/genotype assignment and the detection of variants that may interfere with the efficacy of PI.
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Affiliation(s)
- V C Di Maio
- Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy
| | - V Cento
- Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy
| | - D Di Paolo
- Hepatology Unit, University Hospital of Rome 'Tor Vergata', Rome, Italy
| | - M Aragri
- Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy
| | - F De Leonardis
- Hepatology Unit, University Hospital of Rome 'Tor Vergata', Rome, Italy
| | - M Tontodonati
- Infectious Disease Unit, Pescara General Hospital, Pescara, Italy
| | - V Micheli
- Unit of Microbiology, Hospital Sacco of Milan, Milan, Italy
| | - M C Bellocchi
- Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy
| | - F P Antonucci
- Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy
| | - A Bertoli
- Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy
| | - I Lenci
- Hepatology Unit, University Hospital of Rome 'Tor Vergata', Rome, Italy
| | - M Milana
- Hepatology Unit, University Hospital of Rome 'Tor Vergata', Rome, Italy
| | - L Gianserra
- Infectious Diseases, Sant'Andrea Hospital-'La Sapienza' University, Rome, Italy
| | - M Melis
- Infectious Diseases Unit, Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - A Di Biagio
- Infectious Diseases Unit, Department of Social Health (DISSAL) of the University of Genoa, IRCCS S. Martino-IST, Genova, Italy
| | - C Sarrecchia
- Infectious Disease, University Hospital of Rome 'Tor Vergata', Rome, Italy
| | - L Sarmati
- Infectious Disease, University Hospital of Rome 'Tor Vergata', Rome, Italy
| | - S Landonio
- Division of Infectious Disease, Hospital Sacco of Milan, Milan, Italy
| | - S Francioso
- Hepatology Unit, University Hospital of Rome 'Tor Vergata', Rome, Italy
| | - L Lambiase
- Infectious Diseases, Sant'Andrea Hospital-'La Sapienza' University, Rome, Italy
| | - L A Nicolini
- Infectious Diseases Unit, Department of Social Health (DISSAL) of the University of Genoa, IRCCS S. Martino-IST, Genova, Italy
| | - S Marenco
- Department of Internal Medicine, Gastroenterology Unit, University of Genova, Genova, Italy
| | - L Nosotti
- Hepatology Unit, National Institute of Health, Migration and Poverty, Rome, Italy
| | - V Giannelli
- Gastroenterology Unit, Department of Clinical Medicine, 'La Sapienza' University, Rome, Italy
| | - M Siciliano
- Gastroenterology, Catholic University of Rome, Rome, Italy
| | - D Romagnoli
- Department of Biomedical, Metabolic and Neural Sciences, NOCSAE Baggiovara, Modena, Italy
| | - A Pellicelli
- Hepatology Unit, San Camillo Forlanini Hospital, Rome, Italy
| | - J Vecchiet
- Infectious Disease Clinic, Chieti, Italy
| | - C F Magni
- Division of Infectious Disease, Hospital Sacco of Milan, Milan, Italy
| | - S Babudieri
- Infectious Diseases Unit, Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - M S Mura
- Infectious Diseases Unit, Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - G Taliani
- Department of Clinical Medicine, Policlinico Umberto I, 'Sapienza' University of Rome, Rome, Italy
| | - C Mastroianni
- Department of Infectious Diseases, University of Rome 'Sapienza' (Polo Pontino), Latina, Italy
| | | | - M Romano
- S. Pertini Hospital, Rome, Italy
| | - F Morisco
- Università 'Federico II', Naples, Italy
| | - A Gasbarrini
- Gastroenterology, Catholic University of Rome, Rome, Italy
| | - V Vullo
- Department of Public Health and Infectious Diseases, University of Rome 'Sapienza', Rome, Italy
| | - S Bruno
- Department of Internal Medicine, Humanitas University, Rozzano, Milan, Italy
| | - C Baiguera
- Hospital Niguarda Ca'Granda, Milan, Italy
| | - C Pasquazzi
- Infectious Diseases, Sant'Andrea Hospital-'La Sapienza' University, Rome, Italy
| | - G Tisone
- Liver Transplant Centre, Tor Vergata University, Rome, Italy
| | - A Picciotto
- Department of Internal Medicine, Gastroenterology Unit, University of Genova, Genova, Italy
| | - M Andreoni
- Infectious Disease, University Hospital of Rome 'Tor Vergata', Rome, Italy
| | - G Parruti
- Infectious Disease Unit, Pescara General Hospital, Pescara, Italy
| | - G Rizzardini
- Division of Infectious Disease, Hospital Sacco of Milan, Milan, Italy
| | - M Angelico
- Hepatology Unit, University Hospital of Rome 'Tor Vergata', Rome, Italy
| | - C F Perno
- Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy Molecular Virology Unit, University Hospital of Rome 'Tor Vergata', Rome, Italy
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Barreiro P, Labarga P, de Mendoza C, Benítez-Gutiérrez L, Fernandez-Montero JV, Peña JM, Soriano V. High serum HCV RNA in chronic hepatitis C patients coinfected with HIV despite successful antiretroviral therapy. Antivir Ther 2016; 21:489-494. [DOI: 10.3851/imp3038] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2016] [Indexed: 10/22/2022]
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About F, Oudot-Mellakh T, Niay J, Rabiéga P, Pedergnana V, Duffy D, Sultanik P, Cagnot C, Carrat F, Marcellin P, Zoulim F, Larrey D, Hézode C, Fontaine H, Bronowicki JP, Pol S, Albert ML, Theodorou I, Cobat A, Abel L, ANRS CO20-CUPIC study group. Impact of IL28B, APOH and ITPA Polymorphisms on Efficacy and Safety of TVR- or BOC-Based Triple Therapy in Treatment-Experienced HCV-1 Patients with Compensated Cirrhosis from the ANRS CO20-CUPIC Study. PLoS One 2015; 10:e0145105. [PMID: 26670100 PMCID: PMC4682920 DOI: 10.1371/journal.pone.0145105] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 11/29/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Human genetic factors influence the outcome of pegylated interferon and ribavirin hepatitis C therapy. We explored the role of IL28B, APOH and ITPA SNPs on the outcomes of triple therapy including telaprevir or boceprevir in patients with compensated cirrhosis chronically infected with HCV-1. PATIENTS AND METHODS A total of 256 HCV-1 Caucasian treatment-experienced patients with compensated cirrhosis from the ANRS CO20-CUPIC cohort were genotyped for a total of 10 candidate SNPs in IL28B (rs12979860 and rs368234815), APOH (rs8178822, rs12944940, rs10048158, rs52797880, rs1801689 and rs1801690) and ITPA (rs1127354 and rs7270101). We tested the association of IL28B and APOH SNPs with sustained virological response and of ITPA SNPs with anemia related phenotypes by means of logistic regression assuming an additive genetic model. RESULTS None of the six APOH SNPs were associated with sustained virological response. The favorable alleles of the IL28B SNPs rs12979860 and rs368234815 were associated with sustained virological response (rs12979860: OR = 2.35[1.50-3.70], P = 2x10(-4)). Refined analysis showed that the effect of IL28B SNPs on sustained virological response was restricted to prior PegIFN/RBV relapse (OR = 3.80[1.82-8.92], P = 8x10(-4)). We also confirmed the association between ITPA low activity alleles and protection against early hemoglobin decline in triple therapy (P = 2x10(-5)). CONCLUSION Our results suggest that the screening of rs12979860 may remain interesting for decision making in prior relapse HCV-1 Caucasian patients with compensated cirrhosis eligible for a telaprevir- or boceprevir-based therapy.
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Affiliation(s)
- Frédégonde About
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France
- Paris Descartes University, Imagine Institute, Paris, France
| | - Tiphaine Oudot-Mellakh
- Laboratory of Immunity and Infection, Centre d’Immunologie et des Maladies Infectieuses de Paris (CIMI), INSERM U1135, Groupe Hospitalier Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
- Plateforme Génomique Inserm-ANRS, Groupe Hospitalier Pitié Salpétrière, AP-HP, UPMC Université Paris 6, Paris, France
| | - Jonathan Niay
- Laboratory of Immunity and Infection, Centre d’Immunologie et des Maladies Infectieuses de Paris (CIMI), INSERM U1135, Groupe Hospitalier Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
- Plateforme Génomique Inserm-ANRS, Groupe Hospitalier Pitié Salpétrière, AP-HP, UPMC Université Paris 6, Paris, France
| | - Pascaline Rabiéga
- Sorbonne Universités, UPMC Université Paris 06, INSERM, Institut Pierre Louis d’épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France
| | - Vincent Pedergnana
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France
- Paris Descartes University, Imagine Institute, Paris, France
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
| | - Darragh Duffy
- Centre for Human Immunology, Department of Immunology, Institut Pasteur, Paris, France
- The Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, INSERM U818, Paris, France
| | - Philippe Sultanik
- Département d'Hépatologie, Hôpital Cochin, AP-HP, Université Paris Descartes, Paris, France
- INSERM UMS20, Institut Pasteur, Paris, France
| | - Carole Cagnot
- Unit for Basic and Clinical research on Viral Hepatitis, Inserm-ANRS (France REcherche Nord & sud Sida-HIV Hépatites-FRENSH), Paris, France
| | - Fabrice Carrat
- Sorbonne Universités, UPMC Université Paris 06, INSERM, Institut Pierre Louis d’épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France
- Service de Santé Publique, Hôpital Saint Antoine, AP-HP, Paris, France
| | | | - Fabien Zoulim
- Centre de recherche en cancérologie de Lyon (CRCL), INSERM UMR I 1052/CNRS 5286, Lyon cedex 03, France
- Université Claude-Bernard Lyon 1, Villeurbanne, France
- Hospices civils de Lyon, Hôpital de la Croix-Rousse, service d'hépatologie et de gastroentérologie, Lyon, France
| | | | - Christophe Hézode
- Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est Créteil (UPEC), Créteil, France
- Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, UPEC, Créteil, France
| | - Hélène Fontaine
- Département d'Hépatologie, Hôpital Cochin, AP-HP, Université Paris Descartes, Paris, France
- INSERM UMS20, Institut Pasteur, Paris, France
| | - Jean-Pierre Bronowicki
- Department of Hepatogastroenterology, INSERM U954, CHU de Nancy, Université de Lorraine, Vandoeuvre-Lès-Nancy, France
| | - Stanislas Pol
- Département d'Hépatologie, Hôpital Cochin, AP-HP, Université Paris Descartes, Paris, France
- INSERM UMS20, Institut Pasteur, Paris, France
| | - Matthew L. Albert
- Centre for Human Immunology, Department of Immunology, Institut Pasteur, Paris, France
- The Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, INSERM U818, Paris, France
- INSERM UMS20, Institut Pasteur, Paris, France
| | - Ioannis Theodorou
- Laboratory of Immunity and Infection, Centre d’Immunologie et des Maladies Infectieuses de Paris (CIMI), INSERM U1135, Groupe Hospitalier Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
- Plateforme Génomique Inserm-ANRS, Groupe Hospitalier Pitié Salpétrière, AP-HP, UPMC Université Paris 6, Paris, France
| | - Aurélie Cobat
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France
- Paris Descartes University, Imagine Institute, Paris, France
| | - Laurent Abel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France
- Paris Descartes University, Imagine Institute, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, United States of America
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Boursier J, Ducancelle A, Vergniol J, Veillon P, Moal V, Dufour C, Bronowicki JP, Larrey D, Hézode C, Zoulim F, Fontaine H, Canva V, Poynard T, Allam S, De Lédinghen V. The CUPIC algorithm: an accurate model for the prediction of sustained viral response under telaprevir or boceprevir triple therapy in cirrhotic patients. J Viral Hepat 2015. [PMID: 26216230 DOI: 10.1111/jvh.12433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Triple therapy using boceprevir or telaprevir remains the reference treatment for genotype 1 chronic hepatitis C in countries where new interferon-free regimens have not yet become available. Antiviral treatment is highly required in cirrhotic patients, but they represent a difficult-to-treat population. We aimed to develop a simple algorithm for the prediction of sustained viral response (SVR) in cirrhotic patients treated with triple therapy. A total of 484 cirrhotic patients from the ANRS CO20 CUPIC cohort treated with triple therapy were randomly distributed into derivation and validation sets. A total of 52.1% of patients achieved SVR. In the derivation set, a D0 score for the prediction of SVR before treatment initiation included the following independent predictors collected at day 0: prior treatment response, gamma-GT, platelets, telaprevir treatment, viral load. To refine the prediction at the early phase of the treatment, a W4 score included as additional parameter the viral load collected at week 4. The D0 and W4 scores were combined in the CUPIC algorithm defining three subgroups: 'no treatment initiation or early stop at week 4', 'undetermined' and 'SVR highly probable'. In the validation set, the rates of SVR in these three subgroups were, respectively, 11.1%, 50.0% and 82.2% (P < 0.001). By replacing the variable 'prior treatment response' with 'IL28B genotype', another algorithm was derived for treatment-naïve patients with similar results. The CUPIC algorithm is an easy-to-use tool that helps physicians weigh their decision between immediately treating cirrhotic patients using boceprevir/telaprevir triple therapy or waiting for new drugs to become available in their country.
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Affiliation(s)
- J Boursier
- Department of Hepatology and Gastroenterology, CHU d'Angers, Angers, France.,HIFIH, UPRES 3859, SFR 4208, Université LUNAM, Angers, France
| | - A Ducancelle
- HIFIH, UPRES 3859, SFR 4208, Université LUNAM, Angers, France.,Virology Department, CHU d'Angers, Angers, France
| | - J Vergniol
- Department of Hepatology and Gastroenterology, Hôpital Haut-Lévêque, CHU de Bordeaux, Pessac, France
| | - P Veillon
- Department of Hepatology and Gastroenterology, CHU d'Angers, Angers, France.,HIFIH, UPRES 3859, SFR 4208, Université LUNAM, Angers, France.,Virology Department, CHU d'Angers, Angers, France
| | - V Moal
- HIFIH, UPRES 3859, SFR 4208, Université LUNAM, Angers, France.,Biochemistry Department, CHU d'Angers, Angers, France
| | - C Dufour
- Inserm UMR-S1136, Université Pierre-et-Marie-Curie Paris 6, Paris, France
| | - J-P Bronowicki
- Department of Hepatology and Gastroenterology, CHU de Nancy, Université de Lorraine, Inserm U954, Vandoeuvre-lès-Nancy, France
| | - D Larrey
- Liver Unit-IRB-INSERM1040, Hôpital Saint Eloi, CHU de Montpellier, Montpellier, France
| | - C Hézode
- Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France
| | - F Zoulim
- Department of Hepatology, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, INSERM U1052, Lyon, France
| | - H Fontaine
- Department of Hepatology, Hôpital Cochin, AP-HP, Université Paris-René Descartes, Inserm U1016, Paris, France
| | - V Canva
- Department of Hepatology and Gastroenterology, Centre Hospitalier Régional et Universitaire Claude Huriez, Lille, France
| | - T Poynard
- Department of Hepatology and Gastroenterology, Groupe Hospitalier Pitié-Salpétrière AP-HP, Université Pierre et Marie Curie Paris 6, INSERM UMR-S938, Paris, France
| | - S Allam
- Unit for Basic and Clinical Research on Viral Hepatitis, ANRS (France REcherche Nord & sud Sida-HIV Hépatites-FRENSH), Paris, France
| | - V De Lédinghen
- Department of Hepatology and Gastroenterology, Hôpital Haut-Lévêque, CHU de Bordeaux, Pessac, France.,INSERM U1053, Université Bordeaux Segalen, Bordeaux, France
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Crespo J, Berenguer M, Pérez F, Fernández I, González O, Bárcena R, Buti M, López J, Calleja JL. [Lead-in period and week 8 as predictive tools for response to boceprevir therapy: a retrospective study of Spanish real clinical practice]. GASTROENTEROLOGIA Y HEPATOLOGIA 2015; 38:517-24. [PMID: 25976446 DOI: 10.1016/j.gastrohep.2015.04.002] [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: 12/18/2014] [Revised: 03/31/2015] [Accepted: 04/01/2015] [Indexed: 11/23/2022]
Abstract
INTRODUCTION Most discontinuations due to lack of virological response occur during the first few weeks of hepatitis C virus (HCV) triple therapy. Improved knowledge of baseline factors and their correlation with boceprevir decision points may predict treatment success. METHODS An observational, retrospective study was conducted to describe the lead-in period as a clinical decision tool in HCV genotype 1 patients treated with boceprevir. Data were collected from the medical records of 186 consecutive patients distributed across 20 Spanish general hospitals. RESULTS This study included 171 patients. A total of 80% had fibrosis F3/F4, 74% were previously treated, and 26% were treatment-naïve. After the lead-in period, 54.5% of the patients had a reduction of ≥1 log10; this reduction occurred in 52.5% of those with advanced fibrosis. Boceprevir therapy was started in 94% of the patients. Discontinuations at week 4 were limited to null responders with cirrhosis. The baseline factors associated with virological response at week 4 were IL28B, previous response, and fibrosis score. At week 8, HCV-RNA was undetectable in 48.8% of the patients. The correlation between responses at weeks 8 and 12 was 88%. CONCLUSION In the Spanish clinical setting, lead-in was mainly used as a clinical decision point for non-responders with cirrhosis. The good correlation between stopping rules at weeks 8 and 12 could be used to anticipate discontinuation, thus saving adverse events and costs.
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Affiliation(s)
- Javier Crespo
- Departamento de Gastroenterología y Hepatología, Hospital Universitario Marqués de Valdecilla, Santander, España.
| | - Marina Berenguer
- Departamento de Gastroenterología, Hospital Universitario La Fe, Valencia, España
| | - Francisco Pérez
- Departamento de Aparato Digestivo, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, España
| | - Inmaculada Fernández
- Departamento de Gastroenterología y Hepatología, Hospital Universitario 12 de Octubre, Madrid, España
| | - Olga González
- Departamento de Aparato Digestivo, Hospital Arnau de Vilanova, Lérida
| | - Rafael Bárcena
- Departamento de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Madrid, España
| | - María Buti
- Departamento de Medicina Interna, Hospital Universitario Vall d'Hebrón, Barcelona, España
| | - Jesús López
- Medical Affairs Department, MSD, Madrid, España
| | - José Luis Calleja
- Departamento de Gastroenterología y Hepatología, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, España
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Stättermayer AF, Ferenci P. Effect of IL28B genotype on hepatitis B and C virus infection. Curr Opin Virol 2015; 14:50-55. [PMID: 26284971 DOI: 10.1016/j.coviro.2015.07.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Revised: 07/25/2015] [Accepted: 07/27/2015] [Indexed: 12/11/2022]
Abstract
Genetic factors play a major role for treatment response and disease progression of chronic hepatitis B (HBV) and C virus (HCV) infection. In 2009 a genome-wide association study (GWAS) identified a single nucleotide polymorphism near the IL28B gene that was associated with treatment-induced viral clearance in chronic HCV infection treated with pegylated interferon-α (PEG-IFN) and ribavirin (RBV). Further, another GWAS found an association between IL28B genotype and spontaneous viral clearance in acute HCV infection. The effect on sustained viral response (SVR) could also be observed in patients receiving a triple-therapy with a direct antiviral agent (DAA) combined with PEG-IFN/RBV. In the era of all-oral interferon-free treatment regimens with the combination of different DAAs-with SVR rates exceeding 90%-the effect of IL28B was blunt. In contrast, in HBV several retrospective studies yielded conflicting results of the association of IL28B with PEG-IFN-induced treatment response.
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Affiliation(s)
- Albert Friedrich Stättermayer
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Peter Ferenci
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.
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40
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Fülöp B, Biermer M, Cornberg M, Wedemeyer H, Port K, Heyne R, Zeuzem S, Peiffer KH, Welzel T, Herber A, Buggisch P, Moser C, Stoll S, Alshuth U, Berg T. Improved pharmacodynamics and pharmacokinetics after i.v. application of peginterferon alfa-2a in hepatitis C null responders. Liver Int 2015; 35:2275-84. [PMID: 25801095 DOI: 10.1111/liv.12832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 03/06/2015] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIM Mechanisms of non-responsiveness to peginterferon alfa-2a are not completely understood. Inadequate plasma levels may contribute to reduced response. The aim of this prospective, multicentre, crossover, Phase 1 study was to evaluate the pharmacokinetics and viral kinetics of intravenous vs. subcutaneous peginterferon alfa-2a in patients with genotype 1 chronic hepatitis C infection who showed null response to previous peginterferon/ribavirin. METHODS Patients were randomized in four treatment arms to subcutaneous or intravenous peginterferon alfa-2a 180 μg, once or twice weekly for 2 weeks. After a washout phase of 6 weeks, patients first receiving intravenous administration switched to subcutaneous or vice versa for additional 2 weeks. RESULTS Intravenous administration of pegylated interferon resulted in a stronger and faster decline in HCV RNA than subcutaneous administration with a maximum decline of 1.17 log10 vs. 0.41 log10 or 1.32 log10 vs. 0.54 log10 after a once or twice weekly application, respectively. Pharmacokinetic studies revealed significantly higher maximum concentration (C(max))(0-12) h and C(max 0-7) d following intravenous administration, irrespective of dosing frequency A rapid rebound in HCV RNA was observed in all treatment arms. Adverse events occurred more frequently following intravenous administration. CONCLUSION Intravenous administration of peginterferon alfa-2a results in considerably higher plasma concentration and a stronger decline in HCV RNA and offers an interesting approach in order to overcome interferon non-responsive state in patients with full null response to previous peginterferon/ribavirin combination therapy.
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Affiliation(s)
- Balazs Fülöp
- Section of Hepatology, Department of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | | | - Markus Cornberg
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany
| | - Kerstin Port
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany
| | | | - Stefan Zeuzem
- J.W. Goethe University Hospital, Frankfurt/M, Germany
| | | | - Tania Welzel
- J.W. Goethe University Hospital, Frankfurt/M, Germany
| | - Adam Herber
- Section of Hepatology, Department of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | - Peter Buggisch
- Institute for Interdisciplinary Medicine, Hamburg, Germany
| | | | | | | | - Thomas Berg
- Section of Hepatology, Department of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
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41
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Paolucci S, Fiorina L, Mariani B, Landini V, Gulminetti R, Novati S, Maserati R, Barbarini G, Bruno R, Baldanti F. Development and persistence of DAA resistance associated mutations in patients failing HCV treatment. J Clin Virol 2015; 72:114-8. [PMID: 26489401 DOI: 10.1016/j.jcv.2015.08.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Revised: 08/27/2015] [Accepted: 08/28/2015] [Indexed: 10/23/2022]
Abstract
BACKGROUND Direct-acting antiviral agents (DAAs) combined with pegylated-interferon (PegIFN) and ribavirin (RBV) are still a standard treatment in patients with genotype 1HCV infection. However, virologic response could be impaired by baseline or early selection of resistant HCV strains. OBJECTIVES The aim of this study was to determine the onset and persistence of resistance-associated mutations (RAMs) in the NS3 and NS5B genes of DAA-naïve patients failing treatment. STUDY DESIGN Direct sequencing of HCV NS3 was performed in 49 DAA-naïve patients with HCV genotype 1 infection. RESULTS Eight out of 23 patients (34.7%) failed PegIFN/RBV/telaprevir during the 12-weeks of therapy. Treatment failure was associated with the development of RAMs at amino-acids 36,54,80 and 155 of the HCV protease in 6/8 patients (75%). Among patients treated with PegIFN/RBV/boceprevir treatment, 4/18 (22.2%) failed therapy. Of these, 2 (50%) carried virus strains which developed a RAM at amino-acids 54 and 155. Among HCV strains with RAMs, 7 belonged to genotype 1a and 1 to 1b. Finally, in 6/10 (60%) patients, drug-resistant variants could still be detected for up to 3-7 months after stopping therapy. CONCLUSIONS A higher rate (p=0.49) of treatment failure was observed in patients receiving telaprevir- compared to the boceprevir-based combination. In addition, compared with genotype 1b, genotype 1a was associated with higher rates (p=0.01) of treatment failure due to virus resistant strains. Resistance testing at baseline and during DAA treatment should be taken into consideration when treating patients with new HCV combination therapies.
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Affiliation(s)
- Stefania Paolucci
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy
| | - Loretta Fiorina
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy
| | - Bianca Mariani
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy
| | - Viviana Landini
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy
| | - Roberto Gulminetti
- Institute of Infectious Diseases, University of Pavia, 27100, Pavia, Italy
| | - Stefano Novati
- Institute of Infectious Diseases, University of Pavia, 27100, Pavia, Italy
| | - Renato Maserati
- Institute of Infectious Diseases, University of Pavia, 27100, Pavia, Italy
| | - Giorgio Barbarini
- Division of Infectious and Tropical Diseases, Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy
| | - Raffaele Bruno
- Division of Infectious and Tropical Diseases, Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy
| | - Fausto Baldanti
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy; Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, 27100, Pavia, Italy.
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Shuldiner SR, Gong L, Muir AJ, Altman RB, Klein TE. PharmGKB summary: peginterferon-α pathway. Pharmacogenet Genomics 2015; 25:465-74. [PMID: 26111151 PMCID: PMC4757589 DOI: 10.1097/fpc.0000000000000158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
| | - Li Gong
- Department of Genetics, Stanford University, Stanford, California
| | - Andrew J. Muir
- Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA
| | - Russ B. Altman
- Department of Genetics, Stanford University, Stanford, California
- Department of Bioengineering, Stanford University, Stanford, California
| | - Teri E. Klein
- Department of Genetics, Stanford University, Stanford, California
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43
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Hajarizadeh B, Grady B, Page K, Kim AY, McGovern BH, Cox AL, Rice TM, Sacks-Davis R, Bruneau J, Morris M, Amin J, Schinkel J, Applegate T, Maher L, Hellard M, Lloyd AR, Prins M, Geskus RB, Dore GJ, Grebely J. Factors associated with hepatitis C virus RNA levels in early chronic infection: the InC3 study. J Viral Hepat 2015; 22:708-17. [PMID: 25580520 PMCID: PMC4496327 DOI: 10.1111/jvh.12384] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 12/09/2014] [Indexed: 02/06/2023]
Abstract
Improved understanding of natural history of hepatitis C virus (HCV) RNA levels in chronic infection provides enhanced insights into immunopathogenesis of HCV and has implications for the clinical management of chronic HCV infection. This study assessed factors associated with HCV RNA levels during early chronic infection in a population with well-defined early chronic HCV infection. Data were from an international collaboration of nine prospective cohorts studying acute HCV infection (InC(3) study). Individuals with persistent HCV and detectable HCV RNA during early chronic infection (one year [±4 months] postinfection) were included. Distribution of HCV RNA levels during early chronic infection was compared by selected host and virological factors. A total of 308 individuals were included. Median HCV RNA levels were significantly higher among males (vs females; 5.15 vs 4.74 log IU/mL; P < 0.01) and among individuals with HIV co-infection (vs no HIV; 5.89 vs 4.86; P = 0.02). In adjusted logistic regression, male sex (vs female, adjusted odds ratio [AOR]: 1.93; 95%CI: 1.01, 3.69), interferon lambda 4 (IFNL4) rs12979860 CC genotype (vs TT/CT; AOR: 2.48; 95%CI: 1.42, 4.35), HIV co-infection (vs no HIV; AOR: 3.27; 95%CI: 1.35, 7.93) and HCV genotype G2 (vs G3; AOR: 5.40; 95%CI: 1.63, 17.84) were independently associated with high HCV RNA levels (>5.6 log IU/mL = 400 000 IU/mL). In conclusion, this study demonstrated that IFNL4 rs12979860 CC genotype, male sex, HIV co-infection and HCV genotype G2 are associated with high HCV RNA levels in early chronic infection. These factors exert their role as early as one year following infection.
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Affiliation(s)
| | - Bart Grady
- Cluster Infectious Diseases, GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands
| | - Kimberly Page
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | | | | | - Andrea L. Cox
- Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Thomas M. Rice
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Rachel Sacks-Davis
- Burnet Institute, Melbourne, VIC, Australia,Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
| | - Julie Bruneau
- CRCHUM, Université de Montréal, Montreal, QC, Canada
| | - Meghan Morris
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Janaki Amin
- The Kirby Institute, UNSW Australia, Sydney, NSW, Australia
| | | | | | - Lisa Maher
- The Kirby Institute, UNSW Australia, Sydney, NSW, Australia
| | - Margaret Hellard
- Burnet Institute, Melbourne, VIC, Australia,Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
| | - Andrew R. Lloyd
- Inflammation and Infection Research Centre, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia
| | - Maria Prins
- Cluster Infectious Diseases, GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands,Academic Medical Center, Amsterdam, The Netherlands
| | - Ronald B Geskus
- Cluster Infectious Diseases, GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands,Academic Medical Center, Amsterdam, The Netherlands
| | | | - Jason Grebely
- The Kirby Institute, UNSW Australia, Sydney, NSW, Australia
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Bailly F, Virlogeux V, Dufour C, Pradat P, Hézode C, Larrey D, Alric L, Samuel D, Bourlière M, Métivier S, Zarski JP, Fontaine H, Loustaud-Ratti V, Serfaty L, Bronowicki JP, Carrat F, Zoulim F. Early virological assessment during telaprevir- or boceprevir-based triple therapy in hepatitis C cirrhotic patients who failed a previous interferon based regimen - The ANRS CO20-CUPIC study. Clin Res Hepatol Gastroenterol 2015; 39:443-50. [PMID: 25636238 DOI: 10.1016/j.clinre.2014.12.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Revised: 12/09/2014] [Accepted: 12/15/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND OBJECTIVE To assess within the ANRS CO20-CUPIC cohort whether the viral load (VL) at week 2/week 6 for telaprevir/boceprevir-based triple therapy, respectively, was predictive of sustained virological response (SVR) in patients with hepatitis C virus (HCV) infection and to study the relevance of this measurement to early diagnose drug resistance. METHODS Observational study of HCV genotype 1 patients with compensated cirrhosis (Child-Pugh A), non-responders to a prior course of interferon (IFN)-based therapy and who started triple therapy. Patients received either 12 weeks of telaprevir in combination with PEG-IFN/ribavirin (RBV), then 36 weeks of PEG-IFN/RBV, or 4 weeks of PEG-IFN/RBV, then 44 weeks of PEG-IFN/RBV and boceprevir. RESULTS A total of 262 patients were analyzed. For telaprevir-treated patients, 28% had undetectable VL at W2 of whom 81% achieved SVR12 whereas 67% had undetectable VL at W4 of whom 67% achieved SVR12. For boceprevir-treated patients 20% had undetectable VL at W6 and 86% of them achieved SVR12 whereas 36% had undetectable VL at W8 among whom 73% achieved SVR12. Five telaprevir-treated patients had a VL increase between W2 and W4 after a decrease between D0 and W2. Four of them did not achieve SVR12. Similarly, six boceprevir-treated patients had a VL increase between W6 and W8 after a decrease between D0 and W6. Five did not reach SVR12. CONCLUSIONS The assessment of HCV RNA level after two weeks of triple therapy in cirrhotic non-responder patients is a good predictor of SVR. This assessment was useful to do an early diagnosis of viral breakthrough.
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Affiliation(s)
- François Bailly
- Department of Hepatology, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 69004 Lyon, France; Inserm U1052, 69003 Lyon, France; Université Lyon I, 69622 Villeurbanne, France
| | - Victor Virlogeux
- Department of Hepatology, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 69004 Lyon, France; École Normale Supérieure, 69007 Lyon, France
| | - Cécilie Dufour
- Inserm UMR-S 707, Université Pierre-et-Marie-Curie Paris 6, 75012 Paris, France
| | - Pierre Pradat
- Department of Hepatology, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 69004 Lyon, France; Inserm U1052, 69003 Lyon, France; Université Lyon I, 69622 Villeurbanne, France
| | | | - Dominique Larrey
- Hépato-gastroentérologie, CHU de Montpellier, Hôpital Saint-Éloi, 34090 Montpellier, France
| | - Laurent Alric
- Pôle Digestif, CHU Purpan, UMR 152, Université Toulouse 3, 31059 Toulouse, France
| | - Didier Samuel
- Centre Hépato-Biliaire, AP-HP Hôpital Paul-Brousse, 94870 Villejuif, France; Unité 785, Inserm, 94870 Villejuif, France; Université Paris-Sud, 94270 Le Kremlin-Bicêtre, France
| | - Marc Bourlière
- Department of Hepatology and Gastroenterology, Hôpital Saint-Joseph, 13285 Marseille, France
| | - Sophie Métivier
- Pôle Digestif-Gastro-entérologie-Hépatologie, CHU Purpan, 31059 Toulouse, France
| | - Jean-Pierre Zarski
- Clinique universitaire d'Hépato-Gastroentérologie, CHRU Michallon, 38043 Grenoble, France
| | - Hélène Fontaine
- Hôpital Cochin, AP-HP, Université Paris-René Descartes, Inserm U1016, 75014 Paris, France
| | | | - Lawrence Serfaty
- Hépato-gastro-entérologie orienté en hépatologie, CHU Saint-Antoine, 75012 Paris, France
| | - Jean-Pierre Bronowicki
- Department of Hepatology and Gastroenterology, CHU de Nancy, Université de Lorraine, Inserm U954, 54500 Vandœuvre-lès-Nancy, France
| | - Fabrice Carrat
- Inserm UMR-S 707, Université Pierre-et-Marie-Curie Paris 6, 75012 Paris, France
| | - Fabien Zoulim
- Department of Hepatology, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 69004 Lyon, France; Inserm U1052, 69003 Lyon, France; Université Lyon I, 69622 Villeurbanne, France.
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45
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Barreiro P, Labarga P, Fernandez-Montero JV, Mendoza CD, Benítez-Gutiérrez L, Peña JM, Soriano V. Rate and predictors of serum HCV-RNA >6 million IU/mL in patients with chronic hepatitis C. J Clin Virol 2015; 71:63-6. [PMID: 26302484 DOI: 10.1016/j.jcv.2015.08.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Revised: 07/29/2015] [Accepted: 08/03/2015] [Indexed: 12/16/2022]
Abstract
BACKGROUND Baseline serum HCV-RNA predicts sustained virological response in chronic hepatitis C patients treated with antiviral therapy. A threshold at 6 million IU/mL has been proposed to best discriminate treatment outcomes on sofosbuvir-based regimens. In comparison with the general population, immunosuppressed individuals exhibit greater viral load values. OBJECTIVES To estimate the rate and predictors of serum HCV-RNA above 6 millionIU/mL in chronic hepatitis C patients on care outside clinical trials. STUDY DESIGN Serum HCV-RNA values recorded from all chronic hepatitis C patients consecutively attended at our clinic during the last decade were analyzed. Testing had been performed using the COBAS TaqMan HCV test v2.0. RESULTS A total of 816 individuals with detectable serum HCV-RNA were identified. The main characteristics of this population were as follows: mean age 48.6 years-old; 73.4% males; mean ALT 82.6IU/L; mean HCV-RNA 6.02logIU/mL; 80.6% HCV genotypes 1 or 4; 34.9% advanced liver fibrosis; 35.4% IL28B-CC alleles. HIV coinfection in 78.7%, of whom 91% were on antiretroviral therapy. Overall, 127 (15.6%) had serum HCV-RNA values >6 millionIU/mL. This high viremia was found in 18.2% of HIV-positive versus 5.7% of HIV-negative subjects (p<0.001). In multivariate analysis, serum HCV-RNA >6 millionIU/mL was only significantly associated with HIV coinfection (OR: 4.03; 95% CI: 1.98-8.19, p<0.01) and HCV genotypes 1 or 4 (OR: 1.88; 95% CI: 1.05-3.37, p=0.03). CONCLUSIONS Serum HCV-RNA >6 millionIU/mL is roughly seen in 6% of chronic hepatitis C monoinfected patients, and increases up to 18% in HIV coinfection.
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Affiliation(s)
- Pablo Barreiro
- Infectious Diseases Unit, La Paz University Hospital, Madrid, Spain
| | - Pablo Labarga
- Department of Internal Medicine, La Luz Clinic, Madrid, Spain
| | - José V Fernandez-Montero
- Departament of Infectious Diseases, University Hospital Crosshouse, Kilmarnock, Scotland, United Kingdom
| | - Carmen de Mendoza
- Puerta de Hierro Research Institute & University Hospital, Majadahonda, Spain
| | | | - José M Peña
- Infectious Diseases Unit, La Paz University Hospital, Madrid, Spain
| | - Vicente Soriano
- Infectious Diseases Unit, La Paz University Hospital, Madrid, Spain.
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Rembeck K, Lagging M. Impact of IL28B, ITPA and PNPLA3 genetic variants on therapeutic outcome and progression of hepatitis C virus infection. Pharmacogenomics 2015; 16:1179-88. [PMID: 26250055 DOI: 10.2217/pgs.15.65] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Chronic HCV infection comprises a broad spectrum of liver disease, ranging from no or minimal activity to active hepatitis that in time may progress to severe liver fibrosis, cirrhosis and hepatocellular carcinoma if left untreated. This review describes the impact of genetic variants of interleukin 28B (IL28B; also known as interferon-lambda 3), inosine triphosphate pyrophosphatase (ITPA) and patatin-like phospholipase domain-containing 3 (PNPLA3) on therapeutic outcome and liver disease severity in HCV-infected patients.
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Affiliation(s)
- Karolina Rembeck
- Department of Infectious Medicine, Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Guldhedsgatan 10B, SE-413 46, Gothenburg, Sweden
| | - Martin Lagging
- Department of Infectious Medicine, Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Guldhedsgatan 10B, SE-413 46, Gothenburg, Sweden
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Tatum H, Thuluvath PJ, Lawitz E, Martorell C, DeMicco M, Cohen S, Rustgi V, Ravendhran N, Ghalib R, Hanson J, Zamparo J, Zhao J, Cooney E, Treitel M, Hughes E. A randomized, placebo-controlled study of the NS5B inhibitor beclabuvir with peginterferon/ribavirin for HCV genotype 1. J Viral Hepat 2015; 22:658-64. [PMID: 25496007 DOI: 10.1111/jvh.12372] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Accepted: 10/29/2014] [Indexed: 12/31/2022]
Abstract
Beclabuvir is a potent, non-nucleoside inhibitor of the HCV NS5B RNA polymerase, with nanomolar activity against HCV genotypes 1, 3, 4, 5 and 6 in vitro. This study evaluated the efficacy and safety of beclabuvir, in combination with peginterferon alfa-2a (pegIFN) and ribavirin (RBV), in HCV genotype 1. In this randomized (1:1:1), double-blinded, placebo-controlled, dose-ranging phase 2a study, 39 treatment-naive patients chronically infected with HCV genotype 1 were treated for 48 weeks with beclabuvir (75 mg or 150 mg) plus pegIFN (180 μg) and RBV (1000 mg/day [<75 kg] or 1200 mg/day [≥ 75 kg]) vs pegIFN/RBV alone. The primary efficacy endpoint of extended rapid virologic response (undetectable HCV RNA at treatment weeks 4 and 12) was achieved by 76.9% (10/13) of patients receiving beclabuvir 75 mg and 38.5% (5/13) receiving beclabuvir 150 mg vs 0% receiving pegIFN/RBV alone. Higher response rates were observed among patients receiving beclabuvir 75 mg for all secondary efficacy endpoints, including sustained virologic response at follow-up weeks 12 or 24. Three patients experienced virologic breakthrough on treatment, all in the beclabuvir 150-mg treatment group. Beclabuvir was well tolerated at both doses, with the most commonly observed adverse events (headache, fatigue, nausea, decreased appetite, irritability, depression and insomnia) consistent with those observed with pegIFN/RBV. In conclusion, beclabuvir was both effective and well tolerated when administered in combination with pegIFN/RBV for the treatment of chronic HCV GT 1, supporting the study of beclabuvir as part of an all-oral regimen for HCV GT1.
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Affiliation(s)
- H Tatum
- Options Health Research, Tulsa, OK, USA
| | | | - E Lawitz
- The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA
| | - C Martorell
- The Research Institute, Springfield, MA, USA
| | - M DeMicco
- Associated Gastroenterology/Advanced Clinical Research Institute, Anaheim, CA, USA
| | - S Cohen
- University Hospital/Case Western Medical Center, Cleveland, OH, USA
| | - V Rustgi
- Metropolitan Research, Arlington, VA, USA
| | - N Ravendhran
- Digestive Disease Associates, Baltimore, MD, USA
| | - R Ghalib
- Texas Clinical Research Institute, Arlington, TX, USA
| | - J Hanson
- Charlotte Gastroenterology and Hepatology, Charlotte, NC, USA
| | - J Zamparo
- Bristol-Myers Squibb, Wallingford, CT, USA
| | - J Zhao
- Bristol-Myers Squibb, Hopewell, NJ, USA
| | - E Cooney
- Bristol-Myers Squibb, Wallingford, CT, USA
| | - M Treitel
- Bristol-Myers Squibb, Princeton, NJ, USA
| | - E Hughes
- Bristol-Myers Squibb, Princeton, NJ, USA
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48
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Calisti G, Tavares A, Macartney MJ, McCormick A, Labbett W, Jacobs M, Dusheiko G, Rosenberg WM, Haque T. IL28B genotype predicts response to chronic hepatitis C triple therapy with telaprevir or boceprevir in treatment naïve and treatment-experienced patients other than prior partial- and null-responders. SPRINGERPLUS 2015; 4:357. [PMID: 26191484 PMCID: PMC4503705 DOI: 10.1186/s40064-015-1137-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 07/03/2015] [Indexed: 01/26/2023]
Abstract
Single nucleotide polymorphisms (SNPs) in the IL28B gene were shown to have limited utility in predicting response to telaprevir and boceprevir in treatment of chronic HCV infection in clinical trials. Data outside of the clinical trial setting are lacking. We assessed the value of single and combined IL28B SNPs rs12979860 and rs8099917 genotypes in predicting sustained virological response 12 weeks after cessation of triple therapy (SVR12) with telaprevir or boceprevir in a single-centre cohort of treatment-naïve and treatment-experienced patients with genotype 1 HCV mono-infection (n = 105). The overall SVR12 rate was 65.7%. By unadjusted bivariate logistic regression analysis, rs12979860-CC and rs8099917-TT were significantly associated with SVR12 in the subgroup of patients including all naïve patients and all treatment-experienced patients with the exception of partial- and null-responders to previous HCV therapy. The predictive value of rs12979860-CC was stronger than rs8099917-TT and only rs12979860-CC remained significantly predictive of treatment success when the two variants were assessed by adjusted logistic regression analysis in the whole study cohort. In patients presenting the rs12979860-CC variant, the additional determination of rs8099917 genotype had no value. IL28B rs12979860-CC remained significantly associated with SVR12 also in the multivariate analysis including the other baseline characteristics associated to SVR12 in the bivariate analysis (i.e., female gender, HCV genotype 1b, baseline viral load <800,000 IU/mL, advanced liver fibrosis and prior partial- or null-response to HCV therapy). Our study suggests that testing for the IL28B rs12979860 genotype may still be useful in predicting response to triple therapy with boceprevir and telaprevir in naïve patients and treatment-experienced patients other than partial and null-responders.
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Affiliation(s)
- Giorgio Calisti
- Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London, NW5 4AP UK
| | - Amanda Tavares
- Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London, NW5 4AP UK
| | - Malcolm J Macartney
- Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London, NW5 4AP UK
| | - Adele McCormick
- Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London, NW5 4AP UK
| | - Wendy Labbett
- Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London, NW5 4AP UK
| | - Michael Jacobs
- The UCL Institute for Liver and Digestive Health/Royal Free London NHS Foundation Trust Viral Hepatitis Service, London, UK
| | - Geoffrey Dusheiko
- The UCL Institute for Liver and Digestive Health/Royal Free London NHS Foundation Trust Viral Hepatitis Service, London, UK
| | - William M Rosenberg
- The UCL Institute for Liver and Digestive Health/Royal Free London NHS Foundation Trust Viral Hepatitis Service, London, UK
| | - Tanzina Haque
- Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London, NW5 4AP UK
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Cavalcante LN, Lyra AC. Predictive factors associated with hepatitis C antiviral therapy response. World J Hepatol 2015; 7:1617-31. [PMID: 26140082 PMCID: PMC4483544 DOI: 10.4254/wjh.v7.i12.1617] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/16/2014] [Accepted: 05/05/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection may lead to significant liver injury, and viral, environmental, host, immunologic and genetic factors may contribute to the differences in the disease expression and treatment response. In the early 2000s, dual therapy using a combination of pegylated interferon plus ribavirin (PR) became the standard of care for HCV treatment. In this PR era, predictive factors of therapy response related to virus and host have been identified. In 2010/2011, therapeutic regimens for HCV genotype 1 patients were modified, and the addition of NS3/4a protease inhibitors (boceprevir or telaprevir) to dual therapy increased the effectiveness and chances of sustained virologic response (SVR). Nevertheless, the first-generation triple therapy is associated with many adverse events, some of which are serious and associated with death, particularly in cirrhotic patients. This led to the need to identify viral and host predictive factors that might influence the SVR rate to triple therapy and avoid unnecessary exposure to these drugs. Over the past four years, hepatitis C treatment has been rapidly changing with the development of new therapies and other developments. Currently, with the more recent generations of pangenotipic antiviral therapies, there have been higher sustained virologic rates, and prognostic factors may not have the same importance and strength as before. Nonetheless, some variables may still be consistent with the low rates of non-response with regimens that include sofosbuvir, daclatasvir and ledipasvir. In this manuscript, we review the predictive factors of therapy response across the different treatment regimens over the last decade including the new antiviral drugs.
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Affiliation(s)
- Lourianne Nascimento Cavalcante
- Lourianne Nascimento Cavalcante, André Castro Lyra, Hospital Sao Rafael - Gastro-Hepatology Service, Salvador, Bahia 41253-190, Brazil
| | - André Castro Lyra
- Lourianne Nascimento Cavalcante, André Castro Lyra, Hospital Sao Rafael - Gastro-Hepatology Service, Salvador, Bahia 41253-190, Brazil
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50
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Sultanik PS, Casrouge A, Alanio C, Mottez E, Rosa-Hézode I, Hézode C, Renard P, Bousquet L, Pellet P, Uzé G, Pol S, Albert ML, Mallet V. Baseline sensitivity of T cells to alpha-IFN correlates with sustained virological response to IFN-based triple therapy in HCV infection. J Viral Hepat 2015; 22:524-34. [PMID: 25382001 DOI: 10.1111/jvh.12355] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 10/04/2014] [Indexed: 01/22/2023]
Abstract
Chronic infection with HCV is a public health problem with approximately 170 million people infected worldwide. Interferon alpha (IFNα) sensitivity in liver and IL28B genotype has been identified as important determinants of HCV clearance in the setting of pegylated interferon/ribavirin treatment. Herein, we explored IFNα sensitivity in PBMC from 21 healthy donors and 21 HCV-infected patients treated with pegylated interferon/ribavirin and HCV nonstructural protein-3 inhibitors (i.e. telaprevir/boceprevir). We explored phospho-STAT1 level as read-out for IFN signalling pathway activation in PBMC, T cells and monocytes and correlated results with virological response. We found that PBMC from healthy donors are desensitized to IFNα after priming and challenged with IFNα, with a subsequent decrease of phospho-STAT1 and interferon-stimulated genes. Furthermore, we show that CD3+ T cells, but not monocytes, become desensitized after 4 weeks of treatment, with a significant decrease of phospho-STAT1 after ex vivo IFNα stimulation. Finally, we identified baseline phospho-STAT1 level in CD3+ T cells as a potential biomarker of sustained virological response, regardless of the IL28B genotype. In the upcoming costly era of IFN-sparing regimen, baseline IFNα sensitivity could act as biomarker to define cost-effectiveness strategies of treatment by identifying patients who will or will not respond to IFN-based treatments.
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Affiliation(s)
- P-S Sultanik
- INSERM (UMR-S 1016), Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Cochin-Port Royal, Service d'hépatologie, Paris, France
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