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

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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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Most cited references 26

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Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.

M P Manns, J. G. McHutchison, S Gordon … (2001)

A sustained virological response (SVR) rate of 41% has been achieved with interferon alfa-2b plus ribavirin therapy of chronic hepatitis C. In this randomised trial, peginterferon alfa-2b plus ribavirin was compared with interferon alfa-2b plus ribavirin. 1530 patients with chronic hepatitis C were assigned interferon alfa-2b (3 MU subcutaneously three times per week) plus ribavirin 1000-1200 mg/day orally, peginterferon alfa-2b 1.5 microg/kg each week plus 800 mg/day ribavirin, or peginterferon alfa-2b 1.5 microg/kg per week for 4 weeks then 0.5 microg/kg per week plus ribavirin 1000-1200 mg/day for 48 weeks. The primary endpoint was the SVR rate (undetectable hepatitis C virus [HCV] RNA in serum at 24-week follow-up). Analyses were based on patients who received at least one dose of study medication. The SVR rate was significantly higher (p=0.01 for both comparisons) in the higher-dose peginterferon group (274/511 [54%]) than in the lower-dose peginterferon (244/514 [47%]) or interferon (235/505 [47%]) groups. Among patients with HCV genotype 1 infection, the corresponding SVR rates were 42% (145/348), 34% (118/349), and 33% (114/343). The rate for patients with genotype 2 and 3 infections was about 80% for all treatment groups. Secondary analyses identified bodyweight as an important predictor of SVR, prompting comparison of the interferon regimens after adjusting ribavirin for bodyweight (mg/kg). Side-effect profiles were similar between the treatment groups. In patients with chronic hepatitis C, the most effective therapy is the combination of peginterferon alfa-2b 1.5 microg/kg per week plus ribavirin. The benefit is mostly achieved in patients with HCV genotype 1 infections.

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A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.

Ludmila Prokunina-Olsson, Brian Muchmore, Wei Tang … (2013)

Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designated IFNL4, encoding the interferon-λ4 protein (IFNL4), which is moderately similar to IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians. Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.

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Boceprevir for previously treated chronic HCV genotype 1 infection.

Bruce Bacon, Stuart Gordon, Eric Lawitz … (2011)

In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment. To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10) IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls. The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500.).

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Author and article information

Contributors

Chen-Hua Liu: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 15 December 2015

Publication date Collection: 2015

Volume: 10

Issue: 12

Electronic Location Identifier: e0145105

Affiliations

[1 ]Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France

[2 ]Paris Descartes University, Imagine Institute, Paris, France

[3 ]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

[4 ]Plateforme Génomique Inserm-ANRS, Groupe Hospitalier Pitié Salpétrière, AP-HP, UPMC Université Paris 6, Paris, France

[5 ]Sorbonne Universités, UPMC Université Paris 06, INSERM, Institut Pierre Louis d’épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France

[6 ]Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom

[7 ]Centre for Human Immunology, Department of Immunology, Institut Pasteur, Paris, France

[8 ]The Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, INSERM U818, Paris, France

[9 ]Département d'Hépatologie, Hôpital Cochin, AP-HP, Université Paris Descartes, Paris, France

[10 ]INSERM UMS20, Institut Pasteur, Paris, France

[11 ]Unit for Basic and Clinical research on Viral Hepatitis, Inserm-ANRS (France REcherche Nord & sud Sida-HIV Hépatites-FRENSH), Paris, France

[12 ]Service de Santé Publique, Hôpital Saint Antoine, AP-HP, Paris, France

[13 ]Service d’Hépatologie, Hôpital Beaujon, Clichy, France

[14 ]Centre de recherche en cancérologie de Lyon (CRCL), INSERM UMR I 1052/CNRS 5286, Lyon cedex 03, France

[15 ]Université Claude-Bernard Lyon 1, Villeurbanne, France

[16 ]Hospices civils de Lyon, Hôpital de la Croix-Rousse, service d'hépatologie et de gastroentérologie, Lyon, France

[17 ]CHU St Eloi Hospital, Liver Unit, Montpellier, France

[18 ]Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est Créteil (UPEC), Créteil, France

[19 ]Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, UPEC, Créteil, France

[20 ]Department of Hepatogastroenterology, INSERM U954, CHU de Nancy, Université de Lorraine, Vandoeuvre-Lès-Nancy, France

[21 ]St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, United States of America

National Taiwan University Hospital, TAIWAN

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: AC LA IT. Performed the experiments: TOM JN FA. Analyzed the data: FA AC VP. Contributed reagents/materials/analysis tools: PR DD CC PS FC PM FZ DL CH HF JPB SP MLA IT. Wrote the paper: FA AC LA.

¶ Membership of the ANRS CO20-CUPIC study group is listed in the Acknowledgments.

* E-mail: aurelie.cobat@ 123456inserm.fr (AC); laurent.abel@ 123456inserm.fr (LA)

Article

Publisher ID: PONE-D-15-39467

DOI: 10.1371/journal.pone.0145105

PMC ID: 4682920

PubMed ID: 26670100

SO-VID: 452e1208-071d-4e50-a292-f386b4adabe9

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

History

Date received : 7 September 2015

Date accepted : 29 November 2015

Page count

Figures: 2, Tables: 1, Pages: 13

Funding

This work was supported by INSERM-ANRS (France REcherche Nord & sud Sida-HIV Hépatites-FRENSH, Grant n° 2010-A01273-36, http://www.anrs.fr), Institut National de la Santé et de la Recherche Médicale (INSERM, http://www.inserm.fr), University Paris Descartes ( http://www.parisdescartes.fr), the French National Research Agency (ANR, http://www.agence-nationale-recherche.fr) under the ‟Investments for the future” program (grant n°ANR-10-IAHU-01), and in part by the Association Française pour l'Etude du Foie (AFEF, http://www.afef.asso.fr). FA is the recipient of a fellowship from Fondation pour la Recherche Médicale (FRM, Grant n° FDM20140630671, http://www.frm.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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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

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Patients and Methods

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Most cited references 26

Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.

A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.

Boceprevir for previously treated chronic HCV genotype 1 infection.

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