Predictors of the therapeutic response in hepatitis C. A 2013 update

Clin Res Hepatol Gastroenterol. 2013 Nov 20. pii: S2210-7401(13)00177-0. doi: 10.1016/j.clinre.2013.08.003. [Epub ahead of print]

Arnaud C, Trépo C, Petit MA.

Inserm U1052/CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon (CRCL), 151, Cours-Albert-Thomas, 69424 Lyon cedex 03, France; Université Claude-Bernard Lyon 1, 69000 Lyon, France.

Abstract

Chronic hepatitis C is a major cause of cirrhosis and hepatocellular carcinoma. Current therapy based on pegylated-interferon-α (PEG-IFN) and ribavirin (RBV) combination has limited efficacy and is poorly tolerated. Disease progression is highly variable and pre-therapeutic prediction of response to treatment remains difficult. Although viral kinetics proved most useful to monitor duration of therapy, other predictors would be helpful to identify patients with the best chance of subsequent treatment response prior initiation of antiviral therapy (double or triple therapy). The predictive power of IL28B polymorphism is well-recognized and has become the reference biomarker for clinicians in patients treated with double therapy. The combination of serum IP-10 and IL28B SNPs increases predictive value of treatment response. Recently, anti-E1E2 antibodies appear to closely correlate with therapeutic outcome and predict the complete elimination of HCV. They may represent a new relevant prognostic biomarker of double therapy response. Since the introduction of triple therapy including protease inhibitors (telaprevir/boceprevir), the major priority is to help patients who failed on double therapy, and there is now an urgent need for robust pre-therapeutic predictors of response to better select the patients to treat. Indeed, the relevance of IL28B polymorphism and IP-10 serum concentration are limited in triple therapy. Many new drugs are currently under investigation and there is hope that effective and well-tolerated IFN-free regimens may become a part of future therapy. In this context, this will help to identify the most powerful predictive marker and/or to assess the benefit of anti-E1E2 in decision to treat.

Copyright © 2013 Elsevier Masson SAS. All rights reserved.

PMID: 24268305 [PubMed - as supplied by publisher]

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Temperature rise after peginterferon alfa-2a injection in patients with chronic hepatitis C is associated with virological response and is modulated by IL28B genotype

J Hepatol. 2013 Nov;59(5):957-63. doi: 10.1016/j.jhep.2013.07.004. Epub 2013 Jul 10.

Han H, Noureddin M, Witthaus M, Park YJ, Hoofnagle JH, Liang TJ, Rotman Y.

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States.

Abstract

BACKGROUND & AIMS: Interferon treatment for chronic hepatitis C is associated with non-specific symptoms including fever. We aimed to determine the association of temperature changes with interferon antiviral activity.

METHODS: 60 treatment-naïve patients with chronic hepatitis C (67% genotype 1/4/6, 33% genotype 2/3) were admitted to start peginterferon alfa-2a and ribavirin in a clinical trial. Temperature was measured at baseline and 3 times daily for the first 24h and the maximal increase from baseline during that time (ΔTmax) was determined. Serum HCV-RNA, interferon-gamma-inducible protein-10 (IP-10) and expression of interferon-stimulated genes (ISGs - CD274, ISG15, RSAD2, IRF7, CXCL10) in peripheral blood mononuclear cells (PBMCs) were measured at very early time points, and response kinetics calculated. The IL28B single nucleotide polymorphism, rs12979860, was genotyped.

RESULTS: Temperatures rose by 1.2±0.8°C, peaking after 12.5h. ΔTmax was strongly associated with 1st phase virological decline (r=0.59, p<0.0001) and was independent of gender, cirrhosis, viral genotype or baseline HCV-RNA. The association with 1st phase decline was seen in patients with rs12989760CC genotype (r=0.65, p<0.0001) but not in CC/CT (r=0.13, p=0.53) and patients with CC genotype had a higher ΔTmax (1.4±0.8°C vs. 0.8±0.6°C, p=0.001). ΔTmax was associated with 6- and 24-h induction of serum IP-10 and of PBMC ISG expression, but only in patients with rs12989760CC. ΔTmax weakly predicted early virological response (AUC=0.68, CI 0.49-0.88).

CONCLUSIONS: Temperature rise following peginterferon injection is closely associated with virological response and is modulated by IL28B polymorphism, reflecting host interferon-responsiveness.

Published by Elsevier B.V.

KEYWORDS: EVR, Fever, HCV, Hepatitis C, IFN, IL28B, IP-10, ISG, Interferon alfa, PGE2, PegIFN, RVR, SVR, Temperature, Treatment, early virological response, hepatitis C virus, interferon, interferon-gamma-inducible protein-10, interferon-stimulated gene, peginterferon alfa 2a, prostaglandin E2, rapid virological response, sustained virological response

PMID: 23850879 [PubMed - in process]

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IL28B and interferon-gamma inducible protein 10 for prediction of rapid virologic response and sustained virologic response in HIV-HCV-coinfected patients

Eur J Clin Invest. 2012 Jun;42(6):599-606. doi: 10.1111/j.1365-2362.2011.02623.x. Epub 2011 Nov 25.

Payer BA, Reiberger T, Aberle J, Ferenci P, Holzmann H, Rieger A, Peck-Radosavljevic M; Vienna HIV-HCV study group.

Source

Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Abstract

BACKGROUND: A polymorphism near the IL28B gene has been shown to be associated with virologic response to antiviral treatment in HCV-infected patients. The predictive value of interferon-gamma inducible protein 10 (IP10) on treatment outcome has been described in HCV patients. Data on combining these predictors in HIV-HCV-coinfected patients are not available.

METHODS: Virologic parameters, IL28B single nucleotide polymorphisms (SNP) and pretreatment serum IP10 were determined in HIV-HCV-coinfected patients having completed antiviral therapy with pegylated interferon/ribavirin.

RESULTS: A total of 72 HIV-HCV-coinfected patients were included in the study; 68% had HCV genotype (GT)-1/4 and 32% had HCV GT-2/3 infections. Rapid virologic response (63% vs. 28%; P = 0·023) and sustained virologic response (SVR: 81% vs. 51%; P = 0·008) rates were significantly higher in C/C vs. non-C/C patients. Patients with low pretreatment IP10 levels (< 400 pg/mL) achieved significantly higher SVR rates than patients with high (> 400 pg/mL) IP10 levels (78% vs. 13%; P < 0·0001). C/C SNP and low IP10 levels were associated with higher SVR rates in both patients with GT-1/4 and GT-2/3. The C/C patients with low IP10 achieved SVR rates of 97% compared with SVR rates of 9% in non-C/C patients with high IP10.

CONCLUSION: The IL28B SNP influences rapid viral response, relapse rates and SVR. The combination of IL28B and IP10 represents a predictive model of SVR in HIV-HCV coinfection.

© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.

PMID: 22117591 [PubMed - indexed for MEDLINE]

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Vertex's Abstracts at EASL 2012

Email received from Vertex April 4, 2012

Good afternoon,

Vertex will present data on INCIVEK® (telaprevir) tablets, approved for the treatment of hepatitis C, and one of its hepatitis C medicines in development, the non-nucleoside polymerase inhibitor VX-222, at the 47th Annual Meeting of the European Association for the Study of the Liver (EASL) in Barcelona, Spain, April 18 to 22, 2012.

The titles of the 14 accepted abstracts are included below, attached as a pdf and on our website at http://www.vrtx.com/2012-easl.html. The complete abstracts are now available through the EASL website at www.easl.eu.

Oral Presentation: April 20, 2012, 4:00 p.m. – 6:00 p.m. CET

· "Futility Rules in Telaprevir Combination Treatment"

Poster Presentations: April 21, 2012, 12:30 p.m. – 1:30 p.m. CET

· Poster # 1094:"100% SVR in IL28b CC Patients Treated with 12 Weeks of Telaprevir, Peginterferon and Ribavirin in the PROVE2 Trial"

· Poster # 1203: "All IL28b Genotypes Have High SVR Rates in Patients Treated with VX-222 in Combination with Telaprevir/Peginterferon/Ribavirin in the ZENITH Study"

· Poster # 1132: "High Concordance Between SVR12 and SVR24 in Patients Receiving Telaprevir Plus Peginterferon and Ribavirin in Three Phase 3 Clinical Trials: ADVANCE, ILLUMINATE and REALIZE"

· Poster # 1162: "Ribavirin Dose Modification in Treatment-Naïve and Previously Treated Patients Who Received Telaprevir Combination Treatment: No Impact on Sustained Virologic Response in Phase 3 Studies"

· Poster # 1167: "Pre-Treatment IP-10 Levels and IL28b Genotype in Prediction of SVR in Prior Treatment-Experienced Genotype 1 HCV Patients Treated with Telaprevir/ Peginterferon/ Ribavirin in REALIZE Study"

· Poster # 1150: "A Comprehensive Review of Patterns of Viral Load Decline in Patients Treated with Telaprevir Plus Peginterferon and Ribavirin"

· Poster # 1117: "Telaprevir French Cohort Authorisation for Temporary Use in Genotype 1 Hepatitis C Cirrhotic Patients with Prior Partial Response or Relapse"

· Poster # 1116: "Exposure-Response Relationships in Telaprevir Combination Therapy in Treatment-Naïve Genotype 1 Chronic HCV Patients"

· Poster # 1174: "Deep Sequencing Screening for Telaprevir-Resistant Viral Variants in Previous Null Responders Fails to Identify Those Patients at Risk of Failing Telaprevir Plus Peginterferon/Ribavirin Therapy”

· Poster # 1184: "Characterization of HCV Variants in Genotype 1 Treatment-Naïve Patients Administered the Combination of TVR and VX-222 in Dual Arms of ZENITH Study"

· Poster # 1102: "The Cost-Effectiveness of Telaprevir (TVR) in Combination with Pegylated Interferon-Alfa and Ribavirin (PR) for the Treatment of Genotype 1(G1) Chronic Hepatitis C Patients"

· Poster # 1169: "Health-Related Quality-of-Life Among Genotype 1 Treatment-Naïve Chronic Hepatitis C Patients Receiving Telaprevir Combination Treatment: Post-Hoc Analyses of Data from the ADVANCE Trial"

· Poster # 1170: "Predictors of Days Unable to Work Among Genotype 1 Treatment-Naïve Chronic Hepatitis C Patients: Post-Hoc Analyses of Data from Phase 3 ADVANCE and ILLUMINATE Studies"

Media Contacts:
Erin Emlock
Dawn Kalmar
Zachry Barber
617-444-6992

Investor Relations Contact:
Michael Partridge, 617-444-6108

Quantitation of pretreatment serum interferon-γ-inducible protein-10 improves the predictive value of an IL28B gene polymorphism for hepatitis C treatment response

Hepatology. 2011 Jan;53(1):14-22. doi: 10.1002/hep.24056.

Darling JM, Aerssens J, Fanning G, McHutchison JG, Goldstein DB, Thompson AJ, Shianna KV, Afdhal NH, Hudson ML, Howell CD, Talloen W, Bollekens J, De Wit M, Scholliers A, Fried MW.

University of North Carolina, Chapel Hill, NC.

Abstract

Polymorphisms of the IL28B gene are highly associated with sustained virological response (SVR) in patients with chronic hepatitis C treated with peginterferon and ribavirin. Quantitation of interferon-γ-inducible protein-10 (IP-10) may also differentiate antiviral response. We evaluated IP-10 levels in pretreatment serum from 115 nonresponders and 157 sustained responders in the Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C cohort, including African American (AA) and Caucasian American (CA) patients. Mean IP-10 was lower in sustained responders compared with nonresponders (437 ± 31 vs 704 ± 44 pg/mL, P < 0.001), both in AA and CA patients. The positive predictive value of low IP-10 levels (<600 pg/mL) for SVR was 69%, whereas the negative predictive value of high IP-10 levels (>600 pg/mL) was 67%. We assessed the combination of pretreatment IP-10 levels with IL28B genotype as predictors of treatment response. The IL28B polymorphism rs12979860 was tested in 210 participants. The CC, CT, and TT genotypes were found in 30%, 49%, and 21% of patients, respectively, with corresponding SVR rates of 87%, 50%, and 39% (P < 0.0001). Serum IP-10 levels within the IL28B genotype groups provided additional information regarding the likelihood of SVR (P < 0.0001). CT carriers with low IP-10 had 64% SVR versus 24% with high IP-10. Similarly, a higher SVR rate was identified for TT and CC carriers with low versus high IP-10 (TT, 48% versus 20%; CC, 89% versus 79%). IL28B genotype and baseline IP-10 levels were additive but independent when predicting SVR in both AA and CA patients. Conclusion: When IL28B genotype is combined with pretreatment serum IP-10 measurement, the predictive value for discrimination between SVR and nonresponse is significantly improved, especially in non-CC genotypes. This relationship warrants further investigation to elucidate the mechanisms of antiviral response and prospective validation. (Hepatology 2011;).

Copyright © 2010 American Association for the Study of Liver Diseases.

PMID: 21254158 [PubMed - in process]

Source

Hepatitis C: In 2011, a predictive marker for response to therapy

Public release date: 5-Jan-2011

Contact: Matthew Albert
albertm@pasteur.fr
33-670-010-396
INSERM (Institut national de la santé et de la recherche médicale)

Scientists at Inserm and Institut Pasteur have performed biomarker discovery on patients being treated for chronic hepatitis C infection. Their work, published in The Journal of Clinical Investigation, demonstrates that the plasma levels of the protein IP-10 predict, prior to treatment initiation, the efficacy of treatment with pegylated-interferon and ribavirin. Based on these results, the scientists have developed a prognostic test. Commercialization is anticipated in 2011, and will help inform physicians of the chances that patients will respond to standard treatment or if instead they will require new therapeutic cocktails (e.g., inclusion of protease inhibitors).

Importantly, hepatitis C is the leading cause of primary liver cancer (hepatocellular carcinoma) and it remains an important cause of liver failure due to fibrosis and cirrhosis. This infectious disease represents a major public health problem, with greater than 170 million cases worldwide. The World Health Organization estimates 3 to 4 million new cases per year and considers the virus a " viral time bomb" due to the long term sequella of infection.

Currently, there is no approved vaccine available and approximately 80% of individuals infected by the virus develop chronic disease, a risk factor for cirrhosis, liver failure, liver cancer as well as other medical complications (e.g., diabetes).

For the past ten years, treatment has been based on the use of type I interferon given in combination with the anti-viral ribavirin. While effective, it results in a cure for only 50% of patients. Moreover, treatment is long (24 – 48 weeks), and it results in severe side effects (e.g., depression, anemia).

It is in this context that the Inserm and Institut Pasteur sponsored research lab of Dr. Matthew Albert, in close collaboration with the Liver Disease Unit headed by Prof. Stanislas Pol, evaluated plasma biomarkers to define predictors for patients' response to treatment.

With the help of the Centre for Human Immunology at Institut Pasteur, the investigators involved have performed a prospective study. They identified the protein IP-10 as a prognostic biomarker – elevated in those patients for whom treatment was ineffective. This observation was paradoxical as IP-10 is considered a pro-inflammatory molecule, which should have facilitated migration of activated T cells to the liver, the exact cell types responsible for viral immunity. In fact, what was discovered is that the IP-10 had been catabolized and it was a truncated form present in the HCV patients. Strikingly, the short form of IP-10 is an antagonist and inhibits T cell recruitment. Thus, it is suggested that the antagonist form of IP-10 is responsible for the failure to respond to treatment in the 50% of patients who do not benefit from pegylated-interferon / ribavirin treatment.

The investigators worked in close collaboration with an American company, Rules Based Medicine, Inc., who will develop a diagnostic test to distinguish the different forms of IP-10 as a simple blood test. This test will be a significant step towards the improved management of patients with HCV as well as other chronic inflammatory diseases.

###

This scientific work was conducted under the direction of Matthew L. Albert, MD PhD, Mixed Institut Pasteur / Inserm Research Unit; and Stanislas Pol, MD PhD, Univerisity of Paris, Descartes and Institut Cochin. Financial support was provided by the ANRS and promotion of the study was taken by Inserm Medical.

To know more:

Source

Evidence for chemokine antagonisms in human infected chronically with Hepatitis C Virus.
Armanda Casrouge, Jérémie Decalf, Mina Ahloulay, Cyril Lababidi, Hala Mansour, Anaïs Vallet-Pichard, Vincent Mallet, Estelle Mottez, James Mapes, Arnaud Fontanet, Stanislas Pol and Matthew L. Albert.

Journal of Clinical Investigation.

and the related news article

Chemokine antagonism in chronic hepatitis C virus infection.
Edgar D. Charles and Lynn B. Dustin

Journal of Clinical Investigation.

Contact information

Matthew Albert
Unité mixte Institut Pasteur / Inserm
Email : albertm@pasteur.fr
Tel : +33 6 7001 0396

Stanislas Pol
Unité 1016 « Institut Cochin »
Service Hépatologie, Hôpital Cochin
Email : stanislas.pol@cch.aphp.fr

Source