IL28B polymorphism and hepatitis C: A genetic marker of peginterferon-α sensitivity devoid from classical interferon-α side effects?
Authors: Hans Orlent, Robert J. de Knegt, Harry L.A. Janssen
Journal: Journal of Hepatology (2012)

Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patientsJournal of HepatologyVol. 56Issue 2PreviewInterferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-α (pegIFN)-related thrombocytopenia, neutropenia, and leukopenia. Full-Text PDF Reply to “IL28B polymorphism and hepatitis C: A genetic marker of peginterferon-α sensitivity devoid from classical interferon-α side effects?”Journal of HepatologyVol. 56Issue 3PreviewWe appreciate the interest of Orlent et al. in our recent study [1] and would like to comment on the issues raised in their letter. Full-Text PDF Open Access Single nucleotide polymorphism (SNP) in the region of the interleukin-28B (IL28B) gene has recently been associated with spontaneous and treatment-induced clearance of hepatitis C virus infection [1Ge D. Fellay J. Thompson A.J. Simon J.S. Shianna K.V. Urban T.J. et al.Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.Nature. 2009; 461: 399-401Crossref PubMed Scopus (3137) Google Scholar, 2Suppiah V. Moldovan M. Ahlenstiel G. Berg T. Weltman M. Abate M.L. et al.IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy.Nat Genet. 2009; 41: 1100-1104Crossref PubMed Scopus (1724) Google Scholar, 3Tanaka Y. Nishida N. Sugiyama M. Kurosaki M. Matsuura K. Sakamoto N. et al.Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.Nat Genet. 2009; 41: 1105-1109Crossref PubMed Scopus (2016) Google Scholar]. The SNPs are located near the IL28B gene of chromosome 19, implicating a role for its gene product, interferon-λ3, in the immune response to hepatitis C virus. The mechanisms by which IL28B polymorphism effects the sensitivity to exogenous peginterferon-α therapy is unclear at present. We have read with interest the recent genome-wide association study by Thompson et al. on peginterferon-α-induced cytopenia in chronic hepatitis C patients [[4]Thompson A.J. Clark P.J. Singh A. Ge D. Fellay J. Zhu M. et al.Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients.J Hepatol. 2012; 56: 313-319Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar]. The authors state that none of the IL28B polymorphisms known to be associated with treatment induced viral clearance, correlated with the typical peginterferon-α side effects thrombocytopenia and neutropenia after 4 weeks of treatment. The authors suggest a possible liver specificity of interferon-λ by which the favorable IL28B polymorphism might result in increased viral clearance from the liver with a reduced propensity for interferon-α-induced bone marrow suppression. We have three concerns regarding the study that might influence interpretation of the observations made by the authors. In the Individualized Dosing Efficacy versus Flat Dosing to Asses Optimal Pegylated Interferon Therapy (IDEAL) study, 3070 patients were treated, of whom 1654 completed the treatment [[5]McHutchison J.G. Lawitz E.J. Shiffman M.L. Muir A.J. Galler G.W. McCone J. et al.Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection.New Engl J Med. 2009; 361: 580-593Crossref PubMed Scopus (1132) Google Scholar]. The patient group of the current GWAS study consisted of 1284 out of 1604 patients who consented to genetic testing and fulfilled the 80/80/80 adherence criteria. The majority of patients studied in this analysis, therefore, probably derive from the 1654 who completed treatment. Limiting the analysis to adherent patients when studying dose-related side effects such as peginterferon-induced cytopenia may appear justified at first glance. This approach, however, excludes the data from patients who had dose reductions or were not able to complete treatment for other peginterferon side effects, but who may have had concomitant peginterferon-induced cytopenias. In the IDEAL study, patients were treated with either peginterferon-α-2b 1 μg/kg, 1.5 μg/kg or peginterferon-α-2a 180 μg/kg weekly on a 1/1/1 randomized basis in combination with ribavirin oral therapy [[5]McHutchison J.G. Lawitz E.J. Shiffman M.L. Muir A.J. Galler G.W. McCone J. et al.Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection.New Engl J Med. 2009; 361: 580-593Crossref PubMed Scopus (1132) Google Scholar]. The proportions of patients with neutropenia who met the criterion for per protocol peginterferon-dose reduction in this study were 12.5%, 19.4% and 21.1% of the patients treated with the low-dose peginterferon-α-2b (1 μg/kg) versus the standard-dose peginterferon-α-2b (1.5 μg/kg) and peginterferon-α-2a (180 μg/kg), respectively. The inclusion of the low-dose peginterferon-α-2b arm in the current analysis therefore obscures the severity of the observed cytopenias in the two arms that were treated with the standard dose of either peginterferon-α that is relevant for current clinical practice. In two recent publications by our group on peginterferon-α-induced cytopenia, thrombocytopenia and neutropenia progressed to a nadir after 12 and 14 weeks of peginterferon-α treatment, respectively [6Roomer R. Hansen B.E. Janssen H.L. de Knegt R.J. Thrombocytopenia and the risk of bleeding during treatment with peginterferon alfa and ribavirin for chronic hepatitis C.J Hepatol. 2010; 53: 455-459Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 7Roomer R. Hansen B.E. Janssen H.L. de Knegt R.J. Risk factors for infection during treatment with peginterferon alfa and ribavirin for chronic hepatitis C.Hepatology. 2010; 52: 1225-1231Crossref PubMed Scopus (53) Google Scholar]. The analysis performed by the authors after only 4 weeks of treatment might therefore underscore the severity of true peginterferon-α-induced cytopenia, obscuring a possible link with baseline IL28B polymorphism as a marker of interferon sensitivity. To rule out an inclusion bias, it is necessary to demonstrate that the cytopenias observed in the reported 1284 patients do not differ from those observed in the 1466 patients who did not consent to genetic testing or in the 320 patients who did consent but are not included in the analysis. We are also interested to learn from the authors whether the absence of correlation with IL28B polymorphism and peginterferon-induced cytopenia would hold if the analysis were to be performed in both adherent and non-adherent patients under treatment at week 12 and 18 from the two standard peginterferon-α-2b 1.5 μg/kg and peginterferon-α-2a 180 μg dosing groups, omitting the data from the low-dose peginterferon-α-2b (1.0 μg/kg) group. An analysis of the IL28B genotype distribution in the so-called “non-adherent” population that consented to genetic testing in comparison to the reported “adherent” group would further help to clarify whether a favorable IL28B polymorphism does in fact enhance viral clearance without the occurrence of classical interferon-α side effects. H.O. has no conflict of interest to disclose. R.J.dK. Received research funding and has been invited speaker from Merck and Roche. H.L.A.J. received grants from and is a consultant for: Bristol Myers Squibb, Gilead Sciences, Novartis, Roche and Merck.