Triple or dual therapy for HCV-1 naive patients? Optimizing selection tools
Authors: Lucio Boglione, Amedeo De Nicolò, Giovanni Di Perri, Antonio D’Avolio
Journal: Journal of Hepatology (2014)

Identification of naïve HCV-1 patients with chronic hepatitis who may benefit from dual therapy with peg-interferon and ribavirinJournal of HepatologyVol. 60Issue 1PreviewThe pool of HCV genotype 1 patients likely to be cured by peg-interferon and ribavirin remains to be quantified. Full-Text PDF Reply to "Triple or dual therapy for HCV-1 naive patients? Optimizing selection tools"Journal of HepatologyVol. 61Issue 1PreviewWe thank Dr. Boglione and colleagues [1] for their comments on our recently published paper on the identification of naïve HCV-1 patients with chronic hepatitis who may benefit from dual therapy with peg-interferon (PegIFN) and ribavirin (RBV) [2]. To date, several single nucleotide polymorphisms (SNPs) in the genes encoding for IFN-λ1 (IL29), IFN-λ2 (IL28A), IFN-λ3 (IL28B), and IFN-λ4 (IFNL4) have been established as predictors of treatment response to PegIFN/RBV [3,4]. Among the identified SNPs, rs8099917, rs12979860, and the newly ss469415590 polymorphisms have been extensively investigated. Full-Text PDF Open Access We read with interest the paper by Andriulli et al. [[1]Andriulli A. Di Marco V. Margaglione M. Ippolito A.M. Fattovich G. Smedile A. et al.Identification of naive HCV-1 patients with chronic hepatitis who may benefit from dual therapy with peg-interferon and ribavirin.J Hepatol. 2014; 60: 16-21Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar] about the identification of naïve HCV-1 patients who can be treated with dual therapy according to baseline and on-treatment parameters. Important predictive factors of sustained virological response (SVR) are the IL28B single-nucleotide polymorphisms (SNPs), however the authors considered only the rs12979860 SNP, forgetting the more important rs8099917 [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 (1723) Google Scholar, 3D'Avolio A. Ciancio A. Siccardi M. Baietto L. Simiele M. Cariti G. et al.Ribavirin pharmacokinetics and interleukin 28B plus cytochrome P450 27B1 single-nucleotide polymorphisms as predictors of response to pegylated interferon/ribavirin treatment in patients infected with hepatitis C virus genotype 1/4.Hepatology. 2011; 54: 2279Crossref Scopus (27) Google Scholar, 4D'Avolio A. Ciancio A. Siccardi M. Smedile A. Simiele M. Cusato J. et al.Negative predictive value of IL28B, SLC28A2, and CYP27B1 SNPs and low RBV plasma exposure for therapeutic response to PEG/IFN-RBV treatment.Ther Drug Monit. 2012; 34: 722-728Crossref PubMed Scopus (31) Google Scholar]; this is, in our opinion, not just an academic discussion, because the role of rs8099917 has been clarified and deepened in several studies and we think it should be included as best SVR predictor in the genotype 1 [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 (1723) Google Scholar, 3D'Avolio A. Ciancio A. Siccardi M. Baietto L. Simiele M. Cariti G. et al.Ribavirin pharmacokinetics and interleukin 28B plus cytochrome P450 27B1 single-nucleotide polymorphisms as predictors of response to pegylated interferon/ribavirin treatment in patients infected with hepatitis C virus genotype 1/4.Hepatology. 2011; 54: 2279Crossref Scopus (27) Google Scholar, 4D'Avolio A. Ciancio A. Siccardi M. Smedile A. Simiele M. Cusato J. et al.Negative predictive value of IL28B, SLC28A2, and CYP27B1 SNPs and low RBV plasma exposure for therapeutic response to PEG/IFN-RBV treatment.Ther Drug Monit. 2012; 34: 722-728Crossref PubMed Scopus (31) Google Scholar]. The major impact of rs12979860 has been documented on the early response [[5]Stattermayer A.F. Stauber R. Hofer H. Rutter K. Beinhardt S. Scherzer T.M. et al.Impact of IL28B genotype on the early and sustained virologic response in treatment-naive patients with chronic hepatitis C.Clin Gastroenterol Hepatol. 2011; 9: e342Abstract Full Text Full Text PDF Scopus (160) Google Scholar], while rs8099917 in a recent meta-analysis evidenced the best predictive effect on the SVR (OR = 5.171 vs. 4.473) [[6]Luo Y. Jin C. Ling Z. Mou X. Zhang Q. Xiang C. Association study of IL28B: rs12979860 and rs8099917 polymorphisms with SVR in patients infected with chronic HCV genotype 1 to PEG-INF/RBV therapy using systematic meta-analysis.Gene. 2012; 513: 292-296Crossref PubMed Scopus (25) Google Scholar]. In fact, the effect of this SNP explains the higher rate of relapse in patients who achieved both RVR and ETR with the CC rs12979860 genotype, but with the presence of a G allele for the rs8099917 SNP [[5]Stattermayer A.F. Stauber R. Hofer H. Rutter K. Beinhardt S. Scherzer T.M. et al.Impact of IL28B genotype on the early and sustained virologic response in treatment-naive patients with chronic hepatitis C.Clin Gastroenterol Hepatol. 2011; 9: e342Abstract Full Text Full Text PDF Scopus (160) Google Scholar]. Conversely, patients without the CC genotype for rs12979860 retain good probability to reach SVR if they have the TT genotype for rs8099917; this issue could underlie the high rate of SVR in non-CC patients reported by Andriulli et al. [[1]Andriulli A. Di Marco V. Margaglione M. Ippolito A.M. Fattovich G. Smedile A. et al.Identification of naive HCV-1 patients with chronic hepatitis who may benefit from dual therapy with peg-interferon and ribavirin.J Hepatol. 2014; 60: 16-21Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar] and according with the TT prevalence in the Italian population. Therefore, we consider it essential to get both rs12979860 and rs8099917 SNPs as predictors on SVR and, in more detail, we could select the patients with CC/TT or CT/TT, but not with CC/TG or CC/GG genotype, for dual therapy. Another not considered issue in the analysis is the role of therapeutic drug monitoring (TDM) of ribavirin (RBV) as useful early on treatment predictor of response and toxicity. Ribavirin shows a wide inter-individual variability in plasma concentrations (∼25–30%) and weight-based dose results often inadequate without TDM support [3D'Avolio A. Ciancio A. Siccardi M. Baietto L. Simiele M. Cariti G. et al.Ribavirin pharmacokinetics and interleukin 28B plus cytochrome P450 27B1 single-nucleotide polymorphisms as predictors of response to pegylated interferon/ribavirin treatment in patients infected with hepatitis C virus genotype 1/4.Hepatology. 2011; 54: 2279Crossref Scopus (27) Google Scholar, 4D'Avolio A. Ciancio A. Siccardi M. Smedile A. Simiele M. Cusato J. et al.Negative predictive value of IL28B, SLC28A2, and CYP27B1 SNPs and low RBV plasma exposure for therapeutic response to PEG/IFN-RBV treatment.Ther Drug Monit. 2012; 34: 722-728Crossref PubMed Scopus (31) Google Scholar, 7Porte C.J.L. la Back D. Blaschke T. Boucher C.A.B. Fletcher C.V. Flexner C. et al.Updated guideline to perform therapeutic drug monitoring for antiretroviral agents.Rev Antivir Ther. 2006; 2006: 4-14Google Scholar]. Interestingly, RBV concentrations are related both with EVR and SVR [3D'Avolio A. Ciancio A. Siccardi M. Baietto L. Simiele M. Cariti G. et al.Ribavirin pharmacokinetics and interleukin 28B plus cytochrome P450 27B1 single-nucleotide polymorphisms as predictors of response to pegylated interferon/ribavirin treatment in patients infected with hepatitis C virus genotype 1/4.Hepatology. 2011; 54: 2279Crossref Scopus (27) Google Scholar, 4D'Avolio A. Ciancio A. Siccardi M. Smedile A. Simiele M. Cusato J. et al.Negative predictive value of IL28B, SLC28A2, and CYP27B1 SNPs and low RBV plasma exposure for therapeutic response to PEG/IFN-RBV treatment.Ther Drug Monit. 2012; 34: 722-728Crossref PubMed Scopus (31) Google Scholar, 8Arase Y. Ikeda K. Tsubota A. Suzuki F. Suzuki Y. Saitoh S. et al.Significance of serum ribavirin concentration in combination therapy of interferon and ribavirin for chronic hepatitis C.Intervirology. 2005; 48: 138-144Crossref PubMed Scopus (51) Google Scholar, 9Loustaud-Ratti V. Alain S. Rousseau A. Hubert I.F. Sauvage F.L. Marquet P. et al.Ribavirin exposure after the first dose is predictive of sustained virological response in chronic hepatitis C.Hepatology. 2008; 47: 1453-1461Crossref PubMed Scopus (81) Google Scholar] or treatment failure in HCV-1 infected patients, according to different plasma concentrations at different time-points. The optimal therapeutic range of RBV could maximize the SVR achievement and it should be comprised between 2–2.5 mg/L (at week 4 of therapy), according to the majority of the reviewed studies [[10]Morello J. Rodriguez-Novoa S. Jimenez-Nacher I. Soriano V. Usefulness of monitoring ribavirin plasma concentrations to improve treatment response in patients with chronic hepatitis C.J Antimicrob Chemother. 2008; 62: 1174-1180Crossref PubMed Scopus (80) Google Scholar]. In conclusion, we suggest that both IL28B SNPs should be considered in order to refine the selection of candidate patients for dual therapy and then the TDM of RBV should be used to improve the on-treatment management. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.