Week 4 viral response to peginterferon and ribavirin: How should it be used in combination with a baseline predictive factor?
Authors: Hidenori Toyoda, Takashi Kumada, Yoshiaki Katano, Hidemi Goto
Journal: Journal of Hepatology (2012)

Refined prediction of week 12 response and SVR based on week 4 response in HCV genotype 1 patients treated with peginterferon alfa-2a (40KD) and ribavirinJournal of HepatologyVol. 56Issue 6PreviewIt is unclear whether the magnitude of reduction in hepatitis C virus (HCV) RNA between baseline and week 4 of treatment influences the probability of achieving a sustained virological response (SVR) in patients without a week 4 rapid virological response (RVR). Full-Text PDF We read with great interest the article by Marcellin et al. [[1]Marcellin P. Reau N. Ferenci P. Hadziyannis S. Messinger D. Tatsch F. et al.Refined prediction of week 12 response and SVR based on week 4 response in HCV genotype 1 patients treated with peginterferon alfa-2a (40KD) and ribavirin.J Hepatol. 2012; 56: 1276-1282Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar] evaluating the predictive value of week 4 viral response to peginterferon-alpha 2a and ribavirin combination therapy in patients with hepatitis C virus (HCV) genotype 1. They concluded that patients with a ⩾3log10 drop in HCV RNA at week 4 have a high probability of achieving sustained virologic response (SVR), which is consistent with our previous study [[2]Toyoda H. Kumada T. Kiriyama S. Tanikawa M. Hisanaga Y. Kanamori A. et al.High ability to predict the treatment outcome of peginterferon and ribavirin combination therapy based on the reduction in HCV RNA levels at 4 weeks after starting therapy and amino acid substitutions in hepatitis C virus in patients infected with HCV genotype 1b.J Gastroenterol. 2011; 46: 501-509Crossref PubMed Scopus (10) Google Scholar]. Previous studies reported that the genetic polymorphism near the interleukin 28B (IL28B) gene (rs12979860 or rs8099917) is a strong baseline factor associated with the outcome of therapy [[3]Ge 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 (3114) Google Scholar]. However, this variable was not included in the study by Marcellin et al., probably because the actual treatment period in the study predated this finding [4Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales Jr, F.L. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5914) Google Scholar, 5Hadziyannis S.J. Sette Jr., J. Morgan T.R. Bolan V. Diago M. Marcellin P. et al.Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.Ann Intern Med. 2004; 140: 346-355Crossref PubMed Scopus (2771) Google Scholar]. Given these predictors, i.e. week 4 viral response and a baseline variable, how should they be combined to predict response? We evaluated the predictive value of week 4 viral response to combination therapy on SVR in 272 patients infected with HCV genotype 1b [[6]Toyoda H. Kumada T. Tada T. Hayashi K. Honda T. Katano Y. et al.Predictive value of early viral dynamics during peginterferon and ribavirin combination therapy based on genetic polymorphisms near the IL28B gene in patients infected with HCV genotype 1b.J Med Virol. 2012; 84: 61-70Crossref PubMed Scopus (8) Google Scholar]. Overall, a ⩾3log10 drop in HCV RNA at week 4 was a strong predictor of SVR. SVR was achieved in 77.0% of patients with rapid virologic response (RVR) or a ⩾3log10 drop, whereas only 16.7% of patients with a <3log10 drop achieved SVR (p<0.0001). When patients were stratified based on the IL28B genetic polymorphism rs8099917, which corresponds to rs12979860 in more than 99% of Japanese ethnicity [[7]Tanaka Y. Nishida N. Sugiyama M. Tokunaga K. Mizokami M. Λ-interferons and the single nucleotide polymorphisms: a milestone to tailor-made therapy for chronic hepatitis C.Hepatol Res. 2010; 40: 449-460Crossref PubMed Scopus (42) Google Scholar], a ⩾3log10 drop at week 4 was strongly predictive of SVR in patients with the favorable TT rs8099917 genotype (CC rs12979860 genotype). The SVR rate was 79.5% in patients with RVR or a ⩾3log10 drop and 15.6% in patients with a <3log10 drop (p<0.0001). In contrast, among patients with an unfavorable TG/GG rs8099917 genotype, no differences were found in the SVR rate between patients with RVR or a ⩾3log10 drop (20.0%) and those with a <3log10 drop (18.3%, p = 0.9265); the predictive value of week 4 response is low in this subset. In addition, the predictive value of complete early virologic response (EVR) for SVR is lower in patients with the unfavorable TG/GG genotype. The SVR rate was 81.6% in patients with complete EVR and 21.2% in patients without (p<0.0001), when patients had the favorable TT rs8099917 genotype. In contrast, the rate of SVR was 25.0% in patients with complete EVR and 18.0% in patients without (p= 0.7279), when patients had the unfavorable TG/GG genotype. Therefore, it appears to be difficult to identify patients with the unfavorable genotype of the genetic polymorphism near the IL28B gene who have a likelihood to achieve SVR by week 4 viral response, although it can identify patients with a high likelihood of achieving SVR in patients with the favorable genotype. In contrast to our results, a previous large study by Thompson et al. [[8]Thompson A.J. Muir A.J. Sulkowski M.S. Ge D. Fellay J. Shianna K.V. et al.Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus.Gastroenterology. 2010; 139: 120-129Abstract Full Text Full Text PDF PubMed Scopus (657) Google Scholar] reported that patients who attained RVR showed high SVR rate regardless of the genetic polymorphisms near the IL28B gene (rs12979860), although they focused on patients with RVR and did not include patients with non-RVR but with a ⩾3log10 drop at week 4. This discrepancy between their study and ours may be partly explained by the difference in the ethnicity of the study population. The study by Thompson et al. was based on patients from the IDEAL study including Caucasians, African Americans, and Hispanics, whereas all patients were Japanese Asians in our study. Similarly, the ethnicity was different between the population studied by Marcellin et al. and ours. Accordingly, the distribution of rs12979860 or rs8099917 genotypes and the rate of concordance between rs12979860 (analyzed in a study by Thompson et al.) and rs8099917 (analyzed in our study) would be different. For example, the rate of favorable homozygote (CC rs12979860 genotype and TT rs8099917 genotype) was largely different: 33.0% in Thompson’s study and 76.1% in our study. Moreover, our study involved only patients infected with HCV genotype 1b. These factors should be adjusted when comparing the association between the genetic polymorphisms near the IL28B gene and the predictive value of week 4 viral response between studies. Nonetheless, the genetic polymorphism near the IL28B gene appears to have a strong impact on the predictive value of early viral response to therapy; the prediction of SVR by week 4 viral response may have to be modified based on this strong baseline predictive factor. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.