The “pegylated” story continues – Perhaps because both ends (α2a and α2b) are true?
Authors: Thomas Reiberger, Markus Peck-Radosavljevic
Journal: Journal of Hepatology (2012)

Hyporesponsiveness to PegIFNα2B plus ribavirin in patients with hepatitis C-related advanced fibrosisJournal of HepatologyVol. 56Issue 2PreviewThe success of pegylated-interferon (PegIFN)/ribavirin (Rbv) therapy of chronic hepatitis C is compromised by liver fibrosis. Whether fibrosis equally affects the two PegIFNα-based therapies is unknown. To assess the response to the two PegIFN regimens in patients with different degree of liver fibrosis. Full-Text PDF Reply to: “The “pegylated” story continues – Perhaps because both ends (α2a and α2b) are true?”Journal of HepatologyVol. 57Issue 1PreviewWe thank Professors Reiberger and Peck-Radosavljevic for their comment to our article [1], and generally agree with them that results coming from any post hoc analysis need to be interpreted with caution. With respect to our sub-analysis of the MIST study [2], the main concerns mostly rely on the lack of stratification for fibrosis stage in the randomization process, as well as the lack of data on the Interleukin 28B (IL28B) genotype. Indeed, at the time of preparation of the manuscript we had not run the IL28B test in the entire study cohort, but are now able to provide the complete results for the cohort of HCV-1 and 4 patients, a patient population where the IL28B genotype has been shown to be a strong predictor of treatment outcome [3–5]. Full-Text PDF Open Access We want to comment on the article by Prati et al. [[1]Prati G.M. Aghemo A. Rumi M.G. D’Ambrosio R. Nicola S.D. Donato M.F. et al.Hyporesponsiveness to pegifnalpha2b plus ribavirin in patients with hepatitis C-related advanced fibrosis.J Hepatol. 2011; 56: 341-347Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar] showing decreased response rates to pegylated interferon (PegIFNα) 2b plus ribavirin (RBV) in HCV patients with higher Ishak fibrosis stages (S0–2 vs. S3–4 vs. S5–6), while response rates to PegIFNα2a + RBV remained similar (or – to be more precise – did not significantly decrease) across patient groups with mild (S0–2), moderate (S3–4), and severe (S5–6) Ishak fibrosis stages. In logistic regression analysis, PegIFNα2b (vs. PegIFNα2a) treatment was associated with treatment failure in patients with moderate to advanced fibrosis ⩾S3 (OR 2.83) [[1]Prati G.M. Aghemo A. Rumi M.G. D’Ambrosio R. Nicola S.D. Donato M.F. et al.Hyporesponsiveness to pegifnalpha2b plus ribavirin in patients with hepatitis C-related advanced fibrosis.J Hepatol. 2011; 56: 341-347Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar]. The data was derived from a sub-analysis of the prospective MIST study [[2]Rumi M.G. Aghemo A. Prati G.M. D’Ambrosio R. Donato M.F. Soffredini R. et al.Randomized study of peginterferon-alpha2a plus ribavirin vs peginterferon-alpha2b plus ribavirin in chronic hepatitis C.Gastroenterology. 2010; 138: 108-115Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar], a trial that was designed to compare safety and antiviral efficacy of PegIFNα2a + RBV vs. PegIFNα2b + RBV in patients with chronic HCV infection. An important methodological “advantage” of the MIST study (compared to the IDEAL study [[3]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.N Engl J Med. 2009; 361: 580-593Crossref PubMed Scopus (1122) Google Scholar]) is represented by the fact that both patients on PegIFNα2a- and PegIFNα2b-based treatments received exactly the same RBV dosing regimen, while in the IDEAL study RBV was dosed according to the manufacturer’s instructions. In this re-analysis of the MIST study [[2]Rumi M.G. Aghemo A. Prati G.M. D’Ambrosio R. Donato M.F. Soffredini R. et al.Randomized study of peginterferon-alpha2a plus ribavirin vs peginterferon-alpha2b plus ribavirin in chronic hepatitis C.Gastroenterology. 2010; 138: 108-115Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar], PegIFNα2a or PegIFNα2b were randomly assigned to patient groups stratified according to HCV genotype but not by fibrosis stage. Even though the prevalence of advanced fibrosis (Ishak score S5 + 6) was similar between patients treated with PegIFNα2a and PegIFNα2b, the lack of stratification according to fibrosis stage may represent a potential bias in baseline characteristics. In addition, only a small subgroup of patients with advanced fibrosis (S5–6) were included in the MIST study (n = 43 in the PegIFNα2a group; n = 39 in the PegIFNα2b group). Last but not least, IL28B single nucleotide polymorphisms (SNPs) that have not been assessed in the MIST study [[2]Rumi M.G. Aghemo A. Prati G.M. D’Ambrosio R. Donato M.F. Soffredini R. et al.Randomized study of peginterferon-alpha2a plus ribavirin vs peginterferon-alpha2b plus ribavirin in chronic hepatitis C.Gastroenterology. 2010; 138: 108-115Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar] – and have not been retrospectively re-tested – can clearly influence response rates and could have introduced a bias in an important baseline variable with direct influence on response rates [[1]Prati G.M. Aghemo A. Rumi M.G. D’Ambrosio R. Nicola S.D. Donato M.F. et al.Hyporesponsiveness to pegifnalpha2b plus ribavirin in patients with hepatitis C-related advanced fibrosis.J Hepatol. 2011; 56: 341-347Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar]. When taking a closer look at the data of the PegIFNα2a group, a decrease in SVR rates from 71% in S0–2 to 53% in S5–6 patients was also observed in patients treated with PegIFNα2a + RBV – a difference of 18% in the SVR rate. Even if the SVR rates to PegIFNα2a + RBV treatment are statistically not different between patients with S0–2, S3–4, and S5–6, these differences would certainly be significant if the number of included patients was increased. In addition, an advanced fibrosis stage was identified as independent risk factor of treatment failure for both pegylated interferons in combination with ribavirin for treatment of chronic HCV infection [4Thompson 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 (e118): 120-129Abstract Full Text Full Text PDF PubMed Scopus (657) Google Scholar, 5Kau A. Vermehren J. Sarrazin C. Treatment predictors of a sustained virologic response in hepatitis B and C.J Hepatol. 2008; 49: 634-651Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar]. In contrast to SVR rates, RVR rates were similar in patients treated with PegIFNα2b + RBV across fibrosis stages. In this context, it would be important to have more information about dose reductions and early treatment discontinuations in the subgroups with specific fibrosis stages. Overall, more patients allocated to the PegIFNα2b + RBV group had early treatment discontinuation than in the PegIFNα2a + RBV group (n = 73 vs. n = 46). This higher rate of treatment discontinuations in PegIFNα2b + RBV patients despite similar rates of (S)AEs may also have biased SVR data when comparing PegIFNα2a to PegIFNα2b patients. Since the “hyporesponsiveness” to PegIFNα2b + RBV was observed both in moderate (S3/4) and advanced (S5/6) stages of fibrosis [[1]Prati G.M. Aghemo A. Rumi M.G. D’Ambrosio R. Nicola S.D. Donato M.F. et al.Hyporesponsiveness to pegifnalpha2b plus ribavirin in patients with hepatitis C-related advanced fibrosis.J Hepatol. 2011; 56: 341-347Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar], further data in other cohorts of cirrhotic patients treated with different forms of PEGIFN (2a vs. 2b) are of clinical interest. Since in the era of DAAs a PEGIFN + RBV “backbone” is still needed, differences in response rates between PegIFNα2a and PegIFNα2b used in triple therapies may then influence response rates. If PegIFNα2b + RBV performs worse than PegIFNα2a + RBV in advanced fibrosis, we would hypothesize that a difference may be even more evident when restricting the comparison to cirrhotic patients with and without portal hypertension as included in our recent study [[6]Reiberger T. Rutter K. Ferlitsch A. Payer B.A. Hofer H. Beinhardt S. et al.Portal pressure predicts outcome and safety of antiviral therapy in cirrhotic patients with hepatitis C virus infection.Clin Gastroenterol Hepatol. 2011; 9 (e601): 602-608Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar]. Thus, we re-analysed data from our previous study in cirrhotic (F4 METAVIR) patients [[6]Reiberger T. Rutter K. Ferlitsch A. Payer B.A. Hofer H. Beinhardt S. et al.Portal pressure predicts outcome and safety of antiviral therapy in cirrhotic patients with hepatitis C virus infection.Clin Gastroenterol Hepatol. 2011; 9 (e601): 602-608Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar]. This was a prospective, non-randomized study including only patients with histologically proven METAVIR F4 cirrhosis [[6]Reiberger T. Rutter K. Ferlitsch A. Payer B.A. Hofer H. Beinhardt S. et al.Portal pressure predicts outcome and safety of antiviral therapy in cirrhotic patients with hepatitis C virus infection.Clin Gastroenterol Hepatol. 2011; 9 (e601): 602-608Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar]. Since no clear evidence of a difference in the efficacy between PegIFNα2b and PegIFNα2a was available, both types of pegIFN were used in combination with RBV for antiviral therapy. A total of 99 patients with METAVIR F4 cirrhosis were treated with PegIFNα2a + RBV (n = 69) or with PegIFNα2b + RBV (n = 30). Baseline characteristics and known predictors or treatment response (Table 1) were similarly distributed between patients receiving PegIFNα2a- and PegIFNα2b-based antiviral combination therapy. The additional information on IL28B SNP allowed us to perform subgroup analysis in C/C and non-C/C patients to avoid potential bias derived from potentially heterogeneous baseline characteristics in the PegIFNα2a vs. PegIFNα2b groups. In patients with IL28B C/C SNP, RVR (p = 0.730) and SVR (p = 0.376) rates were similar between PegIFNα2a- and PegIFNα2b-based treatment groups.Table 1Comparison of the antiviral efficacy of PegIFNα2a vs. PegIFNα2b in combination with ribavirin in HCV patients with METAVIR F4 cirrhosis. Open table in a new tab Among patients with IL28B non-C/C SNP, PegIFNα2a + RBV and PegIFNα2b + RBV treatments resulted in similar RVR (p = 0.699) and SVR (p = 0.133) rates. Even in the most difficult-to-treat patients with IL28B non-C/C SNP and HCV-GT1/4 infections, response rates were similar between PegIFNα2a- and PegIFNα2b-treated patients, with SVR rates of 24% for PegIFNα2a + RBV and 36% for PegIFNα2b + RBV. Our results have to be interpreted by considering all potential problems of a post hoc analysis performed with data of a prospective study that was not designed to demonstrate non-inferiority of PegIFNα2b to PegIFNα2a (or vice versa). In addition, the drug-compliance to PegIFNα2a/PegIFNα2b and potential bias arising from problems with self-application of PegIFNα2a syringes and PegIFNα2b pens by cirrhotic patients were not addressed and should be investigated in prospective trials. In summary, the recently published data of the MIST study by Prati et al. [[1]Prati G.M. Aghemo A. Rumi M.G. D’Ambrosio R. Nicola S.D. Donato M.F. et al.Hyporesponsiveness to pegifnalpha2b plus ribavirin in patients with hepatitis C-related advanced fibrosis.J Hepatol. 2011; 56: 341-347Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar] provide important information about virologic response rates to PegIFN + RBV combination therapy among patients with specific fibrosis stages. Response rates were reported to be lower in moderate and advanced fibrosis when using PegIFNα2b + RBV therapy but not if PegIFNα2a + RBV is used [[2]Rumi M.G. Aghemo A. Prati G.M. D’Ambrosio R. Donato M.F. Soffredini R. et al.Randomized study of peginterferon-alpha2a plus ribavirin vs peginterferon-alpha2b plus ribavirin in chronic hepatitis C.Gastroenterology. 2010; 138: 108-115Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar]. In contrast, our analysis including data on HCV genotype and IL28B SNPs did not show significant differences in RVR and SVR rates between patients receiving PegIFNα2a + RBV or PegIFNα2b + RBV regimens. Thus – if all known predictors of treatment response were considered – no significant differences in virologic response rates between the two different types of pegylated interferons have been demonstrated in any analysis so far. The authors received grant support from MSD/Roche.