Which is the real efficacy of pegylated interferon alpha 2a or 2b plus ribavirin in HCV infected patients with advanced fibrosis?
Authors: Adriano M. Pellicelli, Mario Romano, Paolo Guarascio, Pascal Vignally
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 We have read with great interest the article of Prati et al. [[1]Prati G.M. Aghemo A. Rumi M.G. D’Ambrosio R. De Nicola S. Donato M.F. et al.Hyporesponsiveness to PegIFNα2B plus ribavirin in patients with hepatitis C-related advanced fibrosis.J Hepatol. 2012; 56: 341-347Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar]. The authors concluded that patients infected with HCV genotypes 1–4 that received PegIFNα-2A plus ribavirin with advanced fibrosis (staging ⩾3 according to Ishak classification) had an end treatment response (ETR) and sustained virological response (SVR) rates that were not influenced by fibrosis stage. In contrast, PegIFNα-2B plus ribavirin was less effective than PegIFNα-2A and led to a lower rate of both ETR and SVR in patients with staging ⩾3. We are concerned about part of the content of the paper. The article analyzed a heterogeneous population of patients infected with HCV that included “difficult to treat patients” infected with genotypes 1–4 and “easy to treat patients” infected with genotypes 2 and 3. Those infected with HCV genotypes 1-4 were analyzed together and stratified according to the Ishak classification staging score. However, several questions remain unanswered: What was the distribution of patients with genotype 4 in the different staging groups? What was the percentage of Egyptian patients in the genotype 4 group included in the study? In Northern Italy, HCV genotype 4 was reported in about 2% of all patients infected with HCV [[2]Roffi L. Ricci A. Ogliari C. Scalori A. Minola E. Colloredo G. et al.HCV genotypes in northern Italy: a survey of 1368 histologically proven chronic hepatitis C patients.J Hepatol. 1998; 29: 701-706Abstract Full Text PDF PubMed Scopus (73) Google Scholar]. In addition, different studies have reported that patients infected with genotype 4 presented a better SVR compared to those infected with genotype 1, particularly in patients that achieved a rapid virological response (RVR) [3Ferenci P. Laferl H. Scherzer T.M. Gschwantler M. Maieron A. Brunner H. et al.Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response.Gastroenterology. 2008; 135: 451-458Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar, 4Varghese R. Al-Khaldi J. Asker H. Fadili A.A. Al Ali H. Hassan F.A. Treatment of chronic hepatitis C genotype 4 with peginterferon alpha-2a plus ribavirin.Hepatogastroenterology. 2009; 56: 218-222PubMed Google Scholar]. Furthermore, Egyptian patients infected with genotype 4 with advanced fibrosis had a better SVR compared to European and African patients with genotype 4 that presented with a similar stage of liver fibrosis [[5]Roulot D. Bourcier V. Grando V. Deny P. Baazia Y. Fontaine H. et al.Epidemiological characteristics and response to peginterferon plus ribavirin treatment of hepatitis C virus genotype 4 infection.J Viral Hepat. 2007; 14: 460-467Crossref PubMed Scopus (106) Google Scholar]. Therefore, we believe that the inclusion of patients with genotype 4 could have influenced the SVR achieved in the genotype 1–4 group of patients with staging ⩾3. According to the Ishak classification staging score, the stage 3 classification is defined as a fibrous expansion over most of the portal area with occasional fibrous bridging from portal to portal regions. In contrast, central-to-portal bridging fibrosis, classified as stage 4 in the Ishak score, is an important component of severe chronic active hepatitis [[6]Ishak K. Baptista A. Bianchi L. Callea F. De Groote J. Gudat F. et al.Histological grading and staging of chronic hepatitis.J Hepatol. 1995; 22: 696-699Abstract Full Text PDF PubMed Scopus (4108) Google Scholar]. It is an important factor for rapid progression to cirrhosis, because contraction of collagen-rich bridges may produce rapid, severe distortion of the normal hepatic microstructure. In our opinion, stage 3 should not be considered as a surrogate of advanced liver fibrosis. The inclusion of stage 3 patients in a group with so called “advanced fibrosis” might have caused an underestimation of the impact of liver fibrosis in patients treated with PegIFNα-2A that achieved SVR. We have studied 388 patients infected with genotype 1a/1b in different stages, according to the Ishak classification. Part of that data was derived from our previous study [[7]Pellicelli A.M. Romano M. Barbarini G. Mazzoni E. Mecenate F. Furlan C. et al.Influence of HCV genotype 1a and genotype 1b on the virological response to antiviral therapy.Hepatology. 2010; 52: 795APubMed Google Scholar]. We stratified the patients according to S0–S3 and S4–S6 groups. We defined advanced fibrosis as stages S4–S6. The patients were treated with PegIFNα-2A at 180 μg/week plus ribavirin or with PegIFNα-2B at 1.5 μg/kg/week plus ribavirin. The two treatment groups, stratified by fibrosis stage (S0–S3 and S4–S6), showed similar clinical and demographic features, except that the S0–S3 group treated with PegIFNα-2B had a lower HCV RNA value (HCV RNA log10, IU/ml) than the group treated with PegIFNα-2A (5.79 ± 0.4 vs. 5.93 ± 0.5 IU/ml; p <0.001). In the S0–S3 group, patients treated with PegIFNα-2B had an ETR of 66.3% compared to 71.7% for those treated with PegIFNα-2A; the SVRs were 58% vs. 53%, respectively. In the S4-S6 group, patients treated with PegIFNα-2B had an ETR of 44.8% compared to 62.5% for those treated with PegIFNα-2A (p <0.06); the SVRs were 34.4% vs. 40.2%, respectively (not statistically significant). By step-logistic regression analysis, significant predictor of treatment failure was a staging ⩾4, in both the PegIFNα-2B and PegIFNα-2A treatment groups. Moreover, significant predictors of SVR were an RVR in both antiviral treatment groups and male sex in the PegIFNα-2B treatment group (Table 1). In conclusion, in Italian patients with genotype 1 HCV infection treated with PegIFNα-2B or PegIFNα-2A plus ribavirin, a staging ⩾4 influenced the achievement of SVR with both treatments. The Chariot study demonstrated that, despite adequate therapeutic dosing with PegIFNα-2A plus ribavirin, there was a low virological response and a high relapse rate in patients infected with genotype 1 that had advanced fibrosis [[8]Cheng W.S. Roberts S.K. McCaughan G. Sievert W. Weltman M. Crawford D. et al.Low virological response and high relapse rates in hepatitis C genotype 1 patients with advanced fibrosis despite adequate therapeutic dosing.J Hepatol. 2010; 53: 616-623Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar]. In fact, a marked step-wise decline in SVR was associated with fibrosis stage, evaluated by the METAVIR score. Advanced liver fibrosis remained the strongest negative predictive factor of SVR in patients infected with genotype 1 and treated with antiviral therapy, despite the use of different types of pegylated interferon.Table 1Odds ratio and corresponding 95% confidence intervals (95% CI) from the multivariate logistic regression analysis including independent predictors of treatment achievement or failure. Open table in a new tab The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.