Focus
Authors: Daniel Shouval
Journal: Journal of Hepatology (2011)

Advanced hepatic fibrosis is associated with a worse prognosis in patients with chronic hepatitis C virus (HCV) infection. Cumulative clinical experience also suggests that response rates to anti-viral therapy with pegylated interferons α2a or α2b and ribavirin are inversely proportional to the degree of fibrosis. The mechanism involved in the overall hyporesponsiveness to anti-viral treatment in patients with advanced fibrosis is not completely understood. At present, it is not clear whether advanced fibrosis per se is a key factor in the reduced responsiveness to anti-viral therapy or whether the different configuration of the pegylated interferon molecules and their impact on various genes expression play a role in this phenomenon. Among the various factors which have been implicated in failure of anti-viral therapy in such patients (i.e. high BMI, older age, ethnic background, genotype, viral load, incomplete adherence to treatment protocols, and cytopenia) it was postulated that the distorted hepatic architecture in advanced fibrosis prevents an optimal access of anti-viral drugs to the HCV infected hepatocytes, but proof for this hypothesis is still lacking. In this context, it was suggested that variations in pharmacodynamics, volume of distribution and pharmacokinetics between pegylated interferon α2a and α2b may explain, at least in part, the reported differences in obtaining an SVR by between the two agents [1Rumi 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 (170) Google Scholar, 2Ascione A. De Luca M. Tartaglione M.T. Lampasi F. Di Costanzo G.G. Lanza A.G. et al.Peginterferon alfa-2a plus ribavirin is more effective than peginterferon alfa-2b plus ribavirin for treating chronic hepatitis C virus infection.Gastroenterology. 2010; 138: 116-122Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar]. In the present issue of the Journal, Prati and co-workers have performed a sub-analysis of the original Italian MIST study database, assessing the therapeutic response to the two different pegylated interferons α2a and α2b combined with ribavirin, administered to chronic hepatitis C patients with various degrees of fibrosis [[1]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 (170) Google Scholar]. The 431 consecutively enrolled treatment naïve patients (genotypes 1–4) were randomized to receive the recommended licensed dose of pegylated interferons α2a or α2b (with ribavirin) for a standard duration based on genotype. Patients were stratified according to genotype and the Ishak classification into three main groups according to degree of fibrosis on liver biopsy: Mild fibrosis S0–S2, moderate fibrosis S3–S4 and cirrhosis S5–S6. The main message of this analysis suggests that efficacy of treatment as determined by end of treatment (ETR) and sustained viral response (SVR), is lower, (mainly in genotypes 1 and 4) in patients with advanced hepatic fibrosis treated by pegylated interferon α2b and ribavirin as compared to treatment with pegylated interferon α2a. This difference in efficacy of the two agents was limited to patients with advanced fibrosis. The lower rates of SVR in patients with cirrhosis treated with pegylated interferon α2b correspond to the lower response rates at ETR. The data also suggest that patients with cirrhosis treated by pegylated interferon α2b who do not reach a rapid viral response (RVR) are unlikely to reach an SVR and treatment should be discontinued. In contrast, about one third of patients with cirrhosis treated by pegylated interferon α2a who did not reach an RVR, still developed an SVR. Finally, the obtained results suggest and confirm that RVR is an independent factor in prediction of success of treatment irrespective of stage of fibrosis or pegylated interferon used. Comparative assessment of the anti-viral efficacy of the two licensed pegylated interferons in patients with or without advanced fibrosis has met so far with some difficulties for a number of reasons. These include among others, differences in dosing of ribavirin as well as in the molecular size of the polyethylene glycol moieties which in turn has an impact on the pharmacokinetic and pharmacodynamic properties of both interferons. Results of an early industry initiated randomized comparative trial (IDEAL study) in 3070 patients revealed overall similar rates of SVR in genotype 1 patients with chronic HCV infection treated either with pegylated interferon α2a or α2b [[3]McHutchison J.G. Lawitz E.J. Shiffman M.L. Muir A.J. Galler G.W. McCone J. et al.IDEAL Study TeamPeginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection.N Engl J Med. 2009; 361: 580-593Crossref PubMed Scopus (1116) Google Scholar]. One year later, two groups in Italy reported higher overall rates of SVR in chronic HCV patients treated with pegylated interferon α2a as compared to α2b [1Rumi 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 (170) Google Scholar, 2Ascione A. De Luca M. Tartaglione M.T. Lampasi F. Di Costanzo G.G. Lanza A.G. et al.Peginterferon alfa-2a plus ribavirin is more effective than peginterferon alfa-2b plus ribavirin for treating chronic hepatitis C virus infection.Gastroenterology. 2010; 138: 116-122Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar]. In these investigator initiated prospective head to head trials across genotypes 1–4, about one fifth had evidence for progressive fibrosis. A recent metanalysis of 12 randomized clinical trials (N = 5008 patients), which compared treatment with peginterferon α2a plus ribavirin to peginterferon α2b plus ribavirin provided further support to the observations from Italy [[4]Awad T. Thorlund K. Hauser G. Stimac D. Mabrouk M. Gluud C peginterferon alpha-2a is associated with higher sustained virological response than peginterferon alfa-2b in chronic hepatitis C: systematic review of randomized trials.Hepatology. 2010; 51: 1176-1184Crossref PubMed Scopus (143) Google Scholar]. Although the overall difference in SVR between the two pegylated interferon reagents was only 6% (in eight trials), it was statistically significant [[4]Awad T. Thorlund K. Hauser G. Stimac D. Mabrouk M. Gluud C peginterferon alpha-2a is associated with higher sustained virological response than peginterferon alfa-2b in chronic hepatitis C: systematic review of randomized trials.Hepatology. 2010; 51: 1176-1184Crossref PubMed Scopus (143) Google Scholar]. The results reported by Prati et al. suggest that the difference in SVR rates between the two pegylated interferon based protocols is mainly limited to patients with advanced fibrosis. The discussed study has a number of limitations, most of which are already acknowledged by the authors. These include the fact that the original MIST study was not designed to examine the degree and impact of fibrosis on the efficacy of the two pegylated interferons. As a result, the size of the various groups studied is relatively small and the study is somewhat underpowered. This drawback is partially compensated for by multivariate logistic regression analysis according to liver fibrosis. It is also not clear yet if the IL28B single nucleotide polymorphism, not included in the present analysis, has an impact on response rates to anti-viral therapy in general and to specific interferons in particular in HCV patients with advanced fibrosis. It is important to note that the new data presented in this analysis by Prati et al. still do not provide a clue to explain the mechanism responsible for the different response rates to treatment with the two interferon molecules. Finally, one should remember that it remains to be seen if the introduction of new directly acting anti-viral agents (DAAs), will blur the observed differences in anti-viral efficacy between the two interferon molecules in patients with advanced fibrosis. The investigators of this study conclude that chronic HCV patients infected with genotypes 1/4 with advanced fibrosis are more likely to benefit from treatment with pegylated interferon α2a and ribavirin as compared to interferon α2b. This may indeed be the case, yet further confirmation of this statement is warranted in view of the fact that these data were obtained through subanalysis of a prospective trial which was not originally designed to address this question. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.