Usefulness of Lead-In phase in determining risk/benefit of telaprevir treatment in patients with HCV cirrhosis
Authors: Savino Bruno, Alessandra Mangia
Journal: Journal of Hepatology (2013)

Sustained virologic response rates with telaprevir by response after 4 weeks of lead-in therapy in patients with prior treatment failureJournal of HepatologyVol. 58Issue 3PreviewFor hepatitis C virus (HCV)-infected patients who have not responded to previous PegIFN/ribavirin treatment, it is unclear whether subsequent direct-acting antiviral therapy outcomes are better predicted by prior treatment response or by on-treatment response to a PegIFN/ribavirin lead-in. Full-Text PDF Reply to: “Usefulness of Lead-In phase in determining risk/benefit of telaprevir treatment in patients with HCV cirrhosis”Journal of HepatologyVol. 58Issue 6PreviewWe are grateful to Drs. Bruno and Mangia for their interest in our work [1], and we agree that data on response rates by the degree of fibrosis would be useful and would help guide physicians and patients in reaching a decision regarding the value of therapy, following a ‘lead-in’ phase. However, in a retrospective analysis of study subpopulations in a trial that was not designed, or powered, to answer the question of interest, there is a difficult line to be drawn between an ‘appropriate analysis’ and ‘data dredging’. Full-Text PDF Open Access We read with interest the paper published by Dr. Foster and co-authors [[1]Foster G.R. Zeuzem Z. Andreone A. Pol S. Lawitz E.J. Diago M. et al.Sustained virologic response rates with telaprevir by response after 4weeks of lead-in therapy in patients with prior treatment failure.J Hepatol. 2013; 58: 488-494Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. As clearly stated in the manuscript, irrespective of the previous definition of response, the overall SVR rates at week 4, after Lead-In phase (LI), were 33% in those with <1 log decline and 82% in the subset with >1 log decline, respectively. Multiple logistic regression analysis confirmed that LI is a strong independent predictor of SVR (OR 5.1, 95% CI 2.6–10.1). This finding enhances the concept that the degree of interferon sensitivity plays a major role in modulating the efficacy of first generation protease inhibitors. Despite this result, the data provided by this study did not fully assess the potential usefulness of LI phase in the context of triple therapy with telaprevir (TVR), because they lack to further detail the effect of LI according to the fibrosis stage. Along this line, it also should be taken into account that patients with advanced fibrosis/cirrhosis represent, in real life, the majority of those to deal with for re-treatment, and missing or unreliable data on virologic on-therapy response during previous treatment is common. In previous subanalyses carried out in the Realize study [2Zeuzem S. Andreone P. Pol S. Lawitz E.J. Diago M. Roberts S. et al.Realize trial final results: telaprevir-based regimen for genotype 1 hepatitis C virus infection in patients with prior null response, partial response or relapse to Peg interferon/ribavirin.J Hepatol. 2011; 54: S3Abstract Full Text PDF PubMed Google Scholar, 3Pol S. Roberts S.K. Andreone A. Younossi Z.M. Diago M. Lawitz E. et al.Efficacy and safety of telaprevir-based regimen in cirrhotic patients with HCV genotype 1 and prior Peg interferon/ribavirin treatment failure.Hepatology. 2011; 54 (abstract 31)PubMed Google Scholar], the overall SVR rates in null and partial responders with cirrhosis (Metavir F4) were 14% and 34% (pooled TVR arms), respectively. More recently, the same group of investigators also reported that the proportion of patients with cirrhosis increased from relapsers to null responders, whatever the response after 4 weeks of therapy [[5]Zeuzem S. Foster G.R. Andreone P. Pol S. Lawitz E.J. Diago M. et al.Different likelihood of achieving SVR on a telaprevir containing regimen among null responders, partial responders and relapsers irrespective of simolar responses after a peginterferon/ribavirin 4-week lead-in phase realize study sub analysis.Hepatology. 2012; 56 (abstract 1331)Google Scholar]. Considering this result, a further decrease of response rate across the prior failure categories, according to the presence of a more severe liver damage, should be suspected. Regrettably, in these reports, SVR rates according to fibrosis stages and LI were not illustrated. In the same way, of main interest, the present paper missed to provide the rate of SVR in F4 patients who had less than 1 log decline after LI (overall and according to their prior definition of response). This information, by contrast, was recently stated for boceprevir (BOC, SPRINT 2 and RESPOND 2 combined) [[4]Bruno S. Vierling J.M. Esteban R. Nyberg L.M. Tanno H. Goodman Z. et al.Efficacy and safety of boceprevir plus peginterferon-ribavirin in patients with HCV G1 infection and advanced fibrosis/cirrhosis.J Hepatol. 2013; 58: 479-487Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar]. To date, while waiting for more effective molecules that will eliminate the need of IFN, a detailed analysis of week 4 response by severity of liver damage represents a no longer deferrable unmet clinical need. Using this information, both Scientific Community and Clinicians worldwide could better determine the utility of LI in assessing the risk/benefit of treatment in cirrhotic patients with either BOC or TVR triple combination therapy [6Bruno S. Mangia A. Futility of antiviral treatments for hepatitis C: an evolving concept entering the direct antiviral agents era.Dig Liver Dis. 2012; (pii: S1590-8658(12)00369-6. [Epub ahead of print])https://doi.org/10.1016/j.dld.2012.09.011Abstract Full Text Full Text PDF Scopus (10) Google Scholar, 7Tillman H.L. Hepatitis C infection and presence of advanced fibrosis: wait or treat? Why wait? There is no time to lose, is there?.J Hepatol. 2013; 58: 412-414Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.