Evidence recommending antiviral therapy in hepatitis C
Authors: Ronald L. Koretz, Kurinchi Gurusamy, Brian Davidson, Andrew Burroughs
Journal: Journal of Hepatology (2014)

Is there sufficient evidence to recommend antiviral therapy in hepatitis C?Journal of HepatologyVol. 60Issue 1PreviewWhile patients with chronic hepatitis C virus (HCV) infection are treated in order to prevent liver-related morbidity and mortality, we rely on sustained virological response (SVR) as a virological biomarker to evaluate treatment efficacy in both clinical practice as well as in drug development. However, conclusive evidence for the clinical benefit of antiviral therapy or validity of SVR as surrogate marker, as derived from trials randomizing patients to a treatment or control arm, is lacking. In fact, the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial recently showed an increased mortality rate among interferon-treated patients compared to untreated controls. Full-Text PDF Open AccessReply to: 'Evidence recommending antiviral therapy in hepatitis C'Journal of HepatologyVol. 60Issue 5PreviewWe thank Dr. Koretz and colleagues for responding to our appraisal of their Cochrane meta-analysis [1,2], The discussion on the clinical benefits of antiviral therapy for chronic hepatitis C virus (HCV) infection is important because physicians should be aware of the strengths of current evidence as well as of the remaining uncertainties. Full-Text PDF Open Access Recently, Dr. Van der Meer and colleagues [[1]Van der Meer A.J. Wedemeyer H. Feld J.J. Nansen B.E. Manns M.P. Zeuzem S. et al.Is there sufficient evidence to recommend antiviral therapy in hepatitis C?.J Hepatol. 2014; 60: 191-196Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar] discussed our systematic review of trials comparing interferon monotherapy to no therapy for retreating individuals infected with hepatitis C virus who had not achieved a sustained virological response (SVR) from previous antiviral therapy [[2]Koretz R.L. Pleguezuelo M. Arvaniti V. Barrera Baena P. Ciria R. Gurusamy K.S. et al.Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C.Cochrane Database Syst Rev. 2013; 1: CD003617PubMed Google Scholar]. Our review made several observations: (1) retreatment with interferon monotherapy provided no relevant clinical benefit; (2) while there was a statistically significant reduction in non-fatal variceal bleeding, the number needed to treat (NNT) was so high (NNT = 67) that the treatment is economically unfeasible; (3) when only the low risk of bias trials were considered, interferon treatment increased all-cause mortality; (4) the recipients of interferon had more adverse events; and (5) the commonly used surrogate outcome of SVR occurred significantly more often in the treated group.Since interferon treatment increased SVRs without improving clinical outcomes, the SVR was not a valid surrogate outcome in this scenario. As such, SVR cannot be universally considered as valid for purposes of clinical practice. We believe that, before it can be considered a trustworthy surrogate outcome in other scenarios, it must be validated in those scenarios, or at least in enough other scenarios that the single example of retreatment of interferon monotherapy could be considered to be an outlier.Validation of a surrogate outcome is a two-step process [[3]Bucher H.C. Guyatt G.H. Cook D.J. Holbrook A. McAlister F.A. Users' guides to the medical literature XIX. Applying clinical trial results A. How to use an article measuring the effect of an intervention on surrogate end points.JAMA. 1999; 282: 771-778Crossref PubMed Scopus (281) Google Scholar]. First, there has to be a strong and consistent association between the surrogate outcome and the clinical one. However, association alone is not adequate to establish validation. It also has to be shown that improving the surrogate outcome also similarly improves the clinical one; in other words, a treatment-related difference between the study groups in the surrogate outcome should be associated with a proportionate treatment-related difference in the clinical outcome. This latter step can only be demonstrated in randomized clinical trial (RCTs). Most RCTs assessing hepatitis C antiviral therapy do not provide clinical outcomes, presumably because these outcomes require years to pass before they begin to appear. Thus, there are limited data available to assess the validity of the SVR. Of note, several other Cochrane reviews also found scenarios in which an improved SVR did not translate into a meaningful beneficial clinical outcome These included comparing interferon with or without ribavirin [[4]Brok J. Gluud L.L. Gluud C. Ribavirin plus interferon vs. interferon for chronic hepatitis C.Cochrane Database Syst Rev. 2010; 1: CD005445PubMed Google Scholar], using ribavirin alone [[5]Brok J. Gluud L.L. Gluud C. Ribavirin monotherapy for chronic hepatitis C.Cochrane Database Syst Rev. 2009; 4: CD005527PubMed Google Scholar], and employing interferon in treatment-naïve patients [[6]Myers R.P. Regimbeau C. Thevenot T. Leroy V. Mathurin P. Opolon P. et al.Interferon for interferon naive patients with chronic hepatitis C.Cochrane Database Syst Rev. 2002; 2: CD000370PubMed Google Scholar]. Dr. van der Meer and his colleagues cited two of these [4Brok J. Gluud L.L. Gluud C. Ribavirin plus interferon vs. interferon for chronic hepatitis C.Cochrane Database Syst Rev. 2010; 1: CD005445PubMed Google Scholar, 6Myers R.P. Regimbeau C. Thevenot T. Leroy V. Mathurin P. Opolon P. et al.Interferon for interferon naive patients with chronic hepatitis C.Cochrane Database Syst Rev. 2002; 2: CD000370PubMed Google Scholar], but only noted that the improvement in SVR was accompanied by improvement in liver histology (another surrogate). Not mentioned by van der Meer et al., adding ribavirin to interferon resulted in a minimal but statistically significant reduction in the combined endpoint of death and hepatic morbidity (0.28% reduced to 0.12%), but the NNT was 625 (compared to an NNT of 4 for achieving an SVR) [[4]Brok J. Gluud L.L. Gluud C. Ribavirin plus interferon vs. interferon for chronic hepatitis C.Cochrane Database Syst Rev. 2010; 1: CD005445PubMed Google Scholar].Van der Meer et al. appeared to be most concerned with our statement that the presence of treatment harm and the failed validation of SVRs "should caution us to stop advocating antiviral interventions of any kind until we have evidence of clinical efficacy and cost-effectiveness" [[2]Koretz R.L. Pleguezuelo M. Arvaniti V. Barrera Baena P. Ciria R. Gurusamy K.S. et al.Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C.Cochrane Database Syst Rev. 2013; 1: CD003617PubMed Google Scholar]. To support their argument that SVR is a good outcome to assess antiviral therapy, they cite a number of lines of evidence that demonstrate the association between SVR and good outcomes. We agree with them that the SVR is a good prognostic sign. However, the key issue is that the SVR has not been validated as a surrogate outcome. In other words, there are no RCTs that have shown that a treatment that increases the number of SVRs equates with improved clinical outcomes. Van der Meer et al. agree that this is the case.We and van der Meer et al. also agree that most infected patients will not develop decompensated liver disease or hepatocellular carcinoma and that the prognostic factors identifying patients who are likely to achieve an SVR are also factors that would predict a good long-term outcome. If it is indeed true that the vast majority (perhaps even all) of individuals achieving SVRs were destined not to develop long-term complications of liver disease, it would follow that SVRs would be associated with non-progressive disease but that antiviral therapy may not provide overall benefit to the treated group.To validate the SVR as a surrogate outcome, RCTs in the future should compare patients treated with regimens that result in larger percentages of SVRs (e.g., 90%) to untreated patients and employ clinical events as the primary outcome. If patients in previous RCTs did not subsequently receive additional treatment, we would encourage the authors of those trials to assess the long-term clinical outcomes retrospectively. As of this time, treatment advocates are supporting treatment that has no level 1 (well designed and executed RCTs) evidence for improved clinical outcomes, but is costly and toxic (including occasional mortal).Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Recently, Dr. Van der Meer and colleagues [[1]Van der Meer A.J. Wedemeyer H. Feld J.J. Nansen B.E. Manns M.P. Zeuzem S. et al.Is there sufficient evidence to recommend antiviral therapy in hepatitis C?.J Hepatol. 2014; 60: 191-196Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar] discussed our systematic review of trials comparing interferon monotherapy to no therapy for retreating individuals infected with hepatitis C virus who had not achieved a sustained virological response (SVR) from previous antiviral therapy [[2]Koretz R.L. Pleguezuelo M. Arvaniti V. Barrera Baena P. Ciria R. Gurusamy K.S. et al.Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C.Cochrane Database Syst Rev. 2013; 1: CD003617PubMed Google Scholar]. Our review made several observations: (1) retreatment with interferon monotherapy provided no relevant clinical benefit; (2) while there was a statistically significant reduction in non-fatal variceal bleeding, the number needed to treat (NNT) was so high (NNT = 67) that the treatment is economically unfeasible; (3) when only the low risk of bias trials were considered, interferon treatment increased all-cause mortality; (4) the recipients of interferon had more adverse events; and (5) the commonly used surrogate outcome of SVR occurred significantly more often in the treated group. Since interferon treatment increased SVRs without improving clinical outcomes, the SVR was not a valid surrogate outcome in this scenario. As such, SVR cannot be universally considered as valid for purposes of clinical practice. We believe that, before it can be considered a trustworthy surrogate outcome in other scenarios, it must be validated in those scenarios, or at least in enough other scenarios that the single example of retreatment of interferon monotherapy could be considered to be an outlier. Validation of a surrogate outcome is a two-step process [[3]Bucher H.C. Guyatt G.H. Cook D.J. Holbrook A. McAlister F.A. Users' guides to the medical literature XIX. Applying clinical trial results A. How to use an article measuring the effect of an intervention on surrogate end points.JAMA. 1999; 282: 771-778Crossref PubMed Scopus (281) Google Scholar]. First, there has to be a strong and consistent association between the surrogate outcome and the clinical one. However, association alone is not adequate to establish validation. It also has to be shown that improving the surrogate outcome also similarly improves the clinical one; in other words, a treatment-related difference between the study groups in the surrogate outcome should be associated with a proportionate treatment-related difference in the clinical outcome. This latter step can only be demonstrated in randomized clinical trial (RCTs). Most RCTs assessing hepatitis C antiviral therapy do not provide clinical outcomes, presumably because these outcomes require years to pass before they begin to appear. Thus, there are limited data available to assess the validity of the SVR. Of note, several other Cochrane reviews also found scenarios in which an improved SVR did not translate into a meaningful beneficial clinical outcome These included comparing interferon with or without ribavirin [[4]Brok J. Gluud L.L. Gluud C. Ribavirin plus interferon vs. interferon for chronic hepatitis C.Cochrane Database Syst Rev. 2010; 1: CD005445PubMed Google Scholar], using ribavirin alone [[5]Brok J. Gluud L.L. Gluud C. Ribavirin monotherapy for chronic hepatitis C.Cochrane Database Syst Rev. 2009; 4: CD005527PubMed Google Scholar], and employing interferon in treatment-naïve patients [[6]Myers R.P. Regimbeau C. Thevenot T. Leroy V. Mathurin P. Opolon P. et al.Interferon for interferon naive patients with chronic hepatitis C.Cochrane Database Syst Rev. 2002; 2: CD000370PubMed Google Scholar]. Dr. van der Meer and his colleagues cited two of these [4Brok J. Gluud L.L. Gluud C. Ribavirin plus interferon vs. interferon for chronic hepatitis C.Cochrane Database Syst Rev. 2010; 1: CD005445PubMed Google Scholar, 6Myers R.P. Regimbeau C. Thevenot T. Leroy V. Mathurin P. Opolon P. et al.Interferon for interferon naive patients with chronic hepatitis C.Cochrane Database Syst Rev. 2002; 2: CD000370PubMed Google Scholar], but only noted that the improvement in SVR was accompanied by improvement in liver histology (another surrogate). Not mentioned by van der Meer et al., adding ribavirin to interferon resulted in a minimal but statistically significant reduction in the combined endpoint of death and hepatic morbidity (0.28% reduced to 0.12%), but the NNT was 625 (compared to an NNT of 4 for achieving an SVR) [[4]Brok J. Gluud L.L. Gluud C. Ribavirin plus interferon vs. interferon for chronic hepatitis C.Cochrane Database Syst Rev. 2010; 1: CD005445PubMed Google Scholar]. Van der Meer et al. appeared to be most concerned with our statement that the presence of treatment harm and the failed validation of SVRs "should caution us to stop advocating antiviral interventions of any kind until we have evidence of clinical efficacy and cost-effectiveness" [[2]Koretz R.L. Pleguezuelo M. Arvaniti V. Barrera Baena P. Ciria R. Gurusamy K.S. et al.Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C.Cochrane Database Syst Rev. 2013; 1: CD003617PubMed Google Scholar]. To support their argument that SVR is a good outcome to assess antiviral therapy, they cite a number of lines of evidence that demonstrate the association between SVR and good outcomes. We agree with them that the SVR is a good prognostic sign. However, the key issue is that the SVR has not been validated as a surrogate outcome. In other words, there are no RCTs that have shown that a treatment that increases the number of SVRs equates with improved clinical outcomes. Van der Meer et al. agree that this is the case. We and van der Meer et al. also agree that most infected patients will not develop decompensated liver disease or hepatocellular carcinoma and that the prognostic factors identifying patients who are likely to achieve an SVR are also factors that would predict a good long-term outcome. If it is indeed true that the vast majority (perhaps even all) of individuals achieving SVRs were destined not to develop long-term complications of liver disease, it would follow that SVRs would be associated with non-progressive disease but that antiviral therapy may not provide overall benefit to the treated group. To validate the SVR as a surrogate outcome, RCTs in the future should compare patients treated with regimens that result in larger percentages of SVRs (e.g., 90%) to untreated patients and employ clinical events as the primary outcome. If patients in previous RCTs did not subsequently receive additional treatment, we would encourage the authors of those trials to assess the long-term clinical outcomes retrospectively. As of this time, treatment advocates are supporting treatment that has no level 1 (well designed and executed RCTs) evidence for improved clinical outcomes, but is costly and toxic (including occasional mortal). Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.