Reply to: From the CUPIC study: Great times are not coming (?)
Authors: Fabrice Carrat, Yoann Barthe, Christophe Hezode, Helene Fontaine, Jean-Pierre Bronowicki
Journal: Journal of Hepatology (2013)

Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) – NCT01514890Journal of HepatologyVol. 59Issue 3PreviewIn phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme. Full-Text PDF From the CUPIC study: Great times are not coming (?)Journal of HepatologyVol. 60Issue 1PreviewWe read with interest the article by Hézode et al., in which they describe the week 16 interim results from the CUPIC study, a large French multicenter prospective cohort study [1]. Given the strict inclusion criteria of protease inhibitors (PI) phase III trials, the cirrhotic group was underrepresented and composed of highly selected patients in these studies [2–5]. Therefore, efficacy and safety concerns about first-generation PI-based therapy in “real-life” cirrhotic patients were raised. The CUPIC investigators found that albumin levels <35 g/L and platelet count ⩽100,000/mm3 were independent predictors of death and severe complications, and the risk of these events in patients with both predictors was worryingly high (44.1%). Full-Text PDF Open Access Carvalho-Filho and colleagues raised two comments regarding our paper [[1]Hézode C. Fontaine H. Dorival C. Larrey D. Zoulim F. Canva V. et al.Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) – NCT01514890.J Hepatol. 2013; 59: 434-441Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar]. The first comment relates to the fact that the safety interim analysis may have been underpowered, and that the number of variables included in the multivariate analysis did not respect the 10 events per variable ratio (EVR) rule. The second comment relates to bias induced by potential multicollinearity between covariates tested in multivariate models. In reply we will address three points. (1) Might associations between death or complications with albumin and platelet count be a ‘false positive result’? Indeed, the non-respect of the 10 events per variable rule is mostly known to increase the type I error, i.e., the risk of a significant association when no association truly exists. First, the relevance of the 10 events per variable rule has been discussed and further simulation studies showed that, in a logistic model with two binary predictors such as ours, the inflation of type I error is moderate [[2]Vittingoff E. et al.Relaxing the rule of ten events per variable in logistic and Cox regression.Am J Epidemiol. 2007; 165: 710-718Crossref PubMed Scopus (2354) Google Scholar]. Second, and most importantly, the positive associations with albumin and platelet count were not exploratory post hoc findings but were a priori hypothesized associations, which limited the risk of false positive results. Third, we found a clear dose-effect relationship with each of these two factors when considered as a continuous variable and deaths or severe complications (Table 1) – this argues for a direct or indirect causality link between albumin or platelet count and severe outcome.Table 1Dose-effect relationship between albumin or platelets and deaths and/or severe complications. Open table in a new tab Therefore, we do believe that independent associations between albumin and platelet count are real and not the consequence of inflated type I error due to low EVR. (2) Might odds-ratios estimates be biased given the low number of events and potential multicollinearity? First, we performed backward logistic models, and thus, the final model (with an event per variable ratio of 15) did not include any other predictor than albumin and platelet count, which limited the bias in estimating the strengths of association and avoided any collinearity problem in final model estimates. Second, we also performed additional analyses using 1000 bootstrap samples to derive bias-corrected confidence intervals. The bootstrap estimates of confidence intervals were (3.27–15.6) for albumin <35 g/L, and (1.43–7.85) for platelet count ⩽100 × 109/L, confirming our figures. Therefore we do believe that our estimates are robust and were not affected by our analytic strategy. (3) Might there be any other missed predictor of the risk of death or complications? Of course, we cannot exclude that our study may have been underpowered to detect other potential associations. However, as Carvahlo et al. pointed out from our results, the negative predictive values of the two factors were high. The C-statistic – a measure of the predictive accuracy corresponding to the area under the ROC curve of the logistic model including albumin and platelet count was 0.75 which is considered “acceptable discrimination” [[3]Hosmer D.W. Lemeshow S. Applied logistic regression. 2nd ed. John Wiley & Sons, New York, NY2000Crossref Google Scholar] and the Hosmer-Lemeshow’s goodness of fit test indicated a correct fit (p value = 0.15, should be >0.05). While we agree that our findings should be validated in other HCV patients with cirrhosis, we do confirm that these two simple factors can be used to evaluate the risk of severe outcome in patients who start triple HCV therapy. Jean-Pierre Bronowicki: consultancy and speaker fees from MSD, Janssen Christophe Hézode: consultancy and speaker fees from MSD, Janssen Hélène Fontaine: speaker fees from MSD, Janssen.