Reply:
Authors: Robert P. Myers, Abdel Aziz M. Shaheen
Journal: Hepatology (2007)

Poynard and colleagues raise several points regarding our study1 that warrant further comment. Most importantly, our primary objective was to summarize the diagnostic accuracy of the aspartate aminotransferase-to-platelet ratio index (APRI) for hepatitis C virus (HCV)–related fibrosis, not to compare it with other fibrosis measures including the FibroTest. As discussed extensively in our article, the advantage of the APRI is its widespread availability and limited expense due to its inclusion of routinely performed laboratory parameters. These factors make the APRI an attractive first-line estimate of liver fibrosis, particularly in regions with limited health care resources, where the prevalence of HCV tends to be the highest. According to Word Health Organization estimates, over 85% of the 170 million HCV patients worldwide reside outside of the Americas and Europe, the majority in developing countries.2 As we have shown, the APRI can exclude significant fibrosis in approximately one-third of individuals, thus obviating liver biopsy and potentially antiviral therapy in a large group of patients globally. Although some proprietary measures such as the FibroTest can undoubtedly achieve the same results, their expense precludes use in all patients, particularly those in developing countries. The authors have criticized the methodological rigor of our systematic review, although most of their comments were addressed in our article. First, we discussed the APRI's limitations of including aspartate aminotransferase (AST), the assay for which is frequently not standardized, and its upper limit of normal, which often differs between laboratories. In fact, we hypothesized that these factors may have contributed to the heterogeneity in APRI accuracy observed between studies. Moreover, we attempted to address this issue in a sensitivity analysis, but the upper limit of normal for AST was reported in only 1 study. Regardless, the summary area under the receiver operating characteristic curve (AUC) of the APRI for significant fibrosis was acceptable (0.76), and the 95% confidence interval (CI) was quite narrow (0.74-0.79).1 Because these data originated from 22 studies including over 4200 patients from 12 countries on 4 continents, clearly these concerns do not represent a major barrier to the generalizability of these results to the use of the APRI in clinical practice. We have also been criticized for not considering the different spectra of fibrosis stages across studies as a source of heterogeneity in our results. In fact, we addressed this issue in our sensitivity analysis by adjusting for the prevalence of significant fibrosis, which ranged from 9% to 72% in these studies.1 This variable was not significant (P = 0.46) in our meta-regression analysis, although interestingly, it was significant in our recent systematic review of the FibroTest and FibroScan for HCV-related fibrosis, in which the direction of effect was opposite for the 2 measures.3 These findings may reflect a peculiarity of the specific fibrosis measure under investigation and should be explored in additional studies. In their discussion of this issue, Poynard and colleagues advocate using a standardization procedure that they derived using individual patient data on the FibroTest.4, 5 This procedure employs simple linear regression to calculate a "standardized AUC" based on the difference between the prevalence of advanced and nonadvanced fibrosis (DANA) in the study population. Although a critique of this methodology is beyond the scope of this correspondence, it is important to note that it has not been validated for fibrosis measures other than the FibroTest, including the APRI, or histological scoring systems other than the METAVIR classification. Nevertheless, we have performed a post hoc sensitivity analysis of 8 studies that used a 5-point histological scoring system (METAVIR or Scheuer) and from which DANA could be calculated (n = 1595). In this analysis, DANA was not a significant predictor of APRI accuracy [P = 0.20 for significant fibrosis; P = 0.57 for 6 studies (n = 1265) with the METAVIR classification]. Another critique of our work is our comparison of the accuracy of the APRI with that of other fibrosis measures. Obviously, we had to place our results in context with the remainder of the fibrosis marker literature. Regardless, all of our comparisons were based on either data from the same study (and hence no adjustment for the distribution of fibrosis stages is necessary) or the results of systematic reviews of diagnostic test accuracy (the strongest form of evidence). For example, we cited a study by Halfon et al.6 (n = 356) that reported similar AUCs for significant fibrosis for the APRI (0.76), FibroTest (0.79), FibroMeter (0.78), and HepaScore (0.76). We also compared our results for the APRI with that of a meta-analysis by Poynard et al.7 for the FibroTest, and interestingly, the summary AUCs from these studies were identical to those described above [APRI: 0.76 (95% CI 0.74-0.79)1; FibroTest: 0.79 (0.77-0.82)].7 Poynard et al. proceeded to perform a meta-analysis of 7 studies comparing the APRI and FibroTest directly and produced a slightly greater difference between measures (see their figure). It is important to note that the inclusion of Le Calvez et al.'s study8 intrinsically biases this analysis in favor of the FibroTest because it includes the original FibroTest derivation cohort. With this caveat aside, the weighted mean difference in AUCs between these measures was 0.07 (95% CI 0.04-0.10) in favor of the FibroTest. The reader must judge the clinical significance of this difference in AUCs and whether it justifies the added expense of a proprietary measure of fibrosis (100-300€ for the FibroTest).9 Interestingly, this same 7% difference in accuracy was recently reported by Poynard and colleagues9 in favor of proteomic profiling over the FibroTest. Ironically, in reference to this difference, the authors concluded that "despite a statistical significance, the small improvement delivered by proteomics impairs clinical applications because of its cost and variability compared with the well validated FibroTest."9 Finally, the group from Paris has discussed the limitations of liver biopsy and the restrictions that this has placed on our identification of the "perfect biomarker" of fibrosis. However, with advances in imaging techniques and high-throughput technologies including genomics and proteomics,9, 10 we are confident that we will identify tools that are more accurate than those currently available. In the interim, we must evaluate the existing evidence and select the measure of fibrosis that is most applicable to our clinical environment, whether it is liver biopsy, imaging studies such as elastrography, routine tests such as the APRI, or proprietary fibrosis markers. This is perhaps best illustrated by the authors of this correspondence who come from drastically different environments with respect to HCV. One author practices in Canada, a wealthy country with a single, government-funded, universal health insurance system and only 250,000 HCV-infected individuals (0.8% of the population).11 The choice of fibrosis measure depends largely on availability and the physician's comfort with and belief in its accuracy. The second author originates in Egypt, where at least 10 million individuals (∼15%-20% of the population)12 have HCV and a roughly equivalent percentage lives in poverty.13 Clearly inexpensive and accurate surrogate markers of liver fibrosis are necessary to assist in the management of this enormous burden of disease. As discussed in our original report,1 the APRI is one such tool against which future studies of novel fibrosis markers should demonstrate not only improved accuracy but also cost effectiveness. Robert P. Myers M.D., F. R. C. P. C.*, Abdel Aziz M. Shaheen M.D., M.P.H.*, * Liver Unit, Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.