Elsevier

Journal of Hepatology

Volume 60, Issue 4, April 2014, Pages 706-714
Journal of Hepatology

Research Article
Staging chronic hepatitis C in seven categories using fibrosis biomarker (FibroTest™) and transient elastography (FibroScan®)

https://doi.org/10.1016/j.jhep.2013.11.016Get rights and content

Background & Aims

FibroTest™ (FT) and Transient Elastography (TE) have been validated as non-invasive markers of METAVIR fibrosis stages from F0 to F4 using biopsy, and as prognostic markers of liver related mortality in patients with chronic hepatitis C. The aim was to extend the validation of FT and TE as markers of critical steps defined by occurrence of cirrhosis without complications (F4.1), esophageal varices (F4.2), and severe complications (F4.3): primary liver cancer, variceal bleeding, or decompensation (ascites, encephalopathy, or jaundice).

Methods

The updated individual data of 3927 patients (1046 cirrhotics) without complications at baseline were pooled from three prospective cohorts called “EPIC”, “Paris”, and “Bordeaux” cohorts.

Results

At 5 years, among 501 patients without varices at baseline (F4.1) varices occurred in 19 patients [F4.2 incidence of 4.0% (95% CI 2.2–5.8)]. The predictive performance (AUROC) of FT was 0.77 (0.66–0.84; p <0.001).

At 10 years severe complications occurred in 203 patients, [F4.3 incidence of 13.4% (9.6–17.1)], including primary liver cancer in 84 patients [6.4% (3.5–9.3)]. FT was predictive (Cox adjusted on treatment) of severe complications [AUROC 0.79 (76–82); p <0.0001], including primary liver cancer [AUROC 0.84 (80–87); p <0.0001]. Similarly TE was predictive of severe complications [AUROC 0.77 (72–81); p <0.0001], including primary liver cancer [AUROC 0.86 (81–90); p <0.0001].

Conclusions

FibroTest™ and TE increase were associated with the occurrence of all severe complications including hepatocellular carcinoma, hepatic insufficiency, and variceal bleeding. FibroTest™ increase was also associated with the occurrence of esophageal varices.

Introduction

Fibrosis progression is the earlier estimate of severity in patients with chronic hepatitis C (CHC) [1]. Before the stage of cirrhosis, the estimates of fibrosis progression mainly used transition rates between successive stages from normal liver (F0) to cirrhosis (F4), defined by histological score such as the METAVIR scoring system [1], [2]. The last stage F4 included patients with a wide range of severity. As stated by Garcia-Tsao et al., “there was a need to move beyond the characterization of cirrhosis as a single stage and instead, thinking of cirrhosis as a series of critical steps that culminate in hepatic decompensation” [3].

In CHC, FibroTest™ (FT) and transient elastography (TE) have been validated as markers of METAVIR fibrosis stages from F0 to F4 using biopsy [4], [5], [6], [7], [8], of liver fibrosis progression [9], [10] or regression [10], [11] but also validated as prognostic quantitative markers for occurrence of liver related complications, survival without liver related death, and overall survival [12], [13], [14], [15], [16], [17]. In these studies the performances of FT and TE were at least similar to those of biopsy for predicting overall survival and liver related complications. However due to the low incidence of each severe complication at 5 years (Supplementary Table 1), more patients and longer follow-up were needed to assess the specific performance of FT and TE for predicting separately the occurrence of varices, variceal bleeding, hepatic insufficiency (ascites, encephalopathy, or jaundice) and hepatocellular carcinoma.

The aim of the present study was to assess the performance of FT and TE for predicting the main steps in fibrosis progression, from F0 to death. The “seven stages spectrum”, included the 4 non-cirrhotic stages and the 3 critical steps in cirrhosis [3]: F4.1 defined as cirrhosis without varices or severe events, F4.2 defined as the presence of varices without severe events and F4.3 defined by the occurrence of the first severe event. Previously, F4.3 was defined as the occurrence of the following severe events: variceal hemorrhage, and hepatic insufficiency (ascites, encephalopathy, or jaundice the three clinical signs of decompensation in the Child-Turcotte classification) [3]. As primary liver cancer (PLC including hepatocellular carcinoma or cholangiocarcinoma) is the main cause of death in CHC, even in sustained virological responders (SVR) [11], we included also PLC in the stage F4.3 definition.

Section snippets

Materials and methods

To assess the prognostic values of FT and TE on a large sample of CHC with a wide severity spectrum we analyzed the updated individual data of three prospective cohorts called “EPIC”, “Paris”, and “Bordeaux” cohorts (Fig. 1). The cohorts’ characteristics were detailed in previous publications [11], [12], [13], [18] and in the Supplementary data.

The cohorts’ protocols were approved by the appropriate institutional review boards, regulatory agencies and conducted in accordance with principles of

Characteristics of patients (Table 1)

A total of 3927 patients without complications at baseline were pooled.

In the EPIC cohort and in comparison with the two other cohorts, patients had twice more advanced fibrosis, were all previous non-responders, older, and with more genotype 1. Their characteristics were similar to those of the EPIC overall group, and also without significant difference on primary endpoints between randomized groups [16], 286 received maintenance therapy and 288 were observed.

In the Paris cohort and in

Discussion

In patients with chronic hepatitis C both FT and TE, have been extensively validated for the diagnosis of advanced fibrosis stages [4], [5], [6], [7], [8], [9], [10], [11], [12], [13] and prediction of mortality [12], [13], [14], [15], [16], [17]. Due to the low incidence of events in previous studies (Supplementary Table 1), larger cohorts and a longer follow-up were needed to assess the performance of biomarkers for each complication [24].

The strength of the present study is that it

Conclusion

In conclusion, predetermined cut-offs of FibroTest™ and transient elastography (when reliable) permits to rank the severity of chronic hepatitis C in “seven stages”, from no-fibrosis to death, with three stages in cirrhotic patients with increasing morbidity and mortality.

Conflict of interest

TP is the inventor of patented FibroTest™, with a capital interest in BioPredictive the company marketing this test (FibroSure™ in USA). The patents belong to the French Public Organization “Assistance Publique Hopitaux de Paris”.

YN, MM, OD are full employees of BioPredictive, the company marketing FibroTest™.

The other authors have nothing to declare.

Authors’ contribution

TP: Study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; obtained funding, technical, or material support; study supervision.

JV, YN, MM, WM, MC, VT, ES, CB, JA, MR, OD, PL, and DT: Acquisition of data; analysis and interpretation of data.

VR: Acquisition of data; analysis and interpretation of data; critical revision of the manuscript for

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