Pascal Lebray

Assistance Publique – Hôpitaux de Paris, Lutetia Parisorum, Île-de-France, France

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Publications (71)463.87 Total impact

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    ABSTRACT: All trials of severe alcoholic hepatitis (AH) have included patients with “pure” AH, i.e., without concomitant gastrointestinal bleeding (GIB). Severe AH is often suspected in cirrhotics with GIB.Aims1) assess the prevalence of AH in patients with GIB and Maddrey discriminant function (DF) ⩾32; 2) compare the outcome in AH patients with or without GIB (AH-GIB+, AH-GIB-); 3) assess the performance of the Lille model for survival in AH-GIB+ patients.Methods We retrospectively included all patients with alcoholic cirrhosis admitted between January 2005 and March 2011 with the following: 1) jaundice <3 months, 2) DF ⩾32 at admission, 3) bilirubin level >50 μmol/l, 4) active drinking. Exclusion criteria were advanced hepatocellular carcinoma, other etiology of cirrhosis, severe comorbidities and DF <32 after stabilization. In our centre, we systematically plan a liver biopsy for these patients. Patients with severe AH received prednisolone.ResultsWe screened 161 patients (86 GIB+, 75 GIB-), and analyzed data for 58 and 47 patients in each group, respectively. The 2 groups did not differ in prevalence of AH (77.3% vs 81%), demographic data, MELD/Child-Pugh score, or DF. The 2 groups were similar in 6-month probability of survival (73.9±6.0% vs 69.9±7%, p=0.49). The probability of developing infection was lower for AH-GIB+ patients (24.1% vs 44.7%, p=0.04). The AUC for the Lille model for predicting 6-month survival was 0.71±0.06 for all patients and 0.74±0.06 for AH-GIB+ patients (p>0.05).Conclusions Prevalence of AH is 80% for patients with cirrhosis and GIB, recent jaundice and DF>32. Infection was lower for AH-GIB+ patients, which suggests a beneficial role of antibiotic prophylaxis treatment. Survival among subjects with GIB was the same as among subjects without GIB.
    Journal of Hepatology. 11/2014;
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    ABSTRACT: & Aims: Many patients with alcohol-associated cirrhosis also have diabetes, obesity, or insulin resistance-mediated steatosis, but little is known about how these disorders affect the severity of the liver disease. We analyzed the prevalence and prognostic implications of metabolic risk factors (MRF) such as overweight, diabetes, dyslipidemia, and hypertension in patients with alcohol-associated cirrhosis awaiting liver transplants. We performed a retrospective study of 110 patients alcohol-associated cirrhosis (77% male; mean age, 55 years; 71% >6 months of abstinence) who received liver transplants at a single center in Paris, France from 2000 through 2013. We collected data on previous exposure to MRF, steatosis (>10% in the explant), and histologically confirmed hepatocellular carcinoma (HCC). HCC was detected in explants from 29 patients (26%). Steatosis was detected in explants from 47 patients (70% were abstinent for ≥6 months); 50% had a history of overweight or type 2 diabetes. Fifty-two patients (47%) had a history of MRF and were therefore at risk for nonalcoholic fatty liver disease (NAFLD). A higher proportion of patients with MRF had HCC than of those without MRF (46% vs 9%, P<.001). A previous history of overweight or type 2 diabetes significantly increased the risk for HCC (odds ratio=6.23; 95% confidence interval [CI], 2.47-15.76 and odds ratio=4.63; 95% CI, 1.87-11.47, respectively; P<.001). MRF, but not steatosis, was associated with development of HCC (OR=11.76, 95%CI, 2.60-53; P=.001), independent of age, sex, amount of alcohol intake, or severity of liver disease. Patients with alcohol-associated cirrhosis who received transplants frequently also have NAFLD. MRF, particularly overweight, obesity and type 2 diabetes, significantly increase the risk of HCC.Despite a period of abstinence that is variable but usually longer than 6 months, some patients transplanted for alcoholic liver disease (ALD) still have steatosis on the explanted liver. In the general population, a frequent cause of steatosis, unrelated to alcohol consumption, is nonalcoholic fatty liver disease (NAFLD). NAFLD is usually due to long-term exposure to obesity, diabetes or different features of the metabolic syndrome and therefore is currently a very prevalent chronic liver disease. Because both at-risk alcohol consumption and exposure to metabolic risk factors are frequent in the general population, theoretically ALD and NAFLD can coexist. Some studies have notably shown that this association can result in heightened liver damage(1).For instance, excessive drinkers that are obese have cirrhosis and alcoholic hepatitis more often than non-obese drinkers (2). Central obesity and high serum glucose are also associated with more severe fibrosis in a population of patients with ALD(3). On the other hand, the severity of steatosis has been identified as an independent predictor of fibrosis progression and development of cirrhosis (4). Carcinogenesis might also be modulated by the association of these comorbidities. For example, overweight and obesity increase the risk of hepatocellular carcinoma (HCC) (5), while diabetes increases both liver cancer incidenceand mortality due to liver cancer (6). Steatosis was also associated with a higher risk of HCC (7). As it becomes increasingly clear that the association between ALD and NAFLD is clinically relevant, a better understanding of the prevalence and prognostic implications of metabolic risk factors (MRF, i.e. components of the metabolic syndrome such as obesity, diabetes, dyslipidemia, arterial hypertension) in patients with ALD is useful. In this study we attempted to investigate the prevalence and consequences of steatosis and MRF in a cohort of patients that had undergone liver transplantation for ALD. We hypothesized that the presence of steatosis on the native liver reflects concurrent NAFLD and that patients with steatosis and MRF are at higher risk of developing HCC. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
    10/2014;
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    ABSTRACT: Background In cardiometabolic disorders, non-alcoholic fatty liver disease is frequent and presumably associated with increased mortality and cardiovascular risk.AimTo evaluate the prognostic value of non-invasive biomarkers of liver fibrosis (FibroTest) and steatosis (SteatoTest) in patients with type-2 diabetes and/or dyslipidaemia.MethodsA total of 2312 patients with type-2 diabetes and/or dyslipidaemia were included and prospectively followed up for 5–15 years. The cardiovascular Framingham-risk score was calculated; advanced fibrosis and severe steatosis, were defined by FibroTest >0.48 and SteatoTest >0.69, respectively, as previously established.ResultsDuring a median follow-up of 12 years, 172 patients (7.4%) died. The leading causes of mortality were cancer (31%) and cardiovascular-related death (20%). The presence of advanced fibrosis [HR (95% CI)] [2.98 (95% CI 1.78–4.99); P < 0.0001] or severe steatosis [1.86 (1.34–2.58); P = 0.0002] was associated with an increased risk of mortality. In a multivariate Cox model adjusted for confounders: the presence of advanced fibrosis was associated with overall mortality [1.95 (1.12–3.41); P = 0.02]; advanced fibrosis at baseline [n = 50/677; 1.92 (1.04–3.55); P = 0.04] and progression to advanced fibrosis during follow-up [n = 16/127; 4.8 (1.5–14.9); P = 0.007] were predictors of cardiovascular events in patients with type-2 diabetes. In patients with a Framingham-risk score ≥20%, the presence of advanced fibrosis was predictive of cardiovascular events [2.24 (1.16–4.33); P < 0.05].Conclusions Liver biomarkers, such as FibroTest and SteatoTest, have prognostic values in patients with metabolic disorders. FibroTest has prognostic value for predicting overall survival in patients with type-2 diabetes and/or dyslipidaemia. In type-2 diabetes, FibroTest predicted cardiovascular events and improved the Framingham-risk score.
    Alimentary Pharmacology & Therapeutics 09/2014; · 4.55 Impact Factor
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    ABSTRACT: & Aims: Transient elastometry is a non-invasive procedure used to measure fibrosis when patients are diagnosed with liver disease; it might be used to monitor changes over time. We investigated whether there are short-term variations in stiffness measurements not attributable to changes in fibrosis by studying patients with stable liver disease.
    07/2014;
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    ABSTRACT: The first aim was to extend the validation of FibroTest (FT) and transient elastography (TE) as markers of occurrence of cirrhosis without complications (F4.1), esophageal varices (F4.2), and severe complications (F4.3) in patients with chronic hepatitis B (CHB). The second aim was to validate a previous definition of inactive carrier based on normal FT and ActiTest (normal-FTAT). The third aim was to assess the long-term dynamics of fibrosis in patients with sustained virological response.
    Journal of hepatology. 07/2014;
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    ABSTRACT: There is no established therapy for hepatitis E virus (HEV) infection. The aim of this retrospective, multicenter case series was to assess the effects of ribavirin as monotherapy for solid-organ transplant recipients with prolonged HEV viremia. We examined the records of 59 patients who had received a solid-organ transplant (37 kidney-transplant recipients, 10 liver-transplant recipients, 5 heart-transplant recipients, 5 kidney and pancreas-transplant recipients, and 2 lung-transplant recipients). Ribavirin therapy was initiated a median of 9 months (range, 1 to 82) after the diagnosis of HEV infection at a median dose of 600 mg per day (range, 29 to 1200), which was equivalent to 8.1 mg per kilogram of body weight per day (range, 0.6 to 16.3). Patients received ribavirin for a median of 3 months (range, 1 to 18); 66% of the patients received ribavirin for 3 months or less. All the patients had HEV viremia when ribavirin was initiated (all 54 in whom genotyping was performed had HEV genotype 3). At the end of therapy, HEV clearance was observed in 95% of the patients. A recurrence of HEV replication occurred in 10 patients after ribavirin was stopped. A sustained virologic response, defined as an undetectable serum HEV RNA level at least 6 months after cessation of ribavirin therapy, occurred in 46 of the 59 patients (78%). A sustained virologic response was also observed in 4 patients who had a recurrence and were re-treated for a longer period. A higher lymphocyte count when ribavirin therapy was initiated was associated with a greater likelihood of a sustained virologic response. Anemia was the main identified side effect and required a reduction in ribavirin dose in 29% of the patients, the use of erythropoietin in 54%, and blood transfusions in 12%. This retrospective, multicenter study showed that ribavirin as monotherapy may be effective in the treatment of chronic HEV infection; a 3-month course seemed to be an appropriate duration of therapy for most patients.
    New England Journal of Medicine 03/2014; 370(12):1111-20. · 54.42 Impact Factor
  • Journal of hepatology. Supplement / EASL 01/2014; 60(1):S348.
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    ABSTRACT: Background The aspartate aminotransferase platelet ratio index (APRI) is a validated, non-patented blood test for diagnosing fibrosis or cirrhosis in patients with chronic hepatitis C. We assess the impact of two limitations, the variability of the upper limit of normal for aspartate aminotransferase (AST-ULN) and the risk of overestimating fibrosis stage due to necroinflammatory activity. Methods The variability of AST-ULN was assessed by an overview of the literature and an assessment of AST-ULN in 2 control populations 7521 healthy volunteers and 393 blood donors. We assessed the impact of AST-ULN variability on APRI performance for estimating fibrosis prevalence and on the Obuchowski measure using individual data of 1651 patients with APRI, FibroTest and biopsy. Results The overview, and the analysis of the control populations found that ULN-AST ranged from 26 to 49 IU/L according to gender, body mass index and serum cholesterol. When this AST-ULN variability was applied to the chronic hepatitis group, the prevalence of advanced fibrosis and cirrhosis as presumed by APRI varied (P < 0.001) from 34.7% to 68.5%, and from 11.4% to 32.3%, respectively. This spectrum effect induced variability in APRI performance, which could be similar 0.862 (if AST-ULN = 26 IU/L) or lower 0.820 (AST-ULN ≥ 30IU/L) than the stable FibroTest performance (0.867; P = 0.35 and P < 0.0001 respectively). When applied to 18 acute hepatitis C patients, the rate of false positives of APRI varied from 0% to 61% due to AST-ULN. Conclusion The AST-ULN variability is high highly associated with the variability of metabolic risk factors between the different control groups. This variability induces a spectrum effect, which could cause misleading interpretations of APRI performance for the staging of fibrosis, comparisons of APRI with other non-invasive tests, and estimates of false positive rate.
    Clinics and Research in Hepatology and Gastroenterology. 01/2014;
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    ABSTRACT: Background. The partially-blinded, randomized, phase IIa C210 study evaluated the antiviral activity of telaprevir-based regimens in treatment-naïve, genotype 4 chronic hepatitis C virus (HCV)-infected patients.Methods. Patients (n=24) received 15 days of telaprevir 750&emsp14;mg every 8 hours (T; n=8), telaprevir in combination with peginterferon alfa-2a and ribavirin (Peg-IFN/RBV; TPR; n=8), or Peg-IFN/RBV plus placebo (PR; n = 8), followed by Peg-IFN/RBV for 46 or 48 weeks. The primary objective was to assess the effect of telaprevir on HCV RNA levels.Results. HCV RNA levels decreased slightly with T and PR; TPR produced substantial, rapid declines. At Day 15, median HCV RNA reductions from baseline were -0.77, -4.32, and -1.58&emsp14;log10 IU/mL for T, TPR and PR, respectively, and 0 (T), 1 (TPR), and 0 (PR) patients had undetectable HCV RNA. Five/eight patients who received telaprevir monotherapy had viral breakthrough within 15 days of treatment. Adverse event incidence was similar across treatments and comparable with previous clinical trials. One patient (T group) had a serious adverse event (considered unrelated to telaprevir) that led to treatment discontinuation.Conclusions. Telaprevir with Peg-IFN/RBV had greater activity against HCV genotype 4 than Peg-IFN/RBV or telaprevir monotherapy. Telaprevir was generally safe and well tolerated. Further investigation of telaprevir combination therapy in genotype 4 patients is warranted.
    The Journal of Infectious Diseases 06/2013; · 5.85 Impact Factor
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    ABSTRACT: BACKGROUND AND AIM: Real-time shear wave elastography (SWE) is a new two-dimensional transient elastography which had no assessment of factors associated with reliability, and has had limited comparisons with other validated fibrosis biomarkers. The aim was to assess the applicability and the performances of SWE for the diagnosis of fibrosis as compared with FibroTest (FT) and liver stiffness measurement (LSM) by transient elastography using two probes (TE-M and TE-XL). METHODS: without a gold standard were applied: the strength of concordance, discordance analysis and latent class analysis (LCM). RESULTS: 422 patients were included. The applicability of SWE (90.0%) was significantly lower than that of FT (97.9%; P<0.0001) and did not differ from those of TE-M (90.5%) and TE-XL (90.3%); it was higher though for SWE (86%) in 22 patients with ascites vs. 55% using TE-M (P=0.04). For the diagnosis of all fibrosis stages as presumed by FT, the performance of SWE was highly significant (Obuchowski measure 0.807 ± 0.013 [m ± se]), but lower than those of TE-M (0.852; P=0.0007) and TE-XL (0.834; P=0.046). SWE had a low performance for discrimination between F0 and F1. For the diagnosis of cirrhosis using LCM, the SWE specificities were all equal to 99%, and SWE sensitivities ranged from 0.47 to 0.64. For the diagnosis of non-cirrhotic stages, the results were heterogeneous. CONCLUSION: The performance of SWE for the diagnosis of cirrhosis was similar to those of FT and TE. The SWE applicability was lower than that of FT, but greater than that of TE in patients with ascites.
    Journal of Hepatology 01/2013; · 9.86 Impact Factor
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    ABSTRACT: Background and Aims FibroTest (FT) and Transient Elastography (TE) have been validated as noninvasive 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. Conclusion 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.
    Journal of Hepatology 01/2013; · 9.86 Impact Factor
  • Journal of Hepatology 01/2013; 59(3):550. · 9.86 Impact Factor
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    ABSTRACT: The aim of this study was to generate an improved prognostic model for predicting recurrence in liver transplant candidates with hepatocellular carcinoma (HCC). Predictors of recurrence were tested by a Cox model analysis in a training cohort of 537 patients transplanted for HCC. A prognostic score was developed and validated in a national cohort of 435 patients followed up prospectively. α-Fetoprotein (AFP) independently predicted tumor recurrence and correlated with vascular invasion and differentiation. At a Cox score threshold of 0.7 (area under the receiver operating characteristic curve, 0.701; 95% confidence interval, 0.63-0.76; accuracy, 75.8%), a model combining log(10) AFP, tumor size, and number was highly predictive of tumor recurrence and death. By using a simplified version of the model, with untransformed AFP values, a cut-off value of 2 was identified. In the validation cohort, a score greater than 2 predicted a marked increase in 5-year risk of recurrence (50.6% ± 10.2% vs 8.8% ± 1.7%; P < .001) and decreased survival (47.5% ± 8.1% vs 67.8% ± 3.4%; P = .002) as compared with others. Among patients exceeding Milan criteria, a score of 2 or lower identified a subgroup of patients with AFP levels less than 100 ng/mL with a low 5-year risk of recurrence (14.4% ± 5.3% vs 47.6% ± 11.1%; P = .006). Among patients within Milan criteria, a score greater than 2 identified a subgroup of patients with AFP levels greater than 1000 ng/mL at high risk of recurrence (37.1% ± 8.9% vs 13.3% ± 2.0%; P < .001). Net reclassification improvement showed that predictability of the AFP model was superior to Milan criteria. Prediction of tumor recurrence is improved significantly by a model that incorporates AFP. We propose the adoption of new selection criteria for HCC transplant candidates, taking into account AFP.
    Gastroenterology 06/2012; 143(4):986-994.e3. · 12.82 Impact Factor
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    ABSTRACT: Physiopathology and prognosis of peptic ulcer bleeding (PUB) have never been described in cirrhotic patients. To assess risk factors and outcome of PUB in two groups of patients with PUB with or without cirrhosis. We included prospectively all patients with PUB referred to our ICU of Hepatology and Gastroenterology between January 2008 and March 2011. All patients were treated according to international recommendations. Diagnosis of cirrhosis was based on clinical, biological and morphological exams. Aetiologies, characteristics and outcomes of PUB were compared in cirrhotic vs. noncirrhotic patients. A total of 203 patients with PUB were included prospectively. Twenty-nine patients had cirrhosis (group Cirr+), and 174 patients had no cirrhosis (group Cirr-). Demographic data were similar between the two groups except for age and alcohol consumption. Aetiology of cirrhosis was alcohol in 97% of cirrhotic patients. Characteristics of PUB were not different between the two groups. Ninety-three per cent of patients with cirrhosis had endoscopic portal hypertension. Aetiology of PUB was different between the group Cirr+ and Cirr- (Helicobacter pylori = 10.3% vs. 48.8%, P < 0.0001; NSAID's = 17.2% vs. 54.0%, P < 0.0001; idiopathic PUB = 79.3% vs. 23.8%, P < 0.0001). Outcome was comparable concerning re-bleeding (7.0% vs. 6.9%, P = 0.31), need for arterial embolisation (10.3 vs. 8.6%, P = 0.76), need for salvage surgery (0 vs. 1.7%, P = 0.31) and mortality (3.0% vs. 1.1%, P = 0.87). Physiopathology of PUB seems to be different in patients with cirrhosis. In cirrhotic patients, PUB occurs almost only in alcoholics. In our series, prognosis was similar to general population. PUB in cirrhosis might be related to portal hypertension and/or alcohol.
    Alimentary Pharmacology & Therapeutics 05/2012; 36(2):166-72. · 4.55 Impact Factor
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    ABSTRACT: Two widely used biomarkers of fibrosis, FibroTest and liver stiffness measurement (LSM), have been mostly validated in patients with chronic hepatitis C (CHC) using the standard area under the ROC curve (sAUROC) which is not the most appropriate method due to the risk of fibrosis spectrum effect. Furthermore the performance of these biomarkers have not been assessed in "intention to diagnose" which takes into account the failures and non-reliable results. The aim was to compare the accuracy of FibroTest and LSM for the diagnosis of fibrosis using sAUROC, the pairwise comparison of fibrosis stages by Obuchowski measure (wAUROC), and these AUROCs reassessed after taking into account the applicability rates. One thousand two hundred and eighty-nine patients with CHC and 604 healthy volunteers were analyzed. The performances of biomarkers assessed were compared in a patients-only group (P1: n=1289), in a population combining both patients and healthy volunteers (P2: n=1893) and in a simulated population (P3: n=1893) with the prevalence of stages observed in a reference population, to demonstrate the impact of spectrum effect. Applicability rates were estimated prospectively in 24,872 consecutive FibroTest and in 13,669 consecutive LSM examinations. Using wAUROC, the conclusions of studies with reliable results in P1 were different than in those of P2 and in P3. There was a lower performance of FibroTest versus LSM in P1 (0.864 [0.855-0.873] vs. 0.883 [0.874-0.892]; P=0.002) which was not found in P2 (0.893 [0.887-0.900] vs. 0.894 [0.887-0.901]; P=0.86) and in P3 (0.899 [0.893-0.905] vs 0.902 [0.895-0.909]; P=0.60). Using the sAUROC, in P1, P2 and P3, there was no significant difference between FibroTest and LSM performance for advanced fibrosis and a lower performance of FibroTest versus LSM for cirrhosis. In intention to diagnose, using wAUROCs performances were higher for FibroTest vs. LSM in P1 (0.857 [0.848-0.866] vs. 0.814 [0.807-0.821]; P<0.0001) and P2 (0.885 [0.879-0.892] vs. 0.743 [0.737-0.749]; P<0.0001), without difference in P3 (0.891 [0.885-0.897] vs. 0.894 [0.887-0.901]; P=0.90). Using sAUROC, the significant differences in favor of FibroTest vs LSM persisted also for the diagnosis of advanced fibrosis, both in P1 and P2 (P<0.0001) and for the diagnosis of cirrhosis in P1 (P<0.001). When the spectrum effects and applicability rates were taken into account, LSM had lower performance results than FibroTest for the diagnosis of fibrosis stages.
    Gastroentérologie Clinique et Biologique 08/2011; 35(11):720-30. · 0.80 Impact Factor
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    ABSTRACT: Aims and Methods: Several serum biomarkers such as FibroTest, aspartate transaminase-platelet ratio index (APRI), FIB-4, and liver stiffness measurement by FibroScan have been validated as alternatives to biopsy for the diagnosis of fibrosis in patients with chronic liver disease. This paper aims to assess the 5-year prognostic values of these biomarkers. A meta-analysis combined all published prognostic studies. Baseline biopsy and APRI data were used as references. Results: Only 3 biomarkers had several prognostic validations: FibroTest (4 studies; 2,396 patients), APRI (5 studies; 2,422 patients), and FIB-4 (3 studies; 1,184 patients). For the prediction of survival without liver-related death, the areas under the receiver operating characteristic curves (AUROCs) were 0.86 for biopsy (95% confidence interval [CI], 0.77-0.95), 0.88 for FibroTest (95% CI, 0.79-0.98), 0.73 for FIB-4 (95% CI, 0.62-0.85), and 0.66 for APRI (95% CI, 0.57-0.75). APRI had a significantly lower prognostic value versus biopsy, with a mean difference between AUROCs of -0.21 (95% CI, -0.33 to -0.10; P<.001); FIB-4 had a significantly lower prognostic value versus biopsy, with a mean difference between AUROCs of -0.21 (95% CI, -0.20 to -0.02; P=.02). Only FibroTest did not show a significant difference in prognostic value versus biopsy, with a mean difference in AUROCs of +0.02 (95% CI, -0.05 to +0.09; P=.85). Conclusion: FibroTest is a validated biomarker for the prognosis of patients with chronic liver disease.
    Gastroenterology and Hepatology 07/2011; 7(7):445-54.
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    ABSTRACT: BACKGROUND: In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment. METHODS: To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. RESULTS: A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10) IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls. CONCLUSIONS: The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500.).
    New England Journal of Medicine 03/2011; 364(13-364):1195-206. · 54.42 Impact Factor
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    ABSTRACT: BACKGROUND: In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment. METHODS: To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. RESULTS: A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10) IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls. CONCLUSIONS: The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500.).
    New England Journal of Medicine 03/2011; 364(13-364):1207-17. · 54.42 Impact Factor
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    ABSTRACT: Hepatitis E virus (HEV) infection can cause chronic hepatitis in recipients of solid organ transplants. However, the factors that contribute to chronic infection and the outcomes of these patients are incompletely understood. We performed a retrospective analysis of data from 17 centers from Europe and the United States that described the progression, outcomes, and factors associated with development of chronic HEV infection in recipients of transplanted solid organs. We studied data from 85 recipients of solid organ transplants who were infected with HEV. Chronic HEV infection was defined by the persistent increases in levels of liver enzymes and polymerase chain reaction evidence of HEV in the serum and/or stool for at least 6 months. Fifty-six patients (65.9%) developed chronic hepatitis. Univariate analysis associated liver transplant, shorter times since transplant, lower levels of liver enzymes and serum creatinine, lower platelet counts, and tacrolimus-based immunosuppressive therapy (rather than cyclosporin A) with chronic hepatitis. On multivariate analysis, the independent predictive factors associated with chronic HEV infection were the use of tacrolimus rather than cyclosporin A (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.49-1.97; P = .004) and a low platelet count at the time of diagnosis with HEV infection (OR, 1.02; 95% CI, 1.001-1.1; P = .04). Of patients with chronic hepatitis, 18 (32.1%) achieved viral clearance after the dose of immunosuppressive therapy was reduced. No HEV reactivation was observed after HEV clearance. HEV infection causes chronic hepatitis in more than 60% of recipients of solid organ transplants. Tacrolimus therapy is the main predictive factor for chronic hepatitis. Dose reductions of immunosuppressive therapy resulted in viral clearance in more than 30% of patients.
    Gastroenterology 02/2011; 140(5):1481-9. · 12.82 Impact Factor
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    ABSTRACT: The epidemic history of HCV genotype 5a is poorly documented in France, where its prevalence is very low, except in a small central area, where it accounts for 14.2% of chronic hepatitis C cases. A Bayesian coalescent phylogenetic investigation based on the E1 envelope gene and a non-structural genomic segment (NS3/4) was carried out to trace the origin of this epidemic using a large sample of genotype 5a isolates collected throughout France. The dates of documented transmissions by blood transfusion were used to calibrate five nodes in the phylogeny. The results of the E1 gene analysis showed that the best-fitting population dynamic model was the expansion growth model under a relaxed molecular clock. The rate of nucleotide substitutions and time to the most recent common ancestors (tMRCA) of genotype 5a isolates were estimated. The divergence of all the French HCV genotype 5a strains included in this study was dated to 1939 [95% HPD: 1921-1956], and the tMRCA of isolates from central France was dated to 1954 [1942-1967], which is in agreement with epidemiological data. NS3/4 analysis provided similar estimates with strongly overlapping HPD values. Phylodynamic analyses give a plausible reconstruction of the evolutionary history of HCV genotype 5a in France, suggesting the concomitant roles of transfusion, iatrogenic route and intra-familial transmission in viral diffusion.
    Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 01/2011; 11(2):496-503. · 3.22 Impact Factor

Publication Stats

1k Citations
463.87 Total Impact Points

Institutions

  • 2011–2014
    • Assistance Publique – Hôpitaux de Paris
      • Département de Biochimie
      Lutetia Parisorum, Île-de-France, France
    • Polytech Paris-UPMC
      Lutetia Parisorum, Île-de-France, France
  • 2007–2014
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
  • 2006–2014
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      • Service d’Hépato - Gastro - Entérologie
      Lutetia Parisorum, Île-de-France, France
  • 2012
    • UPMC
      Pittsburgh, Pennsylvania, United States
  • 2009
    • Hôpitaux Universitaires La Pitié salpêtrière - Charles Foix
      Lutetia Parisorum, Île-de-France, France
  • 2008
    • Hôpital Paul-Brousse – Hôpitaux universitaires Paris-Sud
      Île-de-France, France
    • BioPredictive
      Lutetia Parisorum, Île-de-France, France
  • 2004
    • Centre Hospitalier Régional et Universitaire de Besançon
      Becoinson, Franche-Comté, France
  • 2002
    • Unité Inserm U1077
      Caen, Lower Normandy, France