Clinical and genetic definition of serum bilirubin levels for the diagnosis of Gilbert syndrome and hypobilirubinemia.

BACKGROUND AND AIMS: Gilbert syndrome (GS) is genotypically predetermined by UGT1A1*28 homozygosity in Europeans and is phenotypically defined by hyperbilirubinemia using total bilirubin (TB) cutoff ≥1mg/dL (17 µmol/L). The prevalence of illnesses associated with GS and hypobilirubinemia has never been studied prospectively. As TB varies with UGT1A1*28 genotyping, sex, and age, we propose stratified definitions of TB reference intervals and report the prevalence of illnesses and adjusted 15 years survival. METHODS: UK Biobank with apparently healthy liver participants (middle-aged, n=138,125) were analyzed after the exclusion of of nonhealthy individuals. The stratified TB was classified as GS when TB >90th centile; <10th centile indicated hypobilirubinemia, and between the 10th and 90th centile was normobilirubinemia. We compared the prevalence and survival rates of 54 illnesses using odds ratio (OR), logistic regression, and Cox models adjusted for confounders, and causality by Mendelian randomizations. RESULTS: In women, we identified 10% (7,741/76,809) of GS versus 3.7% (2,819/76,809) using the historical cutoff of ≥1 mg/dL (P<0.0001). When GS and hypobilirubinemia participants were compared with normobilirubinemia, after adjustment and Mendelian randomizations, only cholelithiasis prevalence was significantly higher (OR=1.50; 95% CI [1.3-1.7], P=0.001) in men with GS compared with normobilirubinemia and in causal association with bilirubin (P=0.04). No adjusted survival was significantly associated with GS or hypobilirubinemia. CONCLUSIONS: In middle-aged Europeans, the stratified TB demonstrates a careless GS underestimation in women when using the standard unisex 1 mg/dL cutoff. The prevalence of illnesses is different in GS and hypobilirubinemia as well as survivals before adjusting for confounding factors. With the exception of cholelithiasis in men, these differences were no more significant after adjustment and Mendelian randomization.

Hepatitis C virus infection impacts work productivity and fatigue: An epidemiologic real-life study.

INTRODUCTION AND OBJECTIVE: Hepatitis C virus (HCV) infection and treatment impact the patient's daily life and work productivity. Until recently, treatments were associated with side effects and insufficient virologic and hepatic results. This study evaluated fatigue, work productivity, and treatment modalities in patients with HCV infection. MATERIALS AND METHODS: This cross-sectional, non-interventional, multicenter study was conducted in real-life settings between March and December 2015 at 109 sites in France. RESULTS: Data from 1269 patients were evaluable. The mean patient age was 55.8±12.5 years; 53.3% (676) patients were male. A total of 80.1% (1015) of patients were Caucasian and 62.3% (791) had a genotype 1 infection, 34.2% (433) had at least one comorbidity and 15.6% (198) had ≥1 clinical sign/symptom. Illicit drug use was the main route of HCV transmission and accounted for 36.8% (466) of all infections. Fibrosis stage F0/F1 was reported in 41.4% (525) of patients. A majority of patients (60.4%, 764) had never been treated. In patients previously treated, 85.8% (430) received ribavirin and pegylated interferon and only 13.4% (67) direct-acting antivirals. The mean percent of global impairment due to health was highest (34.8±30.9%) in patients 18-45 years of age. The prevalence of active employed patients with a total fatigue score≥its median value (45/160) was 38.6%. The mean percent work time missed due to health was 9.6±23.6% for working patients of 18-45 years of age and 7.3±21.8% for working patients of 45-65 years of age. The mean overall prevalence of employed patients with impairment due to health issues was 21.8±26.8%. The prevalence of patients with a reduced work activity of ≥50% due to their health status was 32.1%. CONCLUSION: These data reinforce the request for improved disease management in France, allowing patients with HCV infection to increase work productivity, reduce fatigue, and, hopefully, cure their disease.

LCR1 and LCR2, two multi-analyte blood tests to assess liver cancer risk in patients without or with cirrhosis.

BACKGROUND: No blood test has been shown to be effective in the prediction of primary liver cancer in patients without cirrhosis. AIM: To construct and internally validate two sequential tests for early prediction of liver cancer. These tests enable an algorithm which could improve the performance of the standard surveillance protocol recommended (imaging with or without AFP), limited to patients with cirrhosis. METHODS: We performed a retrospective analysis in prospectively collected specimens from an ongoing cohort. We designed an early sensitive high-risk test (LCR1) that combined (using Cox model) hepatoprotective proteins (apolipoproteinA1, haptoglobin) with known risk factors (gender, age, gammaglutamyltranspeptidase), and a marker of fibrosis (alpha2-macroglobulin). To increase the specificity, we then combined (LCR2) these components with alpha-fetoprotein. RESULTS: A total of 9892 patients, 85.9% without cirrhosis, were followed up for 5.9 years [IQR: 4.3-9.4]. LCR1 and LCR2 time-dependent AUROCs were not different in construction and validation randomised subsets. Among 2027 patients with high-LCR1 then high-LCR2, 167 cancers (113 with cirrhosis, 54 without cirrhosis) were detected, that is 12 patients needed to screen one cancer. The negative predictive value was 99.5% (95% CI 99.0-99.7) in the 2026 not screened patients (11 cancers without cirrhosis) higher than the standard surveillance, which detected 113 cancers in 755 patients screened, that is seven patients needed to screen one cancer, but with a lower negative predictive value 98.0% (97.5-98.5; Z = 4.3; P < 0.001) in 3298 not screened patients (42 cancers without cirrhosis). CONCLUSIONS: In patients with chronic liver disease the LCR1 and LCR2 tests identify those with a high risk of liver cancer, including in those without cirrhosis. NCT01927133.

Long-term prognostic value of the FibroTest in patients with non-alcoholic fatty liver disease, compared to chronic hepatitis C, B, and alcoholic liver disease.

BACKGROUND: Although the FibroTest has been validated as a biomarker to determine the stage of fibrosis in non-alcoholic fatty liver disease (NAFLD) with results similar to those in chronic hepatitis C (CHC), B (CHB), and alcoholic liver disease (ALD), it has not yet been confirmed for the prediction of liver-related death. AIM: To validate the 10-year prognostic value of FibroTest in NAFLD for the prediction of liver-related death. METHOD: Patients in the prospective FibroFrance cohort who underwent a FibroTest between 1997 and 2012 were pre-included. Mortality status was obtained from physicians, hospitals or the national register. Survival analyses were based on univariate (Kaplan-Meier, log rank, AUROC) and multivariate Cox risk ratio taking into account age, sex and response to anti-viral treatment as covariates. The comparator was the performance of the FibroTest in CHC, the most validated population. RESULTS: 7082 patients were included; 1079, 3449, 2051, and 503 with NAFLD, CHC, CHB, and ALD, respectively. Median (range) follow-up was 6.0 years (0.1-19.3). Ten year survival (95% CI) without liver-related death in patients with NAFLD was 0.956 (0.940-0.971; 38 events) and 0.832 (0.818-0.847; 226 events; P = 0.004) in CHC. The prognostic value (AUROC / Cox risk ratio) of FibroTest in patients with NAFLD was 0.941 (0.905-0.978)/1638 (342-7839) and even higher than in patients with CHC 0.875 (0.849-0.901; P = 0.01)/2657 (993-6586). CONCLUSIONS: The FibroTest has a high prognostic value in NAFLD for the prediction of liver-related death. (ClinicalTrials.gov number, NCT01927133).

Variability in definitions of transaminase upper limit of the normal impacts the APRI performance as a biomarker of fibrosis in patients with chronic hepatitis C: "APRI c'est fini ?".

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.

Recommendations for the management of hepatitis C virus infection among people who inject drugs.

In the developed world, the majority of new and existing hepatitis C virus (HCV) infections occur among people who inject drugs (PWID). The burden of HCV-related liver disease in this group is increasing, but treatment uptake among PWID remains low. Among PWID, there are a number of barriers to care that should be considered and systematically addressed, but these barriers should not exclude PWID from HCV treatment. Furthermore, it has been clearly demonstrated that HCV treatment is safe and effective across a broad range of multidisciplinary healthcare settings. Given the burden of HCV-related disease among PWID, strategies to enhance HCV assessment and treatment in this group are urgently needed. These recommendations demonstrate that treatment among PWID is feasible and provides a framework for HCV assessment, management, and treatment. Further research is needed to evaluate strategies to enhance assessment, adherence, and SVR among PWID, particularly as new treatments for HCV infection become available.

Telaprevir activity in treatment-naive patients infected hepatitis C virus genotype 4: a randomized trial.

BACKGROUND: This partially blinded, randomized, phase 2a C210 study evaluated the antiviral activity of telaprevir-based regimens in treatment-naive patients with chronic hepatitis C virus (HCV) genotype 4 infection. METHODS: Twenty-four patients received telaprevir 750 mg every 8 hours for 15 days (T; n = 8), telaprevir in combination with pegylated interferon alfa-2a and ribavirin (Peg-IFN/RBV) for 15 days (TPR; n = 8), or Peg-IFN/RBV plus placebo for 15 days (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. On day 15, median reductions in the HCV RNA load from baseline were -0.77, -4.32, and -1.58 log10 IU/mL for T, TPR, and PR, respectively, and 0 patients in the T group, 1 in the TPR group, and 0 in the PR group had undetectable HCV RNA. Five of 8 patients who received telaprevir monotherapy had viral breakthrough within 15 days of treatment. Adverse event incidence was similar across treatments and comparable with the incidences from previous clinical trials. One patient (in 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 than Peg-IFN/RBV treatment or telaprevir monotherapy against HCV genotype 4. Telaprevir was generally safe and well tolerated. Further investigation of telaprevir combination therapy in patients with HCV genotype 4 infection is warranted.

Slow regression of liver fibrosis presumed by repeated biomarkers after virological cure in patients with chronic hepatitis C.

BACKGROUND & AIMS: Chronic hepatitis C is both a virologic and fibrotic disease and complications can occur in patients with sustained virologic response (SVR) with residual fibrosis. Due to the limitations of repeated biopsies, no studies have assessed the dynamic of fibrosis before and after treatment. Using biopsy as reference, FibroTest™ has been validated as a biomarker of fibrosis progression and regression, with similar prognostic values. The aim was to estimate the impact of SVR on the dynamic of fibrosis presumed by FibroTest™. METHODS: In a prospective cohort, the main end point was the 10-year regression rate of fibrosis, defined as a minimum 0.20 decrease in FibroTest™, equivalent to one METAVIR stage. RESULTS: A total of 933 patients with both repeated FibroTest™ and transient elastography were included. At 10 years, among the 415 patients with baseline advanced fibrosis, 49% (95% CI 33-64%) of the 108 SVR had a regression, which was greater than in the 219 non-responders [23% (14-33%; p < 0.001 vs. SVR)] and not lower than in the 88 non-treated [45% (10-80%; p = 0.39 vs. SVR)] patients. In all 171 SVR, cirrhosis regressed in 24/43 patients, but 15 new cirrhosis cases occurred out of 128 patients, that is only a net reduction of 5.3% [(24-15) = 9/171); (2.4-9.8%)]. Four cases of primary liver cancer occurred in SVR [4.6% (0-9.8)], and 13 in non-responders [5.6% (1.5-9.8); p = 0.07]. CONCLUSIONS: In patients with chronic hepatitis C, and as presumed by FibroTest™, virological cure was associated with slow regression of fibrosis 10years later, a disappointing 5% decrease in cirrhosis cases, and a remaining 5% risk of primary liver cancer.

FibroTest and Fibroscan performances revisited in patients with chronic hepatitis C. Impact of the spectrum effect and the applicability rate.

BACKGROUND: 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. AIM: 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. METHODS: 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. RESULTS: 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). CONCLUSION: When the spectrum effects and applicability rates were taken into account, LSM had lower performance results than FibroTest for the diagnosis of fibrosis stages.

Prognostic value of liver fibrosis biomarkers: a meta-analysis.

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.

Factors to improve the management of hepatitis C in drug users: an observational study in an addiction centre.

Barriers to management of HCV in injection drug users are related to patients, health providers, and facilities. In a primary care drug user's addiction centre we studied access to HCV standard of care before and after using an onsite total care concept provided by a multidisciplinary team and noninvasive liver fibrosis evaluation. A total of 586 patients were seen between 2002 and 2004. The majority, 417 patients, were HCV positive and of these patients 337 were tested positive for HCV RNA. In 2002, patients were sent to the hospital. with the Starting of 2003, patients were offered standard of care HCV management in the center by a team of general practitioners, a consultant hepatologist, psychiatrists, nurses, and a health counsellor. Liver fibrosis was assessed by a non invasive method. In 2002, 6 patients had liver fibrosis assessment at hospital facilities, 4 patients were assessed with liver biopsy and 2 patients with Fibrotest-Actitest. 2 patients were treated for HCV at hospital. In 2003 and 2004, 224 patients were assessed with Fibrotest-Actitest on site. Of these, 85 were treated for HCV. SVR was achieved in 43%. We conclude that the combination of an onsite multidisciplinary team with the use of a noninvasive assessment method led to improved management of HCV infection in drug users' primary care facility.

Biomarkers of liver injury for hepatitis clinical trials: a meta-analysis of longitudinal studies.

BACKGROUND: Liver biopsy and virological end points are standard references for assessing the effect of viral hepatitis treatments. We aimed to review evidence-based published data of biomarkers that have been validated as non-invasive alternatives to biopsy as end points for HBV and HCV infection trials. METHODS: Studies were included if there were at least two repeated estimates of fibrosis per patient using biomarkers with at least two studies and a control group. Meta-analysis of the percentage of fibrosis progression per year (pFPy) was performed. RESULTS: Two biomarkers were included, FibroTest and liver stiffness measurement (LSM; FibroScan. A total of 1,413 patients with chronic hepatitis C (11 populations) and 772 with chronic hepatitis B (6 populations) were analysed. In a comparison of HCV patients with controls, the FibroTest pFPy was -18% (95% confidence interval [CI] -23--14; P<0.001) in treated patients and the LSM pFPy was -15% (95% CI -28--1; P=0.01), both with differences according to virological responses. In HBV patients, there was a significant decrease of the pFPy only in patients with baseline advanced fibrosis (mean difference -5% [95% CI -10--0.1]; P=0.02). In patients with advanced fibrosis, stratified by virological response, there were similar differences between pFPy estimated either using FibroTest or biopsy, both in HCV and HBV infections. Repeated LSM in HBV patients had an early variability related to necroinflammatory activity. CONCLUSIONS: In patients with chronic hepatitis C and B, the treatment effect on fibrosis progression rate was similarly estimated using FibroTest or biopsy. The same concordance was observed for FibroScan but with a possible overestimation of the fibrosis regression during the first weeks of treatment.

An accurate definition of the status of inactive hepatitis B virus carrier by a combination of biomarkers (FibroTest-ActiTest) and viral load.

BACKGROUND: The combination of transaminases (ALT), biopsy, HBeAg and viral load have classically defined the inactive status of carriers of chronic hepatitis B. The use of FibroTest (FT) and ActiTest (AT), biomarkers of fibrosis and necroinflammatory activity, has been previously validated as alternatives to biopsy. We compared the 4-year prognostic value of combining FT-AT and viral load for a better definition of the inactive carrier status. METHODS AND FINDINGS: 1,300 consecutive CHB patients who had been prospectively followed since 2001 were pre-included. The main endpoint was the absence of liver-related complications, transplantation or death. We used the manufacturers' definitions of normal FT (< = 0.27), normal AT (< = 0.29) and 3 standard classes for viral load. The adjustment factors were age, sex, HBeAg, ethnic origin, alcohol consumption, HIV-Delta-HCV co-infections and treatment. RESULTS: 1,074 patients with baseline FT-AT and viral load were included: 41 years old, 47% African, 27% Asian, 26% Caucasian. At 4 years follow-up, 50 complications occurred (survival without complications 93.4%), 36 deaths occurred (survival 95.0%), including 27 related to HBV (survival 96.1%). The prognostic value of FT was higher than those of viral load or ALT when compared using area under the ROC curves [0.89 (95%CI 0.84-0.93) vs 0.64 (0.55-0.71) vs 0.53 (0.46-0.60) all P<0.001], survival curves and multivariate Cox model [regression coefficient 5.2 (3.5-6.9; P<0.001) vs 0.53 (0.15-0.92; P = 0.007) vs -0.001 (-0.003-0.000;P = 0.052)] respectively. A new definition of inactive carriers was proposed with an algorithm combining "zero" scores for FT-AT (F0 and A0) and viral load classes. This new algorithm provides a 100% negative predictive value for the prediction of liver related complications or death. Among the 275 patients with the classic definition of inactive carrier, 62 (23%) had fibrosis presumed with FT, and 3 died or had complications at 4 year. CONCLUSION: In patients with chronic hepatitis B, a combination of FibroTest-ActiTest and viral load testing accurately defined the prognosis and the inactive carrier status.

[Management of hepatitis C among drug user patients]. / Prise en charge de l'hépatite C chez les patients utilisateurs de drogues.

Opiate substitution treatments radically changed the care management of HCV among drug user patients. Thanks to substitution, it is possible to treat HCV among these patients even with ongoing drug abuse. Overall, in terms of response to treatment, observance, adverse side effects and premature interruptions of treatment, the results are comparable with those observed among non drug addict patients. It is advisable nevertheless to create specific conditions which favour this total care management. The non-invasive fibrosis tests largely improve access to care as compared to liver biopsy. A multidisciplinary team is essential in addressing the associated problem of addiction, hepatitis C and psychiatric co-morbidities. HCV prevails strongly among patients in centres for drug users. These structures are particularly adapted to the management of HCV with the assistance of multidisciplinary teams and access to the non-invasive tests.

A prospective analysis of the prognostic value of biomarkers (FibroTest) in patients with chronic hepatitis C.

BACKGROUND: FibroTest, a noninvasive method of measuring biomarkers of liver fibrosis, is an alternative to liver biopsy for determining the severity of chronic hepatitis C virus (HCV) infection. We compared the 5-year prognostic value of the FibroTest with biopsy staging for predicting cirrhosis decompensation and survival in patients with chronic HCV infection. METHODS: Fibrosis stage was assessed on the same day by FibroTest and biopsy in a prospective cohort of 537 patients. Disease classification at baseline was 157 patients with severe fibrosis (FibroTest >0.58), 137 with moderate fibrosis (FibroTest 0.32-0.58), and 243 with no or minimal fibrosis (FibroTest <0.32). RESULTS: In 64 untreated patients with severe fibrosis, survival without HCV complications was 73% [95% confidence interval (CI), 59%-086%; 13 complications], and survival without HCV-related death was 85% (95% CI, 73%-96%; 7 HCV deaths). Survival rates were higher in patients with moderate fibrosis, [99% (95% CI, 97%-100%; 1 complication; P <0.001) and 100% (no HCV death; P <0.001) for patients with and without HCV-related complications, respectively], and in patients with minimal fibrosis [100% (no complication; P <0.001 vs severe) and 100% (no HCV death; P <0.001 vs severe), respectively]. FibroTest was a better predictor than biopsy staging for HCV complications, with area under the ROC curves (AUROC) = 0.96 (95% CI, 0.93%-0.97%) vs 0.91 (95% CI, 0.85%-0.94%; P = 0.01), respectively; it was also a better predictor for HCV deaths: AUROC = 0.96 (95% CI, 0.93%-0.98%) vs 0.87 (95% CI, 0.70%-0.94%; P = 0.046), respectively. The prognostic value of FibroTest was still significant (P <0.001) in multivariate analyses after taking into account histology, treatment, alcohol consumption, and HIV coinfection. CONCLUSION: The FibroTest measurement of HCV biomarkers has a 5-year prognostic value similar to that of liver biopsy.

Natural history and predictors of disease severity in chronic hepatitis C.

Cirrhosis is the end-stage consequence of fibrosis progression in patients with chronic hepatitis C. The median time from infection to cirrhosis is 30 years, with a high inter-individual variability, which is now better understood. Several factors have been clearly shown to be associated with fibrosis progression rate: duration of infection, age, male gender, alcohol consumption, HIV co-infection and low CD4 count. Metabolic conditions such as steatosis, being overweight and diabetes are emerging as independent co-factors of fibrogenesis. The recent validation of non-invasive biomarkers should facilitate the study of fibrosis progression in large populations.

Progression of liver fibrosis in women infected with hepatitis C: long-term benefit of estrogen exposure.

Female sex is a protective factor for the progression of fibrosis in patients with chronic hepatitis C virus (HCV) infection. Experimental data suggest that estrogens may have an antifibrotic effect. The objective of this study was to evaluate the influence of past pregnancies, oral contraceptives, menopause, and hormone replacement therapy (HRT) on liver fibrosis progression in HCV-infected women. Four hundred seventy-two HCV-infected women received a survey regarding prior pregnancies, menopause, and the use of oral contraceptives and HRT. The impact of these variables on liver fibrosis and its progression were evaluated using multivariate analyses considering all putative confounding factors. Two hundred one women completed the survey (43% response rate), 157 of whom had an estimated date of HCV infection (96 postmenopausal women, 96 women with previous pregnancies, and 105 women with past use of oral contraceptives). Through multivariate analyses, the estimated rate of fibrosis progression was higher in postmenopausal (P < .05) and nulliparous (P = .02) women and was associated with greater histological activity (P < .001). Prior use of oral contraceptives had no significant influence. Among postmenopausal women, the estimated rate of fibrosis progression (+/-SE) was lower in women who received HRT compared with untreated patients (0.099 +/- 0.016 vs. 0.133 +/- 0.006 METAVIR units/yr; P = .02) and was similar to that of premenopausal women (0.093 +/- 0.012 METAVIR units/yr; P value not significant). In conclusion, menopause appears to be associated with accelerated liver fibrosis progression in HCV-infected women, an effect that may be prevented by HRT. Pregnancies may have a beneficial impact on the long-term progression of liver fibrosis.

Prospective analysis of discordant results between biochemical markers and biopsy in patients with chronic hepatitis C.

BACKGROUND: The FibroTest and ActiTest are noninvasive biochemical markers of liver injury that are intended for use as alternatives to liver biopsy in patients with chronic hepatitis C. The aims of this study were to assess the quality of biopsy and the prevalence of discordances between biopsy and markers, to identify factors associated with discordances, and to attribute these discordances to either markers or biopsy failure. METHODS: Fibrosis stage and activity grade were prospectively assessed on the same day by a liver biopsy and by markers. On the basis of risk factors for failure and independent endpoints, discordance was classified as being attributable to biopsy or to markers. RESULTS: Only 74 of 537 patients (14%) had a biopsy size > or =25 mm. Discordance was observed in 154 of 537 patients (29%), including 16% for fibrosis staging and 17% for activity grading. Steatosis, an inflammatory profile, and biopsy size were associated with discordance. Discordance was attributable to failure of markers in 13 patients (2.4%) and to biopsy failure in 97 (18%; P <0.001 vs Fibrotest and Actitest), and was nonattributable in 44 patients (8.2%). The most frequent failures attributable to markers were false negatives (1.3%) attributable to inflammation. The most frequent failures attributable to biopsy were false negatives of activity grading (10.1%) and of fibrosis staging (4.5%), both associated with smaller biopsy size and steatosis. False positives of fibrosis staging (3.5%) were associated with fragmented biopsies. CONCLUSION: In this series, the size of liver biopsy is adequate in only a minor proportion (approximately 14%) of patients with chronic hepatitis C. When biopsy and marker results are discordant, a reason can be identified in more than two-thirds of cases and, in those cases, biopsy failure is >7 times more common than diagnostic failure of markers.

Sarcoidosis and interferon therapy: report of five cases and review of the literature.

BACKGROUND: Sarcoidosis is a multi-system disease of unknown etiology. Interferons (IFN) have been implicated in its pathogenesis. The objective of this study was to examine the causal relationship between sarcoidosis and IFN therapy. METHODS: Patients admitted for sarcoidosis (n=60) were reviewed for a history of IFN therapy. In addition, all cases of sarcoidosis in a cohort of hepatitis C-infected patients treated with IFN-alpha (n=1159) were analyzed. RESULTS: Five patients with prior IFN-alpha therapy and sarcoidosis were identified; an additional 23 have been reported in the literature. The median age of the 28 reported patients was 50 years, 16 (57%) were female, and 16 (57%) had isolated cutaneous disease. The median time to diagnosis was 4 months (range 1-16 months) following the introduction of IFN. A remission was observed in all patients with adequate follow-up (n=27): 15 (53%) upon dosage reduction or IFN discontinuation, seven (25%) with systemic corticosteroids, three (11%) with topical treatment, and three (11%) despite ongoing IFN therapy. Relapse was observed in both of the patients rechallenged with IFN. CONCLUSIONS: There is a potential causal relationship between IFN therapy and sarcoidosis. In patients with sarcoidosis in the setting of IFN therapy, the majority respond to IFN withdrawal or dosage reduction; however, some require corticosteroid therapy.