Rami Moucari

Eradication of Hepatitis C Virus in Patients Successfully Treated for Chronic Hepatitis C

BACKGROUND & AIMS It is unclear whether hepatitis C virus (HCV) is eradicated in patients with chronic hepatitis C who achieved a sustained virologic response (SVR). METHODS In this long-term follow-up study, including chronic hepatitis C patients who achieved SVR after interferon-based therapy, the presence of residual HCV RNA in serum, liver, and peripheral blood mononuclear cells (PBMCs) was assessed, using transcription-mediated amplification (sensitivity, <9.6 IU/mL). The benefit of SVR on liver fibrosis was evaluated using the METAVIR score. RESULTS A total of 344 patients were followed up for a median duration of 3.27 years (range, 0.50-18 y; interquartile range [IQR], 1.68-5.35 y). A total of 114 patients had a posttreatment liver tissue (median, 0.50 y; range, 0-14 y; IQR, 0-3.5 y) and a total of 156 had one PBMC (median, 3.0 y; range, 0.50-18 y; IQR, 1.25-5.50 y). Serum HCV RNA remained undetectable (1300 samples), indicating that none of the patients had a relapse. HCV RNA was detectable in 2 of 114 (1.7%) liver specimens, and in none of 156 PBMC specimens. Histologic analysis of 126 paired pretreatment and posttreatment liver biopsy specimens (median, 0.50 y; range, 0-14 y; IQR, 0-3.5 y) showed that fibrosis stage was improved in 56%, stable in 32%, deteriorated in 12%. Regression of cirrhosis was observed in 9 of 14 (64%) (95% confidence interval, 39-89) patients. No cirrhosis decompensation was observed, and 3 patients developed hepatocellular carcinoma. CONCLUSIONS In this large cohort of chronic hepatitis C patients, SVR was durable up to 18 years after treatment cessation, in addition to fibrosis stability/improvement (88%) and cirrhosis regression (64%). The presence of residual HCV RNA was observed only in liver tissue (1.7%). This result strongly suggests that SVR may be considered to show eradication of HCV infection.

Hepatocellular carcinoma in budd-chiari syndrome: characteristics and risk factors

Background and aim: To analyse the characteristics of and the factors associated with the development of hepatocellular carcinoma (HCC) in patients with Budd–Chiari syndrome (BCS). Patients and methods: 97 consecutive patients with BCS and a follow-up ⩾1 year were evaluated retrospectively. Liver nodules were evaluated using serum α-fetoprotein (AFP) level and imaging features (CT/MRI). Biopsy of nodules was obtained when one of the following criteria was met: number ⩽3, diameter ⩾3 cm, heterogeneity, washout on portal venous phase, increase in size on surveillance, or increase in AFP level. Results: Patients were mainly Caucasian (69%) and female (66%). Mean age at the diagnosis of BCS was 35.8 (SE 1.2 years), and median follow-up 5 years (1–20 years). The inferior vena cava (IVC) was obstructed in 13 patients. Liver nodules were found in 43 patients, 11 of whom had HCC. Cumulative incidence of HCC during follow-up was 4%. Liver parenchyma adjacent to HCC showed cirrhosis in nine patients. HCC was associated with male sex (72.7% v 29.0%, p = 0.007); factor V Leiden (54.5% v 17.5%, p = 0.01); and IVC obstruction (81.8% v 4.6%, p<0.001). Increased levels of serum AFP were highly accurate in distinguishing HCC from benign nodules: PPV = 100% and NPV = 91% for a cut-off level of 15 ng/ml. Conclusion: The incidence of HCC in this large cohort of BCS patients was similar to that reported for other chronic liver diseases. IVC obstruction was a major predictor for HCC development. Serum AFP appears to have a higher utility for HCC screening in patients with BCS than with other liver diseases.

Evidence for a role of nonalcoholic steatohepatitis in hepatitis C: A prospective study

Although steatosis is a common histological feature in chronic hepatitis C (CHC), nonalcoholic steatohepatitis (NASH) has not yet been clearly characterized in this context. The aim of this prospective study was to investigate the characteristics of patients with NASH and CHC. Biopsies were categorized as CHC alone (178 patients [57%]), CHC+steatosis (94 patients [34%]), or CHC+NASH (24 patients [9%]). Patients with CHC+NASH had significantly higher AST and triglyceride levels and lower high‐density lipoprotein (HDL) cholesterol or total cholesterol than patients with CHC+steatosis. They also showed more steatosis and higher METAVIR fibrosis stage than patients with CHC+steatosis. Genotype 3 was more frequent in patients with CHC+NASH than in patients with CHC+steatosis or CHC alone. Patients with genotype 3 and CHC+NASH were similar to those with CHC+steatosis or with CHC alone according to triglyceride or the homeostasis model for assessment of insulin resistance (HOMA‐IR), whereas in patients with genotype 1, HOMA‐IR and triglyceride increased progressively from CHC alone to CHC+steatosis to CHC+NASH. In multivariate analysis, triglyceride and HDL cholesterol were predictors of NASH in patients with genotype 1, whereas in patients with genotype 3, AST was the only predictor. Conclusion: Patients with CHC+NASH differ significantly from those with CHC+steatosis and CHC alone in terms of biological and metabolic parameters and more advanced histopathological lesions. NASH is more common in genotype 3 and is not associated with metabolic dysfunctions in this subgroup, suggesting that NASH may complicate steatosis in CHC irrespective of etiology of steatosis. (HEPATOLOGY 2007.)

Influence of genotype on hepatitis B surface antigen kinetics in hepatitis B e antigen-negative patients treated with pegylated interferon-α2a

BACKGROUND The aim of this study was to assess the influence of hepatitis B virus (HBV) genotypes on serum hepatitis B surface antigen (HBsAg) kinetics in hepatitis B e antigen (HBeAg)-negative patients treated with pegylated interferon-alpha2a (PEG-IFN-alpha2a). METHODS A total of 48 consecutive patients treated with PEG-IFN-alpha2a (180 microg/week) for 48 weeks were assessed. HBV genotype was determined. Serum HBV DNA and HBsAg were assessed at baseline, during treatment (weeks 12, 24 and 48) and during follow-up (weeks 72 and 96). RESULTS The distribution of HBV genotype was A 27%, B 17%, C 12%, D 29% and E 14%. Mean +/-sd pretreatment serum HBV DNA (6.9 +/-1.5 log(10) copies/ml) was not different between genotypes and decreased under treatment in all genotypes without significant difference. Mean +/-sd pretreatment serum HBsAg (3.6 +/-0.6 log(10) IU/ml) was significantly different between genotypes (P<0.001), with high levels in genotypes A and C, intermediate levels in genotypes D and E, and low levels in genotype B (4.0 +/-0.3, 4.1 +/-0.7, 3.6 +/-0.5, 3.6 +/-0.4 and 2.7 +/-0.6 log(10) IU/ml, respectively). Serum HBsAg decreased under treatment in all genotypes with a significant difference. At the end of treatment, mean +/-sd decrease was high in genotype A, intermediate in genotypes B and D, and low in genotypes C and E (1.3 +/-1.6, 0.7 +/-0.7, 0.6 +/-0.9, 0.4 +/-1.0 and 0.4 +/-0.9 log(10) IU/ml, respectively; P<0.001). During follow-up, serum HBsAg continued to decrease in genotypes A and D, whereas rebound was observed in genotypes B, C and E. CONCLUSIONS HBV genotype has a strong influence on serum HBsAg kinetics during PEG-IFN-alpha2a therapy in HBeAg-negative patients.

Pregnancy in women with known and treated Budd–Chiari syndrome: Maternal and fetal outcomes

BACKGROUND/AIMS Budd-Chiari syndrome (BCS) mainly affects women of childbearing age. We aimed to clarify whether pregnancy, a thrombotic risk factor, should be contraindicated in patients with known and treated BCS. METHODS A retrospective study of pregnancy in women with known and treated BCS. RESULTS Sixteen women had 24 pregnancies. Nine women had undergone surgical or radiological treatment. Anticoagulation was administered during 17 pregnancies. Seven fetuses were lost before gestation week 20. Deliveries occurred between week 20 and 31 in two patients, week 32 and 36 in eleven and after week 37 in four. There was one stillbirth, but 16 infants did well. Factor II gene mutation was a factor for a poor outcome of pregnancies. In two patients, symptomatic thrombosis recurred during pregnancy or postpartum. All patients were alive after a median follow-up of 34 months after the last delivery. Bleeding at delivery, although non-lethal, occurred only on anticoagulation therapy. CONCLUSIONS When known and treated BCS is well controlled, pregnancy should not be contraindicated as maternal outcome, and fetal outcome beyond gestation week 20, are good. The risk-benefit ratio of anticoagulant therapy needs to be further clarified. Patients should be fully informed of the persistent risks of such pregnancies.

Sustained virological response is associated with clearance of hepatitis C virus RNA and a decrease in hepatitis C virus antibody

Background/Aim: Viral eradication in chronic hepatitis C patients with sustained virological response (SVR) after interferon (IFN) therapy remains controversial.

Prognostic Indices for Budd-Chiari Syndrome : Valid for Clinical Studies but Insufficient for Individual Management

OBJECTIVES:Several prognostic indices (PIs) have been proposed for Budd–Chiari syndrome (BCS). However, patient characteristics, causal factors, and treatment outcomes have changed since these indices have been elaborated. Validation in a recent patient population and comparison of predictive accuracy between these PIs are needed.METHODS:A database of 96 BCS patients diagnosed between 1995 and 2005 was analyzed. Cox survival models were fitted with time to liver transplantation or death, and time to invasive therapy or death, as end points. The prognostic values of known indices (Child–Pugh score, model for end-stage liver disease (MELD), Clichy, Rotterdam BCS index, New Clichy, and BCS–TIPS (transjugular intrahepatic portosystemic shunt)) at diagnosis were assessed in Cox models using the chi-square test, the Kent and O’Quigley measure of dependence, and unrestricted bootstrapping analysis. Areas under receiver operating characteristic curves (AUROCs) were built for both end points and compared.RESULTS:All prognostic indices, except BCS–TIPS, were significant predictors of transplant-free and invasive therapy–free survival. However, only 31 and 37% of the variance in transplant-free and invasive therapy–free survival, respectively, were explained by the best performing indices. For transplant-free survival, AUROCs were <0.70. For invasive therapy–free survival, AUROCs were <0.80. For both end points, BCS–TIPS PI AUROCs were significantly lower than others.CONCLUSIONS:Most PIs are valid for transplant-free survival and invasive therapy–free survival in a population of current BCS patients, and thus can be used for stratification in clinical studies. However, predictive accuracy is insufficient to be used for individual patients.

Bleeding in patients with Budd–Chiari syndrome

BACKGROUND & AIMS Anticoagulation therapy is recommended for patients with Budd-Chiari syndrome (BCS). This study aimed to assess the incidence, severity, and risk factors of major bleeding in patients with Budd-Chiari syndrome (BCS) receiving anticoagulation therapy. METHODS We evaluated 94 consecutive BCS patients. Major bleeding required hospitalization, and/or transfusion of ≥ 2 red blood cell units, and/or was located intracranially, and/or retroperitoneally, and/or was fatal. RESULTS After a median follow-up of 43 months, 47 patients had 92 major bleeding episodes (22.8 per 100 patient-years). Forty episodes were related to invasive therapy for BCS. The origin of the 52 other episodes was gastrointestinal in 26 (including 15 related to portal hypertension) and genital in 10; 26 were spontaneous and 26 provoked. Excess anticoagulation was identified in 13 (27%) out of 49 documented episodes. Bleeding was managed by interrupting or reducing anticoagulation in 34 episodes, surgery in 18, endoscopy in 12, and radiological intervention in 8. The presence of esophageal varices was an independent predictor of bleeding unrelated to invasive therapy for BCS. Bleeding contributed to death in five patients and caused neurological complications in two. These poor outcomes were associated with more severe liver disease at baseline. CONCLUSIONS Major bleeding is common in BCS patients receiving anticoagulation therapy. Invasive procedures and portal hypertension are major factors, while excess anticoagulation plays a secondary role. Baseline BCS severity is the main determinant of prognosis at bleeding. Reducing anticoagulation intensity during invasive therapy and reinforced prophylaxis for portal hypertension could improve the benefit-risk ratio of anticoagulation.

Pregnancy: a risk factor for Budd–Chiari syndrome?

In a review on Recent Advances in Clinical Practice for Budd–Chiari syndrome (BCS) ( Gut 2008; 57 :1469–78), one of us emphasised that multiple thrombotic risk factors are usually present in patients with BCS. Below, we report recent results from our group which further support this paradigm and extend it to the context of pregnancy. An influence of female sex hormones on the risk of BCS has long been recognised on the basis of an increased risk of BCS among oral contraceptive users.1 2 However, the role of pregnancy in causing BCS remains unclear: although 6–47% of reported BCS cases encountered in women presented in pregnancy or postpartum (hereafter referred to as time-related to pregnancy), other risk factors for thrombosis were not investigated.3–6 Among 96 patients with primary BCS diagnosed in our centre between January 1995 and December 2005, there were …

Influence of acetaminophen at therapeutic doses on surrogate markers of severity of acute viral hepatitis.

OBJECTIVES Data on the influence of acetaminophen intake on acute viral hepatitis is scarce, but it could play a role in the worsening of this disease. The aim of this study was to determine whether the intake of acetaminophen at therapeutic doses affects the severity of acute viral hepatitis. METHODS This was a prospective study concerning 37 consecutive patients hospitalized for acute viral hepatitis. Acetaminophen consumption and time since last intake were assessed by a questionnaire. Parameters of severity were studied in comparison to time related serum concentrations of acetaminophen. RESULTS Patients hospitalized for acute viral hepatitis (18 male, 19 female patients) had a mean age of 29.2 +/- 11.5 years. The causal virus was HAV (n=23), HBV (n=7) and other viruses (n=8). The mean cumulated dose of acetaminophen was 7.7 +/- 5.65 g. The daily dose did not exceed the therapeutic dosage and the mean was 1.95 +/- 0.81 g (1-3 g). Patients who received 7.5 g of acetaminophen or more had a lower prothrombin index 52.4 +/- 30.3% vs 74.2 +/- 17.2% (P=0.039), and a lower factor V 54.7 +/- 33.2% vs 83.3 +/- 19.6% (P=0.033). Prothrombin index and bilirubinemia were negatively correlated with time related plasma acetaminophen concentrations. CONCLUSIONS The use of acetaminophen at therapeutic doses was associated with greater alterations of surrogate markers of the severity of acute viral hepatitis especially hepatitis A. This was related to cumulated dosages and correlated to the time related acetaminophen plasma concentrations. Acetaminophen use should be interrupted when acute hepatitis is suspected.