Risk Of Liver Fibrosis Progression Research Articles

Management of chronic hepatitis B patients in immunetolerant phase: what latest guidelines recommend.

The natural history of chronic hepatitis B (CHB) is complex and may run through different immune phases that may overlap. In particulars, the immune-tolerant phase is the most interesting and not as well understood as we thought. The concept of true immune tolerance have been under challenged from immunology points of view. The major international guidelines have not yet reached a consensus on the definition of the immune-tolerant phase. While positive hepatitis B e antigen (HBeAg), high serum hepatitis B virus (HBV) DNA and normal serum alanine aminotransferase (ALT) levels are the three key features of this phase, some guidelines also put age into consideration. A new nomenclature, Phase 1 or HBeAg-positive chronic HBV infection, is given by the latest European Association for the Study of the Liver (EASL) published in April 2017. While current guidelines advise against starting antiviral treatment for immune-tolerant CHB patients, some new data suggest treating such patients may reduce the risk of liver fibrosis progression and hepatocellular carcinoma.

Aspirin may reduce liver fibrosis progression: Evidence from a multicenter retrospective study of recurrent hepatitis C after liver transplantation

There is evidence for an association between thrombosis in the hepatic microcirculation and liver fibrosis. The aim of this study was to evaluate the role of daily low-dose aspirin (75 or 100mg, given for prevention of hepatic artery thrombosis) in fibrosis progression to ≥ F2 fibrosis score in liver-transplant recipients with recurrent hepatitis C virus (HCV). All HCV-positive patients who had undergone liver transplantation (LT) between 2000 and 2010 were included. Exclusion criteria were negative HCV RNA, previous LT or death within a year of LT. Liver fibrosis was assessed by histological evaluation. Data were censored at the date of the last histological evaluation before starting anti HCV therapy. Progression to fibrosis F ≥ 2 was analyzed with a multistate model with time-dependent covariables. One hundred and eighty-eight patients were included. In univariate analysis, older recipient and donor age, male donor gender, activity score ≥ A2 after LT, number of steroid boluses and aspirin intake (HR: 0.75 [0.57-0.97]; P=0.03) influenced the risk of progression to fibrosis ≥ F2. In multivariate analysis, adjusted on site, older donor age, male donor gender, activity score ≥ A2 and number of steroids boluses, remained independent predictors of fibrosis progression, while younger recipient age and aspirin intake (HR: 0.65 [0.47-0.91]; P=0.01) were associated with a slower fibrosis progression. Low-dose aspirin treatment might be associated with a lower risk of liver fibrosis progression in patients with HCV recurrence after LT.

Commentary: coincidental metabolic syndrome increases the risk of liver fibrosis progression in patients with chronic hepatitis B.

In thiswell-designed and important study, the authors describepotential progression of liver fibrosis in a large cohort oftreatment-na€ive chronic hepatitis B South East Asianinfected individuals. A cohort of the group developedliver fibrosis progression, defined as liver stiffness mea-surement (LSM) ≥30% from baseline.Within this cohort, a number of factors were associ-ated with LSM progression, independent of viral loadand hepatitis activity: coincidental metabolic syndrome(presence of metabolic syndrome at follow-up, not seenat baseline), central obesity and low HDL cholesterol.The significance levels for central obesity and low HDLcholesterol were modest (P values 0.05 and 0.04 respec-tively); however, coincidental metabolic syndrome wasmore impressive (P value 0.015, odds ratio 1.1–3.5).It should be noted, however, that the mean follow-upperiod was 44 7 months, a relatively short period inthe development and progression of fibrosis. The authorsalso describe and concede the difficulties in performingtransient elastography (TE) in an obese population. Per-haps what is of most interest is within the cohort ofindividuals who develop LSM progression, with coinci-dental metabolic syndrome development. The authors donot describe the potential for the development ofnon-alcoholic steatohepatitis (NASH) within this group,nor indeed the impact this may have on LSM.By definition, development of coincidental metabolicsyndrome is a risk factor for the development of NASH.Although TE is validated in both viral hepatitis andNASH,

Commentary: coincidental metabolic syndrome increases the risk of liver fibrosis progression in patients with chronic hepatitis B - authors' reply.

Commentary: coincidental metabolic syndrome increases the risk of liver fibrosis progression in patients with chronic hepatitis B - authors' reply.

Coincidental metabolic syndrome increases the risk of liver fibrosis progression in patients with chronic hepatitis B – a prospective cohort study with paired transient elastography examinations

Metabolic syndrome is a known risk factor of cirrhosis in chronic hepatitis B (CHB). To investigate the effects of coincidental metabolic syndrome on liver fibrosis progression in treatment-naïve CHB patients. A total of 1466 CHB patients underwent liver stiffness measurement (LSM) by transient elastography in 2006-2008; 663 patients remained treatment-naïve and had second LSM in 2010-2012. Liver fibrosis progression was defined as an increase in LSM ≥30% at the second assessment. The impact of coincidental metabolic syndrome and its factors on liver fibrosis progression were evaluated after adjustment for viral load and hepatitis activity. At baseline, the mean age was 43±12years, 55% were males, serum alanine aminotransferase (ALT) was 44±40IU/L, HBV DNA was 4.0±2.0logIU/mL and LSM was 6.3±3.6kPa. Metabolic syndrome was diagnosed in 80 (12%) and 142 (21%) patients at baseline and follow-up visit, respectively; 84 (13%) and 22 (3%) patients had coincidental and resolved metabolic syndrome respectively. After an interval of 44±7months, 107 (16%) patients developed liver fibrosis progression. Coincidental metabolic syndrome [adjusted odds ratio (aOR) 2.0, 95% confidence interval (CI) 1.1-3.5, P=0.015], central obesity (aOR 2.0, 95% CI 1.0-4.1, P=0.05) and low level of high-density lipoprotein cholesterol (aOR 1.9, 95% CI 1.0-3.7, P=0.04) were associated with liver fibrosis progression independent of change in viral load and ALT level. The effects of coincidental metabolic syndrome were most apparent in the immune-tolerant phase. Coincidental metabolic syndrome increases the risk of liver fibrosis progression in patients with chronic hepatitis B infection, independent of viral load and hepatitis activity.

Liver fibrosis progression in chronic hepatitis B patients positive for hepatitis B e antigen: A prospective cohort study with paired transient elastography examination

Chronic hepatitis B patients in immune-reactive hepatitis B e antigen (HBeAg)-positive phase may have more rapid progression than those in immune-tolerant phase. We aimed to evaluate the risk of liver fibrosis progression in HBeAg-positive patients at different phases. Two hundred forty-seven HBeAg-positive patients without advanced fibrosis at baseline underwent liver stiffness measurement (LSM) by transient elastography in 2006-2008 and again in 2010-2012. Liver fibrosis progression was defined as increase in LSM by 30% or more to levels suggestive of advanced fibrosis at the second assessment. At baseline, the mean age was 38 ± 11 years, 58% were males, alanine aminotransferase (ALT) was 65 ± 52 IU/L, hepatitis B virus DNA was 4.2 ± 1.2 log IU/mL, and LSM was 6.3 ± 2.1 kPa. At an interval of 42 ± 6 months, 13 patients (5.2%) developed liver fibrosis progression, and 106 patients (42.9%) required antiviral therapy. None of the clinical parameters (e.g., gender, age, ALT, hepatitis B virus DNA, hepatitis B surface antigen level, etc.) was associated with liver fibrosis progression. Among 74 and 137 patients in immune-tolerant and immune-reactive phase, 4.1% and 6.6% had liver fibrosis progression, and 12.2% and 67.2% received antiviral therapy respectively (P = 0.45 and P < 0.001). Immune-tolerant patients with low-normal (< 0.5× upper limit of normal) or high-normal ALT (0.5-1× upper limit of normal) also had similar risk of liver fibrosis progression (5.7% vs. 2.6%; P = 0.49). Liver fibrosis progression is uncommon in HBeAg-positive patients. Patients in immune-reactive phase treated with antiviral therapy did not have increased risk of liver fibrosis progression.

346 THE HAZARDS OF TRANSAMINASE ALT VALUE AS A MARKER OF LIVER FIBROSIS PROGRESSION: A GLOBAL ASSESSMENT IN PATIENTS USING VALIDATED BIOMARKER FIBROTEST®

Background: It is well known for Hepatologists, but not for nonspecialists and patients, that advanced fibrosis can occur in patients with chronic liver disease despite normal serum ALT. Validated non-invasive biomarkers, such as FibroTest (FT) which does not include ALT in its combination, now permit estimate of liver fibrosis progression (LFP) on very large populations. Aim: To assess the risk of LFP among patients with normal ALT. Patients and Methods: Consecutive and interpretable FT and ALT, prospectively measured between 2002 and 2009 on fresh samples, were analyzed. LFP was estimated using hazard rate (H) from birth to first bridging fibrosis (F2F3F4) and to cirrhosis (F4) presumed by FT (0.48 and 0.74 threshold respectively), age being the time exposure as previously published for biopsy (J Hepatol 2003). Comparisons of LFP according to ALT values used hazard-ratio (HR), Log-rank test and proportional hazard regression analysis to take into account gender, residency continent and HIV-coinfection). Sensitivity analysis used shorter time exposure, and FT adjustments on age and gender to prevent co-linearity effects.

History of Hepatitis B or C Does Not Affect Safety and Efficacy of Deferasirox (Exjade®) in Thalassemia Major Patients: Sub-Analysis of the EPIC Trial.

Abstract 5107 BackgroundMany thalassemia major (TM) patients have concomitant hepatitis B and/or C infection and data suggest that iron overload in these patients increases the risk of liver fibrosis progression. Deferasirox (Exjade®), which has demonstrated efficacy and safety in reducing iron overload in a variety of transfusion dependent anemias, has been uncommonly associated with elevations of transaminases suggestive of hepatitis (0.3%). However, whether patients' viral hepatitis status affects the overall and liver safety of deferasirox remains unclear. The prospective, multicenter EPIC study of deferasirox enrolled some patients with a history of hepatitis B or C. This sub-analysis of EPIC assesses the overall and liver safety of deferasirox over 1 year of treatment in TM patients with and without a history of hepatitis B or C. MethodsPatients aged ≥2 years with transfusion-dependent TM and serum ferritin (SF) levels of ≥1000 ng/mL, or <1000 ng/mL with a history of multiple transfusions (>20 transfusions or >100 mL/kg of red blood cells), or R2 MRI-confirmed liver iron concentration of >2 mg Fe/g dry weight were enrolled. Deferasirox starting dose was 10–30 mg/kg/day depending on the frequency of blood transfusions. Protocol-specified dose adjustments of 5–10 mg/kg/day (range 0–40) were performed every 3 months based on SF trends and safety markers. Safety was evaluated through continuous monitoring and recording of adverse events (AEs), as well as monthly blood chemistry assessments including alanine aminotransferase (ALT) and aspartate aminotransferase (AST). ResultsOf 937 enrolled patients with TM, 258 (27.5%) had a history of hepatitis B or C and 679 (72.5%) did not. Compared with patients with no viral hepatitis, patients with a history of hepatitis B or C were older (mean age 26.5 ± 9.9 vs 15.3 ± 9.5 years), more commonly splenectomized (50.4 vs 29.9%), received more transfusions (195 vs 188 mL/kg) and were chelated for longer prior to study entry (15.9 ± 10.5 vs 8.7 ± 7.4 years). In total, 212 (82.2%) and 636 (93.7%) of patients with and without viral hepatitis, respectively completed the study. The most common drug-related AEs were gastrointestinal disorders, such as diarrhea (14.7% vs 6.2%, respectively; P<0.0001), abdominal pain (7.4% vs 4.7%, respectively; P=0.110) and nausea (5.0% vs 3.5%, respectively; P=0.291), as well as skin rash (10.5% vs 13.5%, respectively; P=0.205). Three patients (1.2%) with hepatitis had two consecutive increases in ALT 10 x the upper limit of normal (ULN); all three patients had elevated baseline levels (mean 95.6 U/L). Two patients (0.3%) without hepatitis had similar increases, one of whom had elevated baseline levels (225 U/L). Mean ALT and AST levels decreased during deferasirox treatment in both groups; decreases were significant in patients without hepatitis (Figure). 12 (4.7%) and 25 (3.7%) patients with and without a history of viral hepatitis, respectively had serum creatinine >33% above baseline and ULN on two consecutive visits [Display omitted] Overall median SF decreased from baseline (3157 ng/mL) by 129 ng/mL after 1 year (P=0.0007) at a mean actual dose of 24.2 ± 5.6 mg/kg/day and mean transfusional iron intake of 0.43 ± 0.2 mg/kg/day. Reduction in SF was similar in patients with or without a history of viral hepatitis (–113 and –148 ng/mL, respectively). ConclusionsThis sub-analysis of EPIC demonstrates that once-daily deferasirox is well tolerated in patients with TM irrespective of viral hepatitis history with no significant difference in the incidence of abdominal pain, nausea and skin rash. Increases in ALT >10 x ULN were very low and occurred at a comparable frequency in patients with and without viral hepatitis. Mean liver transaminases, although higher at baseline in patients with a history of hepatitis B or C compared to those without, decreased in both groups, suggesting an overall improvement in liver function with deferasirox treatment. Reduction in SF was similar in both patient groups. Further confirmatory data are required to evaluate the effect of hepatitis viral load on the response to deferasirox therapy. DisclosuresCappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Chan:Novartis: Honoraria, Research Funding. Lin:Taiwan Pediatric Onclogy Group (TPOG): Consultancy; Novartis: Honoraria, Speakers Bureau. Sutcharitchan:Novartis: Honoraria, Research Funding; Novo Nordisk: Honoraria. Taher:Novartis: Honoraria, Research Funding. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Roubert:Novartis Pharma AG: Employment. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees.