Successful rescue therapy with tenofovir in a patient with hepatic decompensation and adefovir resistant HBV mutant

BACKGROUND: Prolonged adefovir therapy exposes to the emergence of adefovir resistant hepatitis B virus mutants. Initial reports of the rtN236T mutation showed preserved sensitivity to lamivudine; however, complex mutations are emerging with reduced susceptibility to lamivudine. CASE PRESENTATION: After 2 years of therapy, a cirrhotic patient developed the rtN236T and rtA181T adefovir resistant mutations. He had been previously treated with lamivudine, developed lamivudine resistance and, despite good compliance, had an incomplete response to adefovir. Adefovir resistance resulted in viral breakthrough with hepatitis flare-up and liver decompensation. Tenofovir had an excellent antiviral effect allowing sustained control of viral replication and reversal of hepatic failure. CONCLUSION: In patients with cirrhosis, adefovir resistance can lead to severe hepatitis. Tenofovir appears to be an effective treatment of adefovir resistant mutants. Incomplete control of viral replication with adefovir requires monitoring for viral resistance and should prompt a change in antiviral treatment

A position statement on NAFLD/NASH based on the EASL 2009 special conference

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are increasingly relevant public health issues owing to their close association with the worldwide epidemics of diabetes and obesity. NAFLD/NASH is one of the most common chronic liver diseases and increases the 5-year direct and indirect health care costs by an estimated 26% [1]. Although evidencebased clinical practice guidelines for this condition are badly needed, currently not enough evidence is available to formulate guidelines in an unbiased, responsible, and unequivocal way. This position statement summarizes the proceedings of the 2009 EASL Special Conference on NAFLD/NASH and proposes expert opinion for different aspects of the clinical care of these patients

From NAFLD in clinical practice to answers from guidelines

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A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH

BACKGROUND Management of nonalcoholic steatohepatitis (NASH) is an unmet clinical need. Lanifibranor is a pan-PPAR (peroxisome proliferator–activated receptor) agonist that modulates key metabolic, inflammatory, and fibrogenic pathways in the pathogenesis of NASH. METHODS In this phase 2b, double-blind, randomized, placebo-controlled trial, patients with noncirrhotic, highly active NASH were randomly assigned in a 1:1:1 ratio to receive 1200 mg or 800 mg of lanifibranor or placebo once daily for 24 weeks. The pri- mary end point was a decrease of at least 2 points in the SAF-A score (the activity part of the Steatosis, Activity, Fibrosis [SAF] scoring system that incorporates scores for ballooning and inflammation) without worsening of fibrosis; SAF-A scores range from 0 to 4, with higher scores indicating more-severe disease activity. Secondary end points included resolution of NASH and regression of fibrosis. RESULTS A total of 247 patients underwent randomization, of whom 103 (42%) had type 2 diabetes mellitus and 188 (76%) had significant (moderate) or advanced fibrosis. The percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher among those who received the 1200-mg dose, but not among those who received the 800-mg dose, of lanifibranor than among those who received placebo (1200-mg dose vs. placebo, 55% vs.33%, P = 0.007; 800-mg dose vs. placebo, 48% vs. 33%, P = 0.07). The results favored both the 1200-mg and 800-mg doses of lanifibranor over placebo for resolution of NASH without worsening of fibrosis (49% and 39%, respectively, vs. 22%), improvement in fibrosis stage of at least 1 without worsening of NASH (48% and 34%, respectively, vs. 29%), and resolution of NASH plus improvement in fibrosis stage of at least 1 (35% and 25%, respectively, vs. 9%). Liver enzyme levels decreased and the levels of the majority of lipid, inflammatory, and fibrosis biomarkers improved in the lanifibranor groups. The dropout rate for adverse events was less than 5% and was similar across the trial groups. Diarrhea, nausea, peripheral edema, anemia, and weight gain occurred more frequently with lanifibranor than with placebo. CONCLUSIONS In this phase 2b trial involving patients with active NASH, the percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher with the 1200-mg dose of lanifibranor than with placebo. These findings support further assessment of lanifibranor in phase 3 trials. (Funded by Inventiva Pharma; NATIVE ClinicalTrials.gov number, NCT0300807

NAFLD and liver transplantation: Current burden and expected challenges

Because of global epidemics of obesity and type 2 diabetes, the prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing both in Europe and the United States, becoming one of the most frequent causes of chronic liver disease and predictably, one of the leading causes of liver transplantation both for end-stage liver disease and hepatocellular carcinoma. For most transplant teams around the world this will raise many challenges in terms of preand post-transplant management. Here we review the multifaceted impact of NAFLD on liver transplantation and will discuss: (1) NAFLD as a frequent cause of cryptogenic cirrhosis, end-stage chronic liver disease, and hepatocellular carcinoma; (2) prevalence of NAFLD as an indication for liver transplantation both in Europe and the United States; (3) the impact of NAFLD on the donor pool; (4) the access of NAFLD patients to liver transplantation and their management on the waiting list in regard to metabolic, renal and vascular comorbidities; (5) the prevalence and consequences of post-transplant metabolic syndrome, recurrent and de novo NAFLD; (6) the alternative management and therapeutic options to improve the long-term outcomes with particular emphasis on the correction and control of metabolic comorbidities

Statins, antidiabetic medications and liver histology in patients with diabetes with non-alcoholic fatty liver disease

Background: Type-2 diabetes mellitus (T2DM) is a risk factor for progressive non-alcoholic fatty liver disease (NAFLD). Drugs commonly prescribed in patients with T2DM may affect liver histology by interfering with lipid metabolism and insulin resistance/secretion. Aim: We studied if statins or antidiabetic agents were associated with non-alcoholic steatohepatitis (NASH) and significant fibrosis (SF). Methods: We performed a cross-sectional study of 346 diabetics with biopsy-proven NAFLD. T2DM was defined as fasting glucose ≥7 mmol/L or glycated haemoglobin ≥6.5% and/or use of antidiabetics. NASH was defined according to the FLIP algorithm and SF as F2-4 Kleiner's stages. Results: 84% of patients were on antidiabetic therapy and 45% on statins. NASH and SF were present in 57% and 48% of patients. Statin-treated patients were older, more frequently male and with poorer glycaemic control despite more frequent antidiabetic therapy than those without statins; however, the prevalence of NASH (57%vs56%, p=0.868) and SF (48%vs48%, p=0.943) was not different between statin users and non-users. NASH was more common in patients on metformin or insulin than in those not treated with these drugs (60% vs47%, p=0.026; 68%vs53%, p=0.017). SF was more common in those treated with sulfonylureas (57% vs44%, p=0.030). Multivariate analyses confirmed that use of statins was independently and negatively associated with both NASH (OR (95% CI) 0.57 (0.32 to 1.01), p=0.055) and SF (OR (95% CI) 0.47 (0.26 to 0.84), p=0.011). Moreover, we found independent associations between insulin use and NASH (OR (95% CI) 2.24 (1.11 to 4.54), p=0.025) and sulfonylureas use and SF (OR (95% CI) 2.04 (1.11 to 3.74), p=0.022). Conclusions: Several medications used in patients with diabetes are differently associated with NAFLD histology. Statin use is negatively associated, while insulin and sulfonylureas are positively associated with NASH and SF. A wider use of statins may be warranted in this high-risk population

Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C

BACKGROUND: Recent studies strongly suggest that due to the limitations and risks of biopsy, as well as the improvement of the diagnostic accuracy of biochemical markers, liver biopsy should no longer be considered mandatory in patients with chronic hepatitis C. In 2001, FibroTest ActiTest (FT-AT), a panel of biochemical markers, was found to have high diagnostic value for fibrosis (FT range 0.00–1.00) and necroinflammatory histological activity (AT range 0.00–1.00). The aim was to summarize the diagnostic value of these tests from the scientific literature; to respond to frequently asked questions by performing original new analyses (including the range of diagnostic values, a comparison with other markers, the impact of genotype and viral load, and the diagnostic value in intermediate levels of injury); and to develop a system of conversion between the biochemical and biopsy estimates of liver injury. RESULTS: A total of 16 publications were identified. An integrated database was constructed using 1,570 individual data, to which applied analytical recommendations. The control group consisted of 300 prospectively studied blood donors. For the diagnosis of significant fibrosis by the METAVIR scoring system, the areas under the receiver operating characteristics curves (AUROC) ranged from 0.73 to 0.87. For the diagnosis of significant histological activity, the AUROCs ranged from 0.75 to 0.86. At a cut off of 0.31, the FT negative predictive value for excluding significant fibrosis (prevalence 0.31) was 91%. At a cut off of 0.36, the ActiTest negative predictive value for excluding significant necrosis (prevalence 0.41) was 85%. In three studies there was a direct comparison in the same patients of FT versus other biochemical markers, including hyaluronic acid, the Forns index, and the APRI index. All the comparisons favored FT (P < 0.05). There were no differences between the AUROCs of FT-AT according to genotype or viral load. The AUROCs of FT-AT for consecutive stages of fibrosis and grades of necrosis were the same for both moderate and extreme stages and grades. A conversion table was constructed between the continuous FT-AT values (0.00 to 1.00) and the expected semi-quantitative fibrosis stages (F0 to F4) and necrosis grades (A0 to A3). CONCLUSIONS: Based on these results, the use of the biochemical markers of liver fibrosis (FibroTest) and necrosis (ActiTest) can be recommended as an alternative to liver biopsy for the assessment of liver injury in patients with chronic hepatitis C. In clinical practice, liver biopsy should be recommended only as a second line test, i.e., in case of high risk of error of biochemical tests

Intra-individual fasting versus postprandial variation of biochemical markers of liver fibrosis (FibroTest) and activity (ActiTest)

BACKGROUND: Biochemical marker combinations, including α(2)-macroglobulin, haptoglobin, apolipoprotein A1, γ-glutamyl transpeptidase, and total bilirubin (all part of FibroTest) plus alanine aminotransferase (all part of ActiTest), are being developed as alternatives to liver biopsy in patients with chronic hepatitis C and other various chronic liver diseases. Considering this premise, the primary aim of this study was to assess the impact of meal intake on FibroTest and ActiTest results. Such studies are very important for patients, as many clinical errors have been related to the absence of baseline evidence. RESULTS: Intra-individual variation was assessed for the 6 above components and for FibroTest and ActiTest, by measuring time dependent variations before and one hour after a standard meal in 64 subjects. These consisted of 29 healthy volunteers and 35 patients with chronic liver diseases. Meal intake had no significant impact on any of the six components, or on FibroTest or ActiTest, as assessed by repeated measure variance analyses (ANOVA all p > 0.90); the Spearman correlation coefficient ranged from 0.87 (total bilirubin) to 0.995 (γ-glutamyl transpeptidase). The coefficients of variation (CV) between fasting and postprandial measurements fluctuated for the six components from 0.09 (apolipoprotein A1) to 0.14 (α(2)-macroglobulin), and from 0.09 for FibroTest to 0.13 for ActiTest. In contrast, meal intake had a significant impact on triglycerides (ANOVA p = 0.01, CV = 0.65) and glucose (ANOVA p = 0.04, CV = 0.31). As for the prediction of liver injury, the concordance between fasting and postprandial predicted histological stages and grades was almost perfect, both for FibroTest (kappa = 0.91, p < 0.001) and ActiTest (kappa = 0.80, p < 0.001). CONCLUSIONS: The intra-individual variation of biochemical markers was low, and it was shown that measurements of FibroTest, ActiTest and their components are not significantly modified by meal intake. This fact makes the screening of patients at risk of chronic liver diseases more convenient