A phase 2, randomized, double‐blind, placebo‐controlled study of GS‐9450 in subjects with nonalcoholic steatohepatitis

In nonalcoholic steatohepatitis (NASH), the extent of hepatocyte apoptosis correlates with disease severity. Reducing hepatocyte apoptosis with the selective caspase inhibitor GS‐9450 has a potential for altering the course of the liver disease. In this phase 2, double‐blind study, 124 subjects with biopsy‐proven NASH were randomized to once‐daily placebo or 1, 5, 10, or 40 mg GS‐9450 for 4 weeks. Absolute and percent changes from baseline in ALT levels, AST levels, and caspase‐3–cleaved cytokeratin (CK)‐18 fragments at week 4 were assessed by an analysis of covariance model with adjustment for baseline values. In the 40‐mg group, mean (SD) ALT decreased by 47 (43) U/L from baseline to week 4 ( P < 0.0001 versus placebo), and the proportion of subjects with normal ALT increased from 0% to 35% at week 4. In the 40‐mg group, mean AST decreased by 13 U/L from baseline (not significant), and the proportion with normal AST increased from 20% at baseline to 48% at week 4. By week 4, mean CK‐18 fragment levels had decreased to 393 (723) U/L in the GS‐9450 10‐mg group and 125 (212) U/L in the 40‐mg group, but these reductions were not statistically significant. No serious adverse events were reported during treatment, and the percentage of subjects with at least one treatment‐emergent grade 3 or 4 laboratory abnormality ranged from 11.5% to 17% across the GS‐9450 treatment groups versus 35% in the placebo group. Conclusion : GS‐9450 treatment induced significant reductions in ALT levels in NASH patients. Reductions in CK‐18 fragment levels also occurred, although they were not statistically significant. At appropriate therapeutic indices, selective caspase inhibitors may be a promising treatment option in patients with NASH. (H epatology 2012)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90118/1/24747_ftp.pd

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

L'intégration de l'APC dans les programmes de l'enseignement technologique et de formation professionnelle : un défi pour les principaux acteurs, limites et conditions

Les réformes récentes apportées dans de nombreux systêmes éducatifs proposent d'inscrire le processus d'enseignement-apprentissage dans l'approche par les compétences (l'APC). Deux raisons sont invoquées principalement : celles de l'efficacité et de l'équité. Il s'agit d'une part que les élêves acquiêrent réellement les compétences indispensables pour devenir des citoyens responsables et actifs et d'autre part, que le « socle » de compétences soit maà®trisé par tous les élêves, y compris ceux qui rencontrent le plus de difficultés. Au Maroc, la réforme des programmes selon l'approche par les compétences, amorcée en 2003, est actuellement bien enclenchée et le Ministêre de l'Education Nationale du Maroc espêre voir les résultats attendus dans les prochaines années. Plus spécifiquement, les programmes de l'enseignement technologique ont été conçus afin d'assurer l'adéquation entre la formation technologique et les besoins qualitatifs et quantitatifs de la nation dans le domaine de l'industrie, en préparant les élêves à  la poursuite des études scientifiques et techniques. Il s'agit donc d'un cadre o๠une réforme importante a été réalisée, mais cette réforme se trouve encore à  mi-parcours puisque tous les programmes n'ont pas encore été révisés et les enseignants n'ont pas été tous formés. Au Vietnam, ces derniêres années, le systême d'éducation a connu des avancées notables. Les bases matérielles, le corps enseignant et les programmes de formation ont été renouvelés contribuant ainsi à  améliorer la qualité du systême. Malgré ces progrês, la formation professionnelle réalisée n'est pas toujours conforme aux besoins et aux attentes des bénéficiaires et du marché du travail. C'est donc cet état de fait qui nous a amené à  questionner, à  partir d'entretiens avec les principaux acteurs concernés, la suite pédagogique de ces réformes

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

Southern Europe as an example of interaction between various environmental factors: a systematic review of the epidemiologic evidence

Hepatitis B virus (HBV), hepatitis C virus (HCV) and alcohol consumption are major causes of hepatocellular carcinoma (HCC) worldwide. We performed a systematic review of epidemiologic studies carried out on HCC aetiology in Southern Europe, an area with an intermediate– high prevalence of these agents as well as of putative risk factors such as tobacco smoking, diabetes and obesity. To retrieve the articles, we performed a Medline search for titles and abstracts of articles. After the Medline search, we reviewed the papers and reference lists to identify additional articles. A synergism between HCV infection and HBV infection, overt (hepatitis B virus antigen (HbsAg) positivity) or occult (HBsAg negativity with presence of HBV DNA in liver or serum), is suggested by the results of some studies. The pattern of the risk for HCC due to alcohol intake shows a continuous dose–effect curve without a definite threshold, although most studies found that HCC risk increased only for alcohol consumption above 40–60 g of ethanol per day. Some evidence supports a positive interaction of alcohol intake probably with HCV infection and possibly with HBV infection. A few studies found that coffee has a protective effect on HCC risk due to various risk factors. Some data also support a role of tobacco smoking, diabetes and obesity as single agents or preferably cofactors in causing HCC. In countries with a relatively high alcohol consumption and intermediate levels of HCV and HBV infections (1–3% of population infected by each virus), such as Mediterranean countries, the three main risk factors together account for about 85% of the total HCC cases, leaving little space to other known risk factors, such as haemochromatosis, and to new, still unrecognised, factors as independent causes of HCC. Oncogene (2006) 25, 3756–3770. doi:10.1038/sj.onc.120955

Evolving Role for Pharmacotherapy in NAFLD/NASH

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent, dynamic disease that occurs across the age spectrum and can lead to cirrhosis and hepatocellular carcinoma. There are currently no US Food and Drug Administration (FDA) approved treatments for NAFLD; however, this is a field of active research. This review summarizes emerging pharmacotherapies for the treatment of adult and pediatric NAFLD. Investigated pharmacotherapies predominantly target bile acid signaling, insulin resistance, and lipid handling within the liver. Three drugs have gone on to phase III trials for which results are available. Of those, obeticholic acid is the single agent that demonstrates promise according to the interim analyses of the REGENERATE trial. Obeticholic acid showed reduction of fibrosis in adults with nonalcoholic steatohepatitis (NASH) taking 25 mg daily for 18 months (n = 931, reduction in fibrosis in 25% vs. 12% placebo, P \u3c 0.01). Ongoing phase III trials include REGENERATE and MAESTRO-NASH, which investigates thyroid hormone receptor-β agonist MGL-3196. Outcomes of promising phase II trials in adults with NASH are also available and those have investigated agents, including the fibroblast growth factor (FGF)19 analogue NGM282, the GLP1 agonist liraglutide, the FGF21 analogue Pegbelfermin, the sodium glucose co-transporter 2 inhibitor Empagliflozin, the ketohexokinase inhibitor PF-06835919, the acetyl-coenzyme A carboxylase inhibitor GS-0976, and the chemokine receptor antagonist Cenicriviroc. Completed and ongoing clinical trials emphasize the need for a more nuanced understanding of the phenotypes of subgroups within NAFLD that may respond to an individualized approach to pharmacotherapy

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