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Hôpital-Camfrout, France

Marcellin P.,Service dHepatologie | Marcellin P.,French Institute of Health and Medical Research | Liang J.,U.S. National Institutes of Health
Antiviral Therapy | Year: 2010

In a treatment-naive patient with chronic hepatitis B, a personalized approach allows treatment efficacy to be optimized. Firstly, the selection of good candidates for therapy is crucial. Patients with chronic active hepatitis B - with relatively low levels of HBV DNA replication (<109 copies/ml) and relatively high alanine aminotransferase (ALT) levels - are good candidates for therapy. By contrast, patients with chronic hepatitis B in the immunotolerance phase, who have high levels of HBV DNA and persistently normal ALT levels, as well as inactive hepatitis B surface antigen (HBsAg) carriers with low HBV DNA and normal ALT levels do not have an indication for therapy as they are poor responders. Secondly, the characteristics of the patient (for example, gender, age, immune status, general health status and comorbidities), the characteristics of the liver disease (for example, presence of cirrhosis and liver function) and the characteristics of the virus (for example, genotype) are important when assessing the chance of success and when choosing the best therapeutic strategy (nucleoside/nucleotide analogue or interferon). Thirdly, during therapy, the antiviral effect - assessed by decrease in HBV DNA level - allows an individualized response-guided approach. In addition, quantification of HBsAg after 3-6 months of interferon therapy appears to be a good predictor of sustained virological response after treatment and HBsAg clearance. Continuing interferon therapy until week 48 is justified in patients with a significant decrease in HBsAg. Ongoing and future studies will provide useful information regarding prolonging interferon therapy beyond 48 weeks in some patients in order to increase efficacy, and also regarding the role of combination therapy with interferon and potent nucleoside/nucleotide analogues, such as entecavir or tenofovir disoproxil fumarate. ©2010 International Medical Press. Source

Serfaty L.,Service dHepatologie
Liver International | Year: 2014

Boceprevir and telaprevir-based triple therapy is now the standard of care for the treatment of genotype 1 patients. However, dual therapy with pegylated interferon and ribavirin should be discussed in treatment-naïve patients with good predictors of response. A recent published trial has shown in non-cirrhotic patients with low viral load at baseline, similar efficacy of a 24-week course of dual therapy vs a 24-week course of boceprevir-based triple therapy in case of rapid virological response. Accordingly, addition of protease inhibitor should be discussed after 4 weeks of dual therapy in this easy-to-treat population. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Source

Rolas L.,French Institute of Health and Medical Research | Makhezer N.,University of Science and Technology Houari Boumediene | Hadjoudj S.,University of Science and Technology Houari Boumediene | El-Benna J.,French Institute of Health and Medical Research | And 4 more authors.
Hepatology | Year: 2013

Cirrhosis is commonly accompanied by impaired defense functions of polymorphonuclear leucocytes (PMNs), increased patient susceptibility to infections, and hepatocellular carcinoma (HCC). PMN antimicrobial activity is dependent on a massive production of reactive oxygen species (ROS) by nicotinamide adenine dinucleotide phosphate (NADPH) 2 (NADPH oxidase 2; NOX2), termed respiratory burst (RB). Rapamycin, an antagonist of mammalian target of rapamycin (mTOR), may be used in the treatment of HCC and in transplanted patients. However, the effect of mTOR inhibition on the PMN RB of patients with cirrhosis remains unexplored and was studied here using the bacterial peptide, formyl-Met-Leu-Phe (fMLP), as an RB inducer. fMLP-induced RB of PMN from patients with decompensated alcoholic cirrhosis was strongly impaired (30%-35% of control) as a result of intracellular signaling alterations. Blocking mTOR activation (phospho-S2448-mTOR) with rapamycin further aggravated the RB defect. Rapamycin also inhibited the RB of healthy PMNs, which was associated with impaired phosphorylation of the NOX2 component, p47phox (phox: phagocyte oxidase), on its mitogen-activated protein kinase (MAPK) site (S345) as well as a preferential inhibition of p38-MAPK relative to p44/42-MAPK. However, rapamycin did not alter the fMLP-induced membrane association of p47phox and p38-MAPK in patients' PMNs, but did prevent their phosphorylation at the membranes. The mTOR contribution to fMLP-induced RB, phosphorylation of p47phox and p38-MAPK was further confirmed by mTOR knockdown in HL-60 cells. Finally, rapamycin impaired PMN bactericidal activity, but not bacterial uptake. Conclusion: mTOR significantly up-regulates the PMN RB of patients with cirrhosis by p38-MAPK activation. Consequently, mTOR inhibition by rapamycin dramatically aggravates their PMN RB defect, which may increase patients' susceptibility to infection. Thus, concerns should be raised about the use of rapamycin in immuno-depressed patients. © 2012 American Association for the Study of Liver Diseases. Source

Das V.,Service de Reanimation medicale | Boelle P.-Y.,University Pierre and Marie Curie | Galbois A.,Service de Reanimation medicale | Guidet B.,Service de Reanimation medicale | And 4 more authors.
Critical Care Medicine | Year: 2010

Objectives: To reassess the prognosis of patients with cirrhosis admitted to the intensive care unit. Design: A retrospective study in a medical intensive care unit in a teaching hospital in France. Patients: All patients with cirrhosis without previous liver transplantation admitted in the period from 2005 to 2008. InterventionS: None. MAIN Results: One hundred thirty-eight patients were studied. Survival rates in the intensive care unit, in hospital, and at 6 months were 59% (95% confidence interval, 50%-67%), 46% (95% confidence interval, 38%-54%), and 38% (95% confidence interval, 30%-47%), respectively. In-hospital survival rates for patients requiring vasopressors, mechanical ventilation, or renal replacement therapy were 20%, 33%, and 31%, respectively. On day 1, independent risk factors for inhospital mortality were age, albuminemia, international normalized ratio, and the Sequential Organ Failure Assessment score computed after discarding points for hematologic failure (modified Sequential Organ Failure Assessment score). Liver disease severity, assessed using a clinical classification, did not correlate with in-hospital mortality. In patients still alive after 3 days, the only prognostic factor was the modified Sequential Organ Failure Assessment score computed after 3 days. To predict inhospital mortality, the modified Sequential Organ Failure Assessment score on day 1 had a greater area under the receiver operating characteristic curve (0.84) than the Simplified Acute Physiology Score II (0.78), the Child-Pugh score (0.76), the model for end-stage liver disease score (0.77), or the model for end-stage liver disease-natremia score (0.75). The inhospital mortality rate with three or four nonhematologic organ failures on day 1 was not >70%, whereas it was 89% with three nonhematologic organ failures after 3 days spent in the intensive care unit. Conclusion: In-hospital survival rate of intensive care unit-admitted cirrhotic patients seemed acceptable, even in patients requiring life-sustaining treatments and/or with multiple organ failure on admission. The most important risk factor for in-hospital mortality was the severity of nonhematologic organ failure, as best assessed after 3 days. A trial of unrestricted intensive care for a few days could be proposed for select critically ill cirrhotic patients. Copyright © 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins. Source

Moreno C.,Free University of Colombia | Deltenre P.,Service dHepatologie | Pawlotsky J.-M.,French Institute of Health and Medical Research | Henrion J.,Service dHepato Gastroenterologie | And 3 more authors.
Journal of Hepatology | Year: 2010

Background & Aims: In hepatitis C virus genotype 1 (HCV-1) patients with a rapid viral decline within the first month of therapy, a 24-week course of pegylated interferon (PEG-IFN) alpha and ribavirin treatment has been claimed to be as efficient as the standard 48-week duration. Methods: We performed a meta-analysis of 7 randomized controlled trials comparing less than 48 weeks to 48 weeks PEG-IFN alpha/ribavirin treatment in 807 HCV-1 patients with rapid viral decline. Results: SVR was significantly less frequent with short treatment duration than with 48 weeks of therapy, with a mean difference of -13.6% (95% CI: -22.8% to -4.4%, p = 0.004). This difference was related to a higher relapse rate (mean difference: 9.9%, 95% CI: 4.1-15.7%, p < 0.001). In a sensitivity analysis restricted to studies using only a weight-based ribavirin regimen, shorter therapy was also less efficient. In the subgroup of patients with undetectable HCV-RNA at week 4 and a low baseline HCV-RNA level (≤400,000 IU/ml), there was no significant difference in SVR rates between 24 and 48 weeks of treatment (mean difference: -3.10%, 95% CI: -8.6% to 2.4%, NS). Conclusions: In HCV-1 patients with a rapid virological response, 24 weeks of combination therapy with PEG-IFN alpha and ribavirin should be considered only in subjects with low baseline viral load. However, the optimal cut-off defining low baseline viral load and the impact of the presence of other factors capable of altering treatment response, remain subject to debate. © 2009 European Association for the Study of the Liver. Source

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