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.
Hezode C.,University Paris Est Creteil |
Asselah T.,University Paris Diderot |
Reddy K.R.,University of Pennsylvania |
Hassanein T.,Southern California Liver Centers and Southern California Research Center |
And 10 more authors.
The Lancet | Year: 2015
Summary Background Hepatitis C virus (HCV) genotype 4 accounts for about 13% of global HCV infections. Because interferon-containing treatments for genotype 4 infection have low efficacy and poor tolerability, an unmet need exists for effective all-oral regimens. We examined the efficacy and safety of an all-oral interferon-free regimen of ombitasvir, an NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (ombitasvir plus paritaprevir plus ritonavir), given with or without ribavirin. Methods In this multicentre ongoing phase 2b, randomised, open-label combination trial (PEARL-I), patients were recruited from academic, public, and private hospitals and clinics in France, Hungary, Italy, Poland, Romania, Spain, Turkey, and the USA. Eligible participants were aged 18-70 years with non-cirrhotic, chronic HCV genotype 4 infection (documented ≥6 months before screening) and plasma HCV RNA levels higher than 10 000 IU/mL. Previously untreated (treatment-naive) patients were randomly assigned (1:1) by computer-generated randomisation lists to receive once-daily ombitasvir (25 mg) plus paritaprevir (150 mg) plus ritonavir (100 mg) with or without weight-based ribavirin for 12 weeks. Previously treated (treatment-experienced) patients who had received pegylated interferon plus ribavirin all received the ribavirin-containing regimen. The primary endpoint was a sustained virological response (HCV RNA <25 IU/mL) 12 weeks after the end of treatment (SVR12). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01685203. Findings Between Aug 14, 2012, and Nov 19, 2013, 467 patients with HCV infection were screened, of whom 174 were infected with genotype 4. 135 patients were randomly assigned to treatment and received at least one dose of study medication; 86 patients were treatment-naive, of whom 44 received ombitasvir plus paritaprevir plus ritonavir and 42 received ombitasvir plus paritaprevir plus ritonavir with ribavirin, and 49 treatment-experienced patients received the ribavirin-containing regimen. In previously untreated patients, SVR12 rates were 100% (42/42 [95% CI 91·6-100]) in the ribavirin-containing regimen and 90·9% (40/44 [95% CI 78·3-97·5]) in the ribavirin-free regimen. No statistically significant differences in SVR12 rates were noted between the treatment-naive groups (mean difference -9·16% [95% CI -19·61 to 1·29]; p=0·086). All treatment-experienced patients achieved SVR12 (49/49; 100% [95% CI 92·7-100]). In the ribavirin-free group, two (5%) of 42 treatment-naive patients had virological relapse, and one (2%) of 44 had virological breakthrough; no virological failures were recorded in the ribavirin-containing regimen. The most common adverse event was headache (14 [29%] of 49 treatment-experienced patients and 14 [33%] of 42 treatment-naive patients). No adverse event-related discontinuations or dose interruptions of study medications, including ribavirin, were noted, and only four patients (4%) of 91 receiving ribavirin required dose modification for haemoglobin less than 100 g/L or anaemia. Interpretation An interferon-free regimen of ombitasvir plus paritaprevir plus ritonavir with or without ribavirin achieved high sustained virological response rates at 12 weeks after the end of treatment and was generally well tolerated, with low rates of anaemia and treatment discontinuation in non-cirrhotic previously untreated and previously treated patients with HCV genotype 4 infection. Funding AbbVie. © 2015 Elsevier Ltd.
Afdhal N.,Beth Israel Deaconess Medical Center |
Zeuzem S.,Goethe University Frankfurt |
Kwo P.,Indiana University |
Chojkier M.,University of California at San Diego |
And 20 more authors.
New England Journal of Medicine | Year: 2014
BACKGROUND: In phase 2 studies, treatment with the all-oral combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir resulted in high rates of sustained virologic response among previously untreated patients with hepatitis C virus (HCV) genotype 1 infection. METHODS: We conducted a phase 3, open-label study involving previously untreated patients with chronic HCV genotype 1 infection. Patients were randomly assigned in a 1:1:1:1 ratio to receive ledipasvir and sofosbuvir in a fixed-dose combination tablet once daily for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis, 12% were black, and 67% had HCV genotype 1a infection. The rates of sustained virologic response were 99% (95% confidence interval [CI], 96 to 100) in the group that received 12 weeks of ledipasvir-sofosbuvir; 97% (95% CI, 94 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir plus ribavirin; 98% (95% CI, 95 to 99) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 97 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir plus ribavirin. No patient in either 12-week group discontinued ledipasvir- sofosbuvir owing to an adverse event. The most common adverse events were fatigue, headache, insomnia, and nausea. CONCLUSIONS: Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection. (Funded by Gilead Sciences; ION-1 ClinicalTrials.gov number NCT01701401.) Copyright © 2014 Massachusetts Medical Society.
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.
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.
Smalberg J.H.,Rotterdam University |
Arends L.R.,Erasmus University Rotterdam |
Arends L.R.,Erasmus Medical Center |
Valla D.C.,Service dHepatologie |
And 3 more authors.
Blood | Year: 2012
Myeloproliferative neoplasms (MPNs) are the most common cause of Budd-Chiari syndrome (BCS) and nonmalignant, non-cirrhotic portal vein thrombosis (PVT). In this meta-analysis, we determined the prevalence of MPNs and their subtypes as well as JAK2V617F and its diagnostic role in these uncommon disorders. MEDLINE and EMBASE databases were searched. Prevalence of MPNs, JAK2V617F, and MPN subtypes were calculated using a random-effects model. A total of 1062 BCS and 855 PVT patients were included. In BCS, mean prevalence of MPNs and JAK2V617F was 40.9% (95% CI, 32.9%-49.5%) and 41.1% (95% CI, 32.3%-50.6%), respectively. In PVT, mean prevalence of MPNs and JAK2V617F was 31.5% (95% CI, 25.1%-38.8%) and 27.7% (95% CI, 20.8%-35.8%), respectively. JAK2V617F and MPNs were more frequent in BCS compared with PVT (P = .03 and P = .09, respectively). Polycythemia vera was more prevalent in BCS than in PVT (P = .001). JAK2V617F screening in splanchnic vein thrombosis (SVT) patients without typical hematologic MPN features identified MPN in 17.1% and 15.4% of screened BCS and PVT patients, respectively. These results demonstrate a high prevalence of MPNs and JAK2V617F in SVT patients and show differences in underlying etiology between these disorders. Furthermore, these results validate routine inclusion of JAK2V617F in the diagnostic workup of SVT patients. © 2012 by The American Society of Hematology.
Lemoinne S.,University Pierre and Marie Curie |
Thabut D.,University Pierre and Marie Curie |
Housset C.,University Pierre and Marie Curie |
Moreau R.,University Paris Diderot |
And 3 more authors.
Nature Reviews Gastroenterology and Hepatology | Year: 2014
Microvesicles (MVs) are extracellular vesicles released by virtually all cells, under both physiological and pathological conditions. They contain lipids, proteins, RNAs and microRNAs and act as vectors of information that regulate the function of target cells. This Review provides an overview of the studies assessing circulating MV levels in patients with liver diseases, together with an insight into the mechanisms that could account for these changes. We also present a detailed analysis of the implication of MVs in key processes of liver diseases. MVs have a dual role in fibrosis as certain types of MVs promote fibrolysis by increasing expression of matrix metalloproteinases, whereas others promote fibrosis by stimulating processes such as angiogenesis. MVs probably enhance portal hypertension by contributing to intrahepatic vasoconstriction, splanchnic vasodilation and angiogenesis. As MVs can modulate vascular permeability, vascular tone and angiogenesis, they might contribute to several complications of cirrhosis including hepatic encephalopathy, hepatopulmonary syndrome and hepatorenal syndrome. Several results also suggest that MVs have a role in hepatocellular carcinoma. Although MVs represent promising biomarkers in patients with liver disease, methods of isolation and subsequent analysis must be standardized. © 2014 Macmillan Publishers Limited.
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.
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.
Asselah T.,Service dHepatologie |
Asselah T.,French Institute of Health and Medical Research |
Asselah T.,University Paris Diderot |
Marcellin P.,Service dHepatologie |
And 2 more authors.
Liver International | Year: 2014
With the approval of second-wave direct-acting antivirals simeprevir, sofosbuvir and faldaprevir in 2014-2015, for genotype 1 hepatitis C, patients and doctors will have more treatment options. During a first period, these treatments will still be used with peginterferon and ribavirin. The second wave of IFN-based triple therapy will have benefits and risk. These treatments have the following advantages: higher efficacy with more patient candidates for a shorten treatment duration (12-24 weeks, instead of 48 weeks). These new treatments appear to have a better safety profile than first generation, with no additional increase in anaemia over peginterferon/ribavirin. Then, these treatments are to take for patients with a decrease in pill burden (these three direct-acting antivirals are given orally one pill a day). Simeprevir and sofosbuvir may be approved in the US and Europe, in 2014, at the time this manuscript will be released. Approval of faldaprevir will follow. These direct-acting antivirals with many others will hopefully be combined in future interferon-free regimens. The goal of this review to summarize the results and safety of simeprevir, faldaprevir and sofosbuvir, to advise physicians and to inform patients on the benefits and risks of these second-wave IFN-based regimens for HCV genotype infection. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.