Publications (82)509.63 Total impact
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Article: Long-term therapy for chronic hepatitis B: HBV DNA suppression leading to cirrhosis reversal.
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ABSTRACT: Since the licensing of the first treatment for chronic hepatitis B (CHB) in the nucleoside/tide analogue (NA) class almost 15 years ago, considerable progress has been made in improving drug efficacy and safety with highly potent NAs exhibiting a high barrier to resistance. Physicians are now able to treat patients safely for many years and to be able to see convincing improvements in histology, including regression of fibrosis and even reversal of cirrhosis. The robust data that have been generated help us build confidence that we can now offer patients with CHB long-term, disease-modifying therapy that can alter the natural course of disease and help prevent the morbidity and mortality associated with it.Journal of Gastroenterology and Hepatology 04/2013; · 2.87 Impact Factor -
Article: Faldaprevir (BI 201335), BI 207127 and ribavirin oral therapy for treatment-naive HCV genotype 1: SOUND-C1 final results.
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ABSTRACT: BACKGROUND: Faldaprevir (BI 201335) and BI 207127 are direct-acting antiviral agents under development for the treatment of chronic hepatitis C virus infection. This article describes the final results of the phase 1b SOUND-C1 study which evaluated the interferon-free oral combination of faldaprevir, BI 207127, and ribavirin in 32 treatment-naïve patients infected with hepatitis C virus genotype 1. METHODS: Patients were randomized to receive BI 207127 400 mg (n=15) or 600 mg (n=17) three times daily plus faldaprevir 120 mg once daily and weight-based ribavirin for 4 weeks. Interferon-free therapy was followed by response-guided faldaprevir plus pegylated interferon alfa-2a/ribavirin to week 24 or 48. RESULTS: At week 4, 73% (11/15) and 100% (17/17) of patients in the BI 207127 400 mg and 600 mg groups achieved hepatitis C virus (HCV) RNA <25 IU/mL, respectively. During interferon-free treatment, virological breakthrough was reported in one patient and re-increase of HCV RNA in one patient. Both patients were successfully treated with interferon-containing therapy. The rate of sustained virological response 24 weeks after completion of treatment was 73% (11/15) in the BI 207127 400 mg group and 94% (16/17) in the 600 mg group. During faldaprevir plus pegylated interferon alfa-2a/ribavirin treatment, the most common adverse events were pruritus (38% of patients), rash (31%), and asthenia (31%); these were severe in ≈3% of patients. CONCLUSIONS: Potent antiviral activity and favourable safety of the treatment regimen were demonstrated. Furthermore, the results suggest that patients with breakthrough at week 4 may be rescued with an interferon-containing regimen.Antiviral therapy 04/2013; · 3.16 Impact Factor -
Article: Insulin resistance: a major factor associated with significant liver fibrosis in Egyptian patients with genotype 4 chronic hepatitis C.
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ABSTRACT: The role of insulin resistance (IR) in chronic hepatitis C genotype 4 (CHC-4) patients is still under assessment. The aims of this study are to assess the prevalence and predictors of IR and its influence along with clinical, metabolic, virological, and histological factors on the severity of liver fibrosis in 100 Egyptian patients with CHC-4. In 100 untreated patients with CHC-4, IR was assessed using the Homeostasis Model Assessment and defined greater than 3. By logistic regression (LR), independent factors associated with IR and significant fibrosis (SF=fibrosis, Metavir score≥F2) were assessed in nondiabetic and noncirrhotic patients. One hundred patients were included; 54% were men and 46% were women. The mean age of the patients was 40.46±9.41 years. Of the total patients, 55% were overweight and 28% were obese. Metabolic syndrome was observed in 26% of patients; five of them were known to be diabetic. All patients were genotype 4. Most of our patients had mild viremia (<2 00 000 IU/ml), whereas only 16% had higher viral load (>2 00 000 IU/ml). There was no correlation between IR and hepatitis C virus viremia (r=-0.069; P=0.492). Necroinflammation was moderate-severe (A2-A3) in 25% of patients. SF (F2-F4) was found in 46% of patients and 11% had cirrhosis (F4). Most of our patients, 54%, had moderate steatosis and 21% had severe steatosis. IR was present in 46% of patients; 39 (42.9%) were nondiabetic, which is correlated significantly with BMI (r=0.395; P<0.01). IR was found to increase significantly with the fibrosis stage (P=0.001), insignificant fibrosis, 18.5%, SF (F2-F4), 71.4%, and cirrhosis (F4), 100%. By LR, IR was independently and significantly associated with age more than 40 years, obesity (BMI>30 kg/m), SF, and severe steatosis (>30%). IR was also significantly associated with metabolic syndrome. SF was present in 46 patients (46%). It was associated with IR, moderate-severe necroinflammation, and severe steatosis. By LR, in noncirrhotic patients, SF was associated with age more than 40 years, obesity (BMI>30 kg/m), moderate/severe liver inflammation, and severe steatosis. In CHC-4 patients, IR is highly prevalent and independently associated with age, obesity, SF, and severe steatosis. Management of IR might significantly improve the prognosis of CHC-4 patients.European journal of gastroenterology & hepatology 04/2013; 25(4):421-7. · 1.66 Impact Factor -
Article: Hepatitis B surface antigen serum level is associated with fibrosis severity in treatment-naïve, e antigen-positive patients.
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ABSTRACT: BACKGROUND & AIMS: Little is currently known about the association between serum HBsAg or HBV DNA levels and the severity of liver disease in chronic hepatitis B (CHB) patients. Therefore, we investigated these relationships in a large cohort of unselected, well-characterized, treatment-naïve CHB patients. METHODS: CHB patients were assessed at the Hôpital Beaujon in Paris, France, between 2000 and 2008. Serum samples and liver biopsies were obtained on the same day. HBsAg, HBV DNA, and HBV genotype were investigated using commercial diagnostic assays and liver histology was scored using the METAVIR system. RESULTS: 406 patients were included in this cross-sectional study. Serum HBsAg and HBV DNA levels in hepatitis B e antigen-positive (HBeAg[+]) patients showed strong correlation (r=0.44, p<0.0001), as did serum HBsAg levels and fibrosis severity (r=0.43, p<0.0001). HBeAg(+) patients with moderate to severe fibrosis exhibited significantly lower serum HBsAg and HBV DNA levels compared with patients with no or mild fibrosis. Modeling analysis suggested a serum HBsAg cutoff of 3.85 log IU.mL(-1) would provide a theoretical sensitivity of 100% (95% CI: 0-100), theoretical specificity of 86% (95% CI: 50-100), and a negative predictive value of 100% (95% CI: 67-100) in HBeAg(+) patients infected with HBV genotype B or C. CONCLUSIONS: We found an association between low serum HBsAg levels and moderate to severe fibrosis in HBeAg(+) CHB patients. Furthermore, we describe a serum HBsAg cutoff for the prediction of fibrosis severity in CHB patients infected with HBV genotype B or C.Journal of Hepatology 01/2013; · 9.26 Impact Factor -
Article: Reply to "Association between IL28B polymorphism and treatment response in patients with genotype 4 chronic hepatitis C": HCV genotype 4 infection: A major medical need.
Journal of Hepatology 06/2012; · 9.26 Impact Factor -
Article: Genomics and HCV infection: Progression of fibrosis and treatment response.
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ABSTRACT: HCV infection is a global health problem that affects 170 million people worldwide. The severity of the disease varies from asymptomatic chronic infection to cirrhosis and hepatocellular carcinoma (HCC). Recently, the standard of care for genotype 1 patients has greatly improved with the addition of protease inhibitors (telaprevir or boceprevir) to pegylated interferon (PegIFN) and ribavirin (RBV). The prediction of fibrosis progression and the response to antiviral treatment are two major issues in the management of patients with chronic hepatitis C. Differential expression of mRNAs was first analyzed for both progression of fibrosis and treatment response. Specific polymorphisms, associated with either fibrosis or viral response, were identified thanks to major improvements in genome scanning technologies. Since 2009, several independent genome wide association studies (GWAS) have reported an association between genetic polymorphisms within the IL-28B promoter and both natural and treatment-induced clearance in genotype 1 infected patients. These different studies showed the strong association and the importance of IL-28B polymorphisms in the treatment response. Combining the different genetic factors could improve their predictive value and help identify patients at a high risk of progression of fibrosis as well as those with a lower chance of responding to treatment. The aim of this review was to discuss the genomic factors (mRNAs, miRNAs, and SNPs) and HCV infection with clinical implications for either progression of fibrosis or treatment response. Recent findings on the IL-28B polymorphism and its application in clinical practice will also be discussed.Journal of Hepatology 05/2012; 57(5):1110-25. · 9.26 Impact Factor -
Article: Editorial: Towards the eradication of hepatitis C virus.
Liver international: official journal of the International Association for the Study of the Liver 02/2012; 32 Suppl 1:1. · 3.82 Impact Factor -
Article: Direct acting antivirals for the treatment of chronic hepatitis C: one pill a day for tomorrow.
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ABSTRACT: Chronic hepatitis C is one of the leading causes of chronic liver disease with approximately 170 million people infected worldwide. Sustained virological response (SVR) is equivalent to viral eradication and associated with a reduction in the risk of cirrhosis. Nowadays the treatment for hepatitis C virus (HCV) genotype 1 chronic infection is the addition of direct acting antivirals (DAA) with a protease inhibitor (telaprevir or boceprevir) to the pegylated interferon (PEG-IFN) plus ribavirin (RBV) regimen. The future management of patients with these new molecules will require good clinical practice, knowledge of indications, management of side effects and monitoring for antiviral resistance. Certain major medical needs are still unmet and require studies in special populations (HIV-HCV coinfected patients, transplanted patients, etc.…) and also in HCV non-1 genotype patients and in non-responders. Second generation DAA are in development. Combinations of antivirals with additive potency that lack cross resistance and with a good safety profile may provide new regimens in the future to make HCV the first chronic viral infection eradicated worldwide with a finite duration of combination DAA therapy without IFN. The aim of this review is to summarize mechanisms of action and results obtained with DAAs.Liver international: official journal of the International Association for the Study of the Liver 02/2012; 32 Suppl 1:88-102. · 3.82 Impact Factor -
Article: Direct comparison of diagnostic performance of transient elastography in patients with chronic hepatitis B and chronic hepatitis C.
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ABSTRACT: Accuracy of transient elastography (TE) in hepatitis B virus (HBV) infection has not been well established. We aimed to compare the performances of TE for the assessment of liver fibrosis in patients with chronic HBV or hepatitis C virus (HCV) infection. A secondary analysis was performed to assess whether or not alanine aminotransferase (ALT) levels would impact on the accuracy of TE. This cross-sectional study, carried out in a single centre, included treatment-naïve patients with compensated chronic HBV or HCV infection, consecutively admitted between 2006 and 2008 for a liver biopsy and TE measurement on the same day. A total of 202 HBV patients and 363 HCV subjects were evaluated. Overall diagnostic accuracy of TE in the HBV group was comparable to that observed in HCV patients [area under the receiver-operating characteristics (AUROCs) 0.867 ± 0.026 vs. 0.868 ± 0.019 for predicting F ≥ 2, P = 0.975; 0.902 ± 0.029 vs. 0.894 ± 0.020 for F ≥ 3, P = 0.820; and 0.935 ± 0.024 vs. 0.947 ± 0.027 for F4, P = 0.740 respectively]. TE exhibited comparable accuracies, sensitivities, specificities, predictive values and likelihood ratios in HBV and HCV groups. AUROC analysis showed no influence of ALT levels on the performance of TE in HBV individuals. ALT-specific cut-off values did not exhibit significantly higher diagnostic performances for predicting fibrosis in HBV patients with elevated ALT. In HBV patients, TE measurement accurately predicts the absence or presence of significant fibrosis, advanced fibrosis or cirrhosis and shows similar performances as compared to HCV patients. The use of TE cut-off values adjusted to ALT level did not improve performances for estimating liver fibrosis in HBV patients.Liver international: official journal of the International Association for the Study of the Liver 11/2011; 32(4):612-21. · 3.82 Impact Factor -
Article: CMV drives clonal expansion of NKG2C+ NK cells expressing self-specific KIRs in chronic hepatitis patients.
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ABSTRACT: Natural killer (NK) cells are affected by infection with human cytomegalovirus (HCMV) manifested by increased expression of the HLA-E binding activating receptor NKG2C. We here show that HCMV seropositivity was associated with a profound expansion of NKG2C(+) CD56(dim) NK cells in patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Multi-color flow cytometry revealed that the expanded NKG2C(+) CD56(dim) NK cells displayed a highly differentiated phenotype, expressed high amounts of granzyme B and exhibited polyfunctional responses (CD107a, IFN-γ, and TNF-α) to stimulation with antibody-coated as well as HLA-E expressing target cells but not when stimulated with IL-12/IL-18. More importantly, NKG2C(+) CD56(dim) NK cells had a clonal expression pattern of inhibitory killer cell immunoglobulin-like receptors (KIRs) specific for self-HLA class I molecules, with predominant usage of KIR2DL2/3. KIR engagement dampened NKG2C-mediated activation suggesting that such biased expression of self-specific KIRs may preserve self-tolerance and limit immune-pathology during viral infection. Together, these findings shed new light on how the human NK-cell compartment adjusts to HCMV infection resulting in clonal expansion and differentiation of educated and polyfunctional NK cells.European Journal of Immunology 11/2011; 42(2):447-57. · 5.10 Impact Factor -
Article: Role of hepatic HCV-RNA level on the severity of chronic hepatitis C and response to antiviral therapy.
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ABSTRACT: Correlation between hepatic HCV-RNA and serum HCV-RNA, severity of liver disease and response to therapy is poorly known. To assess the influence of hepatic HCV-RNA level on severity of liver disease and response to therapy in a large cohort of chronic hepatitis C (CHC) patients. HCV-RNA was measured in frozen liver biopsies and serum samples from 130 CHC patients the day of liver biopsy prior to treatment. Liver fibrosis was assessed by Ishaq scoring. A Sustained Virological Response (SVR) was observed in 52% of the patients, non-response (NR) in 34%. Mean±standard deviation hepatic HCV-RNA level was 7.69±0.67 log(10) copies/mg of liver. Mean serum HCV-RNA level was 6.21±0.72 log(10) copies/ml. There was a correlation between hepatic and serum HCV-RNA in genotype 1 and 4 (p=0.008 and p=0.03) and age (p=0.006). Mean hepatic HCV-RNA was 7.70±0.69 vs 7.67±0.68 log(10) copies/mg of liver, in patients with significant fibrosis vs those with mild fibrosis, respectively (p=0.7); 8.04±0.68; 7.44±0.47; 7.43±0.49 and 7.44±0.71 log(10) copies/mg of liver in genotypes 1, 2, 3 and 4, respectively (p=0.0001); higher in women than in men (p=0.04); 7.60±0.63, 7.71±0.54 and 7.96±0.73 log(10) copies/mg in SVR, relapsers and NR, respectively (p=0.1). Multivariate analysis showed that high hepatic HCV-RNA level was independently associated with genotype and response to therapy was associated with genotype independently from hepatic HCV-RNA level. Hepatic HCV-RNA level was not associated with severity of liver disease. High level was strongly associated with HCV genotype independently from response to therapy.Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 11/2011; 53(1):43-7. · 3.12 Impact Factor -
Article: IL28B polymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C.
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ABSTRACT: Polymorphisms in the region of the interleukin (IL)28B gene have been associated with pegylated-interferon (PEG-IFN) and ribavirin treatment response mainly in genotype 1 HCV infections. However, there are few data on HCV genotype 4 (HCV-4) infection. We evaluated, in a unique well-characterized cohort of HCV-4 patients, the association of IL28B polymorphism with response to treatment or liver disease severity. This study included 164 HCV-4 patients from different ethnic groups (Egyptian, European, and Sub-Saharan African). Among these patients, 82 were studied for response and 160 for disease severity. Free DNA extracted from all the 164 patient's serum samples was analyzed by direct sequencing of the SNP rs12979860 of IL28B. Genetic and bio-clinical features from patients having sustained virological response (43 SVR patients) and from those who did not respond to treatment or had a relapse after the end of the treatment (39 NR patients) were compared. IL28B polymorphism was compared between the 78 patients with mild fibrosis (Metavir score F0-F1) and the 82 with advanced fibrosis (F2-F4). Our data showed a better treatment response rate of the C allele of the IL28B gene SNP rs12979860 (p=0.0008). The response rates were 81.8%, 46.5%, and 29.4% for genotype CC, CT, and TT, respectively. No significant relationship was found between rs12979860 and the severity of the disease. The SNP rs12979860 is strongly associated with SVR in patients infected with HCV-4, but not with liver disease severity. Analysis of IL28B genotype might be used to guide treatment for these patients.Journal of Hepatology 09/2011; 56(3):527-32. · 9.26 Impact Factor -
Article: Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection.
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ABSTRACT: Therapeutic regimens are being developed for patients with hepatitis C virus (HCV) infection that do not include the combination of peginterferon alfa and ribavirin. We investigated the antiviral effect and safety of BI 201335 (an inhibitor of the NS3/4A protease) and BI 207127 (an inhibitor of the NS5B non-nucleoside polymerase) with ribavirin. Thirty-two treatment-naïve patients with chronic HCV genotype 1 infection were randomly assigned to groups that were given 400 mg or 600 mg BI 207127 3 times daily plus 120 mg BI 201335 once daily and 1000 to 1200 mg/day ribavirin for 4 weeks. The primary efficacy end point was virologic response (HCV RNA level <25 IU/mL at week 4). Thirty-two patients received treatment; 31 completed all 4 weeks of assigned combination therapy. In the group given BI 207127 400 mg 3 times daily, the rates of virologic response were 47%, 67%, and 73% at days 15, 22, and 29; a higher rate of response was observed in patients with genotype-1b compared with genotype-1a infections. In the group given BI 207127 600 mg 3 times daily, the rates of virologic response were 82%, 100%, and 100%, respectively, and did not differ among genotypes. One patient in the group given 400 mg 3 times daily had virologic breakthrough (≥1 log(10) rebound in HCV RNA) at day 22. The most frequent adverse events were mild gastrointestinal disorders, rash, and photosensitivity. There were no severe or serious adverse events; no patients discontinued therapy prematurely. The combination of the protease inhibitor BI 201335, the polymerase inhibitor BI 207127, and ribavirin has rapid and strong activity against HCV genotype-1 and did not cause serious or severe adverse events.Gastroenterology 09/2011; 141(6):2047-55; quiz e14. · 11.68 Impact Factor -
Article: Realize the advance in HCV treatment, but remain cautious.
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ABSTRACT: COMMENTARY ON: Telaprevir for previously untreated chronic hepatitis C virus infection. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R, George J, Rizzetto M, Shouval D, Sola R, Terg RA, Yoshida EM, Adda N, Bengtsson L, Sankoh AJ, Kieffer TL, George S, Kauffman RS, Zeuzem S; ADVANCE Study Team. N Engl J Med. 2011 Jun 23;364(25):2405-2416. Copyright (2011). Abstract reprinted with permission of the Massachusetts Medical Society.http://www.ncbi.nlm.nih.gov/pubmed/21696307 BACKGROUND: In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients. METHODS: In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12weeks (T12PR group), followed by peginterferon-ribavirin alone for 12weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8weeks and placebo with peginterferon-ribavirin for 4weeks (T8PR group), followed by 12 or 36weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12weeks, followed by 36weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24weeks after the last planned dose of study treatment (sustained virologic response). RESULTS: Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; p<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group. CONCLUSIONS: Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.) And Telaprevir for retreatment of HCV infection. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, Focaccia R, Younossi Z, Foster GR, Horban A, Ferenci P, Nevens F, Müllhaupt B, Pockros P, Terg R, Shouval D, van Hoek B, Weiland O, Van Heeswijk R, De Meyer S, Luo D, Boogaerts G, Polo R, Picchio G, Beumont M; REALIZE Study Team. N Engl J Med. 2011 Jun 23;364(25):2417-28. Copyright (2011). Abstract reprinted with permission of the Massachusetts Medical Society.http://www.ncbi.nlm.nih.gov/pubmed/21696308 BACKGROUND: Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin. METHODS: In this randomized, phase 3 trial, we evaluated the addition of telaprevir to peginterferon alfa-2a plus ribavirin in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response. A total of 663 patients were assigned to one of three groups: the T12PR48 group, which received telaprevir for 12weeks and peginterferon plus ribavirin for a total of 48weeks; the lead-in T12PR48 group, which received 4weeks of peginterferon plus ribavirin followed by 12weeks of telaprevir and peginterferon plus ribavirin for a total of 48weeks; and the control group (PR48), which received peginterferon plus ribavirin for 48weeks. The primary end point was the rate of sustained virologic response, which was defined as undetectable HCV RNA 24weeks after the last planned dose of a study drug. RESULTS: Rates of sustained virologic response were significantly higher in the two telaprevir groups than in the control group among patients who had a previous relapse (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group), a partial response (59%, 54%, and 15%, respectively), and no response (29%, 33%, and 5%, respectively) (p<0.001 for all comparisons). Grade 3 adverse events (mainly anemia, neutropenia, and leukopenia) were more frequent in the telaprevir groups than in the control group (37% vs. 22%). CONCLUSIONS: Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase. (Funded by Tibotec and Vertex Pharmaceuticals; REALIZE ClinicalTrials.gov number, NCT00703118.).Journal of Hepatology 08/2011; 55(6):1457-60. · 9.26 Impact Factor -
Article: HEP-09-1639.R1 correspondence invitation Twelve weeks post-treatment follow-up is as relevant as 24 weeks to determine the SVR in patients with HCV receiving PEG-IFN and ribavirin.
Hepatology 07/2011; · 11.66 Impact Factor -
Article: Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: the ANRS HCEP-23 study.
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ABSTRACT: Blood tests and transient elastography (Fibroscan™) have been developed as alternatives to liver biopsy. This ANRS HCEP-23 study compared the diagnostic accuracy of nine blood tests and transient elastography (Fibroscan™) to assess liver fibrosis, vs. liver biopsy, in untreated patients with chronic hepatitis C (CHC). This was a multicentre prospective independent study in 19 French University hospitals of consecutive adult patients having simultaneous liver biopsy, biochemical blood tests (performed in a centralized laboratory) and Fibroscan™. Two experienced pathologists independently reviewed the liver biopsies (mean length=25±8.4 mm). Performance was assessed using ROC curves corrected by Obuchowski's method. Fibroscan™ was not interpretable in 113 (22%) patients. In the 382 patients having both blood tests and interpretable Fibroscan™, Fibroscan™ performed similarly to the best blood tests for the diagnosis of significant fibrosis and cirrhosis. Obuchowski's measure showed Fibrometer® (0.86), Fibrotest® (0.84), Hepascore® (0.84), and interpretable Fibroscan™ (0.84) to be the most accurate tests. The combination of Fibrotest®, Fibrometer®, or Hepascore® with Fibroscan™ or Apri increases the percentage of well classified patients from 70-73% to 80-83% for significant fibrosis, but for cirrhosis a combination offers no improvement. For the 436 patients having all the blood tests, AUROC's ranged from 0.82 (Fibrometer®) to 0.75 (Hyaluronate) for significant fibrosis, and from 0.89 (Fibrometer® and Hepascore®) to 0.83 (FIB-4) for cirrhosis. Contrarily to blood tests, performance of Fibroscan™ was reduced due to uninterpretable results. Fibrotest®, interpretable Fibroscan™, Fibrometer®, and Hepascore® perform best and similarly for diagnosis of significant fibrosis and cirrhosis.Journal of Hepatology 07/2011; 56(1):55-62. · 9.26 Impact Factor -
Article: Activation of unfolded protein response and autophagy during HCV infection modulates innate immune response.
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ABSTRACT: Autophagy, a process for catabolizing cytoplasmic components, has been implicated in the modulation of interactions between RNA viruses and their host. However, the mechanism underlying the functional role of autophagy in the viral life cycle still remains unclear. Hepatitis C virus (HCV) is a single-stranded, positive-sense, membrane-enveloped RNA virus that can cause chronic liver disease. Here we report that HCV induces the unfolded protein response (UPR), which in turn activates the autophagic pathway to promote HCV RNA replication in human hepatoma cells. Further analysis revealed that the entire autophagic process through to complete autolysosome maturation was required to promote HCV RNA replication and that it did so by suppressing innate antiviral immunity. Gene silencing or activation of the UPR-autophagy pathway activated or repressed, respectively, IFN-β activation mediated by an HCV-derived pathogen-associated molecular pattern (PAMP). Similar results were achieved with a PAMP derived from Dengue virus (DEV), indicating that HCV and DEV may both exploit the UPR-autophagy pathway to escape the innate immune response. Taken together, these results not only define the physiological significance of HCV-induced autophagy, but also shed light on the knowledge of host cellular responses upon HCV infection as well as on exploration of therapeutic targets for controlling HCV infection.Journal of Hepatology 06/2011; 55(5):1150-3. · 9.26 Impact Factor -
Article: A sprint to increase response to HCV treatment: expectancies but caution.
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ABSTRACT: Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies. We conducted a double-blind study in which previouslyuntreated adults with HCV genotype 1 infection were randomly assigned to one of the three groups. In all the three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately. A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (p < 0.001), and in 213 of the 311 patients (68%) in group 3 (p < 0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (p = 0.04), and in 29 of the 55 patients (53%) in group 3 (p = 0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively. The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared to standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment. To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of the three groups. In all the three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, p < 0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10)IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41-46% of boceprevir-treated patients and 21% of controls. The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared to peginterferon-ribavirin alone.Journal of Hepatology 06/2011; 55(5):1154-8. · 9.26 Impact Factor -
Article: Changes in autophagic response in patients with chronic hepatitis C virus infection.
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ABSTRACT: Autophagy is a regulated process that can be involved in the elimination of intracellular microorganisms and in antigen presentation. Some in vitro studies have shown an altered autophagic response in hepatitis C virus infected hepatocytes. The present study aimed at evaluating the autophagic process in the liver of chronic hepatitis C (CHC) patients. Fifty-six CHC patients and 47 control patients (8 with nonalcoholic steatohepatitis or alcoholic liver disease, 18 with chronic heptatitis B virus infection, and 21 with no or mild liver abnormalities at histological examination) were included. Autophagy was assessed by means of electron microscopy and microtubule-associated protein light chain 3 immunoblotting. Using light chain 3 immunoblotting, the form present on autophagic vesicle (light chain 3-II) was significantly higher in CHC patients than in controls (P < 0.05). Using quantitative electron microscopy analysis, the median number of autophagic vesicles observed in hepatocytes from CHC patients was sixfold higher than in overall controls (P < 0.001). In contrast, there was no difference between CHC patients and controls in the number of mature lysosomes with electron-dense contents arguing in favor of a lack of fusion between autophagosome and lysosome. Neither genotype nor viral load influenced the autophagy level. In conclusion, autophagy is altered in hepatocytes from CHC patients, likely due to a blockade of the last step of the autophagic process.American Journal Of Pathology 06/2011; 178(6):2708-15. · 4.89 Impact Factor -
Article: Detection of bacterial DNA in serum and ascitic fluid of asymptomatic outpatients with cirrhosis and non-neutrocytic ascites.
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ABSTRACT: Bacterial DNA (bactDNA) has been found in serum and ascitic fluid (AF) of 30-40% of hospitalized patients with cirrhosis and non-neutrocytic ascites, but its prevalence in outpatients is unknown. The aim of this prospective study was to investigate the presence of bactDNA in AF and serum among cirrhotic outpatients with non-neutrocytic ascites. Thirty-one consecutive patients with cirrhosis and non-neutrocytic ascites, who underwent therapeutic paracentesis in our outpatient clinic, were enrolled over a 13-week period. Of these patients, 13 had a single paracentesis and 18 patients had several consecutive paracenteses (2-10) over the study period. Overall, 98 serum and non-neutrocytic AF specimens were obtained and tested for the presence of bactDNA by polymerase chain reaction amplification of the 16S ribosomal RNA gene. The main causes of cirrhosis were alcohol (53.5%) and hepatitis C (30%). The median MELD score was 16 and there were 54.8% Child-Pugh C patients. BactDNA was negative in all samples from 28 of the 31 patients, including 15 patients with several paracentesis. One patient had a single AF sample culture positive and bactDNA positive for Streptococcus mitis, whereas the simultaneous blood sample was negative. For each of the last two patients, DNA from Lactococcus lactis was detected in a single blood sample but not in the simultaneous AF sample. In contrast to that reported previously in hospitalized patients, bactDNA is rarely detected in serum and AF of outpatients with cirrhosis and non-neutrocytic ascites.Liver international: official journal of the International Association for the Study of the Liver 04/2011; 31(4):494-8. · 3.82 Impact Factor
Top co-authors
Top Journals
Institutions
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2013
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Theodor Bilharz Research Institute
Al Jīzah, Muhafazat al Jizah, Egypt
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2008–2013
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Université Paris Diderot - Paris 7
- Centre de recherche biomédicale Bichat, Beaujon (CRB3) UMR-S 773
Paris, Ile-de-France, France -
Hôpital Saint-Louis – Hôpitaux universitaires "Sant-Louis, Laboisière, Fernand-Widal"
Paris, Ile-de-France, France
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2009–2012
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Hôpital Beaujon – Hôpitaux Universitaires Paris Nord Val de Seine
Clichy, Ile-de-France, France
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2011
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Université Paris Descartes
Paris, Ile-de-France, France
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2009–2010
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INSERM, GIP CYCERON
Caen, Basse-Normandie, France
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2006–2010
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Assistance Publique – Hôpitaux de Paris
Paris, Ile-de-France, France
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2002–2010
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Institut national de la santé et de la recherche médicale
- Centre de Recherche Biomédicale Bichat-Beaujon U773
Paris, Ile-de-France, France -
University of Toronto
- Sunnybrook Health Sciences Centre
Toronto, Ontario, Canada
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2007
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French National Centre for Scientific Research
Lyon, Rhone-Alpes, France -
University of Texas Medical Branch at Galveston
Galveston, TX, USA
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