Marie-Pierre Ripault

Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C

Background and Aims: The gold standard treatment of chronic hepatitis C (CHC) is combined pegylated interferon and ribavirin. Considering side effects and treatment cost, prediction of treatment response before therapy is important. The aim of this study was to identify a liver gene signature to predict sustained virological response in patients with CHC. Methods: Group A (training set) comprised 40 patients with CHC including 14 non-responders (NRs) and 26 sustained virological responders (SVRs). Group B (validation set) comprised 29 patients including 9 NRs and 20 SVRs. Eleven responder–relapsers were also included. A total of 58 genes associated with liver gene expression dysregulation during CHC were selected from the literature. Real-time quantitative RT-PCR assays were used to analyse the mRNA expression of these 58 selected genes in liver biopsy specimens taken from the patients before treatment. Results: From the Group A data, three genes whose expression was significantly increased in NRs compared with SVRs were identified: IFI-6-16/G1P3, IFI27 and ISG15/G1P2. These three genes also showed significant differences in their expression profiles between NRs and SVRs in the independent sample (Group B). Supervised class prediction analysis identified a two-gene (IFI27 and CXCL9) signature, which accurately predicted treatment response in 79.3% (23/29) of patients from the validation set (Group B), with a predictive accuracy of 100% (9/9) and of 70% (14/20) in NRs and SVRs, respectively. The expression profiles of responder–relapsers did not differ significantly from those of NRs and SVRs, and 73% (8/11) of them were predicted as SVRs with the two-gene classifier. Conclusion: NRs and SVRs have different liver gene expression profiles before treatment. The most notable changes occurred mainly in interferon-stimulated genes. Treatment response could be predicted with a two-gene signature (IFI27 and CXCL9).

IL28B polymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C

BACKGROUND & AIMSnPolymorphisms 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.nnnMETHODSnThis 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 patients 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).nnnRESULTSnOur 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.nnnCONCLUSIONSnThe 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.

Twelve weeks posttreatment follow-up is as relevant as 24 weeks to determine the sustained virologic response in patients with hepatitis C virus receiving pegylated interferon and ribavirin.

A sustained virologic response (SVR) in patients with chronic hepatitis C receiving pegylated interferon (PEG‐IFN) plus ribavirin is defined as undetectable serum HCV‐RNA at 24 weeks (W+24) posttreatment follow‐up. Viral load outcome in patients with virological relapse (VR) has not been explored. This study evaluated whether the assessment of serum HCV‐RNA 12 weeks (W+12) after the end of treatment was as relevant as W+24 to evaluate SVR in 573 patients who received combination PEG‐IFN and ribavirin and had a virological response at the end of treatment. Serum HCV‐RNA was measured, using a new assay based on transcription‐mediated amplification (TMA) with a lowest detection limit of 5‐10 IU/mL, at W+12 and W+24 after the end of treatment. VR was defined as reappearance of detectable HCV‐RNA at W+24 posttreatment follow‐up. The positive predictive value (PPV) of undetectable serum HCV‐RNA at W+12 was evaluated to identify patients with SVR, and the viral load outcome was measured in relapse patients. At the W+24 posttreatment follow‐up, 408 (71%) patients had an SVR, 181 (71.2%) were treated with PEG‐IFNα‐2a and ribavirin, and 227 (71.1%) were treated with PEG‐IFNα‐2b and ribavirin. At W+12, serum HCV‐RNA was undetectable in 409 patients, and 408 patients were SVR (PPV 99.7%, 95% confidence interval 99.1‐100). In relapse patients, serum HCV‐RNA levels were 5.623 ± 0.748, 4.979 ± 0.870, and 5.216 ± 0.758 log10 IU/mL at baseline, W+12, and W+24, respectively. Conclusion: Our results show that the assessment of serum HCV‐RNA 12 weeks after the end of treatment, using the highly sensitive TMA assay (PPV 99.7%), is as relevant as after 24 weeks to predict SVR and make decisions on the management of treated patients, suggesting a new definition for SVR. (HEPATOLOGY 2010.)

Influence of genotype on hepatitis B surface antigen kinetics in hepatitis B e antigen-negative patients treated with pegylated interferon-α2a

BACKGROUNDnThe aim of this study was to assess the influence of hepatitis B virus (HBV) genotypes on serum hepatitis B surface antigen (HBsAg) kinetics in hepatitis B e antigen (HBeAg)-negative patients treated with pegylated interferon-alpha2a (PEG-IFN-alpha2a).nnnMETHODSnA total of 48 consecutive patients treated with PEG-IFN-alpha2a (180 microg/week) for 48 weeks were assessed. HBV genotype was determined. Serum HBV DNA and HBsAg were assessed at baseline, during treatment (weeks 12, 24 and 48) and during follow-up (weeks 72 and 96).nnnRESULTSnThe distribution of HBV genotype was A 27%, B 17%, C 12%, D 29% and E 14%. Mean +/-sd pretreatment serum HBV DNA (6.9 +/-1.5 log(10) copies/ml) was not different between genotypes and decreased under treatment in all genotypes without significant difference. Mean +/-sd pretreatment serum HBsAg (3.6 +/-0.6 log(10) IU/ml) was significantly different between genotypes (P<0.001), with high levels in genotypes A and C, intermediate levels in genotypes D and E, and low levels in genotype B (4.0 +/-0.3, 4.1 +/-0.7, 3.6 +/-0.5, 3.6 +/-0.4 and 2.7 +/-0.6 log(10) IU/ml, respectively). Serum HBsAg decreased under treatment in all genotypes with a significant difference. At the end of treatment, mean +/-sd decrease was high in genotype A, intermediate in genotypes B and D, and low in genotypes C and E (1.3 +/-1.6, 0.7 +/-0.7, 0.6 +/-0.9, 0.4 +/-1.0 and 0.4 +/-0.9 log(10) IU/ml, respectively; P<0.001). During follow-up, serum HBsAg continued to decrease in genotypes A and D, whereas rebound was observed in genotypes B, C and E.nnnCONCLUSIONSnHBV genotype has a strong influence on serum HBsAg kinetics during PEG-IFN-alpha2a therapy in HBeAg-negative patients.

Sustained virological response is associated with clearance of hepatitis C virus RNA and a decrease in hepatitis C virus antibody

Background/Aim: Viral eradication in chronic hepatitis C patients with sustained virological response (SVR) after interferon (IFN) therapy remains controversial.

Prospective evaluation of the management of hepatocellular carcinoma in the elderly.

BACKGROUNDnAn increasing proportion of patients with hepatocellular carcinoma are older than 75 years. Previous studies suggested that ageing does not adversely impact survival but they have the drawback of being retrospective and spanning a prolonged period of time.nnnGOALSnEvaluate management and prognosis of hepatocellular carcinoma in elderly.nnnPATIENTS AND METHODSnA multidisciplinary oncology meeting prospectively evaluated all patients with hepatocellular carcinoma. Management were standardised according to European and American guidelines. Forty patients older than 75 years were matched with younger patients for tumour extension and liver function. Both groups were compared for the type of treatment and survival.nnnRESULTSnMale/female ratio was 1.2 as compared to 7 in controls. Cirrhosis was related mostly to hepatitis C virus in elderly, and equally to hepatitis C or B virus and alcohol in controls. Curative treatments were recommended in 55% of elderly and 75% of controls. Treatment actually performed was curative in 25% in elderly as compared to 63% in controls. Median survival (30 months) was identical in both groups.nnnCONCLUSIONnDespite more restricted access to curative treatments, survival of elderly patients with hepatocellular carcinoma is comparable to that of younger patients.

Effects of Long-term Norfloxacin Therapy in Patients with Advanced Cirrhosis.

BACKGROUND & AIMSnThere is debate over the effects of long-term oral fluoroquinolone therapy in patients with advanced cirrhosis. We performed a randomized controlled trial to evaluate the effects of long-term treatment with the fluoroquinolone norfloxacin on survival of patients with cirrhosis.nnnMETHODSnWe performed a double-blind trial of 291 patients with Child-Pugh class C cirrhosis who had not received recent fluoroquinolone therapy. The study was performed at 18xa0clinical sites in France from April 2010 through Novemberxa02014. Patients were randomly assigned to groups given 400 mg norfloxacin (nxa0= 144) or placebo (nxa0= 147) once daily for 6 months. Patients were evaluated monthly for thexa0first 6 months and at 9 months and 12 months thereafter. The primary outcome was 6-month mortality, estimated by the Kaplan-Meier method, censoring spontaneous bacterial peritonitis, liver transplantation, or loss during follow-up.nnnRESULTSnThe Kaplan-Meier estimate for 6-month mortality was 14.8% for patients receiving norfloxacin and 19.7% for patients receiving placebo (Pxa0= .21). In competing risk analysis that took liver transplantation into account, the cumulative incidence of death at 6 months was significantly lower inxa0the norfloxacin group than in the placebo group (subdistribution hazard ratio, 0.59; 95% confidence interval, 0.35-0.99). The subdistribution hazard ratio for death at 6xa0months with norfloxacin vs placebo was 0.35 (95% confidence interval, 0.13-0.93) in patients with ascites fluid protein concentrations <15 g/L and 1.39 (95% confidence interval, 0.42-4.57) in patients with ascites fluid protein concentrations ≥15 g/L. Norfloxacin significantly decreased the incidence of any and Gram-negative bacterial infections without increasing infections caused by Clostridium difficile or multiresistant bacteria.nnnCONCLUSIONSnIn a randomized controlled trial of patients with advanced cirrhosis without recent fluoroquinolone therapy, norfloxacin did not reduce 6-month mortality, estimated by the Kaplan-Meier method. Norfloxacin, however, appears to increase survival of patients with low ascites fluid protein concentrations. ClinicalTrials.gov ID: NCT01037959.