Denis Ouzan

Comparison of 1 or 3 MU of interferon alfa-2b and placebo in patients with chronic non-A, non-B hepatitis

Ninety patients with histologically documented chronic non-A, non-B hepatitis were randomly allocated to receive SC injections of placebo or of 1 or 3 MU of recombinant interferon alfa-2b three times weekly for 24 weeks. Complete normalization of alanine aminotransferase levels occurred posttreatment in 43.3% of patients receiving 3 MU, in 20% of those receiving 1 MU, and in 6.7% of untreated patients (P less than 0.0005 vs. those treated with 3 MU). Alanine aminotransferase normalization was sustained for 6 months after therapy in 13.3% of the patients treated with 3 MU and in 3.3% of those given 1 MU or placebo. The decline of alanine aminotransferase levels following interferon therapy showed independent, positive correlations with female sex (P less than 0.03) and younger age (P less than 0.05). The Knodells fibrosis score was strongly positively correlated with age (P less than 0.0001). It is concluded that 3 MU of interferon is a more effective dose than 1 MU for controlling disease activity in non-A, non-B chronic hepatitis patients. Women and younger and noncirrhotic patients are more likely to respond.

Independent Prospective Multicenter Validation of Biochemical Markers (Fibrotest-Actitest) for the Prediction of Liver Fibrosis and Activity in Patients with Chronic Hepatitis C: The Fibropaca Study

OBJECTIVES:Fibrotest (FT) and Actitest (AT) are biochemical markers of fibrosis and activity for use as a non-invasive alternative to liver biopsy in patients with chronic hepatitis C virus (HCV). The aim of this study was to perform an external validation of FT and AT and to study the discordances between FT/AT and liver biopsy in patients with chronic hepatitis C.METHODS:A total of 519 consecutive patients with chronic HCV were prospectively included in five centers, with liver biopsy and biochemical markers taken at the same day. Fifteen patients were excluded because their biopsies could not be interpreted. Diagnostic accuracies were assessed by receiver operating characteristic (ROC) curve analysis.RESULTS:Median biopsy size was 15 mm (range: 2–58), with 9 portal tracts (1–37) and 1 fragment (1–12). 46% (230/504) were classified F2–F4 in fibrosis and 39% A2–A3 in activity. FT area under ROC curve for diagnosis of activity (A2–A3), significant fibrosis (F2–F4), and severe fibrosis (F3–F4) were 0.73 [0.69–0.77], 0.79 [0.75–0.82], and 0.80 [0.76–0.83], respectively. Among the 92 patients (18%) with 2 fibrosis stages of discordance between FT and biopsy, the discordance was attributable to FT in 5% of cases, to biopsy in 4%, and undetermined in 9%.CONCLUSIONS:This prospective independent and multicenter study confirms the diagnostic value of FT and AT found in the princeps study and suggests that FT and AT can be an alternative to biopsy in most patients with chronic HCV.

Accuracy of hyaluronic acid level for predicting liver fibrosis stages in patients with hepatitis C virus.

BackgroundIn patients with chronic hepatitis C virus, liver biopsy is the gold standard for assessing liver disease stage; nevertheless, it is prone to complications, some of them serious. Non-invasive methods have been proposed as surrogate markers for liver fibrosis. It was shown that serum hyaluronic acid (HA) level increases with the development for liver fibrosis. The aim of this study was to evaluate the diagnostic value of HA as well as to determine the HA level cut-off for predicting the presence or absence of fibrosis, severe fibrosis, and cirrhosis.Results405 patients with chronic hepatitis C were prospectively included with biomarker measurement and liver biopsy done the same day: 151 in the training set (only biopsy lengths of 25 mm or more) and 254 in the validation set. For the discrimination of significant fibrosis, severe fibrosis, and cirrhosis in the training set, the areas under curve (AUCs) were 0.75 ± 0.03, 0.82 ± 0.02, and 0.89 ± 0.03, respectively. Absence of significant fibrosis, severe fibrosis, and cirrhosis can be predicted by HA levels of 16, 25, and 50 μg/l, respectively (with negative predictive values of 82%, 89%, and 100%, in the same order). Presence of significant fibrosis, severe fibrosis, and cirrhosis can be predicted by HA levels of 121, 160, and 237 μg/l, respectively (with positive predictive values of 94%, 100%, and 57%, in the same order).ConclusionIn the validation set, HA was accurate in predicting significant fibrosis, severe fibrosis, and cirrhosis with AUCs of 0.73, 0.77, and 0.97, respectively. Moreover, accurate HA level cut-offs were defined for predicting significant fibrosis, severe fibrosis, and cirrhosis. Thus, the study supports that HA level may be clinically useful as a non-invasive marker for liver fibrosis and/or cirrhosis.

Validation and comparison of indexes for fibrosis and cirrhosis prediction in chronic hepatitis C patients: proposal for a pragmatic approach classification without liver biopsies.

Summary.  Noninvasive indexes have been developed to predict fibrosis staging. The aim of this study was to assess the diagnostic accuracy of these indexes in comparison with liver histology in hepatitis C virus (HCV)‐infected patients. A total of 235 consecutive patients with HCV infection from the Fibropaca multicentre independent study were included in this paper. FibroTest (FT), aspartate aminotransferase to platelet ratio index (APRI) and Forns score were assessed in the cohort and compared with liver histology performed on the same day. The main end point was the area under characteristic curves (AUCs) for the diagnosis of significant fibrosis (F2–F4) and cirrhosis (F4) by the METAVIR classification. Mean age was 46 (±11) years, 55% were males, 42% (n = 99) had significant fibrosis (F2–F4) and 7% (n = 16) had cirrhosis (F4). For the diagnosis of significant fibrosis, respective AUCs of FT, APRI and Forns score were 0.81 (95% confidence interval: 0.76–0.86), 0.71 (0.67–0.79) and 0.76 (0.70–0.82); for cirrhosis prognosis, AUCs of FT and APRI were 0.82 (0.77–0.87) and 0.81 (0.76–0.86) (AUCs not significantly different). Using each index independently, all patients were classified by FT, 214 (91%) patients were classified by APRI and 129 (55%) by Forns score. There were significantly more cases of discordances between APRI and liver biopsy than between FT or Forns score and liver biopsy (P < 0.05). Performing all scores (FT, Forns and APRI) without liver biopsy allowed fibrosis to be well evaluated in 191 patients (81.3%), including patients with FT failure. Liver biopsy remained mandatory to evaluate fibrosis in 44 patients (18.7%). Our study shows that performing all the tests and liver biopsy improves the diagnostic accuracy for liver fibrosis in chronic hepatitis C patients without patent comorbidities. The combination of all tests with liver biopsy allowed 225/235 (96%) patients to be correctly classified. The combination of all tests without liver biopsy allowed 191/235 (81.3%) patients to be correctly classified; liver biopsy remained mandatory in some patients (18.7%).

Impact of antiretroviral treatment on progression of hepatic fibrosis in HIV/hepatitis C virus co-infected patients.

Background: The impact of immune reconstitution on liver fibrosis in HIV/hepatitis C virus (HCV) patients is unknown. In this case–control study, we investigated the impact of HIV infection on the severity of liver fibrosis and identified related factors. Methods: We studied 116 HIV/HCV patients and 235 HCV only patients all untreated for HCV. Each co-infected patient was matched with two singly-infected patients according to gender, age at contamination and duration of infection. Liver biopsy was analysed using the METAVIR score. Results: Alcohol consumption and route of contamination differed between HCV-infected and HCV/HIV co-infected patients. Among co-infected patients, a F3–F4 Metavir score was significantly more frequent than in mono-infected patients. Co-infected patients with severe fibrosis (F3–F4) had higher transaminase, ferritin levels and lower CD4 T-cell count than patients with none to moderate fibrosis (F0–F2). Although median duration of treatment with nucleoside analogues, non-nucleoside analogues and protease inhibitors were comparable in both groups, the delay between the presumed date of contamination and treatment initiation with highly active antiretroviral therapy (HAART) was significantly longer for patients with severe fibrosis than those with none to moderate fibrosis. Finally, the mean rate of fibrosis progression was significantly slower among patients exposed to HAART. Conclusion: Early antiretroviral therapy in co-infected HIV-HCV patients may slow liver fibrosis progression.

High sustained virologic response rates in rapid virologic response patients in the large real‐world PROPHESYS cohort confirm results from randomized clinical trials

The ability to predict which patients are most likely to achieve a sustained virologic response (SVR) with peginterferon/ribavirin would be useful in optimizing treatment for hepatitis C virus (HCV). The objective of this large international noninterventional cohort study was to investigate the predictive value (PV) of a virologic response (VR) by weeks 2, 4, and 12 of treatment on SVR. Treatment‐naive HCV monoinfected patients (N = 7,163) age ≥18 years were prescribed peginterferon/ribavirin at the discretion of the treating physician according to country‐specific requirements in accordance with the local label. The main outcome measure was the PV of a VR (HCV RNA <50 IU/mL) by weeks 2, 4, and 12 of treatment for SVR24 (HCV RNA <50 IU/mL after 24 weeks of untreated follow‐up) by HCV genotype. The overall SVR24 rate was 49.4% (3,541/7,163; 95% confidence interval [CI]: 48.3‐50.6%). SVR24 rates in patients with an HCV RNA titer <50 IU/mL by weeks 2, 4, and 12, respectively, were 66.2% (95% CI: 60.4‐71.7%), 68.4% (95% CI: 65.7‐71.0%), and 60.3% (95% CI: 58.5‐62.1%) among genotype 1 patients; 82.0% (95% CI: 76.8‐86.5%), 76.3% (95% CI: 73.3‐79.1%), and 74.2% (95% CI: 71.3‐76.9%) among genotype 2 patients; 67.3% (95% CI: 61.1‐73.1%), 67.3% (95% CI: 64.2‐70.3%), and 63.8% (95% CI: 61.0‐66.6%) among genotype 3 patients; and 59.4% (95% CI: 40.6‐76.3%), 63.3% (95% CI: 54.3‐71.6%), and 54.3% (95% CI: 47.5‐60.9%) among genotype 4 patients. The absence of a VR by week 12 had the highest negative PV across all genotypes. Conclusion: A VR by week 2 or 4 had the highest positive PV for SVR24 and differed according to HCV genotype. (HEPATOLOGY 2012;56:2039–2050)

Hepatitis C Virus Genotyping Based on 5′ Noncoding Sequence Analysis (Trugene)

ABSTRACT Hepatitis C virus (HCV) genotyping of samples from 184 patients with chronic HCV infection by the Trugene 5′NC genotyping kit, based on sequence analysis of the 5′ noncoding region (5′ NCR), and the InnoLiPA assay was evaluated. In addition to these methods, the 184 samples were also analyzed by sequencing of part of the NS5B of the HCV genome after in-house PCR amplification, as a means of validating results obtained with the 5′ NCR. The distribution of the genotypes typed by NS5B sequence analysis was as follows: 1a, 41 samples; 1b, 58 samples; 1d, 1 sample; 2a, 5 samples; 2b, 2 samples; 2c, 7 samples; 3a, 46 samples; 4a, 7 samples; 4c, 1 samples; 4e, 9 samples; 5a, 6 samples; 6a, 1 sample. The Trugene and InnoLiPA assays gave concordant results within HCV types in 100% of cases. The ability to discriminate at the subtype level was 76 and 74% for the Trugene and the InnoLiPA assays, respectively.

Possible Zoonotic Transmission of Hepatitis E from Pet Pig to Its Owner

Hepatitis E is transmitted mainly by water or food, but in industrialized countries, all routes of transmission have not been identified. We describe possible zoonotic transmission of hepatitis E virus that involved direct contact between a pet pig and its owner.

Real-Time PCR Assays for Hepatitis C Virus (HCV) RNA Quantitation Are Adequate for Clinical Management of Patients with Chronic HCV Infection

ABSTRACT Because of the use of viral kinetics during polyethylene glycol (PEG)-interferon-ribavirin therapy and the development of specific new anti-hepatitis C virus (anti-HCV) drugs, assessment of the efficacy of anti-HCV drugs needs to be based not on end-point PCR assays but on real-time PCR. The aim of this study was to determine if the two available commercial real-time PCR assays, the Abbott RealTime HCV assay and the Roche Cobas TaqMan HCV assay, can become the standard for HCV RNA quantification. We investigated the prognostic relevance of HCV RNA viral loads at baseline, week 4, and week 12 to a rapid and early virological response to antiviral therapy by using the two assays. Of 59 naïve patients chronically infected by HCV (41 infected with genotype 1) who were treated with ribavirin plus PEG-interferon alfa-2b for 48 weeks, 24 patients (41%) showed a sustained virological response (SVR). With the two assays, viral loads were highly correlated, irrespective of genotype (R2 = 0.94 for all cases). No difference in diagnostic value was found between the Abbott and Roche assays at week 4, with respective negative predictive values (NPVs) of 84% and 78% and positive predictive values (PPVs) of 62% and 56% (not significant), and at week 12, the respective NPVs were 91% and 90% and PPVs were 44% and 46% (not significant). At week 12, 83% (20/24) and 96% (23/24) of patients with SVR tested negative for HCV RNA by the Abbott and Roche assays, respectively (the difference is not significant). In conclusion, the high sensitivities and large dynamic ranges of the Abbott and Roche assays show that a single real-time quantitative PCR assay is fully adequate for clinical and therapeutic management of HCV.

Histological features and HLA class II alleles in hepatitis C virus chronically infected patients with persistently normal alanine aminotransferase levels

Objective: A significant proportion of individuals with chronic hepatitis C virus (HCV) infection have persistently normal alanine aminotransferase (ALT) levels. Although data are controversial, such patients usually have weaker histological damage and a lower progression rate of fibrosis. The aims of this study were: (1) to compare demographic, virological, and histological parameters of HCV patients with normal ALT values with those of HCV patients with elevated ALT levels; and (2) to determine whether HLA class II alleles contribute to the persistence of normal ALT levels in HCV patients. Patients and methods: Eighty three patients with chronic HCV infection and persistently normal ALT values (group 1) and 233 patients with chronic HCV infection and elevated ALT levels (group 2) were studied. Histological features were expressed using Knodell and Metavir scores. HLA DRB1* and DQB1* genotyping was performed using hybridisation with sequence specific oligonucleotides after genomic amplification. The κ2 and Fisher’s exact tests were used to compare discrete variables and phenotype frequencies between the two groups, and Wilcoxon’s test was used for continuous variables. A multivariate logistic regression model was used to determine which variables predicted normal ALT values. Results: ALT levels were correlated with the severity of liver damage. In group 1, 93% of patients had an F0 or F1 Metavir index of fibrosis compared with 47% of patients in group 2 (p<0.001). A longer duration of infection (p<0.001) and increased DRB1*11 phenotype frequency (pc=0.03) were observed among patients with normal ALT. The two groups did not differ with regard to the mode of contamination or viral genotype. After logistic regression, young age (p=0.0008), female sex (p=0.01), long duration of infection (p=0.0001), and HLA DRB1*11 (p=0.050) were more strongly associated with persistence of normal ALT. Conclusions: Our study confirms that patients with chronic hepatitis C and normal ALT levels have less severe liver disease than those with elevated ALT levels. This particular biochemical outcome may be explained, at least in part, by host immunogenetic factors such as the presence of HLA-DRB1*11.