Safety and efficacy of triple therapy with peginterferon, ribavirin and boceprevir within an early access programme in Spanish patients with hepatitis C genotype 1 with severe fibrosis: SVRw12 analysis.

BACKGROUND & AIMS: The addition of protease inhibitors (PIs) changed the hepatitis C virus (HCV) treatment standards and improved sustained viral response (SVR) rates in patients with genotype 1 HCV infection. METHODS: Prospective, multicentre, national registry that includes naïve and treatment-experienced patients with HCV genotype 1 infection, who had bridging fibrosis or cirrhosis and were treated with triple therapy (peginterferon alfa-2a or alfa-2b, ribavirin and boceprevir) as compassionate use, and in accordance with the Summary of Product Characteristics. RESULTS: Most of the patients (68.2%) were male, with a mean age of 53 years, 75% (n = 128) had HCV 1b genotype and baseline viral load of 6.2 log. According to prior treatment, 20% of patients were treatment-naïve and 80% had received prior treatment. Approximately 36.5% of patients (n = 62) reported at least one serious adverse events (SAEs) (total SAEs = 103). The most common SAEs were neutropenia (57.6%), anaemia (47.6%) and grade 3 thrombopenia (25.9%). Patients with albumin <3.5 g/dl and bilirubin >2 mg/dl had an increased relative risk (greater than one-fold) for SAEs, including infections and hepatic decompensation. In the intent-to-treat analysis (n = 170), the overall percentage of patients with SVRw12 was 46.5%. In patients with 1 log decrease at week 4 (lead-in phase), the overall SVRw12 rate was 67.0%. In the patients initiating triple therapy with boceprevir (n = 139), the global response rate was 56.4%. In a multivariate analysis, an increased probability of achieving SVR was associated with response to prior treatment (relapsers), >1 log decrease in viral load in the lead-in phase and baseline albumin >3.5 g/dl. CONCLUSIONS: Triple therapy in patients with severe fibrosis/cirrhosis is associated with a higher rate of SAE and a lower rate in comparison with patients with mild disease. However, for patients with intact liver function, it could be considered as a treatment option, when other alternatives would not be available.

A predictive model of treatment outcome in patients with chronic HCV infection using IL28B and PD-1 genotyping.

BACKGROUND & AIMS: The advent of new chronic hepatitis C virus (HCV) therapies requires characterization of patients in order to predict adequate treatment. A good candidate marker is Programmed Cell Death-1 (PD-1) which is involved in progression of HCV infection. The aim of this study was to analyse the effect of several single nucleotide polymorphisms of PD-1 gene and several previously associated factors (IL28B and KIR receptors) on treatment responses. METHODS: 407 HCV chronic infected patients treated with PEG-IFN-α and ribavirin were recruited and classified according to their response to treatment. They were genotyped for PD-1 and IL28B polymorphisms, killer immunoglobulin-like receptors (KIR) and HLA genes. A multivariate logistic regression analysis and a Chi-squared Automatic Interaction Detector (CHAID) prediction model of response included these and other clinical parameters. RESULTS: Our results showed that PD-1.3/A allele was significantly associated with sustained virological response (SVR) in a multivariate logistic regression analysis (p<0.01, OR=2.57). Additionally, IL28B C/C genotype was the most significant predictor of an SVR to treatment in all HCV genotypes (74.5%). In IL28B C/C patients, the presence of PD-1.3/A allele increased the probability of an SVR to 93.3%. Moreover, when this analysis was made only with patients infected by HCV-1, the predictive value of IL28B C/C genotype with PD-1.3/A allele was 90%. CONCLUSIONS: PD-1.3/A allele is associated with SVR to treatment and notably increases the predictive value of IL28B C/C genotype. Both markers in conjunction could be a useful tool, more relevant than HCV genotype in some cases, in clinical practice.

Acute hepatitis C in Spain: a retrospective study of 131 cases.

BACKGROUND AND AIMS: The management of acute hepatitis C (AHC) is controversial. We have conducted a retrospective study to determine the epidemiological and biochemical aspects, the genotypes, the spontaneous clearance of HCV (SVC), and the treatment responses in patients with AHC. METHODS: We have retrospectively collected data from 131 patients with AHC from 18 Spanish hospitals. RESULTS: The mean age was 43 ± 16 years (17-83), 69% were symptomatic. The causes of infection were nosocomial in 40% and intravenous drug users in 20%. Eighty two percent had genotype 1. The delay from symptoms-onset to HCV-RNA confirmation was 50 ± 68 days (range, 11-350 days) and to treatment (in 59%) 14±1 3 weeks (range, 2-58 days). In the treated group, 80% achieved sustained virological response (SVR) versus 57% SVC in untreated patients (p = 0.004). Up to 96% of those treated within the first 12 weeks had SVR versus 86% of those treated later (p = 0.04). Patients with HCV-RNA(-) at week 4 resolved with or without treatment more frequently than those HCV-RNA(+) (98% versus 69%, p = 0.005). The treatment was not beneficial if HCV-RNA was undetectable at week 12. No differences in SVR were found in genotype 1 patients treated for 24 or 48 weeks. Patients with low baseline viral load achieved higher SVC and SVR. The SVC in patients with bilirubin > 5 mg/dL was 78 versus 40% in those with lower values (p = 0.004). CONCLUSIONS: The most common transmission route was nosocomial. SVR was higher in patients treated than SVC in non-treated.Early treatment (before week 12) achieved the highest response rate. SVC and SVR were more common in patients with a low baseline viral load. Undetectable HCV-RNA at week 4 was associated with high SVR and SVC rates. Jaundice was related with SVC.

Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex.

Increased age and female sex are suggested risk factors for drug-induced hepatotoxicity (DILI). We studied the influence of these variables on the propensity to develop DILI, as well as its clinical expression and outcome. All cases of DILI submitted to the Spanish Registry between April 1994 and August 2007 were analyzed. Six hundred three DILI cases (310 men; mean age, 54 years) showed a similar sex distribution, reaching two peaks in the 40- to 49-year-old and 60- to 69-year-old age groups. No cases were recorded in the 20- to 29-year-old group. Patients aged > or =60 years accounted for 46% of the cases, with a male predominance (158 males, 118 females; P= 0.009), as opposed to younger patients. Older age was independently associated with cholestatic type of injury (odds ratio for an age interval for 1 year: 1.024 [95% confidence interval: 1.010-1.038]; male/female ratio, 1:2; P = 0.001) and younger age with hepatocellular damage (odds ratio: 0.983 [95% confidence interval: 0.972-0.994]; female/male ratio, 1:2; P = 0.002). In the mixed group, no age effect was evident. Outcome with fulminant liver failure/liver transplantation was more frequently encountered in women (P < 0.01). conclusion: Neither older age nor female sex are predisposing factors to overall DILI. However, older age is a determinant for cholestatic damage with a male predominance, whereas younger age is associated with cytolytic damage and a female overrepresentation. Women distinctly exhibit the worst outcome. Knowledge of these phenotypic associations could guide differential diagnosis and attribution of causality in DILI.

Optical analysis of computed tomography images of the liver predicts fibrosis stage and distribution in chronic hepatitis C.

UNLABELLED: This study was undertaken to evaluate an image processing method for assessing liver fibrosis in conventional computed tomography (CT) scans in patients with chronic hepatitis C. Two cohorts (designated "estimation," n = 34; and "validation," n = 107) of chronic hepatitis C patients were assessed using digitized conventional helical CT. Weighted CT mean fibrosis (Fibro-CT) was calculated as a nonlinear weighted mean F-score for each sample. Fibrosis was defined according to Scheuer on the F0 to F4 scale by 2 pathologists blinded regarding the Fibro-CT data. Fibrosis according to Fibro-CT correlated with histology-determined fibrosis (r = 0.69; P < 0.001) and with increasing F-stage: F0 = 0.23 +/- 0.39; F1 = 0.90 +/- 0.99; F2 = 1.41 +/- 0.94; F3 = 2.79 +/- 0.55; F4 = 3.15 +/- 0.35 [analysis of variance: P < 0.0001). The receiver operating characteristics curve to diagnose significant fibrosis (>/=F2) was 0.83; 95% confidence interval (95%CI), 0.75 to 0.91; and, to diagnose advanced fibrosis (>/=F3), was 0.86, 95%CI: 0.80 to 0.93. The correlation between Fibro-CT and fibrosis was higher in patients with homogeneous distribution of fibrosis than in patients with heterogeneous distribution (r = 0.77 versus r = 0.43; P < 0.05). CONCLUSION: Optical digital analysis of CT images of the liver is effective in determining the stage and distribution of liver fibrosis in chronic hepatitis C. In patients with homogeneous fibrosis distribution, the correlation between Fibro-CT and histology was better than in patients with heterogeneous distribution. Fibro-CT is a simple to use, readily available, and useful method for the diagnosis of fibrosis in patients with chronic hepatitis C.

Diversity of killer cell immunoglobulin-like receptor (KIR) genotypes and KIR2DL2/3 variants in HCV treatment outcome.

The aim of this study was to analyse the distribution of KIR haplotypes and the KIR2DL2/3 alleles in chronic HCV-infected patients in order to establish the influence on the response to pegylated interferon plus ribavirin classical treatment. The alleles study of previously associated KIR2DL2/3 showed that KIR2DL2*001 was more frequent in non-SVR (NSVR) (42.2% vs. 27.5%, p<0.05) and KIR2DL3*001 was associated with sustained viral response (SVR) (41.6% vs. 61.2%, p<0.005). The KIR2DL3*001-HLA-C1 association was also significant (24.5% vs. 45.7%, p<0.001). From the frequencies of KIR obtained, 35 genotypes were assigned on the basis of previous studies. The centromeric A/A genotype was more frequent in SVR (44.1% vs. 34.5%, p<0.005) and the centromeric B/B genotype was found to be significantly more frequent in NSVR (20.9% vs. 11.2%, p<0.001). The logic regression model showed the importance of KIR genes in predicting the response to combined treatment, since the positive predictive value (PPV) was improved (from 55.9% to 75.3%) when the analysis of KIR was included in addition to the IFNL3 rs12979860 polymorphism. The study of KIR receptors may be a powerful tool for predicting the combined treatment response in patients with chronic HCV infection in association with the determination of IFNL3 polymorphism.