Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study

Hepatitis C virus (HCV) induces chronic infection in 50% to 80% of infected persons; approximately 50% of these do not respond to therapy. We performed a genome-wide association study to screen for host genetic determinants of HCV persistence and response to therapy.

Strategies for subacute/chronic type B aortic dissection: the Investigation Of Stent Grafts in Patients with type B Aortic Dissection (INSTEAD) trial 1-year outcome

Endovascular stent grafting represents a novel concept for type B aortic dissection both in the acute and subacute/chronic setting, with an unknown effect on outcomes.

Midterm results of thoracic endovascular aortic repair in patients with aneurysms involving the descending aorta originating from chronic type B dissections

Midterm results of TEVAR (thoracic endovascular aortic repair) in patients with aneurysms involving the descending aorta originating from chronic type B dissections are not known.

Molecular epidemiology of a large community-based outbreak of hepatitis B in Bristol, U.K.

A large outbreak of hepatitis B virus (HBV) infection in the U.K. occurred between 2001 and 2005 in Bristol, U.K.

Investigation of a large community-based outbreak of hepatitis B infection in the United Kingdom

We describe the largest outbreak of hepatitis B virus infection reported to date in the UK. Between July 2001 and December 2005, 237 cases were identified in Avon, South West England. The likely route of transmission was injecting drug use in 44% (104/237) and heterosexual intercourse in 30% (71/237) of cases. A case-control study in injectors showed that injecting crack cocaine [adjusted odds ratio (aOR) 23·8, 95% confidence interval (CI) 3·04-186, P<0·001] and sharing injecting paraphernalia in the year before diagnosis (aOR 16·67, 95% CI 1·78-100, P=0·010) were strongly associated with acute hepatitis B. In non-IDUs number of sexual partners and lack of consistent condom use were high compared to a national sample. We describe the control measures implemented in response to the outbreak. This outbreak has highlighted the problems associated with the low uptake from the national hepatitis B vaccination policy which targets high-risk groups, the difficulties of identifying those at risk of acquiring hepatitis B infection through heterosexual sex, and injecting crack cocaine as a risk factor for hepatitis B.

Impact of a nurse vaccination program on hepatitis B immunity in a Swiss HIV clinic

We evaluated the impact of a nurse program for hepatitis B virus vaccination in a center from the Swiss HIV Cohort Study. Immunity (anti-HBs >10 IU/mL) increased from 32% to 76% in the intervention center (n = 238) where vaccine management was endorsed by nurses, but only from 33% to 39% in control centers (n = 2712, P < 0.001) where management remained in charge of physicians. Immunity against HBV in the HIV population is insufficient in Switzerland. Specific nurse vaccination program may efficiently improve health care.

Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis

Chronic hepatitis C virus (HCV) infection outcomes include liver failure, hepatocellular carcinoma (HCC), and liver-related death.

Characteristics of patients with chronic hepatitis C who develop hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most frequent form of primary liver cancer and chronic infection with hepatitis C virus is one of the main risk factors for HCC. This study analyses the characteristics of the patients with chronic hepatitis C participating in the Swiss Hepatitis C Cohort Study who developed HCC.

A genetic validation study reveals a role of vitamin D metabolism in the response to interferon-alfa-based therapy of chronic hepatitis C

Background To perform a comprehensive study on the relationship between vitamin D metabolism and the response to interferon-α-based therapy of chronic hepatitis C. Methodology/Principal Findings Associations between a functionally relevant polymorphism in the gene encoding the vitamin D 1α-hydroxylase (CYP27B1-1260 rs10877012) and the response to treatment with pegylated interferon-α (PEG-IFN-α) and ribavirin were determined in 701 patients with chronic hepatitis C. In addition, associations between serum concentrations of 25-hydroxyvitamin D3 (25[OH]D3) and treatment outcome were analysed. CYP27B1-1260 rs10877012 was found to be an independent predictor of sustained virologic response (SVR) in patients with poor-response IL28B genotypes (15% difference in SVR for rs10877012 genotype AA vs. CC, p = 0.02, OR = 1.52, 95% CI = 1.061–2.188), but not in patients with favourable IL28B genotype. Patients with chronic hepatitis C showed a high prevalence of vitamin D insufficiency (25[OH]D3<20 ng/mL) during all seasons, but 25(OH)D3 serum levels were not associated with treatment outcome. Conclusions/Significance Our study suggests a role of bioactive vitamin D (1,25[OH]2D3, calcitriol) in the response to treatment of chronic hepatitis C. However, serum concentration of the calcitriol precursor 25(OH)D3 is not a suitable predictor of treatment outcome.

Serum ferritin levels are associated with a distinct phenotype of chronic hepatitis C poorly responding to pegylated interferon-alpha and ribavirin therapy

Elevated serum ferritin levels may reflect a systemic inflammatory state as well as increased iron storage, both of which may contribute to an unfavorable outcome of chronic hepatitis C (CHC). We therefore performed a comprehensive analysis of the role of serum ferritin and its genetic determinants in the pathogenesis and treatment of CHC. To this end, serum ferritin levels at baseline of therapy with pegylated interferon-alpha and ribavirin or before biopsy were correlated with clinical and histological features of chronic hepatitis C virus (HCV) infection, including necroinflammatory activity (N = 970), fibrosis (N = 980), steatosis (N = 886), and response to treatment (N = 876). The association between high serum ferritin levels (> median) and the endpoints was assessed by logistic regression. Moreover, a candidate gene as well as a genome-wide association study of serum ferritin were performed. We found that serum ferritin ≥ the sex-specific median was one of the strongest pretreatment predictors of treatment failure (univariate P < 0.0001, odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.34-0.60). This association remained highly significant in a multivariate analysis (P = 0.0002, OR = 0.35, 95% CI = 0.20-0.61), with an OR comparable to that of interleukin (IL)28B genotype. When patients with the unfavorable IL28B genotypes were stratified according to high versus low ferritin levels, SVR rates differed by > 30% in both HCV genotype 1- and genotype 3-infected patients (P < 0.001). Serum ferritin levels were also independently associated with severe liver fibrosis (P < 0.0001, OR = 2.67, 95% CI = 1.68-4.25) and steatosis (P = 0.002, OR = 2.29, 95% CI = 1.35-3.91), but not with necroinflammatory activity (P = 0.3). Genetic variations had only a limited impact on serum ferritin levels. Conclusion: In patients with CHC, elevated serum ferritin levels are independently associated with advanced liver fibrosis, hepatic steatosis, and poor response to interferon-alpha-based therapy.

Liver kidney microsomal type 1 antibodies reduce the CYP2D6 activity in patients with chronic hepatitis C virus infection

Liver kidney microsomal type 1 (LKM-1) antibodies have been shown to decrease the CYP2D6 activity in vitro and are present in a minority of patients with chronic hepatitis C infection. We investigated whether LKM-1 antibodies might reduce the CYP2D6 activity in vivo. All patients enrolled in the Swiss Hepatitis C Cohort Study and tested for LKM-1 antibodies were assessed (n = 1723): 10 eligible patients were matched with patients without LKM-1 antibodies. Patients were genotyped for CYP2D6 variants to exclude individuals with a poor metabolizer genotype. CYP2D6 activity was measured by a specific substrate using the dextromethorphan/dextrorphan metabolic ratio to classify patients into four activity phenotypes. All patients had a CYP2D6 extensive metabolizer genotype. The observed phenotype was concordant with the CYP2D6 genotype in most LKM-negative patients, whereas only three LKM-1 positive patients had a concordant phenotype (six presented an intermediate and one a poor metabolizer phenotype). The median DEM/DOR ratio was sixfold higher in LKM-1 positive than in LKM-1 negative patients (0.096 vs. 0.016, P = 0.004), indicating that CYP2D6 metabolic function was significantly reduced in the presence of LKM-1 antibodies. In chronic hepatitis C patients with LKM-1 antibodies, the CYP2D6 metabolic activity was on average reduced by 80%. The impact of LKM-1 antibodies on CYP2D6-mediated drug metabolism pathways warrants further translational studies.