All-Cause Mortality and Causes of Death in the Swiss Hepatitis C Cohort Study (SCCS).

With direct-acting antiviral agents (DAAs), mortality rates and causes of death among persons with hepatitis C virus (HCV) infection may change over time. However, the emergence of such trends may be delayed by the slow progression of chronic hepatitis C. To date, detailed analyses of cause-specific mortality among HCV-infected persons over time remain limited. We evaluated changes in causes of death among Swiss Hepatitis C Cohort Study (SCCS) participants from 2008 to 2016. We analyzed risk factors for all-cause and cause-specific mortality, accounting for changes in treatment, fibrosis stage, and use of injectable drugs over time. Mortality ascertainment was completed by linking lost-to-follow-up participants to the Swiss Federal Statistical Office death registry. We included 4700 SCCS participants, of whom 478 died between 2008 and 2016. The proportion of unknown causes of death decreased substantially after linkage, from 42% to 10%. Leading causes of death were liver failure (crude death rate 4.4/1000 person-years), liver cancer (3.4/1000 person-years), and nonliver cancer (2.8/1000 person-years), with an increasing proportion of cancer-related deaths over time. Cause-specific analysis showed that persons with sustained virologic response were less at risk for liver-related mortality than those never treated or treated unsuccessfully. Although the expected decrease in mortality is not yet observable, causes of death among HCV-infected persons have evolved over time. With the wider use of DAAs, liver-related mortality is expected to decline in the future. Continued monitoring of cause-specific mortality will remain important to assess the long-term effect of DAAs and design effective interventions

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

Trends in hepatitis C-related mortality in Switzerland

In order to accurately assess the burden of hepatitis C (HCV) and develop effective interventions, we must understand the magnitude and trends of mortality related to the disease. In the United States, HCV-related mortality is continuously increasing. We have no comparable data for Switzerland and other European countries, although a modelling study predicted a similar increase. We analysed time trends (1 January 1995-31 December 2014) in HCV-specific mortality rates in the Swiss general population using the death registry of the Swiss Federal Statistical Office (SFSO). We compared HCV-related mortality to HIV-related and hepatitis B (HBV)-related mortality. To determine potential under-reporting in HCV-related mortality, we probabilistically linked the SFSO data to persons who died in the Swiss Hepatitis C Cohort Study (SCCS). SFSO data showed that HCV-related mortality more than doubled between 1995 and 2003, but has since stabilized at ~2.5/100 000 person-years. Since 2000, HCV-related mortality has been higher than HIV-related mortality and was about fivefold higher in 2014. HBV-related mortality remained low at ~0.5/100 000 person-years. Of 4556 persons in the SCCS, 421 have died and 86.2% could be linked to the death registry. According to the SCCS, 133 deaths were HCV-related. HCV was not mentioned on the SFSO death certificate of 45% of these (n = 60/133). In conclusion, HCV-related mortality remained constant, possibly because quality of care was high, or because of under-reporting or because mortality has not yet increased. However, HCV-related mortality is now much higher than HIV- and HBV-related mortality, and under-reporting was common

Characteristics of Foreign-Born Persons in the Swiss Hepatitis C Cohort Study: Implications for Screening Recommendations

Switzerland recommends individuals who originate from high-prevalence countries to be screened for hepatitis C virus (HCV) infection. However, not all these persons are equally at risk. We thus aimed to describe the number and characteristics of persons with HCV infection born outside of Switzerland

Characteristics of patients with chronic hepatitis C who develop hepatocellular carcinoma.

BACKGROUND AND AIM: 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. METHODS: Analysis of the database of the Swiss Hepatitis C Cohort Study, a multicentre study that is being carried out in eight major Swiss hospitals since the year 2000. Patients with chronic hepatitis C and HCC were regrouped and compared to the patients without HCC. RESULTS: Among the 3,390 patients of the cohort, 130 developed an HCC. Age was one of the determining factors. Cirrhosis and its complications ascites and porto-systemic encephalopathy were associated with HCC. Males presented a higher risk for HCC than females. Alcohol consumption was associated with HCC. Diabetes mellitus was an important risk factor, especially in patients with low fibrosis. Patients with Hepatitis C genotype 2 had significantly less HCC than patients with other genotypes. A low socioeconomic status (income, education, profession) was associated with HCC. CONCLUSIONS: Beside the expected characteristics (age, gender, cirrhosis, alcohol), these data stress the role of diabetes mellitus and reveal the importance of low socioeconomic status as a risk factor for HCC in Swiss patients infected with hepatitis C virus. This vulnerable population should be closely monitored

IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction.

Approximately 3% of the world population is chronically infected with the hepatitis C virus (HCV), with potential development of cirrhosis and hepatocellular carcinoma. Despite the availability of new antiviral agents, treatment remains suboptimal. Genome-wide association studies (GWAS) identified rs12979860, a polymorphism nearby IL28B, as an important predictor of HCV clearance. We report the identification of a novel TT/-G polymorphism in the CpG region upstream of IL28B, which is a better predictor of HCV clearance than rs12979860. By using peripheral blood mononuclear cells (PBMCs) from individuals carrying different allelic combinations of the TT/-G and rs12979860 polymorphisms, we show that induction of IL28B and IFN-γ-inducible protein 10 (IP-10) mRNA relies on TT/-G, but not rs12979860, making TT/-G the only functional variant identified so far. This novel step in understanding the genetic regulation of IL28B may have important implications for clinical practice, as the use of TT/G genotyping instead of rs12979860 would improve patient management

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