Showing papers by "Beat Müllhaupt published in 2019"

Very Low Hepatitis C Viral Loads in Treatment-naive Persons: Do They Compromise Hepatitis C Virus Antigen Testing?

Abstract: BACKGROUND Hepatitis C virus (HCV) antigen testing is less expensive than quantitative RT-PCR but has lower sensitivity for very low viral loads (VLVL; HCV RNA ≤3,000 IU/ml). Currently the benefits of antigen testing for screening are discussed, but data on prevalence and outcomes of persons with VLVL are scarce. METHODS We assessed prevalence and predictors of VLVL by logistic regression in treatment-naive participants in the Swiss Hepatitis C Cohort Study. We analyzed if the last viral load after VLVL was low, compared cirrhosis and mortality in persons with and without VLVL, and evaluated the number of samples with VLVL that were reactive by antigen testing. RESULTS We included 2,533 treatment-naive persons with available quantitative HCV RNA testing results. Overall, 133 persons (5.3%) had a VLVL. Age 18-40 years, female gender and HIV coinfection were associated with VLVL. Of 72 persons with a viral load available after VLVL, 14% had a VLVL and 17% had spontaneous viral clearance. The prevalence and incidence of cirrhosis and mortality were comparable in persons with and without VLVL; all 24 persons with VLVL and cirrhosis had excessive alcohol consumption or immunosuppression. Overall 33% of samples with VLVL were reactive by antigen testing. CONCLUSIONS The frequency of VLVL was low. Among the persons who would probably be missed by antigen screening, some had a favorable disease course, but some had immunosuppression and liver cirrhosis. The benefit of HCV antigen testing for screening may be limited by the risk of missing patients with severe liver disease.

Identification of an Endoglin Variant Associated With HCV-Related Liver Fibrosis Progression by Next-Generation Sequencing.

Abstract: Despite the astonishing progress in treating chronic hepatitis C virus (HCV) infection with direct-acting antiviral agents, liver fibrosis remains a major health concern in HCV infected patients, in particular due to the treatment cost and insufficient HCV screening in many countries. Only a fraction of patients with chronic HCV infection develop liver fibrosis. While there is evidence that host genetic factors are involved in the development of liver fibrosis, the common variants identified so far, in particular by genome-wide association studies, were found to have limited effects. Here, we conducted an exome association study in 88 highly selected HCV-infected patients with and without fibrosis. A strategy focusing on TGF-β pathway genes revealed an enrichment in rare variants of the endoglin gene (ENG) in fibrosis patients. Replication studies in additional cohorts (617 patients) identified one specific ENG variant, Thr5Met, with an overall odds ratio for fibrosis development in carriers of 3.04 (1.39-6.69). Our results suggest that endoglin, a key player in TGF-β signaling, is involved in HCV-related liver fibrogenesis.

Microelimination of chronic hepatitis C in Switzerland: modelling the Swiss Hepatitis Strategy goals in eastern, western and northern regions.

Abstract: Background and aims Direct-acting antiviral agents have revolutionised hepatitis C treatment. In 2014, the Swiss Hepatitis Strategy was developed to eliminate hepatitis C virus (HCV) infection and the associated liver-related morbidity and mortality by 2030. Though numerous national studies and assessments have identified a relatively low prevalence rate of 0.7% in the country, little has been done to identify the epidemiology of HCV on the regional, or micro, level. This study aimed to identify scenarios to achieve the objectives of Swiss Hepatitis Strategy by 2030 in eastern, western and northern regions in Switzerland. Methods Three Excel-based Markov disease burden models, based on hospital- and region-specific data, were developed to forecast the current and future prevalence of HCV infection by fibrosis stage and liver disease stage to 2030. Two scenarios were developed to evaluate the disease burden in St Gallen, Geneva and Zurich: a Base 2016 scenario, representing the current standard of care in each canton, and a second, potential scenario to achieve the Swiss Hepatitis Strategy goals. Results In 2015, the estimated viraemic prevalence in St Gallen was 0.5% (0.5n0.6%) corresponding to 2800 (2600n3100) cases. In Geneva and Zurich, the estimated prevalence was slightly higher, with an estimated 0.7% (0.6n0.7%) viraemic prevalence, or 3300 (3000n3600) cases in Geneva and 0.7% (0.7n0.8%) viremic prevalence, or 10,800 (9900n11,900) infectionsin Zurich. In order to achieve the Swiss Hepatitis Strategy goals of a 30% reduction in new infections, total viraemic infections, liver transplants, and hepatocellular carcinoma cases by 2020 and a 90% reduction by 2030, all regions will need to increase the annual number of treated and diagnosed patients up to 2030. In St Gallen, an up-front investment to treat 430 patients annually by 2020 would be necessary, to achieve the 2020 goals. After 2020, treatment could be reduced to ~150 patients annually until 2030. The number of patients diagnosed, however, would need to be sustained at 130 annually after 2020. In Geneva, 235 patients need to be treated, with 140 diagnosed annually between 2019 and 2030 to achieve both 2020 and 2030 goals. In Zurich, 850 patients will need to be treated annually in 2019 and 2020 and the number of diagnosed will need to expand to 350 individuals annually by 2022. Conclusions Intensified screening for chronic hepatitis C and increased access to direct-acting antivirals are necessary to meet the Swiss hepatitis strategy elimination goals over the next 12 years.

Impact of geographic origin on access to therapy and therapy outcomes in the Swiss Hepatitis C Cohort Study.

Abstract: Late diagnosis and treatment may increase morbidity and mortality among persons with hepatitis C virus (HCV) infection. We included all participants of the Swiss Hepatitis C Cohort Study (SCCS). We used unadjusted and adjusted logistic and Cox regressions to determine the association between the geographic origin of the participants and the following outcomes: antiviral treatment status; sustained virologic response; cirrhosis at enrolment; incident cirrhosis; loss to follow-up (LTFU); and mortality. The analyses were adjusted for sex, baseline age, education, source of income, alcohol consumption, injection drug use (IDU), HCV genotype, HIV or HBV coinfection, duration of HCV infection, time since enrolment, cirrhosis, (type of) HCV treatment, and centre at enrolment. Among 5,356 persons, 1,752 (32.7%) were foreign-born. IDU was more common among Swiss- (64.1%) than foreign-born (36.6%) persons. Cirrhosis at enrolment was more frequent among foreign- than Swiss-born persons, reflecting the high frequency of cirrhosis among Italian-born persons who acquired HCV between 1950 and 1970 in Italian healthcare settings. Although antiviral treatment coverage was similar, the sustained viral response rate was increased and the mortality was lower among foreign-vs. Swiss-born persons, with the lowest mortality in persons from Asia/Oceania. LTFU was more frequent in persons from Germany, Eastern and Southern Europe, and the Americas. In conclusion, in Switzerland, a country with universal healthcare, geographic origin had no influence on hepatitis C treatment access, and the better treatment outcomes among foreign-born persons were likely explained by their lower prevalence of IDU and alcohol consumption than among Swiss-born persons.

Human genomics of acute liver failure due to hepatitis B virus infection: An exome sequencing study in liver transplant recipients.

Abstract: Acute liver failure (ALF) or fulminant hepatitis is a rare, yet severe outcome of infection with hepatitis B virus (HBV) that carries a high mortality rate. The occurrence of a life-threatening condition upon infection with a prevalent virus in individuals without known risk factors is suggestive of pathogen-specific immune dysregulation. In the absence of established differences in HBV virulence, we hypothesized that ALF upon primary infection with HBV could be due to rare deleterious variants in the human genome. To search for such variants, we performed exome sequencing in 21 previously healthy adults who required liver transplantation upon fulminant HBV infection and 172 controls that were positive for anti-HBc and anti-HBs but had no clinical history of jaundice or liver disease. After a series of hypothesis-driven filtering steps, we searched for putatively pathogenic variants that were significantly associated with case-control status. We did not find any causal variant or gene, a result that does not support the hypothesis of a shared monogenic basis for human susceptibility to HBV-related ALF in adults. This study represents a first attempt at deciphering the human genetic contribution to the most severe clinical presentation of acute HBV infection in previously healthy individuals.

A rare cause of a cholestatic jaundice in a North African teenager

Abstract: We report an unusual case of intermittent episodes of cholestasis in a young patient. The cholestatic attacks were preceded in each case by an infection and subsequent antibiotic therapies. After ruling out many possible causes of cholestatic hepatitis, the differential diagnoses were a benign recurrent intrahepatic cholestasis or a drug-induced liver injury. We discuss here the diagnostic approach and interpretation of the genetic analysis.

All-cause mortality and causes of death in the Swiss Hepatitis C Cohort Study

Abstract: Background & Aims With the introduction of direct-acting antiviral agents (DAA), mortality rates and causes of death among persons with hepatitis C virus (HCV) infection are likely to change over time. However, the emergence of such trends may be delayed by the relatively slow progression of chronic hepatitis C. To date, detailed analyses of cause-specific mortality among HCV-infected persons over time remain limited. Methods We evaluated changes in causes of death among the Swiss Hepatitis C Cohort Study (SCCS) participants, from 2008 to 2016. We analysed 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 (SFSO) death registry. Results We included 4,700 SCCS participants, of whom 478 died between 2008 and 2016. Linkage to the SFSO death registry substantially improved the information on causes of death (from 42% of deaths with unknown cause to 10% after linkage). Leading causes of death were liver failure (crude death rate 4.4/1000 person-years), liver cancer (3.4/1000 p-yrs) and non-liver cancer (2.8/1000 p-yrs), with an increasing proportion of cancer-related deaths over time. Cause-specific analysis showed that persons with sustained virologic response (SVR) were less at risk for liver-related mortality than those never treated or treated unsuccessfully. Conclusions Although the expected decrease in mortality is not yet observable, causes of death among HCV-infected persons evolved over time. With the progressive widening of guidelines for DAA use, 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 DAA and to design effective interventions. Lay summary Leading causes of death among persons with hepatitis C virus (HCV) infection in the Swiss Hepatitis C Cohort study evolved over the past years, with an increasing proportion of cancer-related deaths. The positive impact of new potent anti-HCV drugs on mortality among HCV-infected persons is not yet observable, due to both the slow progression of chronic hepatitis C and the progressive relaxation of guidelines for the use of those new drugs.