[Show abstract][Hide abstract] ABSTRACT: The disease burden of hepatitis C virus (HCV) is expected to increase as the infected population ages. A modelling approach was used to estimate the total number of viremic infections, diagnosed, treated and new infections in 2013. In addition, the model was used to estimate the change in the total number of HCV infections, the disease progression and mortality in 2013-2030. Finally, expert panel consensus was used to capture current treatment practices in each country. Using today's treatment paradigm, the total number of HCV infections is projected to decline or remain flat in all countries studied. However, in the same time period, the number of individuals with late-stage liver disease is projected to increase. This study concluded that the current treatment rate and efficacy are not sufficient to manage the disease burden of HCV. Thus, alternative strategies are required to keep the number of HCV individuals with advanced liver disease and liver-related deaths from increasing.
[Show abstract][Hide abstract] ABSTRACT: Chronic infection with hepatitis C virus (HCV) is a leading indicator for liver disease. New treatment options are becoming available, and there is a need to characterize the epidemiology and disease burden of HCV. Data for prevalence, viremia, genotype, diagnosis and treatment were obtained through literature searches and expert consensus for 16 countries. For some countries, data from centralized registries were used to estimate diagnosis and treatment rates. Data for the number of liver transplants and the proportion attributable to HCV were obtained from centralized databases. Viremic prevalence estimates varied widely between countries, ranging from 0.3% in Austria, England and Germany to 8.5% in Egypt. The largest viremic populations were in Egypt, with 6 358 000 cases in 2008 and Brazil with 2 106 000 cases in 2007. The age distribution of cases differed between countries. In most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use. Diagnosis, treatment and transplant levels also differed considerably between countries. Reliable estimates characterizing HCV-infected populations are critical for addressing HCV-related morbidity and mortality. There is a need to quantify the burden of chronic HCV infection at the national level.
[Show abstract][Hide abstract] ABSTRACT: The number of hepatitis C virus (HCV) infections is projected to decline while those with advanced liver disease will increase. A modeling approach was used to forecast two treatment scenarios: (i) the impact of increased treatment efficacy while keeping the number of treated patients constant and (ii) increasing efficacy and treatment rate. This analysis suggests that successful diagnosis and treatment of a small proportion of patients can contribute significantly to the reduction of disease burden in the countries studied. The largest reduction in HCV-related morbidity and mortality occurs when increased treatment is combined with higher efficacy therapies, generally in combination with increased diagnosis. With a treatment rate of approximately 10%, this analysis suggests it is possible to achieve elimination of HCV (defined as a >90% decline in total infections by 2030). However, for most countries presented, this will require a 3-5 fold increase in diagnosis and/or treatment. Thus, building the public health and clinical provider capacity for improved diagnosis and treatment will be critical.
[Show abstract][Hide abstract] ABSTRACT: Background
Genetic factors can play an important role for treatment response and disease progression in chronic viral hepatitis.AimTo review the influence of host genetic factors on the clinical course as well as on treatment response in patients with viral hepatitis.Methods
Review of the literature.ResultsA landmark genome-wide association study (GWAS) identified polymorphisms in the IL28B gene on chromosome 19 (19q13.13) associated with response to therapy with pegylated interferon-α (PEG-IFN) and ribavirin (RBV) and spontaneous viral clearance in acute hepatitis C. Furthermore, IL28B genotype is associated with changes of lipid metabolism and insulin resistance. A further GWAS demonstrated that ITPA genetic variants protect HCV genotype 1 patients from RBV-induced anaemia. Another polymorphism in the patatin-like phospholipase domain containing 3 (PNPLA3) is associated with hepatic steatosis. Difficult-to-treat hepatitis C patients homozygous for GG had an up to five-fold lower chance of viral clearance on PEG/RBV than non-GG patients.In chronic hepatitis B patients treated with PEG-IFN several retrospective analyses of IL28B rs12980275 and rs12979860 genotypes yielded conflicting results which can be explained by the heterogeneity between the study populations. Some variants of the HLA-DP locus (HLA-DPA1 A allele and HLA-DPB1) protect against progression of chronic hepatitis B infection.Conclusions
The determination of IL28B polymorphisms may be useful to individualise treatment options when using PEG/RBV based therapies for chronic hepatitis C infection. In contrast, so far identified genetic factors play only a minor role in chronic hepatitis B infection.
[Show abstract][Hide abstract] ABSTRACT: The IL28B genotype in rs12979860 predicts success of peginterferon/ribavirin (PEG/RBV) therapy in patients with chronic hepatitis C (CHC). Recently, a dinucleotide frame shift variant in ss469415590 (TT or ΔG) was described, which generates the novel interferon lambda 4 protein (IFNL4). IFNL4 ss469415590 (ΔG) allele carriers have an impaired clearance of HCV infection and response to IFN-α therapy. In this study, we compared the role of IFNL4 polymorphism with the two commonly used IL28B SNPs rs12979860 and rs8099917 on response to PEG/RBV in patients with CHC.
To compare the role of IFNL4 polymorphism with the two commonly used IL28B SNPs rs12979860 and rs8099917 on response to PEG/RBV in patients with CHC.
A total of 754 PEG/RBV patients treated (male/female = 484/270; Caucasians: 98.8%; mean age: 42.8 [CI 95%: 42.0-43.6] y; genotype (GT)1: n = 435, GT2: n = 23, GT3: n = 185, GT4: n = 114) were investigated. Liver fibrosis was assessed by liver biopsy in 456 patients. Single nucleotide polymorphisms (SNPs) in ss469415590, rs12979860 and rs8099917 were analysed by RT-PCR system.
Of the patients, 12.9% (n = 97) had the ss469415590 ΔG/ΔG genotype (IFNL4), 51.3% (n = 387) were heterozygous (TT/ΔG) and 35.8% (n = 270) had TT/TT. IFNL4 polymorphism was independently associated with SVR in GT1 (OR: 2.539, CI 95%: 1.629-3.021, P < 0.001) and GT4 (OR: 12.573, CI 95%: 3.427-46.133, P < 0.001), but not in GT3 (OR: 1.514, CI 95%: 0.933-2.458, P = 0.093). IFNL4 correlated strongly with rs12979860 (ρ = 0.988, P < 0.001), but only moderately with rs8099917 (ρ = 0.598, P < 0.001).
These findings underscore the role of IFNL4 for treatment response in patients with CHC genotypes 1 and 4. However, due to its strong correlation with rs12979860 in IL28B, there is no benefit in additional testing for IFNL4 for treatment prediction in Caucasian patients. By contrast, IFNL4 improves prediction of response to interferon-based therapies, if SNP rs8099917 is used.
[Show abstract][Hide abstract] ABSTRACT: Wilson disease is an autosomal recessive disorder that affects copper metabolism, leading to copper accumulation in liver, central nervous system, and kidneys. There are few data on long-term outcomes and survival from large cohorts; we studied these features in well-characterized Austrian cohort of patients with Wilson disease.
We analyzed data from 229 patients diagnosed with Wilson disease from 1961 through 2013; 175 regularly attended a Wilson disease outpatient clinic and/or their physicians were contacted for information on disease and treatment status and outcomes. For 53 patients lost during the follow-up period, those that died and reasons for their death were identified from the Austrian death registry.
The mean observation-period was 14.8±11.4 y (range, 0.5 y-52 y) resulting in 3116 patient-y. Of the patients, 61% presented with hepatic disease, 27% with neurologic symptoms, and 10% were diagnosed by family screening at pre-symptomatic stages. Patients with hepatic presentation were diagnosed younger (21.2±12.0 y) than patients with neurologic disease (28.8±12.0; P<.001). In 2% of patients, neither symptoms nor onset of symptoms could be determined with certainty. Most patients stabilized (35%) or improved on chelation therapy (26% fully recovered, 24% improved), but 15% deteriorated; 8% required liver transplantation and 7.4% died within the observation period (71% of deaths were related to Wilson disease). A lower proportion of patients with Wilson disease survived for 20 y (92%) than healthy Austrians (97%), adjusted for age and sex (P=.03). Cirrhosis at diagnosis was the best predictor of death (odds ratio, 6.8; 95% confidence interval, 1.5-31.03; P=.013) and need for liver transplantation (odds ratio, 07; 95% confidence interval, 0.016-0.307; P<.001). Only 84% of patients with cirrhosis survived 20 y after diagnosis (compared with healthy Austrians, P=.008).
Overall, patients who receive adequate care for Wilson disease have a good long-term prognosis. However, cirrhosis increases risk of death and liver disease. Early diagnosis, at a pre-cirrhotic stage, might increase survival times and reduce the need for liver transplantation.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 09/2013; · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Single nucleotide polymorphisms (SNP's) in the inosine triphosphate pyrophosphatase (ITPA) gene protect patients from ribavirin induced anemia. To investigate other possible protective cofactors gender differences were analyzed in patients with HCV genotype 1.
Hemoglobin levels at baseline (Hb0) and the decline after 4 weeks of treatment (HbΔ4) were analyzed in 308 chronic hepatitis C patients participating in 5 Austrian trials (n=308, age 43.9±11.1, male:185, female:123, BMI 25.3±3.9, no cirrhosis: n=259, liver cirrhosis: n= 49. All patients were treated with 180 mcg peginterferon-alpha 2a and ribavirin [1000-1200mg/d; females: mean (95%CI) 15.8 mg/kg (15.4 - 16.2); males 14.3 (14.1 - 14.5);p<0.001]. The SNP's rs6051702, rs1127354, rs7270101 and IL28B rs12979860 were analyzed by the StepOnePlus Real time PCR System.
188 were major alleles homozygotes; 95 (30.8%) carried the minor allele (C) of rs6051702, 47 (15.3%) of rs1127354 (A) and 69 (22.4%) of rs7270101 (C). The overall Hb0 was 14.8 g/dl (14.6-14.9) [mean (95%CI); females 13.7 (13.5-13.9); males 15.5; 15.3-15.6;p<0.001]). The overall HbΔ4 was greater in major allele homozygotes [2.8 g/dl (2.6-3.0)] than in minor allele carriers [1.6 (1.4-1.9);p<0.001]. Irrespective of the ITPA genotypes HbΔ4 was smaller in female [2.0 (1.7-2.2)] than in male patients [2.6 (2.4-2.8);p<0.001] and among females in premenopausal [1.5 (1.3-1.8)] than in postmenopausal patients [2.7 (2.3-3.1);p<0.001].
Irrespective of the protective effect of ITPA mutations premenopausal females less likely develop ribavirin induced anemia.
Journal of Hepatology 07/2013; · 9.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IL28B-polymorphisms, jaundice, decline in HCV-RNA, IP-10 and gender have been proposed to be indicative for spontaneous clearance of acute hepatitis C virus infection. Aim of this study was to define a score enabling the discrimination of patients with spontaneous clearance of HCV from those with development to viral persistence and need for early antiviral treatment.
136 patients (male:74;35±15years) were analyzed. From variables predictive for spontaneous clearance, calculated by univariate analysis, three scores were built. Analogous cutoffs were evaluated by computing area under the receiver operating characteristic curves. Candidate variables and cutoffs were: (I)presence of IL28B-C/C (P=0.027), (II)age (P=0.031;cutoff:35years), (III)peak-bilirubin (P=0.018;cutoff:6mg/dl), (IV)HCV-RNA-decline within 4 weeks (P<0.001;cutoff:>2.5log), (V)serum IP-10 (P=0.003;cutoff:546pg/ml), (VI)presence of CD4(+)Th1-cells (P=0.024). Each variable was allocated to 0 or 1 point, an HCV-RNA-decline of ⩾1log(10) but <2.5log(10) 1 point, a decline of ⩾2.5log(10) to 2 points. Three scores were evaluated (Score1:I-IV; Score2:I-V; Score3:I-VI).
A cutoff of ⩾3 points out of 5 in Score1 (AUROC:0.82; DeLong95%CI:0.76-0.93) predicted spontaneous clearance with a sensitivity of 71% (95%CI:0.53-0.86) and specificity of 87% (95%CI:0.73-0.95). PPV and NPV were 79% and 82%. Corresponding findings for Score2 including IP-10 (AUROC:0.93; DeLong95%CI:0.86-0.93) at a cutoff ⩾4 were: sensitivity 81%, specificity 95% (PPV:100%;NPV:77%). A cutoff of ⩾5 in Score3 (AUROC:0.98; DeLong95%CI:0.95-1.0) predicted spontaneous resolution with a sensitivity of 75% and specificity of 100% (PPV:100%;NPV:88%).
The scores enable a reliable discrimination between AHC-patients with high potential for spontaneous clearance from candidates for early therapeutic intervention due to marginal chance of spontaneous resolution.
Journal of Hepatology 07/2013; · 9.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In chronic hepatitis C (CHC), steatosis is associated with fibrosis and impaired response to antiviral therapy. Recently, a polymorphism of single nucleotide polymorphism SNP rs2645424 of farnesyl diphosphate farnesyl transferase 1 (FDFT1) was identified in NAFLD/NASH as a possible causal link to steatosis and fibrosis progression. SNP rs738409 in the adiponutrin gene (PNPLA3) is a well described factor for steatosis. This study evaluated the relation of these SNPs on steatosis, fibrosis and treatment response in CHC.
The SNPs rs738409478 and rs2645424 were determined by real-time PCR in 478 patients with CHC (m/f: 314/164; mean age: 44.9 ± 10.7; GT1: 387, GT4: 91) who completed treatment with peg-IFN-α-2a/ribavirin. All had a pretreatment liver biopsy. Steatosis and fibrosis were graded by board-certified pathologists according to Brunt and METAVIR respectively.
The distribution of FDFT1 rs2645424 was GG: 186 (38.9%), AG: 222 (46.4%) and AA: 70 (14.6%) and of the rs738409 PNPLA3 allele: CC: 269 (56.3%), CG: 177 (37.0%) and GG: 32 (6.7%). Overall, FDTF1 polymorphism was not linked to the extent of steatosis or fibrosis. However, in patients without steatosis the AA genotype was associated with advanced fibrosis [AA: 8/20 (40.0%), AG: 6/70 (8.5%), GG: 9/57 (16.1%), P = 0.003]. In contrast, the minor PNPLA3 allele was associated with both steatosis and advanced fibrosis (P < 0.001). Both SNPs did not influence treatment response.
The minor allele in FDFT1 was associated with advanced fibrosis in the non-steatotic but not in the steatotic subgroup. This may reflect different metabolic pathways in fibrosis progression for steatotic and non-steatotic patients with CHC.
Liver international: official journal of the International Association for the Study of the Liver 06/2013; · 3.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: The introduction of direct-acting anti-virals has increased sustained virological response (SVR) rates in chronic hepatitis C genotype 1 infection. At present, data on long-term durability of viral eradication after successful triple therapy are lacking. AIM: To evaluate the long-term durability of viral eradication in patients treated with triple therapy, including direct-acting anti-virals. METHODS: Patients who participated in randomised, controlled trials or an extended access programme of treatment with peginterferon-α2a/ribavirin in combination with a direct-acting anti-viral (telaprevir, danoprevir, faldaprevir, simeprevir, mericitabine, balapiravir) were followed after achieving SVR. The median follow-up after the patients was 21 (range: 7-64) months. RESULTS: One hundred and three patients with chronic hepatitis C genotype 1 infection [f/m: 34/69; GT-1b: 67 GT-1a: 34, GT-4: 2; mean age: 47.6 years (45.5-49.7; 95% CI)] achieving a SVR triple therapy were followed. Two cases of late relapses (2/103, 1.9%; 95% CI: 0.24-6.8) were observed. One patient was cirrhotic, both carried the genotype 1b and completed the prescribed treatment. The relapses occurred 8 and 12 months after cessation of anti-viral treatment. Cloning sequencing revealed identical sequence in both patients. Resistance analysis revealed no presence of viral resistance. CONCLUSION: Like the SVR after peginterferon-α2/ribavirin combination treatment, HCV eradication after triple therapy remains durable after long-term follow-up.
[Show abstract][Hide abstract] ABSTRACT: Background and Aim: The clinical presentation of Wilson disease (WD) is highly variable. The aim of this study was to evaluate the disease presentation in siblings of index patients in order to reveal possible genotype-phenotype correlations.
Patients and Methods: 165 affected siblings of 1077 index patients (mostly from Central and Eastern Europe) identified by genetic testing were studied with complete data available in 137. Age and symptoms at onset, serum ceruloplasmin, presence of Kayser- Fleischer rings and if available, results of liver biopsy were analyzed. H1069Q was assayed by PCR. H1069Q compound heterozygotes and H1069Q negative patients were further examined by denaturating gel HPLC using exon specific primers. Mutations were identified by direct sequencing on an ABI Prism 310 Genetic Analyzer (Perkin Elmer, Norwalk, USA).
Results: 131 of the 137 siblings were brothers or sisters, 5 were children and 1 a second degree relative of an index case. 73 index patients had liver disease (age: 17.2±8.9; 41 female, including 6 cases of fulminant WD and 2 with hemolytic anemia) and 54 neurologic disease (age: 21.0+7.5 years, 28 female). 92 siblings (67%, 47 female) were asymptomatic, 44 had symptoms which were discordant in seven. Ceruloplasmin was normal in 9. 81 had no KF-rings. In 93 and 33 siblings, mutations on both (including 46 H1069Q homozygotes) or one chromosome/s were identified, respectively. At diagnosis, 37 siblings were older and 99 younger than the index patients, one pair were monozygous twins. 52 siblings of patients with hepatic WD were asymptomatic, 24 had liver disease. During follow up, 2 siblings not taking the prescribed medication developed neurologic symptoms. 40 siblings of patients with neurologic WD were asymptomatic (17 of them had no KF-rings, 4 normal CPL), 13 had neurologic symptoms, 5 had liver disease (including the homozygous twin) and one hemolytic anemia.
Conclusion: Of the symptomatic siblings of patients with WD, only a minority (15%) had discordant symptoms, including the monozygous twin sister of a patient with severe neurologic disease. Nevertheless the discordant cases indicate that genetic factors other than ATP7B mutations apparently modify the phenotypic presentation of WD.
Journal of Hepatology 04/2013; 58(Suppl 1):s559. · 9.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Wilson disease (WD), a disorder of copper metabolism is caused by mutations in the ATP7B gene, a copper transporting ATPase. In the present study we describe a novel mutation in exon 9 of the ATP7B gene. The ATP7B gene was analyzed for mutations by denaturing HPLC and direct sequencing. DNA from 100 healthy blood donors from the same geographic area was examined as control. Sixteen (7.4%) out of the 216 patients diagnosed with WD in Austria carried the newly identified R816S(c.2448G>T) point mutation in exon 9 (4 male, age: 19 (6-30) years, median (range)). One patient was homozygous for R816S(c.2448G>T). Thirteen patients were compound heterozygotes (p.H1069Q(c.3207C>A)/R816S(c.2448G>T) (N=6), P539L/R816S(c.2448G>T) (N=3), each one G710S/R816S(c.2448G>T), P767P(2299insC)/R816S(c.2448G>T), W779G/R816S(c.2448G>T), T1220M/R816S(c.2448G>T)). In two patients no second mutation was identified. Interestingly, all but three of the patients originated within a distinct geographical area in Austria. Eleven patients presented with hepatic disease, 3 patients with neurological disease and 2 were asymptomatic sisters of an index case. A liver biopsy was available in 14 patients. Three patients showed advanced liver disease with liver transplantation for acute hepatic failure in two. The remaining patients had only mild histological changes, most commonly steatosis. Chronic hepatitis was described in five patients. Kayser-Fleischer ring was present in five patients. None of the 100 healthy controls carried the mutation. We describe a novel mutation in the ATP7B gene, occurring in patients originated from a distinct geographical area in Austria associated with a variable course of the disease.
Journal of Human Genetics 07/2012; 57(9):564-7. · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Insulin resistance, fibrosis and steatosis are established predictors of response to peg-interferon/ribavirin therapy in chronic hepatitis C (CHC). Several host genetic polymorphisms (IL28B, PNPLA3) modify treatment-outcome, the degree of steatosis or fibrosis. The aim of our study was to evaluate the role of these polymorphisms on insulin resistance (IR) in treatment-naïve patients with chronic hepatitis C.
Two hundred and two non-diabetic CHC patients (GT1: 181, GT4: 21; m = 126, f = 76) undergoing liver biopsy in two tertiary academic centers were studied. The SNPs rs12979860 (IL28B) and rs738409 (PNPLA3) were investigated by RT-PCR. HOMA-IR, BMI, stage of fibrosis, extent of steatosis, and genetic data were analyzed.
Insulin resistance (HOMA-IR ≥ 3.0) was associated with rs12979860 genotype, presence of advanced fibrosis, and higher BMI. HOMA-IR in CC and in TC/TT was 2.08 ± 1.61 (mean ± SD) and 2.94 ± 2.89 (p=0.041), respectively. HOMA-IR was higher in advanced than in mild fibrosis (F3-4: 3.92 ± 3.15; F0-2: 2.38 ± 2.38; p=0.004). The percentage of steatotic hepatocytes was higher in patients with advanced fibrosis (21.3 ± 21.5 vs. 9.1 ± 14.2; p<0.001), HOMA-IR ≥ 3.0 (17.7 ± 17.8 vs. 8.8 ± 15.4%; p<0.001), and BMI > 25.0 kg/m(2) (14.7 ± 17.0 vs. 9.1 ± 16.1; p<0.001). The rs738409 GG genotype was associated with advanced fibrosis and steatosis, but not with HOMA-IR. Multivariable logistic regression identified advanced fibrosis (OR: 2.820, 95% CI: 1.344-5.917; p = 0.006) and the IL28B genotype non-CC (OR: 3.000, 1.348-6.676; p = 0.007) as independent risk factors for insulin resistance.
Insulin resistance is more common in carriers of the T allele of SNP rs12979860 than in CC homozygotes and may partly explain the poor outcome of peginterferon/ribavirin therapy in these patients.
Journal of Hepatology 05/2012; 57(3):492-8. · 9.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary sclerosing cholangitis (PSC) is a chronic inflammatory bile duct disease of unknown etiology, frequently associated with inflammatory bowel disease and leading to end-stage liver disease requiring liver transplantation. Moreover, PSC is a premalignant condition associated with an increased risk for hepatobiliary and colorectal malignancy. Since effective medical therapy for PSC is still lacking, this disorder represents a potentially fatal disease with poor prognosis. This article is a summary of an overview given at the 5th Falk Gastro Conference in Munich 2012 and reviews the challenges associated with diagnosis, surveillance and therapy of PSC.