Michael Gschwantler

Peginterferon Alfa-2a and Ribavirin for 24 Weeks in Hepatitis C Type 1 and 4 Patients With Rapid Virological Response

BACKGROUND & AIMS This analysis reports the rate of sustained virological response (SVR) in patients infected with hepatitis C virus (HCV) genotype 1 or 4 who were assigned to 24 weeks of treatment with pegylated interferon (peginterferon) alfa-2a 180 mug/wk plus ribavirin 1000/1200 mg/day after achieving a rapid virological response (RVR; HCV RNA level <50 IU/mL) at week 4 in a prospective trial investigating response-guided therapy. METHODS Non-RVR patients with an early virological response were randomized to 48 or 72 weeks of therapy (this is a still-ongoing trial). RESULTS A total of 150 of 516 patients (29%) had an RVR, 143 of whom completed 24 weeks of treatment. Younger patients, leaner patients, and those with an HCV RNA level </=400,000 IU/mL and HCV genotype 4 infection were more likely to achieve an RVR; however, among patients with an RVR, no baseline factor predicted SVR. The SVR rate was 80.4% (115/143; 95% confidence interval [CI], 72.9-86.6) in patients who completed 24 weeks of treatment. The SVR rate was 86.7% (26/30; 95% CI, 69.3%-96.2%) in patients infected with genotype 4 and 78.8% in those infected with genotype 1 (89/113; 95% CI, 70.1%-85.9%; intent to treat: 89/120; 74.2%; 65.4-81.7%). Treatment was well tolerated. CONCLUSIONS This prospective study confirms that a 24-week regimen of peginterferon alfa-2a plus ribavirin 1000/1200 mg/day is appropriate in genotype 1 and 4 patients with a low baseline HCV RNA level who achieve an RVR by week 4 of therapy.

Child-Pugh versus MELD score in predicting survival in patients undergoing transjugular intrahepatic portosystemic shunt

Background: In patients undergoing transjugular intrahepatic portosystemic shunt (TIPS), prognostic scores may identify those with a poor prognosis or even those with a clear survival benefit. The Child-Pugh score (CPS) is well established but several drawbacks have led to development of the model of end stage liver disease (MELD). Aim: The aim of the study was to compare the predictive power of CPS and MELD, to validate the original MELD formula, and to assess the predictive value of the determinants used in the two prognostic scores outside of a study setting. Patients: A total of 501 patients underwent elective TIPS placement and 475 patients fulfilled the inclusion criteria. Methods: Data of all patients undergoing elective TIPS in one university hospital and four community hospitals in Vienna, Austria, between 1991 and 2001, were analysed retrospectively. The main statistical tests were Cox proportional hazards regression model, the log rank test, Kaplan-Meier analysis, and concordance c statistics. Results: Median follow up was 5.2 years and median survival was 4.6 years. During follow up, 230 patients died, 75 within three months after TIPS placement. In stepwise proportional hazards analyses, independent predictors of death were creatinine level, bilirubin level, age, and refractory ascites. MELD was better in predicting survival in a stepwise Cox model but both scores were equally predictive in c statistics for one month, three month, and one year survival. Renal function was the strongest independent predictor of survival. Conclusions: Although MELD was the primary predictor of overall survival in multivariate analysis, c statistics showed that both scores can be used for patients undergoing TIPS with equal accuracy. For assessing prognosis in patients undergoing TIPS implantation, there seems little reason to replace the well established Child-Pugh score.

Diagnostic Value of Quantitative Hepatic Copper Determination in Patients With Wilson’s Disease

BACKGROUND & AIMS A 5-fold increase of hepatic copper concentration is considered as the best available test for diagnosis of hepatic Wilsons disease (WD). However, the sensitivity and specificity of this test have never been fully investigated. METHODS Copper content was measured by flame atomic absorption spectroscopy in 114 liver biopsies obtained at diagnosis of WD, in 219 patients with noncholestatic liver diseases (including 144 with chronic hepatitis C and 44 with nonalcoholic fatty liver disease), and in 26 without evidence of liver disease. RESULTS Liver copper content was >250 microg/g in 95 WD patients (83.3%), between 50 and 250 microg/g in 15, and below 50 microg/g in 4. It did not correlate with age (r(2) = .003), the grade of fibrosis, or the presence of stainable copper. Liver copper content was >250 or between 50 and 250 microg/g in 3 (1.4%) and 20 (9.1%) of 219 patients with noncholestatic liver diseases, respectively. By lowering the cutoff from 250 to 75 microg/g, the sensitivity of liver copper content to diagnose WD increased from 83.3% (95% confidence interval, 75.2%-89.6%) to 96.5% (91.3%-99.1%), but the specificity decreased from 98.6% (96.0%-99.7%) to 95.4% (91.8%-97.8%). CONCLUSIONS There is no gold standard for the diagnosis of WD. Liver copper content is a useful parameter, but a value below 250 microg/g does not exclude WD. Diagnosis requires the combination of a variety of clinical and biochemical tests.

High-grade dysplasia and invasive carcinoma in colorectal adenomas: a multivariate analysis of the impact of adenoma and patient characteristics.

Background and aims Most colorectal carcinomas develop from preformed adenomas, but only a minority of adenomas undergo malignant transformation. The clinical significance of polyps of size < 0.5 cm is controversial. The primary goal of this study was to assess the independent risk factors of adenoma and patient characteristics associated with advanced pathological features (APF; i.e. high-grade dysplasia or invasive carcinoma) in colorectal adenomas. A secondary goal was to assess the malignant potential of adenomas with a diameter of < 0.5 cm. Patients and methods Patients who underwent total colonoscopy at our Medical Department between 1978 and 1996 and had at least one colorectal adenoma were considered for this study. Patients with a history of colorectal cancer, prior polypectomy or colorectal surgery were excluded. A total of 7590 adenomas removed from 4216 patients were included in this analysis. Logistic regression analysis was used to study the impact of different adenoma and patient characteristics on the risk of APF. Results Size proved to be the most important risk factor for APF. The percentage of adenomas with APF was 3.4%, 13.5% and 38.5% for adenomas of diameter < 0.5 cm, 0.5–1 cm and > 1 cm, respectively. Villous or tubulovillous histology, left-sided location and age ⩾ 60 years were also associated with APF, whereas sex and number of adenomas had no significant impact. Logistic regression analysis revealed that the risk of an adenoma containing APF was best described by a model incorporating the factors size, location, age, and the age by histology interaction. In the class of adenomas with diameter < 0.5 cm, no invasive carcinoma was found, but 3.4% of adenomas had high-grade dysplasia. Conclusions The risk of a colorectal adenoma containing APF can be estimated only by a complex model taking into account several adenoma and patient characteristics. Size, histological type, location and age are independent risk factors for APF in colorectal adenomas. As a considerable percentage of adenomas with diameter < 0.5 cm contain high-grade dysplasia, the clinical conclusion from our study is that all adenomas, including those with diameter < 0.5 cm, should be removed whenever possible.

Peginterferon Alfa-2a/Ribavirin for 48 or 72 Weeks in Hepatitis C Genotypes 1 and 4 Patients With Slow Virologic Response

BACKGROUND & AIMS This randomized multicenter trial evaluated individualization of treatment duration with peginterferon alfa-2a 180 microg/wk plus ribavirin 1000/1200 mg/day in patients with chronic hepatitis C genotype 1/4 based on the rapidity of virologic response (VR). METHODS Patients with a rapid VR (RVR; undetectable hepatitis C virus [HCV]-RNA level (<50 IU/mL at week 4) were treated for 24 weeks, those with an early VR (EVR; no RVR but undetectable HCV-RNA level or >or=2-log(10) decrease at week 12) were randomized to 48 (group A) or 72 weeks of treatment (group B; peginterferon alfa-2a was reduced to 135 microg/wk after week 48). Patients without an EVR continued treatment until week 72 if they had undetectable HCV-RNA levels at week 24. The primary end point was relapse; sustained VR (SVR; undetectable HCV-RNA level after 24 weeks of follow-up evaluation) was a secondary end point. RESULTS Of 551 genotype 1/4 patients starting treatment, 289 were randomized to group A (N = 139) or group B (N = 150). The relapse rate was 33.6% in group A (95% confidence interval [CI], 24.8%-43.4%) and 18.5% in group B (95% CI, 11.9%-27.6%; P = .0115 vs group A) and the SVR rate was 51.1% (95% CI, 42.5%-59.6%) and 58.6% (95% CI, 50.3%-66.6%; P > .1), respectively. The overall SVR rate was 50.4% (278 of 551; 95% CI, 46.2%-54.7%), including 115 of 150 patients with an RVR treated for 24 weeks and 4 of 78 patients without an EVR. CONCLUSIONS Extending therapy with peginterferon alfa-2a/ribavirin to 72 weeks decreases the probability of relapse in patients with an EVR. If they can be maintained on extended-duration therapy, SVR rates also may improve.

Primary interferon resistance and treatment response in chronic hepatitis C infection: a pilot study

Summary Only 30% of patients with chronic hepatitis C virus genotype 1 (HCV-1) infection achieve a sustained virological response to interferon and ribavirin combination therapy. We prospectively assessed decline in viral load 24 h after one dose of interferon alfa as a predictor of non-response to 6 months of treatment with interferon and ribavirin. Interferon sensitivity was measured before initiation of combination therapy. We measured viral load in 29 consecutive patients, who had not previously been treated with interferon and who were chronically infected with HCV-1 within 24 h after one dose of 5 MU or 10 MU interferon alfa-2b, and 14 days of daily 5 MU interferon alfa-2b. A 24 h viral load decline by less than 70% of baseline after 5 MU interferon was the best pretreatment measure to identify non-responders (specificity 100%, n=10, 95% CI 74–100], sensitivity 83% [15/18], 59–96]).

Unexpected high incidence of hepatocellular carcinoma in cirrhotic patients with sustained virologic response following interferon-free direct-acting antiviral treatment

Please cite this article as: Kozbial, K., Moser, S., Schwarzer, R., Laferl, H., Al-Zoairy, R., Stauber, R., Stättermayer, A.F., Beinhardt, S., Graziadei, I., Freissmuth, C., Maieron, A., Gschwantler, M., Strasser, M., Peck-Radosalvjevic, M., Trauner, M., Hofer, H., Ferenci, P., Unexpected high incidence of hepatocellular carcinoma in cirrhotic patients with SVR following IFN-free DAA treatment, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep. 2016.06.009

A randomized, prospective trial of ribavirin 400 mg/day versus 800 mg/day in combination with peginterferon alfa‐2a in hepatitis C virus genotypes 2 and 3

We compared the efficacy and tolerability of 24 weeks of treatment with ribavirin 800 mg/day (group A) or 400 mg/day (group B) plus peginterferon alfa‐2a 180 μg/week in treatment‐naive patients infected with hepatitis C virus (HCV) genotype 2 or 3. A total of 97 of 141 patients randomized to group A (68.8%, 95% confidence interval [CI] 60.5%‐76.3%) and 90 of 141 patients randomized to group B (63.8; 95% CI 55.3%‐71.7%) achieved a sustained virological response, defined as undetectable serum HCV RNA at the end of untreated follow‐up (week 48). Among patients infected with genotype 3, the rate of sustained virological response was 67.5% (95% CI 58.4%‐75.6%) in group A and 63.9% (95% CI 54.7%‐72.4%) in group B, and among patients infected with genotype 2, the rate of sustained virological response was 77.8% (95% CI 54.2%‐93.6%) in group A and 55.6% (95% CI 38.4%‐83.7%) in group B. Relapse rates in the 2 treatment groups were similar (17% in group A and 20% in group B). The incidence of adverse events, laboratory abnormalities, and dose reductions was similar in the 2 treatment groups. Conclusion: The results suggest that when administered for 24 weeks with peginterferon alfa‐2a, ribavirin doses of 400 and 800 mg/day produce equivalent outcomes in patients infected with HCV genotype 3. (HEPATOLOGY 2008.)

Mutations of the HFE Gene in Patients With Hepatocellular Carcinoma

OBJECTIVE:Hepatocellular carcinoma (HCC) is a late consequence of severe liver disease. Patients with genetic hemochromatosis may be at risk for HCC, but limited information is available on the relationship of HCC and heterozygosity for the HFE gene mutations.METHODS:HFE mutations (C282Y and H63D) were assessed in 162 consecutive patients (131 men/31 women) with HCC. A total of 159 patients had cirrhosis. The most common etiologies of cirrhosis were chronic viral hepatitis (hepatitis C 39%, hepatitis B 9%) and alcoholic liver disease (36%).RESULTS:Five patients were C282Y homozygotes, four C282Y/H63D compound heterozygotes, and three H63D homozygotes. The C282Y and H63D allele frequencies in HCC were 8.3 (95% confidence limit = 5.3–11.3) and 11.1 (7.8–14.6), respectively, and not different from previously published data in healthy subjects or patients with chronic hepatitis C in Austria. Furthermore, there was no difference in the age at diagnosis in patients with or without HFE gene mutations. C282Y homozygotes had a 19-fold increased risk to develop HCC. In contrast, all other HFE allele constellations were not associated with such a risk.CONCLUSIONS:Except for C282Y homozygotes, HFE gene mutations do not increase the risk to develop HCC in patients with cirrhosis.

Development of insulin-dependent diabetes mellitus in a patient with chronic hepatitis C during therapy with interferon-α

Interferon (IFN)-alpha is used for the treatment of chronic viral hepatitis. It has been associated with various forms of autoimmune disease, e.g. autoimmune hepatitis, Hashimoto thyroiditis and insulin-dependent diabetes mellitus. Further, an increase of insulin resistance and development of non-insulin-dependent diabetes mellitus has been described after treatment with IFN-alpha. Several studies have investigated the induction of different autoimmune markers by IFN-alpha, but only few specified patients who developed insulin-dependent diabetes mellitus. We report the case of a 37-year-old man with chronic hepatitis C who was treated with IFN-alpha plus ribavirin. Thirty weeks after the start of treatment, the patient developed insulin-dependent diabetes mellitus and therapy was withdrawn. HLA typing showed an HLA-DR1,3 phenotype. At manifestation of diabetes mellitus, the C-peptide level was 0.37 ng/ml (normal range 0.5-3 ng/ml). The patient had a positive family history for type 2 diabetes. Several autoimmune markers were investigated before, during and 6 months after withdrawal of antiviral treatment. High titres of glutamic acid decarboxylase (GAD) antibodies were present before therapy. A significant increase in titres of islet cell antibodies, parietal cell antibodies and sperm antibodies was present after 14 weeks of IFN-alpha treatment. Six months after withdrawal of IFN-alpha therapy, these antibodies had significantly decreased whereas GAD antibodies remained unchanged. There was no clinical sign of any other autoimmune disease. Our data show that, in patients with a predisposition to insulin-dependent diabetes mellitus, the disease may become manifest as a side-effect during therapy with IFN-alpha. Several pathogenetic factors may be involved in this process, and, in addition to IFN-alpha, hepatitis C itself may induce autoimmune mechanisms. We conclude that screening for autoantibodies specific for type 1 diabetes should be performed before the start of IFN-alpha treatment. In patients found to be at increased risk of developing diabetes mellitus type 1, monitoring of titres of these antibodies during therapy could help to assess the individual risk-benefit ratio of IFN-alpha treatment.