R. Stauber

Comparison and validation of simple noninvasive tests for prediction of fibrosis in chronic hepatitis C

Liver biopsy is recommended before antiviral treatment, particularly for patients with hepatitis C virus (HCV) genotype 1 infection, but it may cause complications and is limited by sampling error. Several non‐invasive tests comprising routine laboratory parameters (simple fibrosis tests) have been proposed to predict fibrosis in chronic HCV. The aim of the current study was to validate and compare the diagnostic accuracies of the simple fibrosis tests, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (AAR), cirrhosis discriminant score (CDS), age‐platelet (AP) index, Pohl score, AST‐to‐platelet ratio index (APRI), and platelet count per se. Staging was performed in liver biopsy specimens of 194 treatment‐naïve patients with chronic HCV according to Ishak et al. by two independent pathologists. Receiver operating characteristic curve analysis showed comparable diagnostic accuracies of CDS, AP index, APRI, and platelet count for prediction of significant fibrosis (F3‐F6) (area under the ROC curve [AUROC], 0.71, 0.74, 0.80, and 0.71, respectively; pathologist A) and for prediction of cirrhosis (F5‐F6) (AUROC, 0.91, 0.91, 0.90, and 0.89, respectively; pathologist A). Diagnostic accuracy of APRI for prediction of significant fibrosis was superior to that of AAR (P < .05). Significant fibrosis was reliably predicted by APRI ≥ 1.5 and platelet count <150 ×109/L in 24% and 22% of the patients, respectively, whereas cirrhosis was reliably excluded by APRI <2.0 and platelet count ≥ 150 ×109/L in 85% and 78% of the patients, respectively. In conclusion, simple fibrosis tests may render liver biopsy unnecessary only in a minority of patients with chronic HCV. Improved serum fibrosis markers with greater sensitivity for severe fibrosis or cirrhosis are needed. (HEPATOLOGY 2005;41:1376–1382.)

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.

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.

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.)

Prognostic factors in patients with advanced hepatocellular carcinoma treated with sorafenib.

Background  Sorafenib is the new reference standard for patients with advanced hepatocellular carcinoma (HCC).

The influence of probiotic supplementation on gut permeability in patients with metabolic syndrome: an open label, randomized pilot study

Background/objectives:Obesity and metabolic disorders are linked to inflammation via gut microbiota and/or gut permeability. Gut-derived endotoxin triggers inflammation leading to metabolic syndrome (MetS) and contributing to oxidative stress. We intended to investigate the effect of Lactobacillus casei Shirota on gut permeability, presence of endotoxin and neutrophil function in MetS.Subjects/methods:Patients with MetS were randomized to receive 3 × 6.5 × 109 CFU L. casei Shirota (probiotic group) or not for 3 months. Gut permeability was assessed by a differential sugar absorption method and by determination of diaminooxidase serum levels, endotoxin by an adapted limulus amoebocyte lysate assay, neutrophil function and toll-like receptor (TLR) expression by flow cytometry and ELISA was used to detect lipopolysaccharide-binding protein (LBP) and soluble CD14 (sCD14) levels.Results:Twenty-eight patients and 10 healthy controls were included. Gut permeability was significantly increased in MetS compared with controls but did not differ between patient groups. None of the patients were positive for endotoxin. LBP and sCD14 levels were not significantly different from healthy controls. High-sensitive C-reactive protein and LBP levels slightly but significantly increased after 3 months within the probiotics group. Neutrophil function and TLR expression did not differ from healthy controls or within the patient groups.Conclusions:Gut permeability of MetS patients was increased significantly compared with healthy controls. L. casei Shirota administration in the MetS patients did not have any influence on any parameter tested possibly due to too-short study duration or underdosing of L. casei Shirota.

Acute Budd-Chiari syndrome with fulminant hepatic failure in a pregnant woman with factor V Leiden mutation

Budd-Chiari syndrome during pregnancy has rarely been reported. This report presents a case of acute hepatic failure in a 20-year-old pregnant woman attributable to Budd-Chiari syndrome with underlying resistance to activated protein C caused by factor V Leiden mutation. The patient delivered a healthy girl by cesarean section in the 31st week of pregnancy. Acute hepatic failure in the 6th week postpartum was successfully treated by emergency liver transplantation, and the patient and her child were doing well at 8-month follow-up. Liver transplantation was lifesaving; normal factor V production by the transplant corrected the underlying coagulopathy. In this patient, latent thrombophilia attributable to activated protein C resistance was apparently aggravated by the hypercoagulable state of pregnancy leading to acute Budd-Chiari syndrome. Activated protein C resistance should be sought as an etiologic factor in patients with Budd-Chiari syndrome.

Daclatasvir combined with sofosbuvir or simeprevir in liver transplant recipients with severe recurrent hepatitis C infection

Daclatasvir (DCV) is a potent, pangenotypic nonstructural protein 5A inhibitor with demonstrated antiviral efficacy when combined with sofosbuvir (SOF) or simeprevir (SMV) with or without ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection. Herein, we report efficacy and safety data for DCV‐based all‐oral antiviral therapy in liver transplantation (LT) recipients with severe recurrent HCV. DCV at 60 mg/day was administered for up to 24 weeks as part of a compassionate use protocol. The study included 97 LT recipients with a mean age of 59.3 ± 8.2 years; 93% had genotype 1 HCV and 31% had biopsy‐proven cirrhosis between the time of LT and the initiation of DCV. The mean Model for End‐Stage Liver Disease (MELD) score was 13.0 ± 6.0, and the proportion with Child‐Turcotte‐Pugh (CTP) A/B/C was 51%/31%/12%, respectively. Mean HCV RNA at DCV initiation was 14.3 × 6 log10 IU/mL, and 37% had severe cholestatic HCV infection. Antiviral regimens were selected by the local investigator and included DCV+SOF (n = 77), DCV+SMV (n = 18), and DCV+SMV+SOF (n = 2); 35% overall received RBV. At the end of treatment (EOT) and 12 weeks after EOT, 88 (91%) and 84 (87%) patients, respectively, were HCV RNA negative or had levels <43 IU/mL. CTP and MELD scores significantly improved between DCV‐based treatment initiation and last contact. Three virological breakthroughs and 2 relapses occurred in patients treated with DCV+SMV with or without RBV. None of the 8 patient deaths (6 during and 2 after therapy) were attributed to therapy. In conclusion, DCV‐based all‐oral antiviral therapy was well tolerated and resulted in a high sustained virological response in LT recipients with severe recurrent HCV infection. Most treated patients experienced stabilization or improvement in their clinical status. Liver Transplantation 22 446‐458 2016 AASLD

Long-term Outcomes of Patients With Wilson Disease in a Large Austrian Cohort

BACKGROUND & AIMS 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 a well-characterized Austrian cohort of patients with Wilson disease. METHODS 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. RESULTS The mean observation period was 14.8 ± 11.4 years (range, 0.5-52.0 years), resulting in 3116 patient-years. Of the patients, 61% presented with hepatic disease, 27% with neurologic symptoms, and 10% were diagnosed by family screening at presymptomatic stages. Patients with a hepatic presentation were diagnosed younger (21.2 ± 12.0 years) 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 a liver transplant, 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 years (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 a liver transplant (odds ratio, 07; 95% confidence interval, 0.016-0.307; P < .001). Only 84% of patients with cirrhosis survived 20 years after diagnosis (compared with healthy Austrians, P =.008). CONCLUSION Overall, patients who receive adequate care for Wilson disease have a good long-term prognosis. However, cirrhosis increases the risk of death and liver disease. Early diagnosis, at a precirrhotic stage, might increase survival times and reduce the need for a liver transplant.

The role of inducible nitric oxide synthase in vascular hyporeactivity of endotoxin-treated and portal hypertensive rats

The involvement of the inducible nitric oxide (NO) synthase in the vascular hyporeactivity in portal vein-ligated rats was assessed in isolated perfused mesenteric arterial beds. Aminoguanidine, a selective inhibitor of the inducible NO synthase, restored the pressor responses to methoxamine in arteries of endotoxin-treated rats, but was ineffective in hyporeactive portal vein-ligated vessels. NG-Nitro-L-arginine methyl ester enhanced the responsiveness both in portal vein-ligated and sham-operated rats, without changing the difference between the two groups. These results not only indicate that the inducible NO synthase is not involved in the hyporeactivity to methoxamine in mesenteric arteries of portal hypertensive rats, but also suggest a role for factors other than NO.