Faculty Bibliography

Background: CTP and MELD scores predict 6-week mortality in patients with AVH. However, their relative value has yet to be evaluated in the U.S. The vapreotide trial was a prospective cohort study of patients with AVH treated with current standard of care with a vasoactive agent (vapreotide, a somatostatin analogue), endoscopic band ligation and antibiotics. Aims: To 1) report outcomes of patients presenting with AVH using a large U.S. cohort; 2) describe predictors of 6-week mortality; and 3) validate a recent "recalibrated" MELD model (Reverter. Gastroenterology 2014). Results: Seventy patients with cirrhosis and endoscopically-proven AVH were enrolled between August 2006 and April 2008 at 15 U.S. centers. Eighteen (26%) died within 6 weeks of index bleed. Data at baseline and univariate analysis comparing survivors and non-survivors are shown in the table. Multivariate models including parameters significant on univariate analysis and either CTP or MELD, showed admission CTP and MELD as independent predictors of survival. The discriminative values of CTP (AUROC 0.75, 95%CI: 0.63-0.87) and MELD (AUROC 0.79, 95%CI: 0.68-0.90) were good and not significantly different (p=0.26). However, calibration (the correlation between observed and predicted mortality), as determined by the Hosmer- Lemeshow Goodness-of-Fit test (in which the smaller the p value, the greater the disagreement between observed and predicted mortality) was significantly better for CTP (p=0.45) than for MELD (p=0.02), with the Reverter model having the worst agreement (p=0.0006). Predicted mortality for CTP-A was <10%, CTP-B 10%-30%, and CTP-C >30%. Conclusions: AVH mortality of 26% in the U.S. is in the upper range limit of recent series (6 to 33%). CTP score has the best overall performance in the prediction of 6-week mortality and should continue to be used in risk stratification and in the application of individualized therapy. (Table Presented)

BACKGROUND: The interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r) and the NS5A inhibitor ombitasvir (also known as ABT-267) plus the nonnucleoside polymerase inhibitor dasabuvir (also known as ABT-333) and ribavirin has shown efficacy against the hepatitis C virus (HCV) in patients with HCV genotype 1 infection. In this phase 3 trial, we evaluated this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned previously untreated patients with HCV genotype 1 infection, in a 3:1 ratio, to an active regimen consisting of a single-tablet coformulation of ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), and dasabuvir (250 mg twice daily) with ribavirin (in doses determined according to body weight) (group A) or matching placebos (group B). The patients received the study treatment during a 12-week double-blind period. The primary end point was sustained virologic response at 12 weeks after the end of treatment. The primary analysis compared the response rate in group A with the response rate (78%) in a historical control group of previously untreated patients without cirrhosis who received telaprevir with peginterferon and ribavirin. Adverse events occurring during the double-blind period were compared between group A and group B. RESULTS: A total of 631 patients received at least one dose of the study drugs. The rate of sustained virologic response in group A was 96.2% (95% confidence interval, 94.5 to 97.9), which was superior to the historical control rate. Virologic failure during treatment and relapse after treatment occurred in 0.2% and 1.5%, respectively, of the patients in group A. The response rates in group A were 95.3% among patients with HCV genotype 1a infection and 98.0% among those with HCV genotype 1b infection. The rate of discontinuation due to adverse events was 0.6% in each study group. Nausea, pruritus, insomnia, diarrhea, and asthenia occurred in significantly more patients in group A than in group B (P<0.05 for all comparisons). Reductions in the hemoglobin level were all of grade 1 or 2; reductions of grade 1 and 2 occurred in 47.5% and 5.8%, respectively, of the patients in group A, whereas grade 1 reductions occurred in 2.5% of the patients in group B. CONCLUSIONS: In previously untreated patients with HCV genotype 1 infection and no cirrhosis, a 12-week multitargeted regimen of ABT-450/r-ombitasvir and dasabuvir with ribavirin was highly effective and was associated with a low rate of treatment discontinuation. (Funded by AbbVie; SAPPHIRE-I ClinicalTrials.gov number, NCT01716585.).

Hepatic encephalopathy (HE) is a frequent complication in cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt (TIPS). Hyponatremia (HN) is a known contributing risk factor for the development of HE. Predictive factors, especially the effect of HN, for the development of overt HE within one week of TIPS placement were assessed. A single-center, retrospective chart review of 71 patients with cirrhosis who underwent TIPS creation from 2006-2011 for non-variceal bleeding indications was conducted. Baseline clinical and laboratory characteristics were collected. Factors associated with overt HE within one week were identified, and a multivariate model was constructed. Seventy one patients who underwent 81 TIPS procedures were evaluated. Fifteen patients developed overt HE within one week. Factors predictive of overt HE within one week included pre-TIPS Na, total bilirubin and Model for End-stage Liver Disease (MELD)-Na. The odds ratio for developing HE with pre-TIPS Na <135 mEq/L was 8.6. Among patients with pre-TIPS Na <125 mEq/L, 125-129.9 mEq/L, 130-134.9 mEq/L and >/=135 mEq/L, the incidence of HE within one week was 37.5%, 25%, 25% and 3.4%, respectively. Lower pre-TIPS Na, higher total bilirubin and higher MELD-Na values were associated with the development of overt HE post-TIPS within one week. TIPS in hyponatremic patients should be undertaken with caution.

BACKGROUND: Chronic hepatitis C is the most common cause of cirrhosis in industrialized countries. Successful treatment of chronic hepatitis C in patients with advanced fibrosis or cirrhosis has significant benefits, including improvements in inflammation, fibrosis, and portal hypertension, with prevention of esophageal varices and clinical decompensation. CASE: In this report, we present two patients with well-compensated hepatitis C cirrhosis who achieved an end-of-treatment response on a direct-acting antiviral therapy-based triple regimen for hepatitis C virus, but subsequently presented with new-onset ascites associated with virologic relapse. CONCLUSION: We propose that the development of ascites in this setting is due to the adverse impact of inflammation of the virologic relapse on portal hypertension. Our observation that ascites formation can be a manifestation of virologic relapse has potentially important clinical implications, as it highlights not only the importance of close monitoring of cirrhotic patients after achieving end-of-treatment response but also the impact of active inflammation on the severity of portal hypertension.

Hepatic encephalopathy (HE) is a multifactorial neuropsychiatric disease that affects patients with cirrhosis. We review the clinical impact, pathogenesis, evaluation, management, and prevention of overt HE in patients with cirrhosis. Articles published between January 1960 and November 2012 were acquired through a MEDLINE search of different combinations of the terms hepatic encephalopathy, pathophysiology, treatment, prophylaxis, prevention, prognosis, and recurrence. The Healthcare Cost and Utilization Project database was used to obtain prevalence and cost information related to hospitalizations of patients with HE. The literature describes significant morbidity and mortality of HE in patients with cirrhosis. Overt HE develops in 30% to 45% of patients with cirrhosis and is associated with a substantial pharmacoeconomic burden, particularly HE-related hospitalizations. The development of HE in patients with cirrhosis portends a worsened prognosis and is incorporated into the Child-Pugh classification of the severity of liver disease. In the hospitalized patient, the development of HE is associated with precipitating events (eg, gastrointestinal bleeding, dehydration, infection), and in some patients, its course is characterized by frequent and severe relapses. In addition, hospitalized patients with overt HE have a 3.9-fold increased mortality risk. Patient management employs nonabsorbable disaccharides, the nonsystemic antibiotic rifaximin, or both, to treat acute HE episodes and prevent HE relapse. In open-label trials, use of the nonabsorbable disaccharide lactulose reduced the risk of overt HE recurrence in patients compared with no-lactulose control groups for