Kimberly L. Beavers

Rifaximin Treatment in Hepatic Encephalopathy

BACKGROUND Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established. METHODS In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy. RESULTS Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events. CONCLUSIONS Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.)

Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study

BACKGROUND & AIMS The Drug-Induced Liver Injury Network is conducting a prospective study of patients with DILI in the United States. We present characteristics and subgroup analyses from the first 1257 patients enrolled in the study. METHODS In an observational longitudinal study, we began collecting data on eligible individuals with suspected DILI in 2004, following them for 6 months or longer. Subjects were evaluated systematically for other etiologies, causes, and severity of DILI. RESULTS Among 1257 enrolled subjects with suspected DILI, the causality was assessed in 1091 patients, and 899 were considered to have definite, highly likely, or probable DILI. Ten percent of patients died or underwent liver transplantation, and 17% had chronic liver injury. In the 89 patients (10%) with pre-existing liver disease, DILI appeared to be more severe than in those without (difference not statistically significant; P = .09) and mortality was significantly higher (16% vs 5.2%; P < .001). Azithromycin was the implicated agent in a higher proportion of patients with pre-existing liver disease compared with those without liver disease (6.7% vs 1.5%; P = .006). Forty-one cases with latency ≤7 days were caused predominantly by antimicrobial agents (71%). Two most common causes for 60 DILI cases with latency >365 days were nitrofurantoin (25%) or minocycline (17%). There were no differences in outcomes of patients with short vs long latency of DILI. Compared with individuals younger than 65 years, individuals 65 years or older (n = 149) were more likely to have cholestatic injury, although mortality and rate of liver transplantation did not differ. Nine patients (1%) had concomitant severe skin reactions; implicated agents were lamotrigine, azithromycin, carbamazepine, moxifloxacin, cephalexin, diclofenac, and nitrofurantoin. Four of these patients died. CONCLUSIONS Mortality from DILI is significantly higher in individuals with pre-existing liver disease or concomitant severe skin reactions compared with patients without. Additional studies are needed to confirm the association between azithromycin and increased DILI in patients with chronic liver disease. Older age and short or long latencies are not associated with DILI mortality.

Patient and graft survival in hepatitis C recipients after adult living donor liver transplantation in the United States

End stage liver disease from chronic hepatitis C is the leading indication for liver transplantation in the United States. Small studies suggest that recurrent hepatitis C may be more common and occur earlier after living donor liver transplantation compared to deceased donor liver transplantation. The objective of our study was to analyze the United Network for Organ Sharing liver transplant database to compare patient and graft survival in recipients transplanted for chronic hepatitis C who received a living donor organ and deceased donor organ between 1999 and 2002. We identified 279 living donor recipients and 3,955 deceased donor recipients. Living donor recipients were less ill at the time of transplant, more likely to be female, and received grafts from younger donors. In the living donor group and deceased donor group, 1‐year graft survival was 77% and 82%, respectively, and 2‐year graft survival was 72% and 75%, respectively, P = .11. One‐year patient survival was 87% in both groups and 2‐year patient survival was 83% and 81% in the living donor group and deceased donor group, respectively, P = .68. Short‐term patient and graft survival are similar between living donor and deceased donor liver transplant recipients with hepatitis C suggesting that recurrent hepatitis C does not seem to affect short‐term outcomes. (Liver Transpl 2004;10:340–346.)

Concordance of sustained virological response 4, 12, and 24 weeks post‐treatment with sofosbuvir‐containing regimens for hepatitis C virus

Historically, clinical trials of regimens to treat chronic infection with hepatitis C virus (HCV) have used, as their primary efficacy endpoint, a sustained virological response (SVR)—defined as HCV RNA levels below a designated threshold of quantification—24 weeks after the end of treatment (SVR24). More recently, regulatory authorities have begun to accept SVR at 12 weeks post‐treatment (SVR12) as a valid efficacy endpoint because of its high rate of concordance with SVR24. However, the concordance between SVR12 and SVR24 has not been systematically assessed with new regimens of recently approved direct‐acting antiviral agents. The aim of this study was to assess the concordance between SVR at various post‐treatment time points in phase III clinical trials of sofosbuvir (SOF)‐containing regimens. We conducted a retrospective analysis of five trials enrolling 863 patients infected with HCV genotypes 1‐6. The concordance between SVR at 4 weeks post‐treatment (SVR4) and SVR12, and between SVR12 and SVR24, were determined, as well as positive predictive values (PPVs) and negative predictive values (NPVs). Overall, 779 of 796 patients (98.0%) with an SVR4 also achieved an SVR12, making the PPV of SVR4 for SVR12 98% and the NPV 100%. Of the 779 patients with an SVR12, 777 (99.7%) also achieved an SVR24, making the PPV of SVR12 for SVR24 >99% and the NPV 100%. Of patients who relapsed post‐therapy, 77.6% did so within 4 weeks of completing therapy. Conclusion: Data from phase III studies demonstrate that with SOF‐based regimens, with or without interferon, SVR12 and SVR24 correlate closely. Thus, SVR12 can be used effectively to determine “cure” rates in trials and in clinical practice. (Hepatology 2015;61:41–45)

Social stigmatization and hepatitis C virus infection.

Goal Our aim was to assess stigmatization by evaluating the impact of hepatitis C virus (HCV) on social interactions, feelings of rejection, internalized shame, and financial insecurity, and behavior. Background HCV patients suffer from slowly progressive disease. Although much research has improved the long-term prognosis of chronic HCV, quality of life may be affected by perceived social stigmatization. Study In a cross-sectional study, HCV patients without cirrhosis or significant comorbidities were recruited from the University of North Carolina viral hepatitis clinic. Subjects completed a questionnaire administered by a trained interviewer that assessed changes in sexual behavior, personal hygiene habits, social function, and interactions. Additionally, subjects completed validated, standardized questionnaires, the Health Status Questionnaire, and the SCL-90-R. Frequencies were calculated for the prevalence of stigmatization and altered social interaction. Correlations between education and behavior changes were assessed. A series of multivariate analyses controlling for age, sex, and education were performed to assess the association between HCV acquisition risk and stigmatization. Results One hundred seventy-five of 217 potential subjects (81%) participated in the survey. The average age was 45.2±7.7 years. Fifty-five percent were men and 53% were single. Twenty-nine percent had some college education. Risk factors for HCV acquisition included transfusion (21%) and injection drug use (29%), whereas 32% had an unknown mode of infection. Among common activities, 47% were less likely to share drinking glasses, 14% were less likely to prepare food, and one-third of subjects were less likely to share a towel. Thirty-five percent of respondents reported changes in their sexual practices. Decreased frequency of kissing and sexual intercourse was reported in 20% and 27% of individuals, respectively. Almost half of the single subjects reported increased use of condoms compared with only 20% among married couples. The majority of subjects perceived financial insecurity, internalized shame, and social rejection. Only 39% reported health impairment. Education level did not influence behavior change. Conclusion The majority of HCV subjects alter common behaviors and report financial insecurity, internalized shame, and social rejection, regardless of the method of HCV acquisition or socioeconomic status. These findings indicate that all HCV individuals be counseled and encouraged to participate in educational programs at the time of diagnosis to reduce unnecessary behavioral changes and stigmatization perceptions to improve quality of life.

Impact of Donor Age and Year of Transplant on Graft Survival in Liver Transplant Recipients with Chronic Hepatitis C

Studies suggest donor age and year of transplantation are associated with low graft survival in liver transplant recipients with hepatitis C. We sought to determine if advanced donor age and recent year of transplantation are associated with graft survival in hepatitis C recipients and to determine if the effect of donor age on graft survival is specific to hepatitis C. We analyzed the United Network for Organ Sharing liver transplant database from 1994 to 2002. Six thousand four hundred and four subjects transplanted for end‐stage liver disease from chronic hepatitis C met our criteria. One‐year graft survival in hepatitis C recipients with organs from donors <40 years old and ≥60 years old was 84% and 73%, p = 0.003, respectively. These rates in recipients with cholestatic liver disease and alcoholic liver disease were 85% and 82%, respectively, p = 0.11 and 82% and 78%, respectively, p = 0.14. Three‐year graft survival in hepatitis C recipients transplanted from 1994 to 1995 and 1996 to 1999 was 67% and 69%, respectively, p = 0.10. Graft survival in hepatitis C recipients has not declined in recent years. Older donor age is associated with lower short‐term graft survival in recipients with hepatitis C, but not in recipients with cholestatic or alcoholic liver disease.

MR imaging findings of infectious cholangitis.

The purpose of this study was to evaluate the appearance of infectious cholangitis on MRI. The MR images of 13 patients (9 women, 4 men; age range, 14-79 years) with clinically confirmed infectious cholangitis, who represent our complete 9.5 year experience with this entity, were retrospectively evaluated. All MR studies were performed at 1.5 T and included: in-phase and out-of-phase T(1)-weighted spoiled gradient echo (SGE), T(2)-weighted fat-suppressed echo train spin echo, single shot T(2)-weighted sequences, and serial postgadolinium T(1)-weighted SGE sequences without and with fat-suppression. The biliary ductal system was evaluated regarding presence of dilatation, stenosis, wall irregularities, wall thickening, and gadolinium enhancement of duct walls. The liver parenchyma was evaluated regarding focal signal abnormalities on precontrast and serial postgadolinium images. Biliary ductal dilatation was observed in 100% of patients. Mild to moderate thickening of bile duct walls combined with increased enhancement on postgadolinium images was observed in 92% of patients. The liver parenchyma showed periportal or wedge-shaped areas of hyperintense signal on T(2)-weighted images in 69% of patients. On T(1)-weighted images, 54% of patients showed areas of hypointense signal and 15% of patients showed wedge-shaped hyperintense areas. Areas with increased enhancement on immediate postgadolinium SGE were observed in 58% of patients, and in 42% of patients increased enhancement persisted on 2 min postgadolinium fat-suppressed images. Distinctive MRI findings on pre- and postgadolinium images are appreciated for infectious cholangitis.

Child-Turcotte-Pugh Class is Best at Stratifying Risk in Variceal Hemorrhage: Analysis of a US Multicenter Prospective Study

Goals/Background: Data on acute variceal hemorrhage (AVH) in the United States is limited and the best method to stratify risk is not clear. Taking advantage of a prospective US cohort study, we aimed to (1) describe clinical outcomes of AVH and their predictors; (2) compare predictors of 6-week mortality. Study: Prospective 15-center US cohort of patients with cirrhosis presenting with endoscopically proven AVH, all of whom received antibiotics, vapreotide (a somatostain analog) infusion and endoscopic band ligation. Patients were enrolled between August 2006 and April 2008. Primary outcome was 6-week mortality. Secondary outcome was 5-day treatment failure. The prognostic value of Child-Turcotte-Pugh (CTP) class, Model for End-stage Liver Disease (MELD) score and a recent recalibrated MELD were compared. Results: Seventy eligible patient were enrolled; 18 (26%) patients died within 6-weeks of index bleed. Demographic, clinical, and laboratory data were compared between survivors and nonsurvivors. Multivariate models showed that admission CTP or the MELD score (separately) were independent predictors of survival. The discriminative values of CTP (area under receiver operating characteristic: 0.75) and MELD (area under receiver operating characteristic: 0.79) were good and not significantly different (P=0.27). However, calibration (correlation between observed and predicted mortality) test was significantly better for CTP than for MELD, with the recently described recalibrated MELD model having the worst agreement. Predicted mortality for CTP-A was <10%, CTP-B 10% to 30%; and CTP-C >33%. Conclusions: AVH mortality of 26% in the United States is in the upper range limit compared with recent series but may be due to inclusion of patients with more advanced cirrhosis. CTP score has the best overall performance in the prediction of 6-week mortality and is best at stratifying risk.

Short Duration Treatment with Sofosbuvir/Velpatasvir plus GS-9857 in Treatment-Naive Genotype 1-6 HCV-Infected Patients with or without Cirrhosis

Edward J. Gane, Mindie Nguyen, Paul Kwo, Kris Kowdley, Nancy Reau, Ira Jacobson, Michael Curry, Brian Pearlman, Omer Khalid, Gregory Everson, Stuart Gordon, John Poulos, Aasim Sheikh, David Bernstein, Jenny C. Yang, Luisa M. Stamm, Di An, Hadas Dvory-Sobol, Diana M. Brainard, John G. McHutchison, Myron Tong, Naoky Tsai, Kimberly L. Beavers, Mordechai Rabinovitz, Mitchell Shiffman, Catherine Stedman, Eric Lawitz Abstract SAT-138

Su1063 Long Term Follow-Up of Patients Treated With Sofosbuvir in the Phase 3 Studies Fission, Positron, Fusion and Neutrino

Of 480 patients with SVR24 from the Phase 3 trials, 435 (91%) and 90 (19%) had available Week 24 and 48 data, respectively SVR24 was durable in 100% of these patients Liver-Related Events SVR Registry – No hepatocellular carcinoma or deaths were reported Sequence Registry – 2 patients had hepatocellular carcinoma at study entry – 1 death reported – 55-year-old male was diagnosed with hepatocellular carcinoma on study and died due to gastrointestinal bleeding 10 months after diagnosis