Jeffrey A. Kahn

Impact of disease severity on outcome of antiviral therapy for chronic hepatitis C: Lessons from the HALT‐C trial

In patients with chronic hepatitis C, advanced fibrosis and cirrhosis are associated with lower rates of sustained virologic response (SVR) to interferon (IFN)‐based therapy. In this study, we assessed virologic response to retreatment with peginterferon alfa‐2a and ribavirin (RBV), as a function of the baseline fibrosis score (Ishak staging) and platelet count, in 1,046 patients enrolled in the Hepatitis C Antiviral Long‐term Treatment against Cirrhosis (HALT‐C) Trial. All patients had failed prior treatment with IFN or peginterferon ± RBV and had Ishak fibrosis scores ≥ 3. Four groups of patients with increasingly severe liver disease were compared: (A) bridging fibrosis (Ishak 3 and 4) with platelet counts >125,000/mm3 (n = 559); (B) bridging fibrosis with platelet counts ≤125,000/mm3 (n = 96); (C) cirrhosis (Ishak 5 and 6) with platelet counts >125,000/mm3 (n = 198); and (D) cirrhosis with platelet counts ≤125,000/mm3 (n = 193). SVR rates were 23%, 17%, 10%, and 9% in groups A, B, C, and D, respectively (P < .0001 for trend). Reduction in SVR as a function of increasingly severe disease was independent of age, percent African American, HCV genotype, HCV level, and type of prior therapy. Dose reduction lowered SVR frequencies, but to a lesser extent than disease severity. By logistic regression, cirrhosis (P < .0001) was the major determinant that impaired virologic response, independent of dose reduction or platelet count. In conclusion, disease severity is a major independent determinant of rate of SVR in patients with advanced chronic hepatitis C. New strategies are needed to optimize antiviral therapy in these “difficult‐to‐cure” patients. (HEPATOLOGY 2006;44:1675–1684.)

Portal hypertensive gastropathy in chronic hepatitis C patients with bridging fibrosis and compensated cirrhosis: results from the HALT-C trial.

OBJECTIVES:The clinical significance of portal hypertensive gastropathy (PHG) in patients with compensated liver disease is not well established. The aim of this study was to determine the prevalence and correlates of PHG in a large cohort of patients with chronic hepatitis C virus (HCV) infection and bridging fibrosis/compensated cirrhosis entering the randomized phase of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis trial (HALT-C).METHODS:The presence and severity of PHG in 1,016 HCV patients with no prior history of gastrointestinal bleeding was determined at surveillance endoscopy using the New Italian Endoscopy Club criteria.RESULTS:Overall, 37% of HALT-C patients had PHG with 34% having mild and 3% with severe changes. The mucosal mosaic pattern was identified in 33%, red marks in 15%, and gastric antral vascular ectasia (GAVE) features in only 3%. Independent correlates of PHG included biochemical markers of liver disease severity (lower serum albumin, higher bilirubin), portal hypertension (lower platelet count), insulin resistance (higher glucose), and non-African American race. Independent correlates of GAVE included a history of smoking, nonsteroidal anti-inflammatory drugs (NSAIDs) use within the past year, and higher serum bilirubin and glucose levels. There was a strong positive association between the presence of PHG and esophageal varices ( p < 0.0001).CONCLUSIONS:PHG is associated with the histological and biochemical severity of liver disease in patients with HCV and advanced fibrosis but is mild in most patients. The clinical relevance of these findings will be further explored during the randomized phase of the HALT-C study.

Factors That Determine the Development and Progression of Gastroesophageal Varices in Patients With Chronic Hepatitis C

BACKGROUND & AIMS We aimed to identify the incidence and predictors of de novo gastroesophageal variceal formation and progression in a large cohort of patients with chronic hepatitis C and advanced fibrosis. METHODS All participants in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial were offered an endoscopy before treatment and again after 4 years. Patients with varices at baseline also had an endoscopy at 2 years. Baseline laboratory and clinical parameters were analyzed as predictors of de novo variceal formation and variceal progression. RESULTS De novo varices developed in 157 of the 598 (26.2%) patients. Most of the new varices were small (76.4%) and only 1% of patients developed variceal hemorrhage. The likelihood of developing varices was associated with subject race (Hispanic > Caucasian > African American; P = .0005), lower baseline levels of albumin (P = .051), and higher levels of hyaluronic acid (P < .001) with an area under the receiver operating characteristic curve = .70. Among 210 patients with existing gastroesophageal varices, 74 (35.2%) had variceal progression or bleeding during follow-up. Patients with higher baseline ratios of serum aspartate/alanine aminotransferase (P = .028) and lower platelet counts (P = .0002) were at greatest risk of variceal progression (area under the receiver operating characteristic = .72). Prolonged, low-dose peginterferon-alpha2a therapy and beta-blockers did not influence the risk of developing new or enlarging varices. CONCLUSION Development of varices in patients with chronic hepatitis C is associated with patient race/ethnicity and laboratory markers of disease severity. Prolonged low-dose peginterferon-alpha2a therapy and beta-blockers do not reduce the risk of variceal development or progression.

Sofosbuvir and Simeprevir Therapy for Recurrent Hepatitis C Infection After Liver Transplantation.

Introduction Antiviral therapy for recurrent hepatitis C in liver transplant recipients has been associated with low efficacy, poor tolerability, and drug-drug interactions. Recent approval of various hepatitis C direct-acting antivirals has resulted in improvement of these parameters. We evaluated the efficacy and safety of 12 week all-oral interferon- and ribavirin-free therapy with sofosbuvir and simeprevir. Methods Thirty-two genotype 1 liver transplant recipients with recurrent hepatitis C infection were retrospectively analyzed. All patients received 12 weeks of sofosbuvir 400 mg and simeprevir 150 mg orally daily. The primary endpoint was sustained virologic response 12 weeks after treatment. Results Sustained virologic response 12 weeks after treatment was achieved in 30 of 32 (94%; 95% confidence interval, 79-99%) patients. All patients enjoyed on-treatment virological response. Both patients who relapsed were cirrhotic, previously treated with Q80K polymorphism. Significant improvements in alkaline phosphatase, albumin, alanine aminotransferase levels, and platelets were seen at 12-week post therapy. Treatment was well tolerated. No grade 3 or 4 adverse events were noted. Headache and fatigue were the most common complaints. Conclusion Combination of sofosbuvir and simeprevir for 12 weeks resulted in 94% sustained virological response-12 rates in patients with hepatitis C genotype 1 and was well tolerated.

S1919 Coated Tips Does Not Improve Thrombocytopenia in Cirrhotic Patients (Preliminary Results From a Retrospective Analysis of Platelet Counts in Cirrhotic Patients After Tips Placement)

patients followed in an academic liver clinic. RESULTS. The study assessed 1,022 patients with a mean 20.0 (3-60) months of follow-up. The mean age was 45.6 (17-86) years; 29.8% (n=304) were elderly (age ≥ 60 years); 54.0% were males; 35.4% were Asians and 41.3%, Caucasians; 44.9% had chronic hepatitis C (CHC) and 19.0%, chronic hepatitis B (CHB). CHC was more common (77.8% vs. 67.4%), but CHB was less common (22.2% vs. 32.6%) in the elderly group than in the younger group, and the frequency of alcoholic liver diseases (ALD) was comparable in both groups (3.3 vs. 3.3%). Elderly patients had significantly higher incidence of history of hypertension (HTN, 50.0% vs. 23.5%), diabetes mellitus (DM, 28.5% vs. 13.6%), but lower incidence of obesity (22.4% vs. 29.0%). They also carried a significantly higher rate of cirrhosis (i.e., stage 3-4 fibrosis) and/or HD (i.e., presence of ascites and/or hepatic encephalopathy, 62.8% vs. 48.5%), and hepatocellular carcinoma (HCC, 8.3% vs. 1.9%). Laboratorially, elderly patients had significantly higher incidence of thrombocytopenia (28.8% vs. 16.4%), hypoalbuminemia (28.2% vs. 17.0%), and AST/ALT ratio ≥ 1 (57.2% vs. 38.3%). Multivariate analyses indicated that the significantly higher frequency of cirrhosis and/or HD in the elderly group was independently associated with age (p=0.003, OR=1.86) and obesity (p=0.0001, OR=2.11). CONCLUSIONS. In this large cohort of patients, elderly patients carried a higher frequency of CHC, history of DM, HTN, cirrhosis and/or HD, and HCC. Cirrhosis was independently associated with age and obesity.