Hepatitis E Virus Does Not Contribute to Hepatic Decompensation Among Patients With Advanced Chronic Hepatitis C.

BACKGROUND & AIMS: Hepatitis E (HEV) can cause acute-on-chronic liver failure in persons with pre-existing liver disease. We investigated whether HEV infection contributes to hepatic decompensation in patients with previously stable, advanced chronic hepatitis C. METHODS: We performed a case-control study using stored serum samples from subjects enrolled in the randomized phase of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial (n = 1050; mean age, 51 y; 70% male; 40% with cirrhosis at baseline). Cases were subjects who developed hepatic decompensation within a 24-week period. Controls (3 per case) were subjects without hepatic decompensation matched for fibrosis stage and followed up for a similar period. A serum sample obtained within 6 months after the decompensation event in cases and the same follow-up period in controls were tested for anti-HEV IgG. Subjects with a positive result had a baseline sample similarly tested for anti-HEV IgG. We measured levels of anti-HEV IgM and HEV RNA in blood samples from incident cases. RESULTS: Of the 1050 subjects analyzed, 314 (30%) experienced a clinical event. Of the 314 subjects who experienced decompensation as defined, 89 (28%) were tested for anti-HEV, along with 267 controls (without decompensation). Similar proportions of cases and controls tested positive for anti-HEV (22.5% and 20.6%, respectively; P = .70). Ten incident HEV infections were identified-4 in cases (4.5%) and 6 in controls (2.2%) (P = .28). HEV RNA was not detected in blood samples from the 10 incident infections. Only 2 of the 4 incident infections among cases were related temporally to the decompensation event. CONCLUSIONS: HEV does not appear to be a significant cause of hepatic decompensation among persons with previously stable, advanced chronic hepatitis C in the United States.

A Variant in PNPLA3 Associated With Fibrosis Progression but not Hepatocellular Carcinoma in Patients With Hepatitis C Virus Infection.

BACKGROUND & AIMS: A single nucleotide polymorphism (SNP) in the patatin-like phospholipase domain containing 3 gene (PNPLA3, rs738409) has been associated with fibrosis and development of hepatocellular carcinoma (HCC) in patients with nonalcoholic steatohepatitis, although its association with outcomes in patients with hepatitis C virus (HCV) infection is less clear. We evaluated the association between this SNP in PNPLA3 and fibrosis progression and development of HCC among HCV-infected patients. METHODS: We performed a secondary analysis of data from participants in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial. Patients were randomly assigned to groups given weekly pegylated interferon or no further therapy for 3.5 y and then followed without further treatment until October 2009. Multivariate logistic regression was used to identify factors associated with fibrosis at baseline, fibrosis progression (defined as 2-point increase in Ishak score), and HCC development. RESULTS: Among 937 HCV patients with known PNPLA3 genotype, 384 (41.0%) had cirrhosis at baseline. The PNPLA3 CG/GG SNP at rs738409 was significantly associated with the presence of cirrhosis (odds ratio [OR], 1.76; 95% confidence interval [CI], 1.34-2.30), after adjusting for age, sex, diabetes, and race. Among 493 patients without cirrhosis at baseline who had at least 1 follow-up biopsy, 142 had fibrosis progression. In multivariate analyses, fibrosis progression was associated with obesity (OR, 1.67; 95% CI, 1.11-2.51) and the PNPLA3 CG/GG genotype (OR, 1.70; 95% CI, 1.13-2.56). PNPLA3 genotype was not associated with HCC development (P = .85). Using these data to update prior meta-analysis results, the rs738409 SNP in PNPLA3 was not significantly associated with development of HCC in HCV-infected patients (OR 1.29; 95% CI, 0.97-1.99). CONCLUSIONS: Based on data from the HALT-C trial, the PNPLA3 CG/GG SNP at rs738409 is associated with fibrosis progression but not development of HCC in patients with HCV infection.

Sex difference in liver-related mortality and transplantation associated with dietary cholesterol in chronic hepatitis C virus infection.

Dietary cholesterol induces hepatic inflammation and fibrosis in animals. We aimed to determine whether dietary cholesterol affects liver-related mortality in hepatitis C virus (HCV)-infected patients. We performed a retrospective cohort study using extended follow-up data from the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial. The study included HCV patients with advanced fibrosis and compensated cirrhosis. The analysis included 657 patients who completed two FFQ. We assessed whether cholesterol intake, measured in mg/4184 kJ (mg/1000 kcal) of energy intake, was associated with liver-related death or transplantation. In 4·7 (sd 1·6) years, the incidence of liver-related death (n 46) or transplantation (n 52) was 31·8/1000 person-years. The relationship between cholesterol intake and liver-related death or transplantation was significantly different between men and women (test for interaction, P value=0·01). Each higher quartile of cholesterol intake was associated with an increased risk for liver-related death or transplantation in women (adjusted hazard ratio (AHR) 1·83; 95 % CI 1·12, 2·99; P trend=0·02), but not in men (AHR 0·96; 95 % CI 0·76, 1·22; P trend=0·73). Compared with women whose cholesterol intake was within the recommended guidelines (300 mg/d with a 8368 kJ (2000 kcal) diet), women who consumed more cholesterol had significantly increased risk for liver-related death or transplantation (AHR 4·04; 95 % CI 1·42, 11·5). High dietary cholesterol was associated with an increased risk for liver-related death and transplantation in HCV-infected women with advanced fibrosis or compensated cirrhosis. Future studies should assess whether reducing cholesterol intake, among women who consume an excessive amount, can decrease HCV-related mortality.

Is there sufficient evidence to recommend antiviral therapy in hepatitis C?

While patients with chronic hepatitis C virus (HCV) infection are treated in order to prevent liver-related morbidity and mortality, we rely on sustained virological response (SVR) as a virological biomarker to evaluate treatment efficacy in both clinical practice as well as in drug development. However, conclusive evidence for the clinical benefit of antiviral therapy or validity of SVR as surrogate marker, as derived from trials randomizing patients to a treatment or control arm, is lacking. In fact, the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial recently showed an increased mortality rate among interferon-treated patients compared to untreated controls. Consequently, the recommendation to treat patients with chronic HCV infection was challenged. Here, we argue that the possible harmful effect of long-term low-dose pegylated interferon mono therapy, as was observed in the HALT-C trial cohort, cannot be extrapolated to potentially curative short-term treatment regimens. Furthermore, we discuss SVR as a surrogate biomarker, based on numerous studies which indicated an association between SVR and improvements in health-related quality of life, hepatic inflammation and fibrosis, and portal pressure as well as a reduced risk for hepatocellular carcinoma (HCC), liver failure and mortality.

Dietary cholesterol intake is associated with progression of liver disease in patients with chronic hepatitis C: analysis of the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis trial.

BACKGROUND & AIMS: Little is known about whether dietary cholesterol affects disease progression in patients with chronic hepatitis C virus infection. METHODS: We analyzed data from the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis trial, which included patients with advanced fibrosis and compensated cirrhosis. Cholesterol intake was determined for 608 participants on the basis of responses to food frequency questionnaires, administered at baseline and 1.8 years later. We investigated whether cholesterol intake was associated with clinical progression (death, variceal bleeding, encephalopathy, ascites, peritonitis, Child-Turcotte-Pugh score ≥ 7, or hepatocellular carcinoma) or histologic progression of disease (an increase in Ishak fibrosis score of 2 or more points in a second liver biopsy compared with the first). RESULTS: After adjustments for age, sex, race, presence of cirrhosis, body mass index, treatment with peginterferon, lifetime alcohol consumption, smoking, health status, and coffee and macronutrient intake, each higher quartile of cholesterol intake was associated with a 46% increase in the risk of clinical or histologic progression (adjusted hazard ratio [AHR], 1.46; 95% confidence interval [CI], 1.13-1.87; P for the trend = .004). Compared with patients in the lowest quartile of cholesterol intake (32-152 mg/day), those in the 3rd (224-310 mg/day; AHR, 2.83; 95% CI, 1.45-5.51) and 4th quartiles (>310 mg/day; AHR, 2.74; 95% CI, 1.22-6.16) had significantly increased risk of disease progression. CONCLUSIONS: On the basis of analysis of data from the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis trial, higher dietary cholesterol intake is associated with higher risk of disease progression in HCV-infected patients with advanced fibrosis or compensated cirrhosis.

Use of noninvasive markers to predict advanced fibrosis/cirrhosis in severe obesity.

BACKGROUND: Nonalcoholic steatohepatitis is observed in 25%-55% of patients with severe obesity and in 2%-12% with bridging fibrosis or cirrhosis. There is currently no noninvasive test for the diagnosis of severe liver fibrosis before bariatric surgery. OBJECTIVES: To determine the best noninvasive test for predicting advanced liver disease in patients with severe obesity. SETTING: University tertiary care hospital, Brazil. METHODS: A cross-sectional retrospective study was conducted with 699 patients with severe obesity undergoing bariatric surgery: 568 without a biopsy (nonbiopsy cohort) and 131 patients who had undergone an intraoperative liver biopsy. The tissues were subjected to histologic diagnosis (Brunt criteria) and classified as advanced fibrosis (stages 3 and 4) or no significant fibrosis (absence of nonalcoholic steatohepatitis and stages 1 or 2). The following predictive indices of cirrhosis were calculated in all patients: aspartate aminotransferase/alanine aminotransferase ratio (AAR), age-platelet (AP) index, aminotransferase-to-platelet ratio index (APRI), cirrhosis discriminant score (CDS), and hepatitis C antiviral long-term treatment against cirrhosis (HALT-C). The cutoff values, sensitivity, specificity, and areas under the receiver operating characteristic curves (AUROCs) were calculated for patients with biopsies. RESULTS: The AUROC of the AAR, AP, APRI, CDS, and HALT-C model for predicting advanced fibrosis or cirrhosis were, respectively, .522, .88, .99, .905, and .921. The calculated cutoff values, sensitivity, and specificity, respectively, were as follows: AAR: .94, .7, .45; AP 5, .7, .93; APRI .44, 1.0, .97; CDS 6, .7, .97; and HALT-C: .76, 1.0, .77. CONCLUSION: APRI index was the best predictor of advanced liver disease in patients with severe obesity.