Iron levels in hepatocytes and portal tract cells predict progression and outcomes of patients with advanced chronic hepatitis C.

BACKGROUND & AIMS: Iron may influence severity and progression of non-hemochromatotic liver diseases. Our aim was to assess the relationship of iron and HFE genetic variations to progression and outcomes in the HALT-C Trial and whether PegIFN therapy influenced iron variables. METHODS: Participants were randomized to receive long-term PegIFN [n = 400] or no therapy [n = 413] for 3.5 y, with follow-up for up to 8.7 y [median 6.0 y]. Associations of patient characteristics with iron variables at baseline and over time were carried out using Kaplan-Meier analyses, Cox regression models, and repeated measures analysis of covariance. RESULTS: Participants who developed clinical outcomes [CTP > 7, ascites, encephalopathy, variceal bleeding, SBP, HCC, death] had significantly higher baseline scores for stainable iron in hepatocytes and in portal tract cells than those without. There were significant direct correlations between stainable iron in portal triads and lobular and total Ishak inflammatory and fibrosis scores [P < 0.0001]. Iron in triads at baseline increased risk of outcomes (HR = 1.35, P = 0.02). Stainable iron in hepatocytes decreased, whereas that in portal stromal cells increased significantly [P < 0.0001] over time. Serum iron and TIBC fell significantly over time [P < 0.0001], as did serum ferritin [P = 0.0003]. Chronic PegIFN treatment did not affect stainable iron. HFE genetic variations did not correlate with outcomes, including development of hepatocellular carcinoma. CONCLUSIONS: Stainable iron in hepatocytes and portal tract cells is a predictor of progression and clinical and histological outcomes in advanced chronic hepatitis C. Chronic low-dose PegIFN therapy did not improve outcomes, nor iron variables.

Maintenance peginterferon therapy and other factors associated with hepatocellular carcinoma in patients with advanced hepatitis C.

BACKGROUND & AIMS: Interferon reportedly decreases the incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial showed that 4 years of maintenance therapy with pegylated interferon (peginterferon) does not reduce liver disease progression. We investigated whether peginterferon decreases the incidence of HCC in the HALT-C cohort over a longer posttreatment follow-up period. METHODS: The study included 1048 patients with chronic hepatitis C (Ishak fibrosis scores ≥ 3) who did not have a sustained virologic response (SVR) to therapy. They were randomly assigned to groups given a half-dose of peginterferon or no treatment (controls) for 3.5 years and followed up for a median of 6.1 (maximum, 8.7) years. RESULTS: Eighty-eight patients developed HCC (68 definite, 20 presumed): 37 of 515 who were given peginterferon (7.2%) and 51 of 533 controls (9.6%; P = .24). There was a significantly lower incidence of HCC among patients given peginterferon therapy who had cirrhosis, but not fibrosis, based on analysis of baseline biopsy samples. After 7 years, the cumulative incidences of HCC in treated and control patients with cirrhosis were 7.8% and 24.2%, respectively (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.24-0.83); in treated and control patients with fibrosis, incidences were 8.3% and 6.8%, respectively (HR, 1.44; 95% CI, 0.77-2.69). Treated patients with a ≥ 2-point decrease in the histologic activity index, based on a follow-up biopsy, had a lower incidence of HCC than those with unchanged or increased scores (2.9% vs 9.4%; P = .03). CONCLUSIONS: Extended analysis of the HALT-C cohort showed that long-term peginterferon therapy does not reduce the incidence of HCC among patients with advanced hepatitis C who did not achieve SVRs. Patients with cirrhosis who received peginterferon treatment had a lower risk of HCC than controls.

Excess mortality in patients with advanced chronic hepatitis C treated with long-term peginterferon.

UNLABELLED: Chronic hepatitis C virus infection can cause chronic liver disease, cirrhosis and liver cancer. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial was a prospective, randomized controlled study of long-term, low-dose peginterferon therapy in patients with advanced chronic hepatitis C who failed to respond to a previous course of optimal antiviral therapy. The aim of this follow-up analysis is to describe the frequency and causes of death among this cohort of patients. Deaths occurring during and after the HALT-C Trial were reviewed by a committee of investigators to determine the cause of death and to categorize each death as liver- or nonliver-related and as related or not to complications of peginterferon. Rates of liver transplantation were also assessed. Over a median of 5.7 years, 122 deaths occurred among 1,050 randomized patients (12%), of which 76 were considered liver-related (62%) and 46 nonliver-related (38%); 74 patients (7%) underwent liver transplantation. At 7 years the cumulative mortality rate was higher in the treatment compared to the control group (20% versus 15%, P = 0.049); the primary difference in mortality was in patients in the fibrosis compared to the cirrhosis stratum (14% versus 7%, P = 0.01); comparable differences were observed when liver transplantation was included. Excess mortality, emerging after 3 years of treatment, was related largely to nonliver-related death; liver-related mortality was similar in the treatment and control groups. No specific cause of death accounted for the excess mortality and only one death was suspected to be a direct complication of peginterferon. CONCLUSION: Long-term maintenance peginterferon in patients with advanced chronic hepatitis C is associated with an excess overall mortality, which was primarily due to nonliver-related causes among patients with bridging fibrosis.

A prospective study of the rate of progression in compensated, histologically advanced chronic hepatitis C.

UNLABELLED: The incidence of liver disease progression among subjects with histologically advanced but compensated chronic hepatitis C is incomplete. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial was a randomized study of 3.5 years of maintenance peginterferon treatment on liver disease progression among patients who had not cleared virus on peginterferon and ribavirin therapy. Patients were followed subsequently off therapy. Because maintenance peginterferon treatment did not alter liver disease progression, we analyzed treated and control patients together. Among 1,050 subjects (60% advanced fibrosis, 40% cirrhosis), we determined the rate of progression to cirrhosis over 4 years and of clinical outcomes over 8 years. Among patients with fibrosis, the incidence of cirrhosis was 9.9% per year. Six hundred seventy-nine clinical outcomes occurred among 329 subjects. Initial clinical outcomes occurred more frequently among subjects with cirrhosis (7.5% per year) than subjects with fibrosis (3.3% per year) (P<0.0001). Child-Turcotte-Pugh (CTP) score≥7 was the most common first outcome, followed by hepatocellular carcinoma. Following occurrence of a CTP score≥7, the rate of subsequent events increased to 12.9% per year, including a death rate of 10% per year. Age and sex did not influence outcome rates. Baseline platelet count was a strong predictor of all clinical outcomes. During the 8 years of follow-up, death or liver transplantation occurred among 12.2% of patients with advanced fibrosis and 31.5% of those with cirrhosis. CONCLUSION: Among patients with advanced hepatitis C who failed peginterferon and ribavirin therapy, the rate of liver-related outcomes, including death and liver transplantation, is high, especially once the CTP score reaches at least 7.

YKL-40 genetic polymorphisms and the risk of liver disease progression in patients with advanced fibrosis due to chronic hepatitis C.

BACKGROUND/AIMS: The aim of this study was to explore the association of a functional YKL-40 promoter polymorphism (rs4950928) with baseline disease stage, response to antiviral therapy and risk of liver disease progression in a group of patients with chronic hepatitis C (CHC). METHODS: YKL-40 promoter polymorphisms were determined in 456 Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial patients with bridging fibrosis or cirrhosis entering a prerandomization lead-in peginterferon/ribavirin 24-week treatment phase and in 462 patients followed for a mean of 3.8 years after randomization to maintenance peginterferon or observation. RESULTS: Mean patient age was 49.5 years, 70.4% were men and 71.2% were Caucasian. The 17% frequency of the YKL-40 minor allele (T) was similar to that reported in the general population. YKL-40 genotype was associated significantly with baseline serum YKL-40 levels but was not associated with the likelihood of a virological response following 24-48 weeks of peginterferon/ribavirin therapy. Serum YKL-40 levels remained significantly lower during follow-up in the randomized TT homozygotes compared with CT heterozygotes and CC homozygotes (P < 0.001). Despite this association, YKL-40 genotype was not associated with the risk of clinical or histological liver disease progression. CONCLUSIONS: A reduced frequency of the protective YKL-40 promoter polymorphism was not observed in the HALT-C Trial patient population. The absence of an association between YKL-40 promoter polymorphisms and baseline liver disease severity as well as with the risk of liver disease progression over time suggests that this polymorphism is not associated with disease progression in CHC patients with established fibrosis.

Development and progression of portal hypertensive gastropathy in patients with chronic hepatitis C.

OBJECTIVES: The objective of this study was to determine the incidence and risk factors associated with new-onset and worsening portal hypertensive gastropathy (PHG) in patients with chronic hepatitis C (CHC). METHODS: A total of 831 CHC patients with bridging fibrosis or cirrhosis at the time of entry were prospectively monitored for clinical and histological liver disease progression while receiving either low-dose peginterferon α2a or no antiviral therapy in the HALT-C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) trial. Upper endoscopy with grading of PHG was performed at baseline and at year 4 of the study. The presence and severity of PHG were determined using the NIEC (New Italian Endoscopy Conference) criteria, and worsening PHG was defined as a score increase of ≥1 point. RESULTS: During a median follow-up of 3.85 years, 50% of 514 subjects without PHG developed new-onset PHG, whereas 26% of 317 patients with baseline PHG had worsening PHG. Independent predictors of new-onset PHG included higher alkaline phosphatase and being diabetic, whereas predictors of worsening PHG were Caucasian race, lower albumin, as well as higher serum aspartate transaminase/alanine transaminase ratio and homeostatic model assessment levels. New-onset and worsening PHG were significantly associated with clinical and histological progression. They were also associated with new-onset and worsening gastroesophageal varices. CONCLUSIONS: New-onset and worsening PHG develop at a rate of 12.9% per year and 6.7% per year, respectively, in non-responder CHC patients with advanced fibrosis. If confirmed in other studies, endoscopic surveillance for PHG may need to be tailored to individual patient risk factors.

Outcome of sustained virological responders with histologically advanced chronic hepatitis C.

UNLABELLED: Retrospective studies suggest that subjects with chronic hepatitis C and advanced fibrosis who achieve a sustained virological response (SVR) have a lower risk of hepatic decompensation and hepatocellular carcinoma (HCC). In this prospective analysis, we compared the rate of death from any cause or liver transplantation, and of liver-related morbidity and mortality, after antiviral therapy among patients who achieved SVR, virologic nonresponders (NR), and those with initial viral clearance but subsequent breakthrough or relapse (BT/R) in the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) Trial. Laboratory and/or clinical outcome data were available for 140 of the 180 patients who achieved SVR. Patients with nonresponse (NR; n = 309) or who experienced breakthrough or relapse (BT/R; n = 77) were evaluated every 3 months for 3.5 years and then every 6 months thereafter. Outcomes included death, liver-related death, liver transplantation, decompensated liver disease, and HCC. Median follow-up for the SVR, BT/R, and NR groups of patients was 86, 85, and 79 months, respectively. At 7.5 years, the adjusted cumulative rate of death/liver transplantation and of liver-related morbidity/mortality in the SVR group (2.2% and 2.7%, respectively) was significantly lower than that of the NR group (21.3% and 27.2%, P < 0.001 for both) but not the BT/R group (4.4% and 8.7%). The adjusted hazard ratio (HR) for time to death/liver transplantation (HR = 0.17, 95% confidence interval [CI] = 0.06-0.46) or development of liver-related morbidity/mortality (HR = 0.15, 95% CI = 0.06-0.38) or HCC (HR = 0.19, 95% CI = 0.04-0.80) was significant for SVR compared to NR. Laboratory tests related to liver disease severity improved following SVR. CONCLUSION: Patients with advanced chronic hepatitis C who achieved SVR had a marked reduction in death/liver transplantation, and in liver-related morbidity/mortality, although they remain at risk for HCC.

Serum fibrosis markers are associated with liver disease progression in non-responder patients with chronic hepatitis C.

OBJECTIVES: The aim of this study was to explore the association of serum fibrosis marker levels with the risk of clinical and histological disease progression in a large cohort of patients with chronic hepatitis C (CHC). METHODS: 462 prior non-responders to peginterferon and ribavirin enrolled in the randomised phase of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial had baseline and annual serum samples tested for hyaluronic acid (HA), N-terminal peptide of procollagen type 3, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and YKL-40. All patients underwent a pretreatment liver biopsy and follow-up biopsies at years 2 and 4. Histological progression was defined as a ≥2 point increase in Ishak fibrosis score in patients without cirrhosis. Clinical outcomes included development of decompensation, hepatocellular cancer, death or an increase in the CTP (Child-Turcotte-Pugh) score to ≥7. RESULTS: Mean patient age was 49.5 years and 39% had histological cirrhosis at entry. Baseline HA, YKL-40 and TIMP-1 levels combined with other laboratory parameters were all significantly associated with clinical outcomes in the 69 (15%) patients with disease progression (p<0.0001). The best multivariate model to predict clinical outcomes included baseline bilirubin, albumin, international normalised ratio (INR) and YKL-40 levels. All of the baseline serum fibrosis marker levels were also significantly associated with histological fibrosis progression that developed in 70 (33%) of the 209 patients with cirrhosis (p <0.0001). However, baseline HA and platelet counts were best at predicting histological progression (area under the curve (AUC)=0.663). CONCLUSION: Pretreatment serum fibrosis marker levels are significantly increased in patients with CHC at risk of clinical and histological disease progression. If validated in additional cohorts, measurement of these markers could help identify patients with CHC who would benefit from more frequent and intensive monitoring.

Effect of HCV RNA suppression during peginterferon alfa-2a maintenance therapy on clinical outcomes in the HALT-C trial.

BACKGROUND & AIMS: The Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial demonstrated that low-dose peginterferon maintenance therapy was ineffective in preventing clinical outcomes in patients with chronic hepatitis C, advanced fibrosis, and failure to achieve a sustained virologic response during lead-in phase treatment with standard dose peginterferon/ribavirin. This analysis was performed to determine whether suppressing HCV RNA during the trial was associated with a reduction in clinical outcomes. METHODS: Seven hundred sixty-four patients treated during the lead-in phase of HALT-C trial were randomized to either peginterferon alfa-2a (90 microg/week) maintenance therapy or no treatment (control) for 3.5 years. Clinical outcomes included an increase in Child-Turcotte-Pugh score, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal hemorrhage, hepatocellular carcinoma, and mortality. RESULTS: During the lead-in, >or=4-log(10) decline in serum HCV RNA occurred in 178 patients; 82% of whom lost detectable HCV RNA and later broke through or relapsed. These patients had significantly (P = .003) fewer clinical outcomes whether randomized to maintenance therapy or control. Following randomization, serum HCV RNA increased significantly in all 90 control patients and in 58 of 88 receiving maintenance therapy. Only 30 patients had persistent suppression of HCV RNA by >or=4 log(10) during maintenance therapy. No significant reduction in clinical outcomes was observed in these patients. CONCLUSIONS: Viral suppression by >or=4 log(10) with full-dose peginterferon/ribavirin is associated with a significant reduction in clinical outcomes. Continuing low-dose peginterferon maintenance therapy, even in patients with persistent viral suppression, does not lead to a further decline in clinical outcomes.

Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease.

BACKGROUND & AIMS: Although the incidence of hepatocellular carcinoma (HCC) is increasing in the United States, data from large prospective studies are limited. We evaluated the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) cohort for the incidence of HCC and associated risk factors. METHODS: Hepatitis C virus-positive patients with bridging fibrosis or cirrhosis who did not respond to peginterferon and ribavirin were randomized to groups that were given maintenance peginterferon for 3.5 years or no treatment. HCC incidence was determined by Kaplan-Meier analysis, and baseline factors associated with HCC were analyzed by Cox regression. RESULTS: 1,005 patients (mean age, 50.2 years; 71% male; 72% white race) were studied; 59% had bridging fibrosis, and 41% had cirrhosis. During a median follow-up of 4.6 years (maximum, 6.7 years), HCC developed in 48 patients (4.8%). The cumulative 5-year HCC incidence was similar for peginterferon-treated patients and controls, 5.4% vs 5.0%, respectively (P= .78), and was higher among patients with cirrhosis than those with bridging fibrosis, 7.0% vs 4.1%, respectively (P= .08). HCC developed in 8 (17%) patients whose serial biopsy specimens showed only fibrosis. A multivariate analysis model comprising older age, black race, lower platelet count, higher alkaline phosphatase, esophageal varices, and smoking was developed to predict the risk of HCC. CONCLUSIONS: We found that maintenance peginterferon did not reduce the incidence of HCC in the HALT-C cohort. Baseline clinical and laboratory features predicted risk for HCC. Additional studies are required to confirm our finding of HCC in patients with chronic hepatitis C and bridging fibrosis.

Evolution of hepatic steatosis in patients with advanced hepatitis C: results from the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial.

UNLABELLED: Hepatic steatosis is a common histologic feature in patients with chronic hepatitis C (CHC) but there are no large longitudinal studies describing the progression of steatosis in CHC. We examined changes in steatosis on serial biopsies among CHC patients participating in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. All 1050 patients in the trial had advanced fibrosis at baseline biopsy and were documented not to have had a sustained virological response to peginterferon and ribavirin. Most (94%) patients had genotype 1 infection. At least one protocol follow-up biopsy was read on 892 patients, and 699 had the last biopsy performed 3.5 years after randomization. At enrollment, 39% had cirrhosis and 61% had bridging fibrosis; 18%, 41%, 31%, and 10% had steatosis scores of 0, 1, 2, and 3 or 4, respectively. The mean steatosis score decreased in the follow-up biopsies in both the interferon-treated patients and controls with no effect of treatment assignment (P = 0.66). A decrease in steatosis score by > or =1 point was observed in 30% of patients and was associated with both progression to cirrhosis and continued presence of cirrhosis (P = 0.02). Compared to patients without a decrease in steatosis, those with a decrease in steatosis had worse metabolic parameters at enrollment, and were more likely to have a decrease in alcohol intake, improvement in metabolic parameters, and worsening liver disease (cirrhosis, esophageal varices, and deterioration in liver function). CONCLUSION: Serial biopsies demonstrated that in patients with CHC, steatosis recedes during progression from advanced fibrosis to cirrhosis. Decreased alcohol intake and improved metabolic parameters are associated with a decline in steatosis and may modulate hepatitis C progression.

Merimepodib, pegylated interferon, and ribavirin in genotype 1 chronic hepatitis C pegylated interferon and ribavirin nonresponders.

UNLABELLED: Merimepodib (MMPD) is an orally administered, inosine monophosphate dehydrogenase inhibitor that has shown antiviral activity in nonresponders with chronic hepatitis C (CHC) when combined with pegylated interferon alfa 2a (Peg-IFN-alfa-2a) and ribavirin (RBV). We conducted a randomized, double-blind, multicenter, phase 2b study to evaluate the antiviral activity, safety, and tolerability of MMPD in combination with Peg-IFN-alfa-2a and RBV in patients with genotype 1 CHC who were nonresponders to prior therapy with Peg-IFN and RBV. Patients received 50 mg MMPD, 100 mg MMPD, or placebo every 12 hours, in addition to Peg-IFN-alfa-2a and RBV, for 24 weeks. Patients with a 2-log or more decrease from baseline or undetectable hepatitis C virus (HCV) RNA levels at week 24 were then eligible to continue Peg-IFN-alfa-2a and RBV for a further 24 weeks, followed by 24 weeks of follow-up. The primary efficacy endpoint was sustained virological response (SVR) rate at week 72 in all randomized patients who received at least one dose of study drug and had a history of nonresponse to standard therapy. A total of 354 patients were randomized to treatment (117 to placebo; 119 to 50 mg MMPD; 118 to 100 mg MMPD), and 286 completed the core study. The proportion of patients who achieved SVR was similar among the treatment groups: 6% (6/107) for 50 mg MMPD, 4% (5/112) for 100 mg MMPD, and 5% (5/104) for placebo (P = 0.8431). Adverse-event profiles for the MMPD combination groups were similar to that for Peg-IFN-alfa and RBV alone. Nausea, arthralgia, cough, dyspnea, neutropenia, and anemia were more common in patients taking MMPD. CONCLUSION: The addition of MMPD to Peg-IFN-alfa-2a and RBV combination therapy did not increase the proportion of nonresponder patients with genotype 1 CHC achieving an SVR.

Coffee intake is associated with lower rates of liver disease progression in chronic hepatitis C.

UNLABELLED: Higher coffee consumption has been associated inversely with the incidence of chronic liver disease in population studies. We examined the relationship of coffee consumption with liver disease progression in individuals with advanced hepatitis C-related liver disease. Baseline coffee and tea intake were assessed in 766 participants of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had hepatitis C-related bridging fibrosis or cirrhosis on liver biopsy and failed to achieve a sustained virological response to peginterferon plus ribavirin treatment. Participants were followed for 3.8 years for clinical outcomes and, for those without cirrhosis, a 2-point increase in Ishak fibrosis score on protocol biopsies. At baseline, higher coffee consumption was associated with less severe steatosis on biopsy, lower serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, alpha-fetoprotein, insulin, and homeostatic model assessment (HOMA2) score, and higher albumin (P < 0.05 for all). Two hundred thirty patients had outcomes. Outcome rates declined with increasing coffee intake: 11.1/100 person-years for none, 12.1 for less than 1 cup/day, 8.2 for 1 to fewer than 3 cups/day, and 6.3 for 3 or more cups/day (P-trend = 0.0011). Relative risks (95% confidence intervals) were 1.11 (0.76-1.61) for less than 1 cup/day; 0.70 (0.48-1.02) for 1 to fewer than 3 cups/day; and 0.47 (0.27-0.85) for 3 or more cups/day (P-trend = 0.0003) versus not drinking. Risk estimates did not vary by treatment assignment or cirrhosis status at baseline. Tea intake was not associated with outcomes. CONCLUSION: In a large prospective study of participants with advanced hepatitis C-related liver disease, regular coffee consumption was associated with lower rates of disease progression.

Variants in interferon-alpha pathway genes and response to pegylated interferon-Alpha2a plus ribavirin for treatment of chronic hepatitis C virus infection in the hepatitis C antiviral long-term treatment against cirrhosis trial.

UNLABELLED: Combination treatment with pegylated-interferon-alpha (PEG IFN-alpha) and ribavirin, the current recommended therapy for chronic hepatitis C virus (HCV) infection, results in a sustained virological response (SVR) in only about half of patients. Because genes involved in the interferon-alpha pathway may affect antiviral responses, we analyzed the relationship between variants in these genes and SVR among participants in the Hepatitis C Antiviral Long-Term treatment Against Cirrhosis (HALT-C) trial. Patients had advanced chronic hepatitis C that had previously failed to respond to interferon-based treatment. Participants were treated with peginterferon-alpha2a and ribavirin during the trial. Subjects with undetectable HCV RNA at week 72 were considered to have had an SVR. Subjects with detectable HCV RNA at week 20 were considered nonresponders. We used TaqMan assays to genotype 56 polymorphisms found in 13 genes in the interferon-alpha pathway. This analysis compares genotypes for participants with an SVR to nonresponders. The primary analysis was restricted to European American participants because a priori statistical power was low among the small number (n = 131) of African American patients. We used logistic regression to control the effect of other variables that are associated with treatment response. Among 581 European American patients, SVR was associated with IFNAR1 IVS1-22G (adjusted odds ratio, 0.57; P = 0.02); IFNAR2 Ex2-33C (adjusted odds ratio, 2.09; P = 0.02); JAK1 IVS22+112T (adjusted odds ratio, 1.66; P = 0.04); and ADAR Ex9+14A (adjusted odds ratio, 1.67; P = 0.03). For the TYK2-2256A promoter region variant, a borderline association was present among European American participants (OR, 1.51; P = 0.05) and a strong relationship among African American patients; all 10 with SVR who were genotyped for TYK2 -2256 carried the A variant compared with 68 of 120 (57%) nonresponders (P = 0.006). CONCLUSION: Genetic polymorphisms in the interferon-alpha pathway may affect responses to antiviral therapy of chronic hepatitis C.

Serum fibrosis marker levels decrease after successful antiviral treatment in chronic hepatitis C patients with advanced fibrosis.

BACKGROUND & AIMS: Serum fibrosis marker levels during the lead-in treatment phase of patients enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial were determined. METHODS: Week 0, 24, 48, and 72 serum samples were analyzed for YKL-40, tissue inhibitor of matrix metalloproteinase-1, amino-terminal peptide of type III procollagen (PIIINP), and hyaluronic acid (HA) levels. All 456 chronic hepatitis C (CHC) patients received peginterferon alfa 2a and ribavirin for 24 to 48 weeks. RESULTS: Mean age was 49.2 years, 71% were male, and 39% had cirrhosis. Lower pretreatment serum YKL-40, tissue inhibitor of matrix metalloproteinase-1, PIIINP, and HA levels were associated significantly with week-20 virologic response (P < .0001). In multivariate analysis, non-1 CHC genotype, non-black race, prior interferon monotherapy, and lower baseline serum aspartate aminotransferase/alanine aminotransferase levels and log(10)YKL-40 levels were associated independently with week-20 virologic response. Statistically significant declines in all marker levels were observed at week 72 compared with baseline in the 81 patients with a sustained virologic response, but not in the 72 patients with breakthrough or relapse. At weeks 24 and 48, significant increases were observed in serum PIIINP and HA levels compared with baseline in virologic responders and nonresponders (P < .0001). CONCLUSIONS: Pretreatment YKL-40 levels are an independent predictor of initial virologic response to peginterferon and ribavirin treatment. Levels of all 4 serum fibrosis markers decreased significantly in the SVR patients, consistent with reduced hepatic fibrogenesis. Measuring serum fibrosis marker levels before and after antiviral therapy may provide important prognostic information in CHC patients.

Herbal product use by persons enrolled in the hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial.

Herbal products, used for centuries in Far Eastern countries, are gaining popularity in western countries. Surveys indicate that persons with chronic hepatitis C (CHC) often use herbals, especially silymarin (milk thistle extract), hoping to improve the modest response to antiviral therapy and reduce side effects. The Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial, involving persons with advanced CHC, nonresponders to prior antiviral therapy but still willing to participate in long-term pegylated interferon treatment, offered the opportunity to examine the use and potential effects of silymarin. Among 1145 study participants, 56% had never taken herbals, 21% admitted past use, and 23% were using them at enrollment. Silymarin constituted 72% of 60 herbals used at enrollment. Among all participants, 67% had never used silymarin, 16% used it in the past, and 17% used it at baseline. Silymarin use varied widely among the 10 participating study centers; men were more frequent users than women, as were non-Hispanic whites than African Americans and Hispanics. Silymarin use correlated strongly with higher education. No beneficial effect of silymarin was found on serum alanine aminotransferase or hepatitis C virus (HCV) RNA levels. Univariate analysis showed significantly fewer liver-related symptoms and better quality-of-life parameters in users than nonusers, but after reanalysis adjusted for covariates of age, race, education, alcohol consumption, exercise, body mass index, and smoking, only fatigue, nausea, liver pain, anorexia, muscle and joint pain, and general health remained significantly better in silymarin users. In conclusion, silymarin users had similar alanine aminotransferase and HCV levels to those of nonusers but fewer symptoms and somewhat better quality-of-life indices. Because its use among these HALT-C participants was self-motivated and uncontrolled, however, only a well-designed prospective study can determine whether silymarin provides benefit to persons with chronic hepatitis C.

Blunted cytopenias and weight loss: new correlates of virologic null response to re-treatment of chronic hepatitis C.

BACKGROUND & AIMS: Peginterferon with ribavirin therapy for chronic hepatitis C leads to sustained loss of serum hepatitis C virus (HCV) RNA in half of treated patients. Although viral kinetic profiles in treatment responders shed light on the mechanism of action of interferon and ribavirin, minimal information is available to explain why some patients experience little or no virologic suppression. METHODS: We evaluated factors that might be associated with the lack of a week-20 virologic response in previous nonresponder patients undergoing peginterferon and ribavirin retreatment. Among 1145 patients enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial's lead-in treatment phase, 588 who received more than 80% of prescribed therapy for 20 weeks were analyzed. RESULTS: By week 20, 245 patients (41.7%) had undetectable HCV RNA (full response), 186 (31.6%) had a 1 log(10) or greater decrease in HCV RNA (partial response), and 157 (26.7%) had less than a 1 log(10) decrease (null response) in HCV RNA. Null response was associated independently with African American race, genotype-1 infection, and less reduction in body weight, platelets, and white blood cells during treatment. CONCLUSIONS: On-treatment variables associated with null response suggest a blunted systemic response to interferon. These observations have important implications for the design and analysis of trial results in which novel agents are evaluated. Further studies are needed to discern whether host interferon resistance, viral drug resistance, or both are playing a role in patients who have no virologic response to interferon treatment.

Efficacy and safety of peginterferon alfa-2a/ribavirin in methadone maintenance patients: randomized comparison of direct observed therapy and self-administration.

BACKGROUND: Adherence to chronic hepatitis C (CHC) treatment may be particularly challenging in methadone maintenance patients. We assessed the safety, tolerability, and efficacy of peginterferon alfa-2a/ribavirin treatment in methadone maintenance patients previously untreated for CHC. METHODS: Patients were randomized 1:1 to direct observed therapy (DOT) or self-administration (SA) of peginterferon alfa-2a. DOT patients were seen weekly at methadone clinics; SA patients were seen less frequently, only at investigative sites. Genotype 1-infected patients were treated for 48 wk with peginterferon alfa-2a (180 microg/wk)/ribavirin (1,000/1,200 mg/day); genotypes 2- and 3-infected patients were treated for 24 wk with peginterferon alfa-2a (180 microg/wk)/ribavirin (800 mg/day). RESULTS: Based on defined efficacy stopping rules, 77% (37/48) completed their targeted length of treatment, and 44% (21/48) achieved sustained virologic response (SVR). Two DOT and 3 SA patients were withdrawn for safety reasons and 6 and 9, respectively, for nonsafety reasons. Over 60% and 50% of each group were >80% compliant with the planned cumulative doses of peginterferon alfa-2a and ribavirin, respectively, and over 60% with overall treatment duration. SVR rates were 54% (13/24) for DOT and 33% (8/24) for SA; 23% (3/13) and 38% (6/16), respectively, for genotype 1 and 91% (10/11) and 25% (2/8), respectively, for genotypes 2 and 3. Stepwise logistic regression analysis, showed that DOT (vs SA; OR 3.27, 95% CI 0.90-11.91, P = 0.073) and Caucasian race (vs Other; OR 13.31, 95% CI 1.42-124.71, P = 0.023) were predictors of SVR. CONCLUSION: Peginterferon alfa-2a/ribavirin can be used safely and successfully in CHC patients receiving methadone maintenance.

Hepatic steatosis in hepatitis C: comparison of diabetic and nondiabetic patients in the hepatitis C antiviral long-term treatment against cirrhosis trial.

BACKGROUND & AIMS: Hepatic steatosis often is observed in patients with chronic hepatitis C and has been reported to be associated with hepatic fibrosis and impaired treatment response in some studies. Our aim was to determine the prevalence of and risk factors for hepatic steatosis among Hepatitis C Antiviral Long-term Treatment against Cirrhosis patients, and to determine the relationship between steatosis, fibrosis, and sustained virologic response (SVR) to re-treatment with pegylated interferon and ribavirin. METHODS: Baseline data from 1143 Hepatitis C Antiviral Long-term Treatment against Cirrhosis patients, with a mean body mass index of 30, 5% with genotype 3, 38% with cirrhosis, and 24% with diabetes were analyzed. RESULTS: Steatosis scores of 0, 1, 2, 3, and 4 were observed in 19%, 42%, 30%, 8%, and 1% of patients, respectively. High body mass index, triglyceride and alanine aminotransferase levels, and genotype 3 were associated with higher grades of steatosis. Among nondiabetic patients, steatosis scores of 0-2 but not scores of 3-4 were associated significantly with cirrhosis. For diabetic patients, there was no association between steatosis and cirrhosis. Similarly, steatosis scores of 2-4 were associated with a lack of SVR among nondiabetic but not among diabetic patients. CONCLUSIONS: In this cohort with predominantly hepatitis C virus genotype 1 infection, steatosis was associated strongly with metabolic factors that contribute to nonalcoholic fatty liver disease. Steatosis correlated with increasing stages of fibrosis up to but not including cirrhosis. Steatosis had a negative impact on SVR among nondiabetic but not diabetic patients. The discordant findings between nondiabetic and diabetic patients indicate that these 2 groups should be considered separately when analyzing metabolic factors and liver disease outcomes.

DNA polymorphisms and response to treatment in patients with chronic hepatitis C: results from the HALT-C trial.

BACKGROUND/AIMS: Certain host genetic polymorphisms reportedly affect the likelihood of a sustained virological response (SVR) to interferon treatment in subjects infected with hepatitis C virus (HCV). As part of the HALT-C trial we evaluated genetic associations among patients infected with HCV genotype 1 who had failed previous interferon treatment. METHODS: SVR was determined 24 weeks after completing treatment with pegylated interferon alfa-2a and ribavirin. Eight single nucleotide polymorphisms (SNPs) were selected on the basis of previously reported associations with treatment response. Genotypes were assessed by polymerase chain reaction-based assays. The percentage of patients who achieved SVR was determined for each genotype and for an IL10 promoter diplotype. RESULTS: Among 637 non-Hispanic Caucasian patients there were no significant associations between genotype for any individual SNP (IL10-1082, IL10-592, TNF-308, TNF-238, TGFB1 codon 25, CCL2-2518, EPHX1 codon 113 and AGT-6) and SVR, but SVR was more common among the patients who were homozygous for the ACC IL10 promoter diplotype (adjusted odds ratio, 3.24; 95% confidence interval, 1.33-7.78; p=0.001). CONCLUSIONS: Among non-Hispanic Caucasian patients treated with peginterferon and ribavirin after failing previous treatment with interferon, homozygosity for the ACC IL10 promoter diplotype was associated with SVR.