Deepa Naishadham

Relationship of serum fibrosis markers with liver fibrosis stage and collagen content in patients with advanced chronic hepatitis C.

This study determined the utility of a panel of serum fibrosis markers along with routine laboratory tests in estimating the likelihood of histological cirrhosis in a cohort of prior nonresponders with chronic hepatitis C. The relationship between serum markers and quantitative hepatic collagen content was also determined. Liver biopsy samples from 513 subjects enrolled in the HALT‐C trial were assigned Ishak fibrosis scores. The collagen content of 386 sirius‐red stained, nonfragmented biopsy samples was quantified using computerized morphometry. Serum tissue inhibitor of matrix metalloproteinase‐1 (TIMP‐1), amino‐terminal peptide of type III procollagen (PIIINP), hyaluronic acid (HA), and YKL‐40 levels were determined using commercially available assays.Sixty‐two percent of patients had noncirrhotic fibrosis (Ishak stage 2‐4) whereas 38% had cirrhosis (Ishak stage 5,6). Multivariate analysis identified a 3‐variable model (HA, TIMP‐1, and platelet count) that had an area under the receiver operating curve (AUROC) of 0.81 for estimating the presence of cirrhosis. This model was significantly better than that derived from the cirrhosis discriminant score (AUROC 0.70), the AST‐to‐platelet ratio (AUROC 0.73), and a prior model developed in HALT‐C patients (AUROC 0.79). Multivariate analysis demonstrated that the serum fibrosis markers correlated substantially better with Ishak fibrosis scores than with the log hepatic collagen content (AUROC 0.84 versus 0.72). Conclusion: A 3‐variable model consisting of serum HA, TIMP‐1, and platelet count was better than other published models in identifying cirrhosis in HALT‐C Trial subjects. The stronger correlation of the serum markers with Ishak scores suggests that serum fibrosis markers reflect the pattern of fibrosis more closely than the quantity of hepatic collagen. (HEPATOLOGY 2008.)

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.)

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. Trial Registration Number NCT00006164.

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†‡

Combination treatment with pegylated‐interferon‐alpha (PEG IFN‐α) 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‐α2a 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‐α pathway may affect responses to antiviral therapy of chronic hepatitis C. (HEPATOLOGY 2009.)

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.

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.

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.

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.

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.

Work-to-family Spillover and Fruit and Vegetable Consumption Among Construction Laborers

Purpose. Spillover is the effect of one role on another as working adults attempt to integrate demands from work and family. We conducted a survey to understand how worker, job, and family characteristics were related to negative work-to-family spillover and how spillover was related to fruit and vegetable consumption to inform intervention design. Design. A combined mail and telephone survey. Setting. A national random sample in the United States. Subjects. 1108 (44% response) unionized construction laborers. Measures. Personal characteristics, job factors, family factors, work-to-family spillover, and fruit and vegetable consumption. Analysis. Multivariable logistic and least-squares regression. Results. A range of 20% to 50% of respondents reported negative work-to-family spillover, agreeing that work demands, time, fatigue, and stress interfered with family meals or food choices. Higher spillover was associated with job factors, being of white race/ethnicity, and having children at home. Lower fruit and vegetable consumption was associated with higher work-to-family spillover (p = .002), being of white race or ethnicity (p < .0001), and working the graveyard or day shift (p = .02). Conclusion. Negative experience of work-to-family spillover may link employment to fruit and vegetable consumption and thus to worker health. Understanding the contribution of spillover to fruit and vegetable consumption aids understanding of how work experience affects health.