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Context Hispanic women are at elevated risk of gestational glucose intolerance and postpartum type 2 diabetes compared with non-Hispanic White women. Identification of potentially modifiable factors contributing to this trajectory of beta-cell dysfunction is warranted. Objective We aimed to determine the association between rate of gestational weight gain (rGWG) and glucose-insulin metabolism in Hispanic pregnant women with overweight and obesity. Methods This cross-sectional, observational study, conducted from 2018-2020 at the clinical research center at University of California, Irvine, included 33 nondiabetic Hispanic pregnant women at 28 to 30 weeks’ gestation with pre-pregnancy body mass index (BMI) 25.0 to 34.9 kg/m2. Participants consumed a standardized liquid mixed meal after an overnight fast. Serial blood samples were collected at fasting and up to 2 hours postprandial. The glucose and insulin area under the curve (AUC), insulin sensitivity index (ISI) and insulin secretion sensitivity index (ISSI)-2 were computed. Results Average rGWG (0.36 ± 0.22 kg/week) was classified as excessive in 60% of women. While rGWG was not associated with the glucose or insulin AUC or ISI, it accounted for 13.4% of the variance in ISSI-2 after controlling for covariates (maternal age, parity, and pre-pregnancy BMI); for each 1 unit increase in rGWG, ISSI-2 decreased 2.1 units (P = 0.015). Conclusion Even in the absence of gestational diabetes, rGWG was inversely associated with beta-cell function in a high-risk population of Hispanic pregnant women with overweight and obesity. Beta-cell decline is an established risk factor for transition to type 2 diabetes, and these cross-sectional findings highlight rGWG as a potentially modifiable contributor to this process.

Dietary advice is a standard component of treatment for pregnant women with impaired glucose tolerance (IGT) and gestational diabetes (GDM), yet few studies report glycemic profiles in response to dietary therapies and the optimal dietary approach remains uncertain. To assess changes in maternal glycemic profile and pregnancy outcomes among women with diet-controlled IGT and GDM. Pregnant women who had one or more elevated values on a 3-h oral glucose tolerance test were enrolled. All participants received dietary advice and glucose monitoring as part of routine clinical care. Fasting and 1-h post-prandial blood samples, collected prior to initiation of clinical treatment and repeated 4–6 weeks later, were analyzed for glucose, insulin, and C-peptide. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Women who required pharmacological therapy for glucose control were excluded from analyses. Participants (N = 93) were of moderately older age (mean 33 years), with a high rate of overweight/obesity (mean body mass index (BMI) = 28.65 kg/m2), and were diagnosed late in gestation (mean 29 weeks). Fasting (mean ± SD 4.82 ± 0.53 to 4.60 ± 0.42 mmol/l; p

Elevated prepregnancy body mass index (pBMI) and excess gestational weight gain (GWG) constitute important prenatal exposures that may program adiposity and disease risk in offspring. The objective of this study is to investigate the influence of pBMI and GWG on the maternal metabolomic profile across pregnancy, and to identify associations with birth weight. This is a longitudinal prospective study of 167 nondiabetic women carrying a singleton pregnancy. Women were recruited between March 2011 and December 2013 from antenatal clinics affiliated to the University of California, Irvine, Medical Center. Seven women were excluded from analyses because of a diagnosis of diabetes during pregnancy. A total of 254 plasma metabolites known to be related to obesity in nonpregnant populations were analyzed in each trimester using targeted metabolomics. The effects of pBMI and GWG on metabolites were tested through linear regression and principle component analysis, adjusting for maternal sociodemographic factors, diet, and insulin resistance. A Bonferroni correction was applied for multiple comparison testing. pBMI was significantly associated with 40 metabolites. Nonesterified fatty acids (NEFA) showed a strong positive association with pBMI, with specificity for mono-unsaturated and omega-6 NEFA. Among phospholipids, sphingomyelins with two double bonds and phosphatidylcholines containing 20:3 fatty acid chain, indicative of omega-6 NEFA, were positively associated with pBMI. Few associations between GWG, quality and quantity of the diet, insulin resistance and the maternal metabolome throughout gestation were detected. NEFA levels in the first and, to a lesser degree, in the second trimester were positively associated with birth weight percentiles. Preconception obesity appears to have a stronger influence on the maternal metabolic milieu than gestational factors such as weight gain, dietary intake and insulin resistance, highlighting the critical importance of preconception health. NEFA in general, as well as monounsaturated and omega-6 fatty acid species in particular, represent key metabolites for a potential mechanism of intergenerational transfer of obesity risk.

Summary Background Interferon-free regimens are needed to treat hepatitis C virus (HCV) infections. We investigated the efficacy of combined simeprevir and sofosbuvir. Methods We enrolled patients with chronic HCV genotype 1 infections who had previously not responded to pegylated interferon (peginterferon) and ribavirin or were treatment naive. Patients were randomly assigned in a 2:1:2:1 ratio to receive 150 mg simeprevir and 400 mg sofosbuvir daily for 24 weeks with (group 1) or without (group 2) ribavirin or for 12 weeks with (group 3) or without (group 4) ribavirin, in two cohorts: previous non-responders with METAVIR scores F0–F2 (cohort 1) and previous non-responders and treatment-naive patients with METAVIR scores F3–F4 (cohort 2). The primary endpoint was sustained virological response 12 weeks after stopping treatment (SVR12). Analysis was done by intention to treat. Safety data from cohorts 1 and 2 were pooled for analysis. This study is registered with ClinicalTrials.gov, number NCT01466790. Findings 168 patients were enrolled and randomised, and 167 started treatment (n=80 in cohort 1 and n=87 in cohort 2). SVR12 was achieved in 154 (92%) patients (n=72 [90%, 95% CI 81–96] in cohort 1 and n=82 [94%, 87–98] in cohort 2). The most common adverse events in the pooled groups were fatigue (n=52 [31%]), headache (n=33 [20%]), and nausea (n=26 [16%]). Grade 4 adverse events were seen in one (2%) of 54 patients in each of groups 1 and 3 and in three (10%) of 31 patients in group 2, whereas grade 3–4 events were reported in less than 5% of all patients, except increased blood amylase concentration. Serious adverse events were seen in four (2%) patients, all in groups 1 and 2. Four (2%) patients discontinued all study treatment because of adverse events, three before week 12. Interpretation Combined simeprevir and sofosbuvir was efficacious and well tolerated. Funding Janssen.

Glucocorticoids play a key role during intrauterine development in cellular growth and differentiation. Evidence suggests that exposure to inappropriate concentrations of glucocorticoids during sensitive developmental periods may produce alterations in physiological systems that impact obesity risk.To elucidate the magnitude and stage-of-gestation-specific association of maternal cortisol concentrations during pregnancy with infant adiposity.Sixty-seven mother-child dyads recruited in early pregnancy at university-based obstetric clinics in Southern California were followed with serial assessments from early gestation through birth until 6 months postnatal age. Maternal cumulative cortisol production was assessed over each of 4 consecutive days in early (≅13 weeks), mid (≅24 weeks), and late pregnancy (≅30 weeks) (5 saliva samples/d × 4 days × 3 trimesters = 60 saliva samples/subject). Infant body composition was serially assessed in newborns (at ∼25 days postnatal age) and at ∼6 months age with dual-energy X-ray absorptiometry imaging.After adjusting for key prenatal, birth, and postnatal covariates, higher maternal cortisol during the early third trimester (conditioned on prior early and midgestation cortisol concentrations) was significantly associated with a greater change in infant percent body fat from 1 to 6 months of age [partial r (adjusted for covariates) = 0.379, P = 0.007], accounting for ∼14% of the variance in this measure of childhood obesity risk.The present findings suggest a stage-of-gestation-specific effect of maternal cortisol on infant adiposity gain in early postnatal life and provide evidence in humans to support the role of glucocorticoids in fetal programming of childhood obesity risk.

During the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial, 3.5 years of maintenance peginterferon-alfa-2a therapy did not affect liver fibrosis progression or clinical outcomes among 1,050 previous interferon nonresponders with advanced fibrosis or cirrhosis. We investigated whether reduced hepatic inflammation was associated with clinical benefit in 834 patients with a baseline and follow-up biopsy 1.5 years after randomization to peginterferon or observation.Relationships between change in hepatic inflammation (Ishak hepatic activity index, (HAI)) and serum alanine aminotransferase level, fibrosis progression and clinical outcomes after randomization, and hepatitis C virus (HCV) RNA decline before and after randomization were evaluated. Histological change was defined as a ≥ 2-point difference in HAI or Ishak fibrosis score between biopsies.Among 657 patients who received full-dose peginterferon/ribavirin "lead-in" therapy before randomization, year-1.5 HAI improvement was associated with lead-in HCV RNA suppression in both the randomized treated (P0.0001) and control (P=0.0001) groups, even in the presence of recurrent viremia. This relationship persisted at year 3.5 in both the treated (P=0.001) and control (P=0.01) groups. Among 834 patients followed for a median of 6 years, fewer clinical outcomes occurred in patients with improved HAI at year 1.5 compared with those without such improvement in both the treated (P=0.03) and control (P=0.05) groups. Among patients with Ishak 3-4 fibrosis at baseline, those with improved HAI at year 1.5 had less fibrosis progression at year 1.5 in both the treated (P=0.0003) and control (P=0.02) groups.Reduced hepatic inflammation (measured 1.5 and 3.5 years after randomization) was associated with profound virological suppression during lead-in treatment with full-dose peginterferon/ribavirin and with decreased fibrosis progression and clinical outcomes, independent of randomized treatment.

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. (HEPATOLOGY 2011)

High-level coffee consumption has been associated with reduced progression of pre-existing liver diseases and lower risk of hepatocellular carcinoma. However, its relationship with therapy for hepatitis C virus infection has not been evaluated.Patients (n=885) from the lead-in phase of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial recorded coffee intake before retreatment with peginterferon α-2a (180 μg/wk) and ribavirin (1000-1200 mg/day). We assessed patients for early virologic response (2 log10 reduction in level of hepatitis C virus RNA at week 12; n=466), and undetectable hepatitis C virus RNA at weeks 20 (n=320), 48 (end of treatment, n=284), and 72 (sustained virologic response; n=157).Median log10 drop from baseline to week 20 was 2.0 (interquartile range [IQR], 0.6-3.9) among nondrinkers and 4.0 (IQR, 2.1-4.7) among patients that drank 3 or more cups/day of coffee (P trend.0001). After adjustment for age, race/ethnicity, sex, alcohol, cirrhosis, ratio of aspartate aminotransferase to alanine aminotransferase, the IL28B polymorphism rs12979860, dose reduction of peginterferon, and other covariates, odds ratios for drinking 3 or more cups/day vs nondrinking were 2.0 (95% confidence interval [CI]: 1.1-3.6; P trend=.004) for early virologic response, 2.1 (95% CI: 1.1-3.9; P trend=.005) for week 20 virologic response, 2.4 (95% CI: 1.3-4.6; P trend=.001) for end of treatment, and 1.8 (95% CI: 0.8-3.9; P trend=.034) for sustained virologic response.High-level consumption of coffee (more than 3 cups per day) is an independent predictor of improved virologic response to peginterferon plus ribavirin in patients with hepatitis C.

Background & Aims With the limited efficacy of current therapy for chronic hepatitis C, modifiable risk factors for liver disease progression are important to identify. Because obesity is associated with liver disease, we examined the effects of weight-related conditions on disease outcomes in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Methods Of 1050 patients, 985 could be evaluated for predefined progression of liver disease not related to hepatocellular carcinoma. Clinical outcomes were determined over 3.5 years for all patients and progression to cirrhosis on protocol biopsy among patients who had bridging fibrosis (56.5% of cohort) at entry. Results At study entry, median body mass index was high (29.2 kg/m 2 ) and accompanied by other weight-related conditions, including diabetes (24.9%), high median waist circumference, and insulin resistance (by updated homeostasis model assessment of insulin resistance; HOMA2-IR). Among noninvasive measures, HOMA2-IR was most strongly associated with outcomes with hazard ratio (HR) of 1.26 per quartile increase (95% CI, 1.09–1.45). Presence of steatosis on baseline biopsy was associated with an increased outcome rate among patients with bridging fibrosis ( P P = .006). Presence of Mallory bodies was associated with outcomes (HR, 1.59; 95% CI, 1.10–2.31) as was significant weight change of ≥5% in the first year after randomization (HR, 1.25 per category increase in weight, 95% CI, 1.01–1.55). Conclusions Insulin resistance, histologic features of fatty liver disease, and weight change were associated with outcomes of chronic hepatitis C. Improvement in these weight-related factors might modify disease progression.

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.)

Hepatic steatosis is a common histologic feature in patients with chronic hepatitis C and has been reported to be associated with fibrosis in cross-sectional studies.1–3 However, very few studies have examined paired biopsies to determine the relationship between steatosis and fibrosis progression and to characterize the evolution of steatosis over time. Baseline data from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial which included predominantly patients with genotype 1 hepatitis C virus (HCV) infection show that steatosis (defined as presence of fat in >5% of hepatocytes) was present in 39% of patients and correlated strongly with metabolic factors associated with nonalcoholic fatty liver.4 Furthermore, increasing severity of steatosis correlated with increasing stages of fibrosis up to but not including cirrhosis. We hypothesize that steatosis plays a role in fibrosis progression during the early stages of liver disease but steatosis regresses during the transition from advanced fibrosis to cirrhosis. Thus, steatosis may have greater use as a predictive tool for fibrosis progression in patients with mild fibrosis on initial biopsy and the role of steatosis in cirrhosis development may have been under-estimated. However, direct evidence supporting our hypothesis is lacking because prior longitudinal studies of hepatic steatosis in patients with chronic hepatitis C included very few patients that progressed from fibrosis to cirrhosis. The HALT-C Trial, which enrolled more than 1,000 hepatitis C patients with bridging fibrosis or cirrhosis who underwent 3 liver biopsies over a 4-year period, provided an opportunity to evaluate changes in hepatic steatosis over time and their impact on progression to cirrhosis. The aims of this study were to (1) characterize changes in steatosis on serial biopsies, (2) determine the factors associated with changes in steatosis, and (3) examine the impact of changes in steatosis on progression to cirrhosis.

The Siemens VERSANT® transcription-mediated amplification (TMA) assay is extremely sensitive for the detection of hepatitis C virus (HCV) RNA in serum. Eleven of 180 subjects in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial who achieved polymerase chain reaction (PCR)-defined sustained virological response (SVR) at week 72 also had TMA-positive results from the same blood draw; six were positive on repeat testing. We report the follow-up on these 11 patients, and the reproducibility of TMA test results from PCR-negative samples in relationship to antiviral treatment outcome. Peginterferon and ribavirin treatment was initiated in 1145 prior interferon nonresponders with advanced hepatic fibrosis. Treatment was continued for 48 weeks if patients had undetectable HCV RNA by PCR at treatment week 20. Frozen serum samples from weeks 12, 20, 24, 48, and 72 were subsequently tested by TMA. Nine of the 11 patients returned for testing (median, 30 months after the week 72 visit), and all had undetectable HCV RNA by TMA and PCR. Among 759 PCR-negative samples obtained during treatment that were tested twice by TMA, 17% overall exhibited consistently positive results, and 21% exhibited inconsistently positive results. SVR was more likely if TMA was consistently negative than if consistently or inconsistently positive. With continued treatment, patients with inconsistently positive TMA results were more likely to become TMA-negative than TMA-positive (P < 0.0001). Conclusion: In PCR-negative samples, positive TMA results may indicate the presence of low levels of HCV RNA. However, because patients with positive TMA results may achieve SVR, management decisions during therapy should not be based on a single positive TMA test result. (HEPATOLOGY 2008.)

Reducing the dose of peginterferon and/or ribavirin to80% when treating chronic hepatitis C virus has been associated with a reduction in sustained virologic response (SVR). However, prior studies did not assess the impact of reducing the dose of peginterferon independent of ribavirin or differentiate between dose reduction or interrupting or prematurely discontinuing treatment.Nine hundred thirty-six patients with chronic hepatitis C genotype 1, advanced fibrosis, or cirrhosis (Ishak 3-6) and prior nonresponse to standard interferon +/- ribavirin were retreated with peginterferon alfa-2a (180 microg/wk) and ribavirin (1000-1200 mg/day) during the lead-in phase of the HALT-C trial. The percentage of each medication actually taken during treatment was calculated.Reducing the total cumulative dose of peginterferon received during the first 20 weeks of treatment from full dose (or =98%) toor =60% reduced week 20 virologic response (W20 VR) from 35% to 12% and SVR from 17% to 5%. Reducing the dose of ribavirin from full dose (or =98%) toor =60% did not affect either W20 VR or SVR as long as ribavirin dosing was not interrupted for more than 7 consecutive days. Prematurely discontinuing ribavirin, even at full-dose peginterferon, reduced W20 VR toor =19% and SVR toor =4%.Reducing the peginterferon dose during the first 20 weeks of treatment reduced viral clearance and SVR. In contrast, reducing ribavirin did not affect either W20 VR or SVR as long as patients remained on full-dose peginterferon. Discontinuing ribavirin prematurely was associated with a marked decline in both VR and SVR.

Treatment of chronic hepatitis C with pegylated interferon (peginterferon) and ribavirin can cause or exacerbate depression but its effects on cognitive function are largely unknown. The aim of this study was to determine whether treatment with peginterferon and ribavirin adversely impacts cognitive function in patients with chronic hepatitis C. Prior nonresponders to interferon were retreated with peginterferon alfa-2a and ribavirin for 24 (n = 177) or 48 weeks (n = 57) in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis trial. Cognitive function was prospectively assessed using a battery of 10 standardized neuropsychological tests at weeks 0, 24, 48, and 72. Cognitive impairment was defined based upon a global deficit score. The Beck Depression Inventory and Brief Symptom Inventory were used to assess mood status. The 57 subjects who completed 48 weeks of antiviral therapy reported significant increases in difficulty concentrating, emotional distress, and symptoms of depression, all of which improved after cessation of therapy [P < 0.0001, analysis of variance (ANOVA)]. Nonetheless, the frequency of cognitive impairment did not increase during the first 24 weeks of treatment in 177 patients (34% versus 32%, P = 0.64) nor in the 57 patients completing 48 weeks of treatment (P = 0.48, ANOVA). Conclusion: Retreatment of prior non-responders with peginterferon and ribavirin was not associated with objective evidence of cognitive impairment as measured by a comprehensive battery of neuropsychological tests. The lack of cognitive impairment is reassuring and suggests that self-reported symptoms of cognitive dysfunction are more likely related to the systemic and psychiatric side effects of antiviral treatment rather than measurable changes in cognition. (HEPATOLOGY 2007;45:1154–1163.)

Background Large for gestational age infants have an increased risk of obesity, cardiovascular and metabolic complications during life. Knowledge of the key predictive factors of neonatal adiposity is required to devise targeted antenatal interventions. Our objective was to determine the fetal metabolic factors that influence regional neonatal adiposity in a cohort of women with previous large for gestational age offspring. Methods Data from the ROLO [Randomised COntrol Trial of LOw Glycaemic Index in Pregnancy] study were analysed in the ROLO Kids study. Neonatal anthropometric and skinfold measurements were compared with fetal leptin and C-peptide results from cord blood in 185 cases. Analyses were performed to examine the association between these metabolic factors and birthweight, anthropometry and markers of central and generalised adiposity. Results Fetal leptin was found to correlate with birthweight, general adiposity and multiple anthropometric measurements. On multiple regression analysis, fetal leptin remained significantly associated with adiposity, independent of gender, maternal BMI, gestational age or study group assignment, while fetal C-peptide was no longer significant. Conclusion Fetal leptin may be an important predictor of regional neonatal adiposity. Interventional studies are required to assess the impact of neonatal adiposity on the subsequent risk of childhood obesity and to determine whether interventions which reduce circulating leptin levels have a role to play in improving neonatal adiposity measures. Electronic supplementary material The online version of this article (doi:10.1186/s12887-015-0499-0) contains supplementary material, which is available to authorized users.

Pregnancy is characterized by a complexity of metabolic processes that may impact fetal development and ultimately, infant health outcomes. However, our understanding of whole body maternal and fetal metabolism during this critical life stage remains incomplete. The objective of this study is to utilize metabolomics to profile longitudinal patterns of fasting maternal metabolites among a cohort of non-diabetic, healthy pregnant women in order to advance our understanding of changes in protein and lipid concentrations across gestation, the biochemical pathways by which they are metabolized and to describe variation in maternal metabolites between ethnic groups. Among 160 pregnant women, amino acids, tricarboxylic acid (TCA) cycle intermediates, keto-bodies and non-esterified fatty acids were detected by liquid chromatography coupled with mass spectrometry, while polar lipids were detected through flow-injected mass spectrometry. The maternal plasma concentration of several essential and non-essential amino acids, long-chain polyunsaturated fatty acids, free carnitine, acetylcarnitine, phosphatidylcholines and sphingomyelins significantly decreased across pregnancy. Concentrations of several TCA intermediates increase as pregnancy progresses, as well as the keto-body β-hydroxybutyrate. Ratios of specific acylcarnitines used as indicators of metabolic pathways suggest a decreased beta-oxidation rate and increased carnitine palmitoyltransferase-1 enzyme activity with advancing gestation. Decreasing amino acid concentrations likely reflects placental uptake and tissue biosynthesis. The absence of any increase in plasma non-esterified fatty acids is unexpected in the catabolic phase of later pregnancy and may reflect enhanced placental fatty acid uptake and utilization for fetal tissue growth. While it appears that energy production through the TCA cycle increases as pregnancy progresses, decreasing patterns of free carnitine and acetylcarnitine as well as increased carnitine palmitoyltransferase-1 rate and β-hydroxybutyrate levels suggest a concomitant upregulation of ketogenesis to ensure sufficient energy supply in the fasting state. Several differences in metabolomic profiles between Hispanic and non-Hispanic women demonstrate phenotypic variations in prenatal metabolism which should be considered in future studies.

Mild neuropsychological impairment has previously been reported in chronic hepatitis C (CHC) patients. The aim of this study was to assess the presence and severity of cognitive impairment among a cohort of CHC patients with advanced fibrosis using clinician ratings compared to classification based upon statistical methods. In addition, we set out to determine the relationship between cognitive scores and functional status. Two experienced neuropsychologists provided "clinician ratings" on a battery of 10 neuropsychological tests performed in 100 randomly selected patients participating in the HALT-C clinical trial. The overall kappa between the 2 graders on level of impairment was 0.59. Clinician ratings (the gold standard) were similarly sensitive to identifying cognitive impairment as was classification based on standard scores (44% vs. 40%). Global Deficit Scores (GDS), derived from pooling standard scores, also identified 44% of patients as having mild impairment and were highly correlated with clinician ratings (r = .81 p = < 0.0001). Neither clinician ratings nor deficit scores correlated with SF-36 subscale or summary scores but did correlate with depression scores (p < .0007). In summary, clinician ratings and deficit scores identified a similar prevalence of cognitive impairment amongst CHC patients with advanced fibrosis. There was a significant correlation between cognitive impairment and self-reported depression.

We sought to assess whether Hispanics have more advanced hepatitis C virus (HCV)-related liver disease than non-Hispanic whites (NHW) and to identify contributory factors.Patients were recruited from the Los Angeles county hepatitis clinic. Liver fibrosis and necroinflammation (NI) were assessed by the Ishak scoring system. Hepatic steatosis was graded as 0-4.A total of 232 patients were evaluated, 63 NHW and 169 Hispanic. Hispanics were older and had a higher prevalence of blood transfusion (40%vs 21%), obesity (body mass index30) (47%vs 21%), diabetes mellitus (DM) (16%vs 5%), and hepatic steatosis (79%vs 47%), p0.02. Independent predictors of hepatic steatosis were Hispanic ethnicity (odds ratio [OR] 3.8, 95% CI 1.7-8.7, p= 0.001) and obesity (OR 5.7, 95% CI 2.3-14.1, p= 0.0002). Compared with NHW, Hispanics also had higher fibrosis stage (3.3 +/- 2 vs 2.3 +/- 6.9, p= 0.001), NI grade (6.4 +/- 1.8 vs 5.6 +/- 1.6, p= 0.002), and faster fibrosis progression/yr (0.14 +/- 0.09 vs 0.09 +/- 0.07, p= 0.0002). Presence of DM (OR 2.9, p= 0.02), grade 1-2 hepatic steatosis (OR 2.3, p= 0.03), AST/ALT1 (OR 4.3, p= 0.01), NI grade (OR 1.7, p0.0001), age at biopsy (OR 1.1, p0.0001), and serum bilirubin (OR 5.4, p0.0001) were independent predictors of fibrosis stageor =4.This study confirms that Hispanics have more advanced hepatic fibrosis than NHW. This is related to older age, higher NI grade, and greater prevalence of hepatic steatosis and DM.

For making treatment decisions related to chronic hepatitis C, the utility of HCV RNA tests with increased sensitivity has not been defined. Prior interferon nonresponders with advanced fibrosis (n = 1,145) were retreated with peginterferon alpha-2a and ribavirin. Patients who were HCV RNA-negative by a polymerase chain reaction (PCR)-based assay (Roche COBAS Amplicor HCV Test, v. 2.0; lower limit of detection [LOD] 100 IU/mL) at week 20 (W20) received treatment for 48 weeks. Stored specimens were tested using the Bayer VERSANT HCV RNA Qualitative (TMA) Assay (LOD 9.6 IU/mL) and compared to PCR results for the ability to predict sustained virological response (SVR; defined as undetectable HCV RNA by PCR at W72). Nearly all PCR-positive samples (1006/1007, 99.9%) were positive as assessed by TMA. Among 1,294 PCR-negative samples, 22% were TMA-positive. Negative TMA results were more predictive of SVR than were negative PCR results at W12 (82% vs. 64%, P < .001) and at W20 (66% vs. 52%, P = 0.001). SVR was more likely the earlier TMA had become negative during treatment (82% at W12, 44% at W20, 20% at W24). Among 45 patients who were TMA-positive but were PCR-negative at W20 and W24, none achieved SVR (95% CI: 0%-8%). Approximately 10% of patients with a single positive TMA result at the end of treatment still achieved SVR. In conclusion, negative TMA results at or after W12 were superior to negative PCR results for predicting SVR. In patients with negative PCR results during treatment, a single positive TMA test did not exclude SVR, although persistently positive tests did.

Background & Aims: The most effective therapy currently available for treatment of chronic hepatitis C virus (HCV) is the combination of peginterferon and ribavirin. This study evaluated the effectiveness of this treatment in patients who were nonresponders to previous interferon-based therapy. Methods: The first 604 patients enrolled in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial were evaluated. All were HCV RNA positive, previous nonresponders to interferon, with or without ribavirin, and had bridging fibrosis or cirrhosis on liver biopsy (Ishak fibrosis stage 3–6). Patients were retreated with peginterferon alfa-2a 180 μg/wk plus ribavirin 1000–1200 mg/day. Those with no detectable HCV RNA in serum at week 20 continued treatment for a total of 48 weeks and were then followed for an additional 24 weeks.Results: Thirty-five percent of patients had no detectable HCV RNA in serum at treatment week 20, and 18% achieved sustained virologic response (SVR). Factors associated with an SVR included previous treatment with interferon monotherapy, infection with genotypes 2 or 3, a lower AST:ALT ratio, and absence of cirrhosis. Reducing the dose of ribavirin from ≥80% to ≤60% of the starting dose during the first 20 weeks of treatment was associated with a decline in SVR from 21% to 11% ( P ≤ 0.05). In contrast, reducing the dose of peginterferon or reducing ribavirin after week 20, when HCV RNA was already undetectable, did not significantly affect SVR.Conclusions: Selected nonresponders to previous interferon-based therapy can achieve SVR following retreatment with peginterferon alfa-2a and ribavirin.

Since the 1997 National Institutes of Health Consensus Development Conference on management of hepatitis C there have been several important advances that significantly impact its therapy; notably the availability of sensitive, specific, and standardized assays for identifying hepatitis C virus (HCV) RNA in the serum, the addition of ribavirin to alpha interferon, the pegylation of alpha interferon, and the demonstration that sustained virological response (SVR) is the optimal surrogate endpoint of treatment. Using pegylated interferon and ribavirin, virological response with relapse and nonresponse are less common, but remain poorly understood. Current studies are evaluating nonvirological endpoints of treatment, namely biochemical response and histological response. To date, definitive treatment trials have primarily been conducted in adult patients with elevated aminotransferase levels, clinically compensated chronic liver disease, and no other significant medical disorder. Limited data are available from studies of other patient populations, and the safety of interferon-based treatment has not yet been established in several patient groups. Future research is needed to elucidate the mechanisms of viral response and clearance, to develop effective therapies for interferon nonresponse or intolerance, to define the role of complementary and alternative medicine and other nonspecific therapies, and to develop strategies for the optimal management and treatment of special patient populations who probably represent the majority of persons with chronic hepatitis C in the United States.

Patient adherence to prescribed antiviral therapy in human immunodeficiency virus infection enhances response. We evaluated the impact of adherence to combination therapy with interferon or peginterferon plus ribavirin in chronic hepatitis C patients.We assessed the effect of dose reduction on sustained virologic response (SVR) from prior trials with interferon alpha-2b plus ribavirin (n = 1010) or peginterferon alpha-2b 1.5 microg/kg/week plus ribavirin (n = 511). The actual treatment administered was verified from drug dispensing/return records and patient diaries. Two groups were defined: (1) patients who receivedor=80% of both their total interferon and ribavirin doses foror=80% of the expected duration of therapy and (2) patients who received reduced doses (80% of one or both drugs foror=80% of the expected duration of therapy). A statistical model provided comparative estimates of the response rates in compliant patients.Most patients were at least 80% compliant with interferon alpha-2b/ribavirin or peginterferon alpha-2b/ribavirin therapy and had SVR rates of 52% and 63%, respectively, for the 2 regimens. This was most apparent for HCV-1-infected patients. The impacts of adherence on efficacy from subgroup analysis and the statistical modeling approach were similar.HCV-1-infected patients who can be maintained on80% of their interferon or peginterferon alpha-2b and ribavirin dosage for the duration of treatment in the setting of a clinical trial exhibit enhanced sustained response rates. Our results suggest that adherence will enhance the likelihood of achieving an initial virologic response. Adherence beyond 12-24 weeks will be advantageous only for those patients who have achieved such an early virologic response.

p.63. 42. Bacon BR, Li J, Britton RS, Wang B-e. Herbal Medicine 861 has direct antiproliferative effects on hepatic stellate cells. Complementary and Alternative Medicine in Chronic Liver Disease. Submitted abstract, p.56. 43. Batey RG, Bensousson A, Fan YY, Bollipo S, Hossain M. Preliminary report of a randomized, double-blind placebo-controlled trial of a Chinese herbal medicine preparation CH100 in the treatment of chronic hepatitis C. J Gastroenterol Hepatol 1998;13:244-247. 602 SEEFF ET AL. HEPATOLOGY September 2001

End-treatment and sustained virologic response rates are similar in large, comparative controlled trials which have compared the standard dosing regimens of interferon alpha-2b to interferon alpha-n1 and consensus interferon, as well as to virologic response rates recently reported with interferon alpha-2b monotherapy for 24 weeks. For patients who have responded and relapsed after an initial course of alpha interferon, retreatment with consensus interferon for 48 weeks demonstrates a high sustained virologic response rate, similar to that reported with interferon alpha-2b combined with ribavirin for 24 weeks. Based on available pharmacokinetic and pharmacodynamic data, pegylation of interferon alpha-2a shows promise in demonstrating high sustained serum levels and 2′,5′ OAS activity. Preliminary data from a Phase II clinical trial of a 48-week treatment in naive patients demonstrates end-treatment and sustained virologic response rates similar to that seen with interferon alpha-2b combined with ribavirin for 48 weeks.

Aims To determine the association of maternal and fetal inflammatory factors with neonatal and infant adiposity Methods Data from 265 mother-child pairs at birth and 280 pairs at 6 months postnatal from a randomised control trial assessing the effect of a low glycaemic index diet on birth weight were analysed. Maternal TNF-alpha (TNFα) and Interleukin 6 (IL-6) were measured in early and late pregnancy and fetal levels from cord blood. Anthropometric measurements were recorded at birth and at 6 months. The sum of all skinfolds and the sum of Subscapular plus Triceps skinfolds [SS+TR] were used as markers of general adiposity and the ratio of SS/TR skinfolds as a marker of central adiposity. Results Maternal TNFα in early pregnancy was associated with neonatal anthropometry including biceps [p = 0.048], triceps [p = 0.027] and subscapular [p = 0.002] skinfold thicknesses. TNFα in early and late pregnancy correlated with general adiposity in the neonate [SS + TR p = 0.003, p = 0.008 respectively; Sum of skinfolds p = 0.011, p = 0.002 respectively] [Table 1]. Maternal early and late pregnancy TNFα was also associated with 6-month-old central adiposity [SS/TR ratio p = 0.002, p = 0.030, respectively]. Fetal TNFα did not exert a significant influence on neonatal anthropometry but was associated with infant triceps skinfold at 6 months. While fetal IL-6 was associated with birth length and waist:height ratio, maternal IL-6 was not significantly associated with adiposity. On multiple linear regression analysis, TNFα contributed significantly to the majority of the final models for both neonatal and infant anthropometry, however, the models themselves were not significant. Any associations between maternal or fetal IL-6 with neonatal and infant anthropometry were no longer significant in the multiple regression models. Conclusion Maternal TNFα significantly correlates with greater offspring adiposity at birth and 6 months and therefore may act as a potential antenatal indicator of a predisposition towards early childhood obesity.

Acute hepatitis A superimposed on chronic liver disease (CLD) has been associated with severe or fulminant hepatitis. An open, multicenter study was performed to compare the safety and immunogenicity of an inactivated hepatitis A vaccine in patients with CLD with that in healthy subjects. A secondary objective was to compare the safety of the hepatitis A vaccine with that of a commercial hepatitis B vaccine in subjects with chronic hepatitis C. A total of 475 subjects over the age of 18 years were enrolled into 1 of 5 groups according to history, serological data, and previous diagnosis. Patients in groups 1 (healthy adults), 2 (chronic hepatitis B), 3 (chronic hepatitis C), and 5 (other CLD not caused by viral hepatitis) were vaccinated with two doses of inactivated hepatitis A vaccine, 6 months apart. Patients in group 4 (chronic hepatitis C) received 3 doses of a recombinant hepatitis B vaccine, according to a 0-, 1-, and 6-month schedule. Local injection-site symptoms were the most common reactions reported following vaccination in all groups (35.5% of all doses), with the hepatitis B vaccine eliciting fewer injection-site symptoms than the hepatitis A vaccine (19.8% compared with 37.5%). Although a higher percentage of healthy subjects (93%) seroconverted after a single dose of the hepatitis A vaccine than did subjects with chronic hepatitis C (73.7%) or CLD of nonviral etiologies (83.1%), more than 94% of all vaccinees were seropositive for anti-HAV after the complete vaccination course. At each time point, a lower geometric mean concentration of anti-HAV was observed for each group of CLD patients compared with the healthy control subjects. In conclusion, hepatitis A vaccine was well tolerated and induced a satisfactory immune response in patients with chronic hepatitis B, chronic hepatitis C, and miscellaneous CLD.

To evaluate response rates to 3, 5, or 10 million units (MU) of interferon alfa-2b, given thrice weekly, and to determine whether higher doses of interferon increase the likelihood or durability of the response, a multicenter, randomized trial was performed at nine academic medical centers in the United States. Two hundred forty eight patients with chronic hepatitis C were randomized to receive 3, 5, or 10 MU of interferon alfa-2b thrice weekly for 12 weeks. Based on the alanine aminotransferase (ALT) response at treatment-week 12, the patients were rerandomized to additional therapy at the same or at increased doses for an additional 12 to 36 weeks; in the case of no response to the highest dose, the patients were discontinued from the study. Serum ALT concentrations and liver histology were measured. The overall complete response rates to 3, 5, or 10 MU were not different at treatment-week 12 (31% vs. 42% vs. 40%, not significant). The majority of week-12 responders continued to respond during additional treatment. When the treatment was discontinued, 15.4% to 19.0% of patients maintained their response. Of the nonresponders to 3 MU at week 12, who were continued on 3 MU for an additional 12 weeks, none responded. However, response to additional therapy occurred in 12% of week-12 nonresponders, whose dose was escalated from 3 or 5 MU to 10 MU. The only baseline features associated with the treatment response were the absence of fibrosis or cirrhosis on the pretreatment liver biopsy and viral genotype. We conclude that the initial response to interferon in patients with chronic hepatitis C is not increased by treatment with higher doses of the drug. Patients who do not respond to 3 MU by treatment-week 12 will not respond with continued therapy at that dose; however, a proportion of patients who do not respond to 12 weeks of treatment with 3 or 5 MU may respond to higher doses. Although the long-term sustained response rates are marginally increased with interferon doses above 3 MU three times per week, the side effects are difficult to tolerate. The analysis of baseline factors in relation to response identified no single baseline factor associated with a low-enough response rate to warrant withholding interferon therapy from patients with chronic hepatitis C.

To determine the optimal conditions for preparation of serum specimens for quantitative hepatitis C virus RNA determination, patient samples were processed such that differences in time from clot formation to centrifugation, centrifugation to separation of serum and collection of serum until freezing could be independently assessed. The effects of multiple cycles of freezing and thawing were also determined. There was progressive and significant loss of hepatitis C virus RNA activity when the time from the formation of the clot until centrifugation was longer than 2 hr. This reduction reached 32% after 6 hr and 49% after 24 hr. If centrifugation was performed immediately after formation of the clot, loss of hepatitis C virus RNA activity was reduced to less than 10% even though the serum remained unseparated from the clot for up to 6 hr. Centrifugation of blood through a paraffin plug (serum separator tube) prevented loss of hepatitis C virus RNA activity for up to 24 hr. There was no loss of hepatitis C virus RNA activity with up to three freeze-thaw cycles. When patient specimens were prepared under these optimal conditions, the sensitivity of the quantitative branched DNA signal amplification assay in patients with hepatitis C virus infection was 83% and the specificity in patients with liver disease was 100%. Fluctuations in hepatitis C virus RNA levels were shown to correlate with biochemical changes observed in patients treated with recombinant inter-feron-α2b. These data demonstrate that improper or inconsistent methods of serum preparation may result in falsely low and unreliable levels of hepatitis C virus RNA. Clinical applications of quantitative hepatitis C virus RNA assays will only be possible when sera are properly prepared. (HEPATOLOGY 1994;19:1337–1341.)

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.

Peginterferon and ribavirin treatment of chronic hepatitis C (CHC) is frequently associated with dose-limiting neuropsychiatric toxicity. The purpose of this study is to determine whether prolonged administration of low-dose peginterferon-α2a is associated with an increase in the rate and severity of depression compared to untreated controls.129 non-responders to full-dose peginterferon and ribavirin treatment were randomized to low-dose maintenance treatment with peginterferon-α2a 90 μg/week or no treatment for 3.5 years. Depression was assessed using the Beck Depression Inventory (BDI-II) and the Composite International Diagnostic Interview (CIDI) at baseline and at 12, 24, 36, and 48 months. "Clinical depression" was defined as BDI-II ≥11 and/or meeting DSM-IV criteria for major depression on the CIDI. Serial cortisol and serotonin plasma concentrations were obtained in a subgroup of patients.Rates of clinical depression did not significantly differ over time or between treatment groups. Baseline clinical depression was the only significant predictor of clinical depression over time (p0.001). Rates of clinical depression were also significantly higher in patients experiencing liver disease progression (p=0.016). Antidepressant use did not significantly differ between groups. Adjusted whole blood serotonin levels dropped significantly over time (p=0.04), but there was no group by time effect.Lack of significant group differences in antidepressant use does not completely preclude significant mood changes masked by antidepressants. Results may differ in treatment naïve CHC patients or in those receiving full-dose peginterferon.Prolonged low-dose peginterferon-α2a treatment is not associated with an increase in the frequency or severity of clinical depression in prior non-responder patients with chronic hepatitis C.

Neuropsychiatric toxicity is a common dose-limiting side effect of interferon therapy. The primary aim of this study was to determine whether patients receiving long-term low-dose peginterferon therapy had a higher incidence of cognitive side effects compared with untreated patients enrolled in the Hepatitis C Antiviral Long-Term treatment against Cirrhosis (HALT-C) Trial.A total of 129 patients with chronic hepatitis C and advanced fibrosis completed a battery of 10 neuropsychological tests and the Beck Depression Inventory at pretreatment baseline and at months 12, 24, 36, and 48 while receiving long-term peginterferonalpha2a (90 microg/week) or no therapy during the randomized phase of the HALT-C Trial. Cognitive impairment was defined as a global deficit score (GDS)or = 1.0.The mean age was 51.2 years, 67% were male, and 42% had cirrhosis. After accounting for baseline GDS scores, the mean GDS scores did not significantly change over time (P=0.46) nor with treatment group (P=0.49). Cognitive function was also not influenced by medication adherence in the 66 patients receiving maintenance peginterferon (P=0.14) after controlling for baseline GDS scores and time. Beck Depression scores did not significantly increase over time (P=0.60), nor did they vary by treatment group (P=0.74). Although 32% of patients experienced objective worsening of their liver disease during follow-up, the frequency and severity of cognitive impairment did not differ in those with and without disease progression (P=0.71).Measures of cognitive function were neither influenced by low-dose peginterferon treatment nor with objective evidence of liver disease progression in patients with advanced chronic hepatitis C prospectively followed up for 3.5 years.

Computer-assisted morphometry can provide precise measurement of hepatic fibrosis on a continuous scale. Previous morphometric studies of large cohorts of patients with treatment refractory chronic hepatitis C have shown a mean increase in fibrosis of 30% to 58% in 1 year. The aim of the present study was to quantify fibrosis progression in biopsy specimens obtained over 1.5 to 5 years from three groups of patients with baseline bridging fibrosis or cirrhosis (Ishak stages 3-6) enrolled in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis Trial. The main group of 346 lead-in nonresponders (viremic after 24 weeks of peginterferon-ribavirin therapy) had a mean fibrosis increase of 61% over pretreatment baseline after 2 years and 80% after 4 years. In contrast, the 78 breakthrough/relapse patients (undetectable serum hepatitis C virus RNA after 24 weeks of peginterferon-ribavirin and receiving antiviral therapy for 48 weeks) showed a mean increase in fibrosis of 48% when biopsied 36 months from pretreatment baseline but no further increase at 60 months. Finally, the 111 express patients with baseline biopsies following unsuccessful peginterferon-ribavirin outside the trial had significantly more baseline fibrosis than the others but an increase of only 21% after 21 months and a slight decrease at 45 months. Maintenance therapy with low-dose peginterferon had no effect on fibrosis changes in any of the groups. Conclusion: Morphometry demonstrated complex, nonlinear changes in fibrosis over time in this heterogeneous cohort of patients with interferon-refractory chronic hepatitis C. (HEPATOLOGY 2009;50:1738-1749.)

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 μg/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, ≥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 ≥4 log 10 during maintenance therapy. No significant reduction in clinical outcomes was observed in these patients. Conclusions Viral suppression by ≥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.

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. (HEPATOLOGY 2009;50:1360-1369.)

In patients with chronic hepatitis C who do not have a response to antiviral treatment, the disease may progress to cirrhosis, liver failure, hepatocellular carcinoma, and death. Whether long-term antiviral therapy can prevent progressive liver disease in such patients remains uncertain.We conducted a randomized, controlled trial of peginterferon alfa-2a at a dosage of 90 microg per week for 3.5 years, as compared with no treatment, in 1050 patients with chronic hepatitis C and advanced fibrosis who had not had a response to previous therapy with peginterferon and ribavirin. The patients, who were stratified according to stage of fibrosis (622 with noncirrhotic fibrosis and 428 with cirrhosis), were seen at 3-month intervals and underwent liver biopsy at 1.5 and 3.5 years after randomization. The primary end point was progression of liver disease, as indicated by death, hepatocellular carcinoma, hepatic decompensation, or, for those with bridging fibrosis at baseline, an increase in the Ishak fibrosis score of 2 or more points.We randomly assigned the patients to receive peginterferon (517 patients) or no therapy (533 patients) for 3.5 years. The level of serum aminotransferases, the level of serum hepatitis C virus RNA, and histologic necroinflammatory scores all decreased significantly (P0.001) with treatment, but there was no significant difference between the groups in the rate of any primary outcome (34.1% in the treatment group and 33.8% in the control group; hazard ratio, 1.01; 95% confidence interval, 0.81 to 1.27; P=0.90). The percentage of patients with at least one serious adverse event was 38.6% in the treatment group and 31.8% in the control group (P=0.07).Long-term therapy with peginterferon did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis, with or without cirrhosis, who had not had a response to initial treatment with peginterferon and ribavirin. (ClinicalTrials.gov number, NCT00006164.)

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.

Background and Methods. Chronic hepatitis B is a common and often progressive liver disorder for which there is no accepted therapy. To assess the efficacy of treatment with interferon, we randomly assigned patients with chronic hepatitis B to one of the following regimens: prednisone for 6 weeks followed by 5 million units of recombinant interferon alfa-2b daily for 16 weeks; placebo followed by 5 million units of interferon daily for 16 weeks; placebo followed by 1 million units of interferon daily for 16 weeks; or observation with no treatment. Results. Hepatitis B e antigen and hepatitis B viral DNA disappeared from serum significantly more often in the patients given prednisone plus interferon (16 of 44 patients, or 36 percent) or 5 million units of interferon alone (15 of 41; 37 percent) than in the untreated controls (3 of 43; 7 percent; P

To assess the efficacy of therapy with the antiviral agent interferon in chronic hepatitis C (non-A, non-B hepatitis), we randomly assigned 166 chronic hepatitis C patients to treatment with either 3 million or 1 million units of recombinant interferon alfa-2b three times weekly for 24 weeks, or to no treatment. The probability of normalization or near normalization of the serum alanine aminotransferase levels after 6 months of interferon therapy was 46% in patients treated with 3 million units of interferon (p less than 0.001) and 28% in those treated with 1 million units (p less than 0.02), but only 8% in untreated patients. Serum alanine aminotransferase levels became completely normal in 22 of the 26 patients (85%) who responded to treatment with 3 million units of interferon and 9 of the 16 patients (56%) who responded to treatment with 1 million units. The patients who received 3 million units of interferon had histological improvement because of the regression of lobular and periportal inflammation. Relapse within 6 months after the completion of treatment occurred in 51% of the patients treated with 3 million units of interferon and 44% of those treated with 1 million units. We conclude that a 24-week course of interferon therapy is effective in controlling disease activity in many patients with hepatitis C, although relapse after the cessation of treatment is common.

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.

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.

Probiotics are live microorganisms that may confer health benefits on the host. Recent trials of probiotic use among healthy pregnant women demonstrate potential for improved glycemic control. The aim of this study was to investigate the effects of a probiotic capsule intervention on maternal metabolic parameters and pregnancy outcome among women with gestational diabetes.This double-blind placebo-controlled randomized trial recruited pregnant women with a new diagnosis of gestational diabetes or impaired glucose tolerance following a 3-hour 100-g glucose tolerance test. Women were randomized to a daily probiotic (Lactobacillus salivarius UCC118) or placebo capsule from diagnosis until delivery. Fasting blood samples were collected at baseline and 4-6 weeks after capsule commencement for analysis of glucose, insulin, c-peptide, and lipids. The primary outcome was difference in fasting glucose postintervention, first analyzed on an intention-to-treat basis and followed by per-protocol analysis that excluded women commenced on pharmacological therapy (insulin or metformin). Secondary outcomes were changes in insulin, c-peptide, homeostasis model assessment and lipids, requirement for pharmacological therapy, and neonatal anthropometry.Of 149 women recruited and randomized, there were no differences between the probiotic and placebo groups in postintervention fasting glucose (4.65 ± 0.49 vs 4.65 ± 0.53 mmol/L; P = 373), requirement for pharmacological therapy (17% vs 14%; P = .643), or birthweight (3.57 ± 0.64 vs 3.60 ± 0.57 kg; P = .845). Among 100 women managed with diet and exercise alone, fasting plasma glucose decreased significantly within both the probiotic (4.76 ± 0.45 to 4.57 ± 0.42 mmol/L; P.001) and placebo (4.85 ± 0.58 to 4.58 ± 0.45 mmol/L; P.001) groups, but the levels between groups did not differ (P = .316). The late gestation-related rise in total and low-density lipoprotein (LDL) cholesterol was attenuated in the probiotic vs the placebo group (+0.27 ± 0.48 vs +0.50 ± 0.52 mmol/L total cholesterol, P = .031; +0.08 ± 0.51 vs +0.31 ± 0.45 mmol/L LDL cholesterol, P = .011). No differences were noted between groups in other metabolic parameters or pregnancy outcome.A probiotic capsule intervention among women with abnormal glucose tolerance had no impact on glycemic control. The observed attenuation of the normal pregnancy-induced rise in total and LDL cholesterol following probiotic treatment requires further investigation, particularly in this obstetric group at risk of future metabolic syndrome.

This study evaluated the influence of cognitive reserve on neuropsychological test performance in 198 patients infected with the hepatitis C virus. IQ scores, educational level, and occupational rating were combined to calculate a Cognitive Reserve Score (CRS) for each patient. Similar to studies of infection with the human immunodeficiency virus, there was a significantly increased risk of impairment in neuropsychological test performance in individuals with lower CRSs. It is important to account for CRS when assessing cognitive findings in large-scale clinical trials.

This placebo-controlled, randomized, multicenter trial compared the effects of MTX plus UDCA to UDCA alone on the course of primary biliary cirrhosis (PBC). Two hundred and sixty five AMA positive patients without ascites, variceal bleeding, or encephalopathy; a serum bilirubin less than 3 mg/dL; serum albumin 3 g/dL or greater, who had taken UDCA 15 mg/kg daily for at least 6 months, were stratified by Ludwig's histological staging and then randomized to MTX 15 mg/m2 body surface area (maximum dose 20 mg) once a week while continuing on UDCA. The median time from randomization to closure of the study was 7.6 years (range: 4.6-8.8 years). Treatment failure was defined as death without liver transplantation; transplantation; variceal bleeding; development of ascites, encephalopathy, or varices; a doubling of serum bilirubin to 2.5 mg/dL or greater; a fall in serum albumin to 2.5 g/dL or less; histological progression by at least two stages or to cirrhosis. Patients were continued on treatment despite failure of treatment, unless transplantation ensued, drug toxicity necessitated withdrawal, or the patient developed a cancer. There were no significant differences in these parameters nor to the time of development of treatment failures observed for patients taking UDCA plus MTX, or UDCA plus placebo. The trial was conducted with a stopping rule, and was stopped early by the National Institutes of Health at the advice of our Data Safety Monitoring Board for reasons of futility. In conclusion, methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone.

Prior studies have demonstrated neuropsychological abnormalities in chronic hepatitis C (CHC) patients even with mild fibrosis. The aim of this study was to determine the frequency, type, and severity of cognitive impairment in a large group of CHC patients with advanced fibrosis.Ten validated neuropsychological tests were administered to 201 CHC patients. Standard scores for individual tests were calculated using normative population data that controlled for age, gender, and/or education. Lifetime psychiatric history, alcohol consumption, and mood status were also determined.33% of patients met criteria for cognitive impairment (i.e. standard score40 on at least 4 tests). Mild impairment in verbal recall and working memory were noted with other domains remaining intact. Liver disease severity and lifetime psychiatric/substance abuse history did not correlate with group mean cognitive test results or the presence of cognitive impairment. In contrast, IQ and depression scores were significant and independent predictors of cognitive impairment (ROC = 0.84).33% of patients entering the HALT-C trial have evidence of a mild, non-focal subcortical processing deficit which was highly correlated with IQ, education, and occupation. Future studies of cognitive function in CHC patients should control for general cognitive ability.

Alpha-fetoprotein (AFP) has been useful in the diagnosis of hepatocellular carcinoma (HCC) but lacks specificity. We assessed serum AFP among patients with chronic hepatitis C and advanced fibrosis to establish predictors of AFP elevations and changes with antiviral therapy.Serum AFP was measured at baseline and on therapy in patients in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C). AFP levels were correlated with patient demographic and clinical features.Baseline AFP wasor = 20 ng/mL in 191 of 1145 patients (16.6%). Mean AFP values were significantly higher in patients with cirrhosis than in those with bridging fibrosis (22.5 vs. 11.4 ng/mL, P0.0001). Factors independently associated with raised serum AFP in patients with cirrhosis were female gender, black race, decreased platelet count, increased serum AST/ALT ratio, serum ferritin, and Mallory bodies in liver biopsies. Serum AFP levels decreased significantly during therapy with pegylated interferon alpha-2a and ribavirin. HCC was identified in six subjects, only three of whom had AFP20 ng/mL.Among patients with advanced chronic hepatitis C, serum AFP values are frequently elevated, even in the absence of HCC. Factors associated with raised AFP include severity of liver disease, female gender and black race. Serum AFP levels decline during antiviral therapy.

Knowledge of the presence of cirrhosis is important for the management of patients with chronic hepatitis C (CHC). Most models for predicting cirrhosis were derived from small numbers of patients and included subjective variables or laboratory tests that are not readily available. The aim of this study was to develop a predictive model of cirrhosis in patients with CHC based on standard laboratory tests. Data from 1,141 CHC patients including 429 with cirrhosis were analyzed. All biopsies were read by a panel of pathologists (blinded to clinical features), and fibrosis stage was determined by consensus. The cohort was divided into a training set (n = 783) and a validation set (n = 358). Variables that were significantly different between patients with and without cirrhosis in univariate analysis were entered into logistic regression models, and the performance of each model was compared. The area under the receiver-operating characteristic curve of the final model comprising platelet count, AST/ALT ratio, and INR in the training and validation sets was 0.78 and 0.81, respectively. A cutoff of less than 0.2 to exclude cirrhosis would misclassify only 7.8% of patients with cirrhosis, while a cutoff of greater than 0.5 to confirm cirrhosis would misclassify 14.8% of patients without cirrhosis. The model performed equally well in fragmented and nonfragmented biopsies and in biopsies of varying lengths. Use of this model might obviate the requirement for a liver biopsy in 50% of patients with CHC. In conclusion, a model based on standard laboratory test results can be used to predict histological cirrhosis with a high degree of accuracy in 50% of patients with CHC.

The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial was designed to determine whether maintenance interferon therapy could slow disease progression in patients who had failed to eradicate hepatitis C virus (HCV) during prior interferon treatment (nonresponders). Ten clinical sites, a virological testing center, and a data coordinating center (DCC) were selected to collaborate in the design and implementation of the final protocol. Eligible patients had been treated previously with interferon for at least 12 weeks, with or without another antiviral, ribavirin, but still had persistent viremia. Because patients had received a variety of prior treatments, and as a perceived benefit of enrollment, we incorporated a Lead-in period of treatment with long-acting pegylated interferon alfa-2a plus ribavirin into the study design, a combination believed to be more effective but not approved by the Food and Drug Administration at the Trial's inception. If patients failed to achieve clearance of virus from the blood after 20 weeks of this Lead-in therapy, they were entered into the main trial at week 24 and randomized to receive either a lower dose of pegylated interferon weekly alone or no further therapy for an additional 3 1/2 years. The original protocol was amended later in three respects to improve enrollment and to adapt to Food and Drug Administration approval of the Lead-in therapy, including allowing patients to proceed directly to the randomized part of the study if treatment resembling the Lead-in had been completed. The protocol changes enhanced enrollment while upholding the original goals of the study and its integrity.