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Most patients in the immunotolerant (IT) phase of chronic hepatitis B (CHB) transition to the immune active (IA-hepatitis B surface antigen [HBeAg]+) phase by early adulthood. We examined characteristics of adults in the IT vs IA-HBeAg+ phase and rate of transition from IT to other phases of CHB, with a focus on those ≥40 years.Demographic, clinical, and virologic characteristics of participants in the Hepatitis B Research Network adult cohort study with IT CHB (alanine aminotransferase ≤1.5 × upper limit of normal, hepatitis B virus DNA10Of 107 adult IT participants, 52 (48%) were30, 33 (31%) were 30 to 39, and 22 (21%) were ≥40 years old (maximum, 71 years). Among IT groups, the proportion born in Asia and duration of CHB were greater in older IT groups, but virologic and liver disease characteristics were similar. Compared with IA-HBeAg+ participants (n = 192), IT participants were younger, fewer were men, more were Asian, and platelets, qHBsAg, and qHBeAg levels were higher. Similar differences were observed when comparisons were made with the ≥40 years IT group. Among IT participants, 60 (56%) transitioned during 206 person-years of follow-up. The phase transition rate per 100 person-years was highest in the30 years group (33.0 [95% confidence interval [CI], 23.4-46.7]) vs the 30 to 39 years group (24.8 [95% CI, 15.6-39.4]) and ≥40 group (27.4 [95% CI, 14.8-50.9]), but 95% CIs overlapped.In a large North American population, over 50% of adults in the IT phase of CHB were ≥30 years and 20% were ≥40 years old, but older IT patients had similar characteristics and rates of transition as younger IT patients.

Introduction and objectives: The prevalence of alcohol, tobacco, and coffee use and association with liver health among North Americans with Chronic Hepatitis B (CHB) infection has not been well described. Materials and methods: The Hepatitis B Research Network includes an observational study of untreated CHB adults enrolled at 21 sites in the United States and Canada. Alcohol use was categorized as none, moderate, and at-risk based on the definition from the National Institute on Alcohol Abuse and Alcoholism; tobacco use as never, current and former; coffee use as none, 1–2 cups/day, and ≥3 cups/day. Linear regression and linear mixed models were used to associate lifestyle behaviors with ALT and FIB-4 values. Results: 1330 participants met eligibility: 53% males, 71% Asian and the median age was 42 years (IQR: 34–52). Median ALT was 33 U/L (IQR: 22–50), 37% had HBV DNA

Despite the availability of a protective vaccine for over 3 decades, the number of persons with chronic hepatitis B virus (HBV) infection remains high. These persons are at risk for cirrhosis and hepatocellular carcinoma. Current treatment is effective at inhibiting viral replication and reducing complications of chronic HBV infection, but is not curative. There is a need for novel, finite therapy that can cure chronic HBV infection. Several agents are in early-phase development and can be broadly viewed as agents that target the virus directly or indirectly or the host immune response. This article highlights key developments in antiviral/immunomodulatory therapy, the rationale for these approaches, and possible therapeutic regimens.

Chronic hepatitis B virus (HBV) infection follows a dynamic and variable course. At different stages in the disease, hepatitis flares may occur, which can be challenging to predict and manage. Flares are believed to be primarily immune-mediated and may mark transitions to inactive disease or even clearance of infection, but in certain scenarios they may also lead to hepatic decompensation or even death. As such, understanding the significance of flares in different patient populations and different clinical scenarios, is critical for optimal management. In this review, what is known about flares in different stages of chronic HBV infection is summarized. Descriptions of flares in the natural history of chronic infection along with definitions of flares, is followed by a summary of the immunological mechanisms underlying flares. Flares are then described in different clinical scenarios including on-treatment flares, treatment withdrawal flares, reactivation flares with immunosuppressive therapy and pregnancy-related flares. Each section reviews existing knowledge and highlights key unanswered questions that need to be addressed to improve our understanding of flares, hopefully providing insights into their pathogenesis which can be used to improve current clinical management and ideally to further development of new curative therapeutic approaches for HBV.

The hepatitis B virus (HBV) is a major cause of cirrhosis and hepatocellular carcinoma worldwide. Despite an effective vaccine, the prevalence of chronic infection remains high. Current therapy is effective at achieving on-treatment, but not off-treatment, viral suppression. Loss of hepatitis B surface antigen, the best surrogate marker of off-treatment viral suppression, is associated with improved clinical outcomes. Unfortunately, this end point is rarely achieved with current therapy because of their lack of effect on covalently closed circular DNA, the template of viral transcription and genome replication. Major advancements in our understanding of HBV virology along with better understanding of immunopathogenesis have led to the development of a multitude of novel therapeutic approaches with the prospect of achieving functional cure (hepatitis B surface antigen loss) and perhaps complete cure (clearance of covalently closed circular DNA and integrated HBV DNA). This review will cover current best practice for managing chronic HBV infection and emerging novel therapies for HBV infection and their prospect for cure.

The prevalence of chronic hepatitis B (CHB) differs globally. CHB is responsible for 30% of all deaths from cirrhosis and 40% from hepatocellular carcinoma. The WHO developed guidelines in 2015 on prevention, care, and treatment of chronic HBV infection targeted to program managers in all health care settings, particularly in low- and middle-income countries. Several of the recommendations differ from those of the major Liver Societies, including the American Association for the Study of Liver Diseases (AASLD). This review highlights key differences between the AASLD and WHO guidelines and discusses the impact on management of CHB.

The cytosolic enzyme N-glycanase 1, encoded by NGLY1, catalyzes cleavage of the β-aspartyl glycosylamine bond of N-linked glycoproteins, releasing intact N-glycans from proteins bound for degradation. In this study, we describe the clinical spectrum of NGLY1 deficiency (NGLY1-CDDG). Prospective natural history protocol. In 12 individuals ages 2 to 21 years with confirmed, biallelic, pathogenic NGLY1 mutations, we identified previously unreported clinical features, including optic atrophy and retinal pigmentary changes/cone dystrophy, delayed bone age, joint hypermobility, and lower than predicted resting energy expenditure. Novel laboratory findings include low cerebral spinal fluid (CSF) total protein and albumin and unusually high antibody titers toward rubella and/or rubeola following vaccination. We also confirmed and further quantified previously reported findings noting that decreased tear production, transient transaminitis, small feet, a complex hyperkinetic movement disorder, and varying degrees of global developmental delay with relatively preserved socialization are the most consistent features. Our prospective phenotyping expands the clinical spectrum of NGLY1-CDDG, offers prognostic information, and provides baseline data for evaluating therapeutic interventions. Genet Med 19 2, 160–168.

Hepatitis C infection is a common cause of cirrhosis and indication for liver transplantation in the United States. The incidence of chronic hepatitis C has been declining, but rates of cirrhosis and hepatocellular carcinoma are projected to increase. The outcome of chronic hepatitis C is variable. It is estimated that 20% to 25% will develop cirrhosis over a 25-year to 30-year period. The rate of disease progression is influenced by many host, viral, and environmental factors. Few can be modified.

BACKGROUND & AIMS: The incidence and outcomes of alanine aminotransferase (ALT) flares during the natural history of chronic HBV infection has not been determined in a large, racially heterogeneous group of patients in North America. METHODS: We collected data from the Hepatitis B Research Network—an observational cohort study of untreated adults with chronic HBV infection enrolled at 21 sites in the United States and Canada. Clinical and laboratory data were collected from 1587 participants (49.9% male, 73.7% Asian, 35.2% genotype B infection, mean age of 42.6 years) at enrollment, at weeks 12 and 24, and every 24 weeks thereafter for a planned 5 years of follow up (from January 2011 through May 2016). Participants were excluded if they had a history of hepatic decompensation, hepatocellular carcinoma, solid organ or bone marrow transplantation, chronic immune suppression, or antiviral therapy within 6 months before enrollment. Levels of ALT were measured in serum samples and flares were defined as at least 10 times the upper limit of normal (300 U/L in males and 200 U/L in females). RESULTS: ALT flares occurred in 102 participants (6%), with 31 flares (30%) occurring at baseline. The 4-year cumulative incidence of ALT flares was 5.7%. The median peak level of ALT was 450 U/L (25th–75th percentile, 330 U/L to 747 U/L) with a maximum of 2578 U/L. In multivariable analysis, factors associated with the occurrence of an ALT flares were: male sex (odds ratio [OR], 3.02; P=.0007), higher baseline HBV DNA values (OR per log10, 1.41; P

The pharmacokinetics and pharmacodynamics of standard interferon alfa-2a and interferon alfa-2b are substantially altered by pegylation. The size, geometry, and site of attachment of the PEG moiety affect the pharmacokinetics and pharmacodynamics as evidenced by the different absorption, volume of distribution, and clearance of the linear 12-kDa peginterferon alfa-2b and the branched 40-kDa peginterferon alfa-2a. Despite these differences, the clinical efficacy, safety, and tolerability of the 2 peginterferons are similar. However, evidence exists that peginterferon alfa-2 plus ribavirin is associated with small but significantly higher sustained virological response rates compared with peginterferon alfa-2b. This article discusses the pharmacokinetics and pharmacodynamics of the 2 peginterferons and their combination with ribavirin.

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.

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.

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

Background & Aims: Error catastrophe from an increase in mutation rate may be a possible mechanism of action of ribavirin in chronic hepatitis C (CHC). We sought to evaluate the mutagenic potential of ribavirin in vivo and to determine if conserved regions of hepatitis C virus (HCV) NS5B are mutated during ribavirin therapy. Methods: Thirty-one patients with CHC genotype 1 who participated in a randomized, placebo-controlled trial of ribavirin for 48 weeks were studied. After 48 weeks, patients on placebo were crossed-over to open-label ribavirin for 48 weeks. Viral RNA was extracted from paired, stored sera at day 0 and week 24 during the randomized phase and weeks 48, 52, and 72 during the cross-over phase. The entire NS5B region was sequenced and the mutation rates were calculated. Results: An increase in mutation rate was observed after 4 weeks (4.4 × 10−2 vs 2.1 × 10−3 per site/y, P = .02) but not after 24 weeks (4.0 × 10−3 vs. 5.5 × 10−3 per site/y, P = .1) in patients who crossed over to ribavirin. Similarly, during the randomized phase no increase in the number of mutations or the mutation rate was observed at week 24 between the ribavirin- and placebo-treated patients 6.6 vs 4.3 × 10−3 per site/y, respectively (P = .4). No mutations were observed in conserved regions of NS5B. Conclusions: Ribavirin therapy is associated with an early, transient increase in the mutation rate of HCV. Lethal mutagenesis and error catastrophe is unlikely to be the sole mechanism of action of ribavirin during therapy for CHC.

Chronic hepatitis B continues to be a major cause of end-stage liver disease and hepatocellular carcinoma worldwide. Nucleos(t)ide analogues have proven to be effective in controlling the disease and perhaps decreasing the incidence of hepatocellular carcinoma. However, development of drug resistance is a major limitation to their long-term effectiveness. Understanding the mechanisms of drug resistance are important for designing new agents and devising strategies to manage and prevent the development of antiviral drug resistance. The development of resistance is determined by an interplay of viral, host, and drug characteristics Homology of the HBV polymerase to the human immunodeficiency virus-1 reverse transcriptase has allowed predictions to be made on the effect mutations have on HBV polymerase structure. In vitro functional studies provide complementary information. Several broad principles on the mechanism of resistance have emerged from these studies. First, most of the primary mutations cluster in the vicinity of the incoming nucleotide and act by directly affecting the position or stability of the bound substrate, template, or primer. In contrast, secondary mutations tend to occur away from the nucleotide-binding pocket. Finally, the structural and functional consequences of mutations are quite variable among the different agents. This paper reviews the key mutations and mechanisms associated with resistance to the nucleos(t)ide analogues approved for clinical use and discuss new targets for drug development.

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.

To describe the association of the rare and serious complication of jaundice with severe thyrotoxicosis, a potentially lethal endocrine disorder.We report the clinical, laboratory, and pathologic findings of 2 cases of severe jaundice (total bilirubin levels: 35.2 mg/dL in case 1 and 42 mg/dL in case 2) associated with thyroid storm in the absence of a history of liver disease, thionamide exposure, or congestive heart failure. We also present other relevant reports available in the literature.Case 1 was a 38-year-old woman who presented with nausea, vomiting, fatigue, pruritus, and frequent nonbloody diarrhea. She was transferred to our institution because of worsening hyperbilirubinemia. Case 2 was a 35-year-old woman admitted to a community hospital with thyroid storm and jaundice. Upon transfer to our institution, the patient was unconscious, mechanically ventilated, and in atrial fibrillation. In case 2, liver biopsy results revealed diffuse hepatocellular ballooning with intrahepatic cholestasis with mild portal lymphocytic infiltration. Both patients presented with severe cholestatic jaundice in the absence of congestive heart failure; underlying liver disease (infectious or autoimmune); or previous exposure to thionamides, other hepatotoxic agents, or complementary and alternative medications. In both cases, jaundice responded to therapy with antithyroid medications. Both patients eventually underwent thyroidectomy with complete resolution of the jaundice.The data strongly suggest that in these patients, the hepatic dysfunction was primarily due to hyperthyroidism. These cases indicate that the mere presence of hyperbilirubinemia during severe thyrotoxicosis should not per se delay the use of potentially life-saving thionamides once a thorough evaluation for other causes of liver disease has been completed.

The factors predictive of the presence or the absence of esophageal varices in hepatitis C virus (HCV) and advanced fibrosis have not been defined.To define the prevalence of esophageal varices and the factors that are positively and negatively with such varices in hepatitis C and advanced fibrosis.A prospective study of esophageal varices and associated risk factors in subjects with hepatitis C and advanced fibrosis.Prerandomization data from the HALT-C (hepatitis C long-term antiviral treatment against cirrhosis) clinical trial.Subjects with bridging fibrosis or cirrhosis, who were virologic nonresponders to treatment with pegylated interferon alpha 2a and ribavirin, underwent endoscopy.Sixteen percent of subjects with bridging fibrosis (95/598) and 39% of subjects with cirrhosis (164/418) had varices (P.0001); 2% of subjects with bridging fibrosis (13/598) and 11% of those with cirrhosis (48/418) had medium or large varices. Subjects with bridging fibrosis and varices had a significantly lower platelet count and higher bilirubin and international normalized ratio (INR) compared with those without varices, suggesting that the biopsy may have underestimated the severity of fibrosis. A platelet count150,000/mm(3) was associated with a negative predictive value of 99% for esophageal varices. By logistic regression modeling, African American race and female sex were protective, whereas a lower platelet count and higher bilirubin and INR predicted varices (c statistic, 0.758).The risk of having varices increases with decreasing platelet counts, increasing bilirubin, and INR. The probability of having medium or large varices at platelet counts150,000/mm(3) is negligible in this population.

Iron overload may cause or contribute to hepatic injury and fibrosis. Mutations in the HFE gene may influence development or progression of chronic liver disease by increasing iron stores or modulating immune responses. The aim of this work was to assess the influence of HFE mutations and serum and hepatic measures of iron status on baseline features and response to lead-in therapy in subjects with advanced chronic hepatitis C enrolled in the Hepatitis C Anti-viral Long-term Treatment to prevent Cirrhosis (HALT-C) Trial.Entry criteria included an Ishak fibrosis score2 and lack of iron overload (Scheuer iron grade3+) according to local study pathologists. All baseline biopsy specimens were rescored by consensus of study pathologists, and detailed assessment of stainable iron was performed. Hepatic iron concentrations were measured on portions of 144 liver biopsy specimens. A total of 1051 out of 1145 subjects agreed to HFE mutational testing (C282Y, H63D, S65C).Thirty-five percent carried at least one HFE gene mutation. There were no significant differences in the prevalence of HFE gene mutations among subjects with fibrosis (35.5%) versus cirrhosis (32.9%). Thirty-three percent of subjects had end-of-treatment and 16% sustained virologic responses. Presence of HFE mutations, in particular the H63D variation, was associated with increased end-of-treatment (40% vs 29%, P = .0078) and sustained virologic responses (20% with HFE mutation vs 14% sustained virologic response without HFE mutation; P = .009).Although HFE mutations (especially the most frequent H63D mutation) are associated with increased iron loading, they are also associated with increased sustained virologic responses in US patients with advanced chronic hepatitis C.

An understanding of the natural history of CHB is critical for the management of the liver disease. Three clinical patterns with different clinical outcomes are recognized: HBeAg-positive CHB, HBeAg-negative CHB,and inactive CHB. Patients with elevated aminotransferase levels and HBV DNA greater than 105 viral copies per mL in serum and with features of chronic hepatitis on liver biopsy are candidates for therapy regardless of HBeAg status. Multiple host and viral factors and safety profiles of current therapies need to be considered carefully before recommending therapy. There appears to be no role for HBV genotyping in the management of patients. Three antiviral agents are approved for use against CHB infection:IFN-a, lamivudine, and adefovir. Efficacy is moderate at best and is limited by the poor tolerability of IFN and the development of resistance, coupled with concerns regarding the long-term safety with nucleoside analogs. Several new nucleoside and nucleotide analogs and novel agents are at various stages of development as potential therapies for CHB. The ideal compound would be one that is active against all replicative intermediates of the virus and has a low toxicity profile. Despite current shortcomings, the future of therapy for HBV is promising, as newer therapeutic options are being developed based on an understanding of the HBV life cycle.

Background/Aims Currently, there are no effective therapies available for patients with chronic hepatitis C who have failed to respond to optimal interferon alfa-based regimens. The aims of this pilot study were to assess the antiviral activity and safety of interferon gamma in chronic hepatitis C. Methods Patients with chronic hepatitis C, genotype 1, who had not responded to or who had relapsed after therapy with interferon alfa and ribavirin were enrolled in a trial of interferon gamma 1b given in doses of 100, 200 or 400μg subcutaneously three times weekly for 4 weeks. Frequent blood samples were obtained for HCV RNA levels. Results Fourteen patients were enrolled. Geometric mean HCV RNA levels remained unchanged. Serum aminotransferase levels also did not change, while there were significant decreases in neutrophil counts (−41% from baseline) and hematocrit (−5%). Low grade fever and malaise were common with the first injection of interferon gamma, but no serious side effects were encountered. Conclusions Although relatively well tolerated, interferon gamma in doses of 100–400μg thrice weekly had no effect on HCV RNA levels in patients with chronic hepatitis C who had failed to achieve a sustained response to interferon alfa-based therapies.

Chronic hepatitis B (CHB) is a major worldwide cause of chronic liver disease and a significant public health issue. Three predominant clinical presentations are recognized: hepatitis B e antigen(HBeAg) or typical CHB, HBeAg-negative or atypical CHB, and inactive CHB. The natural history of CHB infection in an individual may be dominated by one or a combination of these clinical presentations in a sequential fashion. These variations in clinical presentations reflect the viral-host immunology dynamics that form the basis for the development of liver disease. Therapy has been problematic in the past. There are three licensed drugs available for therapy of CHB with varied mechanisms of action. This has introduced the concept of tailored therapy for the individual patient. Many promising new agents and therapeutic approaches should become available in the near future.

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.

Background & Aims T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB). Methods We enrolled 200 adults with CHB who participated in the National Institutes of Health−supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyte-associated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion. Results Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3 + CD127 − regulatory T cells and CD4 + T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg) + than HBeAg − patients (percent responders: 3% vs 23%; P = .00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyte-associated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg + than HBeAg − patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls. Conclusions HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell−based immune signatures for clinical phenotypes. These findings suggest additional T-cell−independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.

study the etiology and prognosis of these patients and determine the proportion of DILI among patients with notably high levels of ALT Methods: In a University Hospital setting with a catchment area of approximately 170, 000 inhabitants, a prospective study identified all patients with serum level of ALT >500 U/L (normal levels

Background & Aims Liver biopsy is the standard for assessing hepatic fibrosis. Ultrasound transient elastography (TE) and the aspartate aminotransferase to platelet ratio index (APRI) are validated, noninvasive tests for identifying patients with cirrhosis. We evaluated discordance among TE, APRI, and histology diagnoses of cirrhosis. Methods We analyzed findings from 109 patients with chronic hepatitis C who underwent TE within 6 months of liver biopsy at the US National Institutes of Health from 2006 to 2011. Fibrosis was scored using the Ishak scale (0–6). APRI scores were calculated using data collected on the day of the biopsy. Area under receiver operator characteristic curves for TE and APRI were calculated to distinguish patients with cirrhosis (Ishak scores, 5–6) from those without cirrhosis (Ishak scores, 0–4). The best cut-off value and corresponding positive predictive value (PPV) and negative predictive value (NPV) were selected. Results Based on biopsy analysis, 18% of the patients had no fibrosis, 52% had mild fibrosis, 17% had bridging fibrosis, and 13% had cirrhosis. A TE cut-off value of 13.1 kPa identified patients with cirrhosis with the highest level of accuracy (100% sensitivity, 89% specificity, 58% PPV, 100% NPV), as did an APRI cut-off value of 1.0 (79% sensitivity, 78% specificity, 34% PPV, 96% NPV). Results from TE and APRI were discordant for 28% of cases. TE identified all cases of cirrhosis and an additional 10 patients who were not found to have cirrhosis based on histology analysis; 7 of these patients had clinical or radiologic evidence of cirrhosis, indicating that the biopsy sample was not staged correctly. Conclusions TE increases the accuracies of biopsy and APRI analyses in identifying patients with cirrhosis. TE also might be used to screen patients for cirrhosis and identify those who should be followed up for development of hepatocellular carcinoma and varices.