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BACKGROUND Peginterferon–ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies. METHODS We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the leadin period). Subsequently, group 1 (the control group) received placebo plus peginterferon–ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon–ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon–ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon–ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately. RESULTS A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P = 0.04), and in 29 of the 55 patients (53%) in group 3 (P = 0.004). In group 2, a total of 44% of patients received peginterferon–ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively. CONCLUSIONS The addition of boceprevir to standard therapy with peginterferon–ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.)

This guideline has been approved by the American Association for the Study of Liver Diseases (AASLD) and represents the position of the Association. 1. Preamble Clinical practice guidelines are defined as ''systematically developed statements to assist practitioner and patient decisions about appropriate heath care for specific clinical circumstances.'' 1 (All references are available in the Supporting Information.) These guidelines on autoimmune hepatitis provide a data-supported approach to the diagnosis and management of this disease. They are based on the following: (1) formal review and analysis of the recently-published world literature on the topic [Medline search]; (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines; 2 (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association Policy Statement on Guidelines; 3 and (4) the experience of the authors in the specified topic. These recommendations, intended for use by physicians, suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the quality of evidence supporting the recommendations, the Practice Guidelines Committee of the AASLD requires a class (reflecting benefit versus risk) and level (assessing strength or certainty) of evidence to be assigned and reported with each recommendation. 4 The grading system applied to the recommendations has been adapted from the American College of Cardiology and the American Heart Association Practice Guidelines, and it is given below (Table 1).

Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this 'secretory phenotype' can have pro- as well as anti-tumorigenic effects. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as 'senescence surveillance'), which depends on an intact CD4(+) T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of Nras(G12V). We also found that CD4(+) T cells require monocytes/macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells.

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Among patients with chronic HBV infection, tenofovir DF at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir dipivoxil at a daily dose of 10 mg through week 48. (ClinicalTrials.gov numbers, NCT00116805 and NCT00117676.)

US children, 9%-12% (14-16) UK children, 38% (13) Age at presentation Peripubertal and adults Usually under 14 years (153) Mode of presentation Chronic symptoms common Acute onset (~40%) Ascites or GI bleeding rare Acute liver failure possible (555,556) Asymptomatic in 25%-34% Relapse frequent (108) Acute in 25%-75% Acute severe in 2%-6% Laboratory features Hypergammaglobulinemia IgA levels may be reduced (153) Autoantibodies ANA Anti-LKM1 SMA, anti-actin [Anti-LC1, Anti-LKM3] SLA Concurrent immune diseases Autoimmune thyroiditis Autoimmune thyroiditis Rheumatic diseases Diabetes mellitus IBD Vitiligo Autoimmune overlap with PSC (ASC in children) Common in children Rare Atypical pANCA-positive Atypical pANCA-negative Overlap with PBC Seen in adults (not children) Not reported Cirrhosis at presentation Adults, 28%-33% (especially elderly) Rare Children, ≤33% Remission after drug withdrawal Possible Rare, usually need long-term immunosuppression Abbreviations: GI, gastrointestinal; IgA, serum immunoglobulin A. *Removed from marketplace. Abbreviation: anti-PD-L1, antibody to programmed death protein ligand 1. taBle 6. Features of Drug-Induced aIH-like Injury and aIH Clinical Features Drug Induced AIH-Like Injury AIH Gender Mainly women (187) Female predominance, but men also affected (2,384,467) Acute onset Majority (>60%) (231) <20% (2,136) Hypersensitivity (fever, rash, eosinophilia) Up to 30% (231,232,613) Unusual (2,384,467) Temporal relationship with drug Positive (231-234) Negative (2,56,188) HLA DRB1*03:01 or DRB1*04:01 association None (236) Common (29) Concurrent autoimmune diseases Unusual (187) Present in 14%-44% (129,149-152) Cirrhosis at presentation Rare (187) 28%-33% (9,104-107) Management Stop offending drug ± glucocorticoids (187,231,232) Glucocorticoids with AZA (2,384,467) Relapse after drug withdrawal Rare (187) 60%-87% (243,244) Progression to cirrhosis Rare (187) 7%-40% (105) Survival without transplantation 90%-100% (187,232) 10-year survival, 89%-91% (105,451