title: Surrogate end points and long-term outcome in patients with chronic hepatitis B.
abstract: OBJECTIVE
  It is unclear whether surrogate end points reported in clinical trials correlate with long-term outcome of patients with chronic hepatitis B.
  
  
  METHODS
  Patients with chronic hepatitis B who participated in any of 4 randomized controlled trials were followed prospectively for liver-related events (hepatocellular carcinoma, ascites, spontaneous bacterial peritonitis, variceal bleeding, liver transplantation, and death). Biochemical (normal ALT levels), virologic (levels of hepatitis B virus DNA below 10,000 copies/mL), and histologic (reduction of necroinflammation grading by 2 points or more with no increase in fibrosis staging) responses were evaluated at the end of each trial.
  
  
  RESULTS
  One hundred ninety-five patients with adequate pretreatment and post-treatment liver biopsies (15 mm long and 6 portal tracts) were followed for 86 months (interquartile range, 77-98). Liver-related events occurred in 12 patients (6%). The risk of liver-related events was lower in patients with biochemical (hazard ratio, 0.21; 95% confidence interval, 0.068-0.68) and histologic (hazard ratio, 0.095; 95% confidence interval, 0.012-0.74) responses. Only 1 patient with a histologic response and 1 patient with an ALT level below Prati's cutoffs (30 IU/L in men and 19 IU/L in women) developed liver-related events. Fifteen of 25 patients (60%) with cirrhosis at baseline had regression of cirrhosis, and none of these patients died or developed liver-related events. In contrast, 3 of these patients still developed liver-related events, despite an initial virologic response, and 2 had virologic breakthrough.
  
  
  CONCLUSIONS
  Biochemical and histologic responses, particularly regression of cirrhosis, in patients with chronic hepatitis B are associated with decreased liver-related complications.
authors.affiliation: Department of Medicine and Therapeutics, the Chinese University of Hong Kong, Hong Kong.
authors.forename: Vincent Wai-Sun
authors.initials: VW
authors.lastname: Wong
authors.forename: Grace Lai-Hung
authors.initials: GL
authors.lastname: Wong
authors.forename: Angel Mei-Ling
authors.initials: AM
authors.lastname: Chim
authors.forename: Paul Cheung-Lung
authors.initials: PC
authors.lastname: Choi
authors.forename: Anthony Wing-Hung
authors.initials: AW
authors.lastname: Chan
authors.forename: Steven Woon-Choy
authors.initials: SW
authors.lastname: Tsang
authors.forename: Alex Yui
authors.initials: AY
authors.lastname: Hui
authors.forename: Hoi-Yun
authors.initials: HY
authors.lastname: Chan
authors.forename: Joseph Jao-Yiu
authors.initials: JJ
authors.lastname: Sung
authors.forename: Henry Lik-Yuen
authors.initials: HL
authors.lastname: Chan
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D015415:Biomarkers; D004279:DNA, Viral / Q000097:blood; D029721:Drosophila Proteins; D005260:Female; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D015415:Biomarkers; D004279:DNA, Viral; D029721:Drosophila Proteins; C518413:loj protein, Drosophila; D000410:Alanine Transaminase