Surrogate end points and long-term outcome in patients with chronic hepatitis B.
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.
Wong
Vincent Wai-Sun
VW
Department of Medicine and Therapeutics, the Chinese University of Hong Kong, Hong Kong.
Wong
Grace Lai-Hung
GL
Chim
Angel Mei-Ling
AM
Choi
Paul Cheung-Lung
PC
Chan
Anthony Wing-Hung
AW
Tsang
Steven Woon-Choy
SW
Hui
Alex Yui
AY
Chan
Hoi-Yun
HY
Sung
Joseph Jao-Yiu
JJ
Chan
Henry Lik-Yuen
HL
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
D015415:Biomarkers; D004279:DNA, Viral; D029721:Drosophila Proteins; C518413:loj protein, Drosophila; D000410:Alanine Transaminase