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42nd Meeting of the European Association for the Study of Liver Diseases
Barcelona, Spain
April 11-15, 2007
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Presence of Biopsy-Proven Histologic Damage (Necroinflammation and Fibrosis) is Common even when ALT is less than 2 X ULN in Patients with Chronic Hepatitis B
  Reported by Jules Levin
EASL, April 11-15, 2007
Barcelona, Spain
Norah Terrault1, Ray Kim2, Solko Schalm3, Seng-Gee Lim4, George
Papatheodoridis5, Alfredo Alberti6, Man-Fung Yuen7, Zachary Goodman8, James
Vaughan9, Richard Wilber9, Bruce Kreter9
1 Gastroenterology Department, UCSF, San Francisco, CA, USA; 2 Mayo Clinic
Medical Center, Rochester, MN, USA; 3 Department of Gastroenterology and
Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands; 4 National University of Singapore, Singapore;
5 Academic Department of Medicine, Hippokration General Hospital, Athens,
Greece; 6 Department of Clinical and Experimental Medicine,
University of Padova, Padova, Italy; 7 Queen Mary Hospital, Pok Fu Lam, Hong Kong, China; 8 Department of Hepatic and Gastrointestinal Pathology,
Armed Forces Institute of Pathology, Washington, DC, USA; 9 Bristol-Myers Squibb
Company, Wallingford, CT, and Princeton, NJ, USA.
In nucleoside-naive HBeAg(+) and HBeAg(-) patients with compensated CHB:
Up to 75% of patients with elevated HBV-DNA had clinically significant
necroinflammation (Knodell necroinflammatory score ≥7) even when ALT is <2 x ULN
-- HBeAg(+): 68% have Knodell necroinflammatory score ≥7
-- HBeAg(-): 75% have Knodell necroinflammatory score ≥7
Up to 17% of patents have advanced fibrosis even when ALT is <2 x ULN:
-- HBeAg(+): 11% have Ishak fibrosis score ≥4
-- HBeAg(-): 17% have Ishak fibrosis score ≥4
These findings underscore the value of liver biopsy in patients with ALT ≦2 xULN to identify patients in need of treatment.
ALT as a biomarker in chronic hepatitis B

Alanine aminotransferase (ALT) can be found in many body tissues, with high levels found in the liver1
Elevated ALT usually reflects short-term hepatocellular damage
In chronic hepatitis B (CHB) there may be a poor correlation between a single ALT measurement and concurrent histopathology1
CHB patients with normal ALT can have significant histologic findings, including fibrosis2-5
CHB Treatment Guidelines
International guidelines for the management of CHB use ALT and HBV DNA to define which patients are candidates for treatment:
-- ALT >2 x the upper limit of normal (ULN) is a key requirement to qualify for treatment6-9
-- ALT ≦2 x ULN and HBV DNA >20,000 IU/mL in HBeAg(+) or >2,000 IU/mL in HBeAg(-) CHB: liver biopsy is recommended in patients >40 years of age, persistently high normal ALT (<2 x ULN) or family history of HCC6
-- Recently updated guidelines suggest lowering 'normal' ALT cut-off values to 30 IU/L for men and 19 IU/L for women6, 9
The objective of these post-hoc analyses was to assess the relationship between histology and baseline ALT in nucleoside-naive, HBeAg(+) and HBeAg(-) CHB patients enrolled in the entecavir Phase III studies.

Phase III studies ETV-022 (HBeAg (+)) and ETV-027 (HBeAg(-)) compared the safety and efficacy of entecavir 0.5 mg once daily (QD) with lamivudine 100 mg QD in nucleoside-naive CHB patients after a minimum of 52 weeks10,11
Selected criteria for study entry
-- Elevated HBV DNA levels by bDNA assay
≥3 MEq/mL (ETV-022) or ≥0.7 MEq/mL (ETV-027)
-- Serum ALT 1.3-10 x ULN
-- Evidence of CHB on a liver-biopsy
-- Compensated liver function
Liver biopsies were required at baseline (≦52 weeks prior to randomization and week 48)
Liver biopsies were evaluated by a central, independent histopathologist who was unaware of patients' treatment assignment, biopsy sequence, and clinical outcome
ALT measurements were performed at local laboratories
Patients with adequate baseline biopsy results from studies ETV-022 (n=658) and ETV-027 (n=596) were included in the analysis regardless of treatment arm
Adequate baseline biopsies were those with >5 portal areas available (to assess inflammation) and ≥2cm (to assess fibrosis)
The analysis assessed baseline Knodell necroinflammatory and Ishak fibrosis scores at baseline by 3 ALT categories:
-- <2 x ULN
-- 2-5 x ULN
-- >5 x ULN
The relationship of HBV DNA and histology was not evaluated due to the study inclusion criteria which required an elevated HBV DNA


81% of biopsies were performed within 12 weeks of baseline




Among 658 nucleoside-naive, HBeAg(+) CHB patients in ETV-022:
-- 78% had a baseline Knodell necroinflammatory score of ≥7
-- 14% had a baseline Ishak fibrosis score of ≥4
Among 237 nucleoside-naive, HBeAg(+) CHB patients in ETV-022 with baseline ALT <2 x ULN:
-- 68% had a baseline Knodell necroinflammatory score of ≥7
-- 11% had a baseline Ishak fibrosis score of ≥4



Among 596 nucleoside-naive, HBeAg(-) CHB patients in ETV-027:
-- 80% had a baseline Knodell necroinflammatory score of ≥7
-- 18% had a baseline Ishak fibrosis score of ≥4
Among 214 nucleoside-naive, HBeAg(-) CHB patients in ETV-027 with baseline ALT <2 x ULN:
-- 75% had a baseline Knodell necroinflammatory score of ≥7
-- 17% had a baseline Ishak fibrosis score of ≥4
1. Pratt DS & Kaplan MM. N Engl J Med. 2000;342:1266-1271
2. Papatheodoris G, et al. Hepatology. 2006;44(S1):541A.Abstract 951
3. Kumar M, et al. J Hepatol. 2006;44(S1):676A.Abstract 1305
4. Wang C, et al. Hepatology. 2005;42(S1):573A. Abstract 961
5. Lai M, et al. Hepatology. 2005;42(S1):720A. Abstract 1322
6. Lok ASF and McMahon BJ. Hepatology 2007;45:507-539
7. The EASL Jury. J Hepatol. 2003; 39:S3-S25
8. Liaw YF, et al. Liver Int. 2005;25:472-489
9. Keefe EB, et al. Clinical Gastro and Hep. 2006, V4, p936-963
10. Chang TT, et al. N Eng J Med. 2006;354:1001-1010
11. Lai CL, et al. N Eng J Med. 2006;354:1010-1020