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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
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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.
AUTHOR CONCLUSIONS
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.
Introduction
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
OBJECTIVE
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.
Methods
Methodology
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
Analysis
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
References
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
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