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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 (CHB) in Entecavir Studies ETV-022 (HBeAg+) and ETV-027 (HBeAg-)
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Reported by Jules Levin
DDW, May 22, 2007, Wash DC
Norah Terrault1, Ray Kim2, Seng-Gee Lim3, George Papatheodoridis4, Alfrddo Albert5, Man-Fung Yuen6, Zachary Goodman7, James Vaughan8, Richard Wilber8, Bruce Kreter8
1Gastroenterology Dept, UCSF, SF, CA, USA; 2Mayo Clinic Med Center, Rochester, MN, USA; 3Natl University of Singapore, Singapore; 4Academic Dept of Med, Hippokration General Hospital, Athens, Greece; 5Dept of Clinical and Experimental Med, University of Padova, Italy; 6Queen Maty Hospital, PokFu Lam, Hong Kong, China; 7Dept of Hepatic & Gastrointestinal Pathology, Armed Forces Institute of Pathology, Wash DC, USA; 8 Bristol-Myers Squibb Co, Wallingford, CT, and Princeton, NJ, USA
STUDY OBJECTIVES
To assess the relationship between histology and baseline ALT in nucleoside-naive, HBeAg(+) and HBeAg(-) CHB patients enrolled in the entecavir Phase III studies (022 & 027 baseline ALT and Histology)
To determine the proportion of patients with ALT <2 x ULN with significant necroinflammation (Knodellscore ≥7) and fibrosis (Ishakscore ≥4)
-Using new AASLD guidelines for elevated ULN of ALT
-30 IU/L for men; 19 IU/L for women
SUMMARY SLIDE
Percent of Patients with Chronic Hepatitis B with Signifucant Liver Disease and ALT <2 x ULN in Enectavir studies ETV-022 (HBeAg+) and ETV-027 (HBeAg-). *presented at EASL 2007; **updated at DDW with revised AASLD guidelines for ALT cut-offs: <30 IU/L males, <19 IU/L females. A significant portion of patients had ALT <2 x ULN but elevated necroinflammatory score >/=7, Fibrosis Score >/=4.
AUTHOR CONCLUSIONS
In nucleoside-naive HBeAg(+) and HBeAg(-) patients with compensated CHB:
-- Up to 71% of patients with elevated HBV DNA had clinically significant necroinflammation (Knodell Necroinflammatory ≥7) even when ALT is <2 x ULN using revised ALT thresholds
-- Up to 13% of patients have advanced fibrosis even when ALT is <2 x ULN using the revised ALT thresholds
These findings underscore the value of liver biopsy in patients with ALT <2 x ULN to identify patients in need of treatment, regardless of cut-off value used for ULN
Prior Analysis of ALT Versus Histology Using Lab ULN for ALT
(presented at EASL 2007)
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 ≥7) even when ALT is <2 x ULN:
-- HBeAg(+): 68% have Knodell Necroinflammatory score ≥7
-- HBeAg(-): 75% have KnodellNecroinflammatoryscore ≥7
Up to 17% of patients had advanced fibrosis even when ALT was <2 x ULN:
-- HBeAg(+): 11% have IshakFibrosis score ≥4
-- HBeAg(-): 17% have IshakFibrosis score ≥4
METHODS
Post-hoc analysis of Phase III studies ETV-022 (HBeAg[+]) and ETV-027 (HBeAg[-]) comparing the safety and efficacy of entecavir0.5 mg once daily (QD) with lamivudine100 mg QD in nucleoside-naive CHB patients1,2
Selected criteria for study entry:
-- Elevated HBV DNA levels by bDNAassay
≥3 MEq/mL(ETV-022) or ≥0.7 MEq/mL(ETV-027)
-- Serum ALT 1.3-10 x ULN (single measurement)
-- Evidence of CHB on a liver biopsy
-- Compensated liver function
1. Chang TT, Gish RG, de Man R, et al N Eng J Med. 2006;354:1001-1010
2. Lai CL, Shouval D, Lok ASF, et al. N Eng J Med. 2006;354:1010-1020
Liver biopsies were required at baseline (≦52 weeks prior to randomization) and at treatment week 48
Liver biopsies were evaluated by a central, independent histopathologistwho 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 regardless of treatment assignment
Adequate baseline biopsies were those with >5 portal areas available (to assess inflammation) and length ≥2 cm (to assess fibrosis)
The analysis assessed Knodell necroinflammatory and Ishak fibrosis score at baseline by 3 ALT categories:
-- <2 x ULN
-- 2-5 x ULN
-- >5 x ULN
The relationship between HBV DNA and histology was not evaluated because the study inclusion criteria required an elevated HBV DNA
Baseline Characteristics of HBeAg+ Patients According to Revised Baseline ALT Categorization (ETV-022)
HBV DNA mean 9.2 to 9.7 log10 copies/ml
Distribution of Baseline Knodell Necroinflammatory Score and ALT in Nucleoside-Naive HBeAg+ Patients
This graph shows how many patients in study ETV-22 (n=658; patients with adequate baseline biopsy and using new AASLD ALT cut-off category guidelines) had Knodell Necroinflammatory Score >/=7 in each ALT category (n=515) including patients with ALT <2 x ULN.
Distribution of Baseline Ishak Fibrosis and ALT in Nucleoside-Naive HBeAg+ Patients
This graph shows how many patients had Ishak Fibrosis Score >/=4 (n=92) in each ALT category.
Frequency of Knodell Necroinflammatory Score >/=7 and Ishak Fibrosis >/=4 by Revised ALT Categories in Nucleoside-Naive HBeAg+ Patients
This slide summarizes the data from ETV-022. Of note, a significant portion of patients had low ALT (<2 x ULN) but also had fibrosis and necroinflammation. Of the 69 patients with ALT <2 x ULN, 65% (n=45) had Knodell NI Score >/=7, and 13% (n=9) had Ishak Fibrosis Score IF>/=4. Of the 337 patients with ALT 2-5 x ULN, 70% (n=235) had Knodell NI Score >/=7 and 10% (n=34) had Fibrosis Score >/=4. Of the 252 patients with ALT >5 x ULN, 93% (n=235) had Knodell NI Score >/=7, and 19% (n=49) had Fibrosis Score >/=4.
Baseline Characteristics of HBeAg(-) Patients According to Revised Baseline ALT Categorization (ETV-027)
Baseline mean HBV DNA was 6.4 log c/ml in patients with <2 x ULN, 7.5 log c/ml in patients with 2-5 x ULN ALT, and 8.2 log c/ml in patients with >5 x ULN ALT.
Frequency of Knodell Necroinflammatory Score >/=7 and Ishak Fibrosis >/=4 by Revised ALT Categories in Nucleoside-Naive HBeAg(-) Patients
This is the summary slide of the data from ETV-027. Again, a significant portion of patients had <2 x ULN ALT but an elevated Knodell Necroinflammatory Score and Ishak Fibrosis Score. Of the 72 patients with <2 x ULN ALT, 51 (71%) had Knodell NI Score >/=7 and 6 (8%) had Ishak Fibrosis Score >/=4. Of the 298 patients with ALT 2-5 x ULN, 79% (n=236) had Knodell NI Score >/=7 and 19% (n=58) had Ishak Fibrosis Score >/=4. Of the 226 patients with ALT >5 x ULN, 80% (n=476) had >/=7 on the Knodell NI Score and 18% (n=108) had an Ishak Fibrosis Score >/=4.
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