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HBV DNA Decline & ALT Normalization Associated with Histologic Improvement
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Reported by Jules Levin
This study was reported in a poster (#530) at the 40th annual meeting of EASl in Paris April 2005.
"DECLINE IN SERUM HBV DNA AND ALT NORMALIZATION IS ASSOCIATED WITH HISTOLOGIC RESPONSE AMONG NUCLEOSIDE-NAIVE PATIENTS IN ENTECAVIR PHASE III TRIALS'
H.C. Thomas1, M.P. Manns2, R.G. Gish3, T.T. Chang4, C.L. Lai5, D. Shouval6, A.S. Lok7, D. Apelian8, L. Fernandes8, K. Klesczewski8, A. Cross8, R. Wilber8
1 Imperial College of Science, Technology and Medicine, St Mary's Hospital, London, UK
2 Medizinische Hochschule Hannover, Hannover, Germany
3 California Pacific Medical Center, San Francisco, CA, USA
4 National Cheng Kung University Hospital, Tainan, Taiwan
5 Queen Mary Hospital, Hong Kong, China
6 Hadassah Medical Organization, Hadassah University Hospital, Jerusalem, Israel
7 University of Michigan, Ann Arbor, MI, USA
8 Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, USA
STUDY OBJECTIVE
To explore the relationship between histological response & laboratory markers of liver inflammation (ALT) & HBV replication (HBV DNA) after 48 weeks of treatment in entecavir Phase III trials (HBeAg+ & HBeAg-). Entecavir was compared to lamivudine (3TC) in treatment for HBV.
KEY STUDY FINDINGS
In nucleoside-naive patients, significantly greater proportions of entecavir-treated patients than lamivudine (3TC)-treated patients achieved Histological Improvement, HBV DNA <400 copies/ml, and normalization of ALT. In HBeAg+ patients: HBV DNA <400 c/ml & ALT <1.0xULN are more likely to demonstrate Histological Improvement. In HbeAg- patients, those achieving ALT normalization are more likely to achieve Histological Improvement: HBV DNA may also apply to this patient group but the analysis had limitations preventing examining this.
Among HBeAg-positive patients, a higher percentage of patients in each treatment group demonstrated Histological Improvement when HBV DNA suppression was the greatest.
In each treatment group, a higher rate of histological response (HBeAg(+): ETV 79%, LVD 80%; HBeAg(-): ETV 79%, LVD 72%) was observed in patients with HBV DNA <1000 copies/ml at week 48 compared to those with HBV DNA >1000 copies/ml (HBeAg(+): ETV 68%, LVD 66%; HBeAg (-): ETV 75%, LVD 60%).
In HBeAg(-) patients, with both histological response & PCR data at week 48, most entecavir-treated patients (95%, 252/265) achieved HBV DNA <400 copies/ml, limiting comparisons to other HBV DNA srata.
More HBeAg(-) patients treated with lamivudine than with entecavir had HBV DNA >1000 copies/ml at week 48 and fewer experienced Histological Improvement.
In each treatment group, a higher rate of histological response (HBeAg(+): ETV 82%, LVD 82%; HBeAg(-): ETV 83%, LVD 74%) was observed in patients achieving ALT <=1.0xULN at week 48 compared to those in higher ALT strata (HBeAg(+): ETV 66%, LVD 54%; HBeAg(-): ETV 62%, LVD 59%).
BACKGROUND:
Liver histology is a principal endpoint in the evaluation of antiviral agents for the treatment of chronic hepatitis B (CHB). Liver biopsy is currently the definitive diagnostic measure for establishing the severity of liver damage. HBV replication has been implicated directly in the progression of liver disease. Improvement in liver histology has been correlated with reductions in serum HBV DNA & ALT levels, and models have been proposed using serum HBV DNA, ALT levels and other lab markers to predict liver inflammation & fibrosis. Contributions from large databases are needed to support the use of surrogate markers of liver damage in managing patients chronically infected with HBV.
Entecavir demonstrated superiority to lamivudine (3TC) for the treatment of chronic HBV in two phase III clinical trials involving:
--nucleoside-naive HBeAg-positive patients, Study ETV-022
--nucleoside-naive HBeAg-negative patients, Study ETV-027.
Methods: Exploratory analyses were conducted on data from two Phase III studies comparing ETV to lamivudine (LVD) in nucleoside-naive HBeAg(+) (ETV-022, n = 709) and HBeAg(_) (ETV-027, n = 638) patients. Histologic response was defined as a decrease of at least two points in the Knodell necroinflammatory score with no increase in the Knodell fibrosis score at Week 48. HBV DNA was measured with the Roche Amplicor PCRȘ assay. Secondary endpoints included proportion of patients with HBV DNA <400 copies/mL (Roche Amplicor) & ALT <=1.0xULN at week 48.
RESULTS
Entecavir was superior to lamivudine in nucleoside-naive HBeAg+ & HBeAg- patients for the primary endpoint of Histological Improvement &
Entecavir was superior to lamivudine for the proportions of patients with HBV DNA <400 copies/ml and for patients with ALT<=1.0xULN after 48 weeks of treatment.
In both studies, higher proportions of ETV than LVD patients achieved HBV DNA <400 copies/ml by PCR (ETV-022: ETV 69%, LVD 38%; ETV-027: ETV 91%, LVD 73%).
In ETV-022, a higher rate of histologic response (80%) was observed for ETV patients with HBV DNA <400 copies/ml compared to those in higher HBV DNA strata. A higher rate of patients taking ETV than LAM achieved ALT<=1.0xULN (68% vs 60%, p=0.02).
In ETV-027, among 207 ETV patients with both histologic response and PCR data at Week 48, 95% (197/207) achieved HBV DNA <400 copies/ml, precluding comparison with higher HBV DNA strata. A higher rate of patients taking ETV than LAM achieved the ALT endpoint (78% vs 71% (p<0.05).
For both studies, ETV patients achieving ALT < 1 _ ULN had higher rates of histologic improvement.
Author Conclusions:
ETV achieved high proportions of patients with HBV DNA <400 copies/ml and serum ALT < 1 _ ULN through 48 weeks. Patients achieving these endpoints also had high rates of histologic improvement compared to those in higher HBV DNA and ALT strata.
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