恩替卡韦治疗E+停药后的24周跟踪(2005.5 DDW)

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Entecavir 24 Week Followup Off-Treatment in HBeAg+ “Entecavir Leads to Sustained Response Off-Treatment in Nucleoside-Naïve, HBeAg(+) Patients Who Met On-Treatment Response Endpoints at 48 Weeks of Therapy in Phase III Study ETV-022” Reported by Jules Levin Robert Gish presented this followup data & information at DDW’s HBV oral session. INTRODUCTION A primary goal of therapy for HBeAg+ chronic hepatitis B is to reduce HBV DNA to undetectable levels & promote loss of HBeAg & HBeAg seroconversion in order to promote the following: --ALT normalization --improvement in liver histology --reduce risk of liver disease progression (note from Jules Levin: a number of studies presented at EASL (April 2005) & at DDW show that reducing HBV DNA to <300 copies/ml & to sustain this appears to provide the best way to prevent liver disease progression to cirrhosis & liver cancer.) Entecavir (ETV) is a potent & selective inhibitor of HBV polymerase. ETV has demonstrated superiority to lamivudine (3TC), during 48 weeks treatment, in three Phase III clinical trials involving: --nucleoside-naïve HBeAg(+) patients: Study ETV-022 --nucleoside-naïve HBeAg(-) patients: Study ETV-027 --lamivudine (LAM) refractory HBeAg(+) patients: Study ETV-026 ETV has a clinical safety profile comparable to LAM. STUDY OBJECTIVE The objective of this analysis is to assess the 24-week off-treatment sustained response rates in HBeAg(+), nucleoside-naïve patients who achieved protocol defined complete response to ETV or LAM therapy by week 48. Patients received ETV 0.5 mg once daily (n=354) or LAM 100 mg once daily (n=355). Following is a picture of the Study design.

INCLUSION CRITERIA (ETV-022) >16 yrs old evidence of chronic hepatitis by liver biopsy during screening or within 52 weeks prior to randomization. HBeAg(+) <12 weeks prior nucleoside/nucleotide treatment. Last dose of any anti-HBV therapy >24 weeks prior to randomization. HBV DNA >=3 MEq/mL at screening. Serum ALT >=1.3xULN Compensated liver function No coinfection with HIV, HCV or HDV BASELINE DISEASE CHARACTERISTICS Mean HBV DNA by PCR: 9.62-9.69 log ALT (mean) IU/L: 140-146 Genotype A: 27%; B: 19-22%; C: 25-31%; D; 10-14%; F; 3-6% DEMOGRAPHICS Males: 75% Age: 35 yrs 40% Caucasian; 57% asian’ 3% other PROTOCOL DEFINED COMPLETE VIROLOGIC RESPONSE, patient cohort for this analysis: HBV DNA <0.7 MEq/mL by bDNA & loss of HBeAg at week 48. WEEK 48 ENDPOINT RESPONSE (HBV DNA <0.7 MEq/mL by bDNA & loss of HBeAg): 21% for ETV (n=74); 19% for LAM (n=67). VIROLOGIC ONLY RESPONSE HBV DNA <0.7 MEq/mL by bDNA but positive for HBeAg 70% for ETV, 46% LAM NON-RESPONSE HBV DNA >=0.7 MEq/mL by bDNA 5% for ETV 26% for LAM ENDPOINTS FOR THIS ANALYSIS Sustained response outcomes at 24 weeks off-treatment assessed as: --ALT normalization (ALT <1.25xULN) --response (HBV DNA <0.7 MEq/mL by bDNA & loss of HBeAg) --combined response & ALT normalization This included: percentage efficacy outcomes & Kaplan-Meier proportion of patients remaining in responder category. SUMMARY OF RESULTS at 24-WEEK OFF-TREATMENT FOLLOW-UP ALT NORMALIZATION (ALT<1.25xULN): 76% ETV 58% LAM RESPONSE (HBV DNA <0.7 MEq/mL & HBeAg loss): 82% ETV 73% LAM RESPONSE & ALT NORMALIZATION: 73% ETV n=74 57% LAM n=67 A POTENTIAL PREDICTOR of OFF-TREATMENT RELAPSE Among the 11 ETV patients who lost their response off-treatment: --8 were late responders (week 36 or later) --3 were early responders (week 24 or earlier) Among the 15 LAM patients who lost their response off-treatment: --8 were late responders (week 36 or later) --7 were early responders (week 24 or earlier) AUTHOR’s CONCLUSIONS: The sustained response with ETV was durable after only 48 weeks of treatment in the majority of patients (82%) who met the treatment response definition & was numerically greater than LAM. In addition: --patients treated with ETV who lost vresponse during off-treatment follow-up were more likely to achieve the protocol definition of response in later weeks of therapy. --This suggests that complete virologic response, defined as HBV DNA <0.7 MEq/mL & loss of HBeAg, may be a strong predictor of sustained off-treatment response to ETV.

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