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Adefovir HBV Resistance Update
INCIDENCE AND PREDICTORS OF EMERGENCE OF ADEFOVIR RESISTANT HBV DURING FOUR YEARS OF ADEFOVIR DIPIVOXIL (ADV) THERAPY FOR PATIENTS WITH CHRONIC HEPATITIS B (CHB)
S. Locarnini1, X. Qi2, S. Arterburn2, A. Snow2, C.L. Brosgart2, G. Currie2, M. Wulfsohn2, M.D. Miller2, S. Xiong2
1 VIDRL, Melbourne, Australia
2 Gilead Science, Inc., Foster City, CA, USA
Background: Lamivudine-resistant (LAM-R) HBV emerged in 70% of CHB patients by 4 years of LAM therapy. Higher baseline HBV DNA, higher body mass index (BMI), and male were predictors for developing LAM-R (Lai_JID_2003;36:687).
Aims: To determine the incidence of ADV resistance (ADV-R) mutations after 192 weeks of ADV therapy and the predictors for ADV-R.
Methods: This analysis included 629, 293, 221, and 67 patients who received ADV through 48, 96, 144, and 192 weeks, respectively, from 5 studies. At baseline, patients had wild-type or LAM-R HBV. The majority of patients received ADV monotherapy. Most patients with LAM-R HBV received 3 years of ADV+LAM. ADV-R mutations were identified by sequencing HBV RT. The cumulative probability (CP) of ADV-R was calculated using the Life Table method. Logistic regression was used to identify predictors of ADV-R.
Results: 22 patients developed ADV-R mutations (N236T and/or A181V) by 4 years. The incidence per period was 0% (0/629) for 0-48 weeks, 2% (6/293) for 49-96 weeks, 5% (11/217) for 97-144 weeks, and 8% (5/62) for 145-192 weeks. The CP for developing ADV-R by week 192 was 15% for all patients (18% for patients in ADV monotherapy trials). No ADV-R mutations were identified in patients on LAM+ADV. The N236T mutation was observed 4 times more frequently than A181V. Dual mutations A181V(/T)+N236T were observed in 4 (18%) patients. Development of ADV-R mutations was associated with serum HBV DNA rebound (≥1 log) in most patients. Logistic regression analyses of baseline HBV DNA, ALT, race, age, gender, BMI, liver histology, prior HBV therapy, and week 48 HBV DNA identified only higher serum HBV DNA at week 48 (median 4.2 log with ADV-R vs. 3 log without ADV-R) as a predictor of ADV-R.
Conclusions: The cumulative probability of developing adefovir resistance was 15% by 192 weeks of ADV therapy in CHB patients. LAM+ADV combination therapy appears to lower the chance of developing ADV-R. Higher HBV DNA at week 48 during ADV therapy predicted emergence of ADV resistance. The chance of developing resistance was over 4-fold lower with ADV monotherapy compared to that reported for LAM monotherapy by 4 years. | 
发表于 2005-4-17 07:22
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