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Adefovir Resistance report: 4 years update
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Reported by Jules Levin
"Incidence and predictors of emergence of HBV Muations Associated with ADV Resistance During 4 years of ADV Therapy for Patients with Chronic HBV"
S Locarnini1, X Qi, s Arterburn2, A Snow2, CL Brosgart2, G Currie2, M Wulfsohn2, MD Miller2, S Xiong2
1 VIDRL, Melbourne, Australia
2Gilead Sciences, Foster City, CA
Here is the data & information presented at EASL Paris 2005, April 13-17 in an oral session.
-SUMMARY by investigators:
---ADV resistance is delayed until the 2nd yr of therapy
---4 yr cumulative probability up to 18% in HBeAg-negative patients (438)
---All cases of resistance occurred in patients on ADV monotherapy
---Two signature ADV-resistance mutations identified
-N236T: susceptible to LAM in vitro and in vivo
-A181V: reduced susceptibility to LAM in vitro, and may be in vivo based on clinical data from 4 patients
---Serum HBV DNA level ³ 6 log at week 48 was associated the highest risk (67%) for subsequent development of ADV-R in HBeAg- patients
-3 to 6 log HBV DNA at wek 48 was associated with 26% risk; <3 log HBV DNA associated with 4% risk
-INTRODUCTION
---HBV resistance mutations have been reported in patients treated with lamivudine (LAM), adefovir (ADV), entecavir (ETV), emtricitabine (FTC), and telbivudine (L-dT)
---LAM is associated with a high incidence of resistance
-24% at 1 yr, 70% at 4 yrs
---Higher baseline HBV DNA, higher BMI, and male gender are predictive factors for LAM-R1
---previously reported ADV resistance is delayed
-0% at 1 yr, <10% at 3 yrs2
---Predictors for ADV resistance need to be evaluated
-STUDY OBJECTIVES
-To report the incidence of ADV resistance mutations to date after 192 weeks. To identify the predictors for emergence of AVR-resistance.
-RESISTANCE SURVEILLANCE POPULATION
-Patients included from 5 ADV clinical studies
-Wild-type HBV: patients received ADV monotherapy
---Study 437 (HBeAg+)
---Study 438 (HBeAg-)
---Study 412 extension (HBeAg+ or -)
-LAM-R HBV: ADV added to ongoing LAM
---Study 435 (pre- and post-liver transplantation)
---Study 460i (HIV/HBV co-infection)
-RESISTANCE SURVEILLANCE METHODS
-Genotypic analyses
---HBV DNA PCR+ samples from 5 major ADV trials
---Entire HBV RT sequenced
---PCR- samples were assumed to not have ADV-R
-Phenotypic analyses
---Conserved site mutations
---HBV lab strain (Wk 48) and patient HBV clones (beyond Wk 48)
---Correlation with serum HBV DNA rebound:
-Confirmed ³ 1 log increase from nadir by PCR assays
-Cumulative probability of resistance calculated by Life Table analysis
-ADV RESISTANCE MUTATIONS
-Two ADV-R mutations (N236T, A181V) identified in 22 patients over 4 yrs
-Four patterns of mutations observed
---15 N236T
- -- 4 A181V
- -- 2 A181V + N236T
- --1 A181T + N236T
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-CUMULATIVE PROBABILITY OF ADV RESISTANCE
-(Life Table analysis)
-HBeAg-negative, study 438: 18% Wk 192
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-RESISTANCE EMERGENCE with ADV MONOTHERAPY COMPARED TO COMBINATION THERAPY
-All 22 ADV-Resistant patients were on ADV monotherapy
---20 from ADV monotherapy trials
---2 from ADV+LAM trials but had stopped LAM
-No ADV resistance observed to date when ADV is added to on-going LAM
-No ADV resistance observed to date in treatment-naïve patients treated with ADV+FTC or ADV+LAM
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-SUSCEPTIBILITY TO LAMIVUDINE
-N236T
--- 2-fold reduced susceptibility to LAM in vitro
--- 5/8 patients added on or switched to LAM achieved undetectable HBV DNA by PCR within 1 yr
-A181V
--- 14-fold reduced susceptibility to LAM in vitro
--- 2 to 3 log reduction in serum HBV DNA after > 6 months of add-on LAM
-ANALYSIS of PREDICTORS for ADV RESISTANCE
-124 HBeAg- patients with 144 wks of ADV (Study 438)
---14 with ADV-R mutations by Wk 144
-Univariate tests and multiple logistic regression
-Factors analyzed
---Baseline HBV DNA, ALT, HBV genotype,
-knodell necro-inflamm. and Ishak fibrosis scores
---BMI, age, sex, race
---Prior LAM and IFN usage
---Dosing compliance
---Change in serum HBV DNA at Wks 4 and 12
---Serum HBV DNA level at Wk 48
-LAM+ADV combination therapy appears to lower the chance of developing ADV-resistance. Higher HBV DNA at week 48 during ADV therapy predicted emergence of ADV resistance, this was the only predictor identified by multiple logistic regression analysis.
-BASELINE PREDICTIVE FACTORS for ADV RESISTANCE at WEEK 144
-HBV DNA
-Bu Univariate Analysis Ishak Inflm Score, & Race were only predictors (p<0.05), but by mulitiple logistic regression analysis none of the parameters below were predictive.
-ALT
-HBV Genotype
-Knodell Inflam Score
-Ishak Fibrosis Score
-Body Mass Index
-Age
-Sex
-Race
-Prior LAM & IFN Usage
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