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Entecavir Resistance 3-Year Update at AASLD
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Reported by Jules Levin
AASLD, Oct 27-31, 2006. Boston, MA
"Assessment At Three Years Shows High Barrier To Resistance Is Maintained In Entecavir-treated Nucleoside Naive Patients While Resistance Emergence Increases Over Time In Lamivudine Refractory Patients"
R. Colonno, R. Rose, K. Pokornowski, C. Baldick, B. Eggers, J. Yang and D. Tenney (Clin Dev: R. Wilber, H. Brett-Smith, R Hindes & A Cross)
Bristol-Myers Squibb Pharmaceutical Research Institute
Rich Colonno from BMS presented a talk on resistance including the 3 year update on entecavir resistance in the Hepatitis B Oral session at AASLD yesterday. His talk followed a 3 year update on the entecavir study 022, which was one of the pivotal studies.
LVD Refractory Patients
29 rebounds due to ETVr substitutions over 3 years of ETV therapy
All had LVDr substitutions M204V + L180M
Frequency of ETVr substitutions:
- T184 (n=9)
- S202 (n=11)
- T184 + S202 (n=6)
- S202 + M250 (n=1)
- T184 + M250 (n=1)
- T184 + S202 + M250 (n=1)
ETVr detected (=0.1%) at baseline in 10 (34%) patients
Median ETV susceptibility decreased 15-fold from baseline and 212-fold from WT virus
ETVr isolates remain susceptible to adefovir
Patients Exhibiting Virologic Rebounds
Nucleoside Naive Patients
Studies 022, 027, & 901
Year 1 treated: 673 (patients with on treatment HBV DNA
determination)
Year 1 virologic rebounds: 14
w/Genotypic ETV resistance: 1 (0.1%) (lam-r at time of study entry)
Year 2 treated: 310
Year 2 virologic rebounds: 8
w/genotypic ETV resistance: 0 (0%)
Year 3 treated: 152
Year 3 virologic rebounds: 2
w/genotypic ETV resistance: 1 (0.7%)
total: 24
ETV resistance = LVD-r + T184, S202 and/or M250 substitutions
Virologic Profiles of Rebounds
Nucleoside Naive Patients
No evidence of LVDr or ETVr substitutions
- 3/19 confirmed
- Only 2 had single emerging changes (V23A & V341I)
- All had WT ETV susceptibility at the time of rebound
2 LVDr substitutions detected at baseline, patients
subsequently became PCR undetectable on 1 mg ETV
1 Patient with an emerging LVDr variant not detectable
(=0.1%) at study entry
- Unconfirmed rebound at Wk 53 = End of Dosing
- Simultaneous appearance of Q1E, D7A, L80I/V, R110G, V115M, S117P, Y135H, N139K M204I, L229V & C256G substitutions
- Variant likely pre-existed at low concentration
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