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Entecavir Resistance in Lamivudine Resistant Patients
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Reported by Jules Levin
"ABSENCE OF ENTECAVIR RESISTANCE EMERGENCE IN LAMIVUDINE-REFRACTORY PATIENTS TREATED FOR AT LEAST ONE YEAR WITH ENTECAVIR IN STUDY AI463-014"
Rich Colonno (Bristol Myers Squibb) reported on this study at the EASL Conference (April 14-18, 2004, Berlin, Germany). Here is Colonno's report at EASL.
Entecavir (ETV) is a highly potent and HBV-selective inhibitor of hepatitis B virus (HBV) currently in Phase III development.
ETV inhibits all three activities of HBV polymerase: priming; reverse transcriptase; and DNA synthesis.
ETV showed superior HBV DNA reduction vs Lamivudine (LVD) in phase II nucleoside-naïve trials.
Clinical safety profile is comparable to Lamivudine (LVD).
PRE-CLINICAL ETV RESISTANCE PROFILE
In Vitro Studies:
--HBV Pol with LVD-R substitutions (L180M+M204V) displays about 100 fold decreased susceptibility to ETV-TP.
--LVD virus displays about 20 fold decreased susceptibility to ETV.
--Intracellular ETV-TP levels at 1 mg dose exceed those needed to cover LVD-Resistant virus.
--Adefovir (ADV) (N236T) HBV pol and virus are fully susceptible to ETV-TP and ETV, respectively.
WOODCHUCKS:
--LVD-R strains emerged after 6 months of treatment
--No resistance evident during 14 to 36 months ETV treatment period, despite use of once weekly dosing: no viral rebound on ETV treatment; no evidence of any genotypic changes within recovered pol gene.
PATIENT "A" & "B" SUMMARY
Two extensively pre-treated patients with LVD-resistant HBV exhibited viral rebound after prolonged ETV or ETV/LVD therapy.
HBV pol substitutions emerged on ETV treatment:
--patient A: I169T and M250V (133 week of ETV)
--patient B: I169T, T184G, and S202I (76 week of ETV)
Viruses with these substitutions in the absence of LVD-R substitutions remained susceptible to ETV.
Combination M250V or T184G/S202I with LVD-R changes (L180M/M204V) required for reduced ETV susceptibility.
Both isolates growth impaired and remained LVD-Resistant and adefovir susceptible.
MONITORING FOR ETV RESISTANCE IN CLINICAL STUDIES
Study AI1463-014
Dose Ranging Study in Patients with
LVD-Refractory HBV
MEAN CHANGE IN SERUM HBV DNA in LVD-Refractory Patients
All three doses of ETV (1.0, 0.5 and 0.1 mg) showed superiority to continued LVD in reducing HBV DNA over 48 wk in Phase II Study AI463-014
Week 24:
100mg LVD, n=47: 0.9 log
0.1mg ETV, n=47: -1.8 log
0.5mg ETV, n=42: -3.7 log
1.0 mg ETV, n=45: -4.2 log
Week 52:
100mg LVD, n=47: -1.4 log
0.1mg ETV, n=47: -2.8 log
0.5mg ETV, n=42: -4.4 log
1.0mg ETV, n=45: -5.0 log
LVD RESISTANCE IN PATIENT ISOLATES
Patients isolates were monitored for ETV resistance by genotypic analysis of RT sequences amplified from serum HBV samples.
At study entry, 132 (87%) of 181 patients treated had isolates that harbored Lamivudine resistant substitutions L180M and M204V/I.
Subsequent genotypic analysis of patient HBV isolates showed no apparent correlation between virologic response on ETV and either LVD-resistant or novel HBV RT substitutions.
Analysis of HBV isolates with paired baseline and on treatment samples showed that most patients with Lamivudine resistant HBV at study entry retained their Lamivudine-R genotypes over 48 wk, 80% of isolates retained same genotype over 48 week treatment period.
Colonno reported there was no evidence of resistance in patients experiencing a viral rebound on ETV; no evidence of ETV selection of Lamivudine resistant substitutions, regardless of the treatment arm, with a small proportion of isolates showing shifts among their Lamivudine resistance substitutions.
A small number of substitutions at conserved residues did emerge on ETV therapy, but none were correlated with virologic rebounds or reduced susceptibility to ETV.
There was no apparent correlation between these observed changes and ETV dose level.
Comparison of 132 paired isolates (108 ETV and 24 LVD) showed no significant difference in the number of other RT substitutions, either in naturally polymorphic positions or in highly conserved residues. No conserved or ploymorphic change observed in greater than 2% of ETV treated isolates.
Colonno reported that there is a low incidence of Entecavir resistance using the 1.0 mg dose of Entecavir compared to lower Entecavir doses examined in LVD experienced patients. After two years on 1.0 mg ETV dose 2 patient isolates exhibited ETV resistance mutations (evidence of change at residues 184, 202, and/or 250). Over course of 3 years in study 13 patients showed genotypic Entecavir resistance and 4 did not experience a viral rebound: all except 2 of these patients received lower ETV dose of 0.1 mg or 0.5 mg.
Colonno also says (1) resistance to ETV has only been observed in patients withLVD resistant virus, 2) ETV resistance appears very infrequently and requires prolonged treatment periods and 3) ETV resistance requires LVD resistant mutations plus 1 or 2 other changes to achieve ETV phenotypic resistance.
Colonno summarized:
--87% of patient isolates had Lamivudine resistance substitutions at study entry.
--80% of patient isolates retained baseline Lamivudine resistant substitutions, regardless of treatment arm or viral load reduction.
--Entecavir doses (0.5 and 1 mg) produced substantial reductions in viral load independent of emergence of Lamivudine resistance or other substitutions.
--Entecavir treatment of patients infected with Lamivudine resistant HBV resulted in unremarkable genotypic consequences by week 48.
--There is growing evidence that substitutions at residues 184, 202, and 250 represent potential signature resistance mutationsfor entecavir.
--Despite the presence of compromising Lamivudine resistant mutations, Entecavir resistance emergence was infrequently observed during >1 year therapy.
--1.0 mg Entecavir dose demonstrates the greatest efficacy and barrier to resistance in Lamivudine refractory population.
--Extensive resistance monitoring of Phase III patient isolates (>500) are in progress.
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