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Selection
of the HIV-1 Reverse Transcriptase Mutation K70E in Antiretroviral-Naïve
Subjects Treated with Tenofovir/Abacavir/Lamivudine Therapy
L
Ross1, P Gerondelis1, Q Liao1,
B Wine1, M Lim1, M Shaefer1, A
Rodriguez2, J Gallant3, K Limoli4,
W Huang4, N Parkin4, R Lanier1
1GlaxoSmithKline, RTP, NC 27709, 2Univ of
Miami, Miami, FL, 3Johns Hopkins Univ, Baltimore, MD,
4ViroLogic, Inc., South San Francisco, CA
The high incidence
of virologic non-response observed with the treatment-naive subjects
of the ESS30009 tenofovir/abacavir/lamivudine
study arm has been associated with selection for K65R
and M184V reverse transcriptase (RT) coding changes (Gallant et
al, 43rd ICAAC, 2003, Abstract #H-840).
Here,
the identification of additional treatment-emergent coding changes
possibly representing alternative resistance pathways associated
with the observed non-response to this regimen is described.
Plasma
HIV drug susceptibility and population genotyping were performed
by ViroLogic. HIV clonal analysis was performed at GlaxoSmithKline.
Results
There were
81 subjects with both baseline and post-baseline (pre-therapy switch)
genotypes on the TDF arm. Available on-therapy time points with
genotype ranged from Weeks 4 through 30. The most commonly selected
IAS USA-defined NRTI mutations detected at any time point, by population
genotype, were M184I or V (78/81, 96%), K65R/K (43/81, 53%), and/or
Y115F/Y (9/81, 11%).
However, the
K70E mutation was also selected in plasma-derived virus from 8/81
subjects (10%) at time points between week 8 to week 20 (p<0.001).
At the time of mutation selection, all subjects were either experiencing
viral rebound or had never responded to therapy.
By population
genotype, the K70E mutation (all as K/E mixtures) was selected along
with M184I/V (8/8), K65R (7/8, all mixtures), and/or Y115Y/F (2/8).
No
subject on either arm (n=318) had detectable K70E at baseline. Clonal
analysis was done for one sample with a population genotype of K65K/R+K70K/E+Y115F+V118I+M184V
(V118I present at baseline). K70E (15/22, 68%) was never detected
on the same clones with K65R (6/22, 27%), while Y115F (21/22, 95%)
was selected with either mutation.
Conclusions
The K70E RT
mutation was selected in 10% of the antiretroviral-naive subjects
receiving ABC/3TC/TDF regimen with both baseline and post baseline
(pre-therapy switch) genotype. This mutation was also previously
reported to be selected in adefovir passage experiments and to be
associated with adefovir resistance, and/or with selection in heavily
antiretroviral-experienced subjects, it was also selected in one
treatment-naïve patient treated with TDF/3TC/EFV, and in one antiretroviral-experienced
subject treated with ABC/3TC/TDF/ddI.
These
data suggest an alternate pathway for tenofovir resistance,
while the clonal data suggests antagonism and exclusivity between
K65R and K70E at the genomic level.
06/17/04
Reference
L
Ross and others. Selection of the HIV-1 Reverse Transcriptase
Mutation K70E in Antiretroviral-Naïve Subjects Treated with Tenofovir/Abacavir/Lamivudine
Therapy. Abstract 92 (poster). XIV International HIV Drug Resistance
Workshop IC Report: Basic Principles and Clinical Implications.
June 7-11, 2005. Québec City, Québec, Canada.
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