602
In a Paired-sample Comparison, the Presence of Thymidine Analogue Mutations, but not Other Common Nucleoside Reverse Transcriptase Inhibitor Mutations Has a Differential Effect on Emtricitabine and Lamivudine Susceptibility
Lisa Ross*1, N Parkin2, M Underwood1, P Gerondelis1, M St Clair1, and R Lanier1
1GlaxoSmithKline, Research Triangle Park, NC, US and 2Monogram Biosci, South San Francisco, CA, US
Background: To better elucidate differences in
susceptibility between lamivudine (3TC) and emtricitabine (FTC), the phenotypic effect of
most commonly observed nucleoside reverse transcriptase inhibitor (NRTI)-resistance
associated mutations in the absence of the M184I or V mutations was examined
using patient samples with paired susceptibility results.
Methods: The Monogram BioScience database was queried
to identify HIV samples without M184I/V, but containing: K65R, L74I/V, Q151M, T69 insertions (thymidine analogue mutations [TAM]
allowed), 2 to 3 TAM
from 41/210/215, 2 to 3 TAM from 67/70/219, any 3 to 4 TAM, any 5 to 6 TAM (with and without
E44D/V118I), or K65R + Q151M. Only samples with both FTC and 3TC susceptibility results were included. The
mean fold change in resistance (MFC) and the percentage of isolates above assay
cutoff were determined for both drugs. Bonferroni’s multiple comparison test
was used to determine significant differences between groups.
Results: MFC to FTC and 3TC in the presence of the
M184I/V mutation only was always above the maximum measurable level. The MFC
and percentage of samples over cutoff for the other mutations are presented
below. For the non-TAM NRTI mutations groups, there was no differential impact
in susceptibility. For all TAM-containing groups, there were significant
differences in each grouping, with MFC consistently higher for FTC than 3TC and
with a >2-fold difference in susceptibility seen for several TAM groups.
|
|
n
|
FTC
|
3TC
|
p
value
|
|
Mutation Group
|
|
MFC
|
% over
cutoff
|
MFC
|
% over
cutoff
|
|
|
65R only
|
135
|
7.0
|
93.3%
|
8.3
|
96.3%
|
p >0.05
|
|
T69ins (TAM allowed)
|
61
|
21.7
|
85.2%
|
10.2
|
67.2%
|
p <0.001
|
|
L74IV
|
23
|
1.5
|
4.3%
|
1.7
|
4.3%
|
p >0.05
|
|
Q151M
|
6
|
3.1
|
16.7%
|
2.5
|
16.7%
|
p >0.05
|
|
K65R+Q151M
|
5
|
81.1
|
100%
|
33.2
|
100%
|
p >0.05
|
|
2 or 3 TAM from 41/210/215
|
419
|
2.5
|
13.8%
|
2.1
|
5.5%
|
p <0.01
|
|
2 or 3 TAM from 67/70/219
|
173
|
4.1
|
23.7%
|
3.2
|
8.7%
|
p <0.001
|
|
any 3-4 TAM
|
544
|
4.9
|
53.7%
|
3.6
|
34.7%
|
p <0.001
|
|
any 5-6 TAM + 44D/118I
|
36
|
10.3
|
97.2.%
|
6.7
|
94.4%
|
p <0.001
|
|
any 5-6 TAM, no 44D/118I
|
42
|
7.1
|
95.2%
|
4.5
|
66.7%
|
p <0.001
|
Conclusions: Using paired results from patient samples in
the absence of M184I/V, significantly higher levels of resistance were seen for
FTC than for 3TC in the presence of TAM, while for other common NRTI-resistance
mutations that did not include TAM, there was no difference in susceptibility.
|
