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The use of genotypic resistance
testing to meaningfully guide therapy in treatment-experienced patients
requires its interpretation in a clinically relevant context . With many
current protease inhibitor (PI) regimens, the presence of 1-2 key protease
mutations is associated with diminished response. ABT-378/r is a new
protease inhibitor that, by virtue of a high inhibitory quotient (IQ,
defined as the Ctrough/serum-adjusted EC50 ratio)
against wt HIV has shown activity in patients with multiple protease
mutations. Previous studies have identified 11 mutations (L10F/I/R/V,
K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V and
L90M) associated with changes in susceptibility to ABT-378. In order to
investigate the clinical significance of genotypic resistance testing with
ABT-378/r, we performed a cross-study analysis of the Week 24 response in
two Phase II studies of ABT-378/r plus an NNRTI and NRTIs in PI-experienced,
NNRTI-naïve patients, with respect to the number of the above mutations at
baseline (ABT-378 mutation score). Baseline genotype was determined by
population sequencing, and the association between the baseline ABT-378
mutation score and the binary response variable (HIV RNA > or <400
copies/mL) at Week 24 (dropouts as censored) was analyzed using Fisher’s
exact test and univariate logistic regression. The median (range) baseline
ABT-378 mutation score (n=116 patients) was 4 (0-10). Observed response
rates at Week 24 (n=109, dropouts as censored) for patients with 0-5, 6-7
and 8-10 baseline mutations were 70/77 (91%), 21/26 (81%) and 2/6 (33%)
(p=0.0015). Using the lower (conservative) 95% confidence limit of a
logistic regression model, the estimated probability of response at Week 24
was 50% or greater in subjects with baseline ABT-378 mutation scores of 7 or
less. These results suggest that clinically relevant resistance to
ABT-378/r, as used in these studies, can be estimated by the baseline
ABT-378 mutation score: the presence of 8 or more mutations may
substantially compromise response. The number of protease mutations, rather
than the presence of any single key mutation, is the best genotypic predictor of virologic response.
These results may be useful to guide the interpretation of genotypic resistance
testing with ABT-378/r.
Interpretation of Genotypic Resistance to ABT-378/Ritonavir (ABT-378/r)
in Protease Inhibitor Experienced Patients Using the ABT-378 Mutation Score
© 2000 Medical Advocates
for Social Justice
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