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Determination of Phenotypic Clinical Cutoffs
for Atazanavir and Atazanavir/Ritonavir
 EP
Coakley, C Chappey, JF Maa, S Wang, M Bates,
V Wirtz, D Seekins ViroLogic,
Inc, South San Francisco, CA, Bristol-Myers Squibb Virology, Plainsboro,
NJ
Atazanavir
(ATV)/ Reyataz)
400mg daily and atazanavir/ritonavir
/ATV/r
(ATV 300mg daily with ritonavir 100 mg daily) are widely used in
combination treatment of HIV-1. The PhenoSense
assay currently utilizes a biologic cutoff for ATV
at 2.3 fold change (FC). The current study seeks to define a phenotypic
clinical cutoff for ATV and ATV/r, above which virologic
response to therapy begins to decrease.
Data
from two clinical trials in subjects with prior PI failure, BMS
AI424-043 (ATV+2NRTIs) and AI424-045 (ATV/r+TDF+1NRTI), were included
for all subjects treated through Week 24 having baseline phenotype,
baseline viral load ≥400 copies/mL, and viral load at Weeks
12 and/or 24 (ATV n=131 and ATV/r n=111).
ATV
phenotyping
(PhenoSense) was performed at baseline and correlated
with virologic outcome within each study. Efficacy outcomes focused
on change in viral load from baseline and the proportion of subjects
with HIV-1 RNA levels <400 copies/mL at Week 24.
Logistic
regression and Fischer’s exact tests were used to identify the ATV and ATV/r FC cutoffs.
Results
· For
the 043 and 045 studies, the median baseline HIV-1 RNA value was
15,477 and 29,898 copies/mL, respectively, and the median (range)
baseline FC to ATV was 1.2 (0.4-90) and 1.2 (0.2-57), respectively.
· In
043, the proportion of subjects with HIV RNA <400 copies/mL at
24 weeks was relatively constant below 2.2-fold but was reduced
at higher FCs (p=0.001).
·
The
proportion with HIV RNA <400 copies/mL at 24 weeks with baseline
ATV FC <2.2 or ≥2.2 was 76% and 45%, respectively.
· In
045, the proportion of subjects with HIV RNA <400 copies/mL at
24 weeks was relatively constant below 5.2-fold but was reduced
at higher FCs (p<0.0001).
· The
proportions with HIV RNA <400 copies/mL at 24 weeks among those
with baseline ATV FC <5.2 or ≥5.2 was 77% and 12%, respectively.
In
conclusion, the authors write, “In these PI-experienced study populations,
the overall treatment responses to ATV and ATV/r were high. Optimum
responses to ATV were observed at FCs <2.2 in the 043 cohort
and to ATV/r at FCs <5.2 in the 045 cohort.
06/15/05
Reference
E
P Coakley and others. Determination of Phenotypic Clinical Cutoffs
for Atazanavir and Atazanavir/Ritonavir: AI424-043 and AI424-045.
Abstract 6 (oral). XIV International HIV Drug Resistance
Workshop: Basic Principles and Clinical Implications. June
7-11, 2005. Québec City, Québec, Canada.
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