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Genotypic Analysis of the Virological Response to Fosamprenavir/Ritonavir in Clinical Trials: Context and Triad
A G Marcelin1, P Flandre1, J M Molina2, C Katlama1, P Yéni3, F Raffi4, M Wirden1, Z Antoun5, M Ait Khaled6, Vincent Calvez*1, and CONTEXT and TRIAD study group
1Ctr Hosp Univ Pitie-Salpetriere, Paris, France; 2Ctr Hosp Univ St Louis, Paris, France; 3Ctr Hosp Univ Bichat, Paris, France; 4Ctr Hosp Univ Nantes, France; 5GlaxoSmithKline, France; and 6GlaxoSmithKline, UK
Background:
The aim of this study was
to identify mutations associated
with virological response to fosamprenavir/ritonavir (fAPV/r) (700/100 mg twice daily) in Context and Triad clinical trials.
Methods: We enrolled 113 protease inhibitor (PI) -experienced patients
in Context and Triad trials,
who received a fAPV/r (700/100-mg twice daily) -containing regimen, and analyzed their data. The virological response was defined
as the decrease in HIV RNA at
week 12. The ieffect of each mutation in the protease gene on the virological response to fAPV/r regimen was studied
in non-parametric univariate
analyses. Mutations with a p-value below 0.10 were
retained for further analysis. A step-by-step analysis was
done using a Jonckheere-Tepstra non-parametric test that retains the group of mutations most
strongly associated to the virological response.
Results: Overall, the median virological response was –1.86 [range; –3.59 to +1.08]
log copies/mL. The median number of major and minor Interanational AIDS Society (IAS) -listed mutations was 2 (range
0 to 5) and 5 (range 1 to 16), respectively. Mutations at 14 codons were associated with a reduced virological response to fAPV/r:
10, 15, 33, 46, 54, 60, 62, 63, 72, 73,
82, 84, 89, and 90. The Jonckheere-Tepstra procedure led to selecting the following genotypic set of mutations: I15V, M46I/L, I54L/M/V, D60E, L63P/T, and I84V,
as providing the strongest association with the virological response (p = 1.45x10–11). In the 9 patients with
0 mutation within this set, the median decrease in HIV RNA was –2.63 log
copies/mL and it was –2.22 (n = 45), –1.50 (n = 26), –0.58
(n = 23), –0.47 (n = 6), –0.13 (n = 3) and
+0.04 (n = 1) log copies/mL in those with 1, 2, 3, 4, 5, and 6 mutations,
respectively.
Conclusions: This study identified a set of mutations
associated to virological response to fAPV/r
in PI-experienced patients enrolled in Context and Triad clinical trials. Some
of these mutations were previously described to be associated with APV
resistance, such as mutations at positions 54 and 84.
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