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Mutations Associated with Response to Boosted Tipranavir in HIV-1-infected PI-experienced Patients
A G Marcelin1, B Masquelier2, D Descamps3, J Izopet4, C Charpentier5, C Alloui6, G Peytavin3, M Lavignon7, P Flandre1, Vincent Calvez*1, and TPV ANRS study group
1Ctr Hosp Univ Pitie-Salpetriere, Paris, France; 2Ctr Hosp Univ Bordeaux, France; 3Ctr Hosp Univ Bichat, Paris, France; 4Ctr Hosp Univ Toulouse, France; 5Ctr Hosp Univ Georges Pompidou, Paris, France; 6Ctr Hosp Univ Avicennes, France; and 7Boehringer Ingelheim, France
Background: The aim of this study was to identify mutations
associated with virological response to tipranavir/ritonavir (TPV/r) -based
regimens in protease inhibitor (PI)-experienced patients.
Methods:
We analyzed 143 treatment-experienced
patients receiving a TPV/r-containing regimen. The virological response was
defined as at least 1 log10
of HIV RNA decrease from baseline or an HIV RNA <400 copies/mL at month 3. The
first step was to investigate the impact of each mutation in the protease gene
on the virological response to TPV/r regimen using Fisher’s exact test. Mutations
present in at least 10% of isolates and providing a p-value below 0.10 were retained for further analysis. A
step-by-step analysis was done using the Cochran-Armitage test that retains the
combination of mutations most strongly associated with the virological response.
Results: Among the 143 patients, median baseline HIV RNA
was 4.7 log10 copies/mL (range, 2.3 to 6) and
median CD4 was 115 cells/mm3 (range, 2 to 871). The median number of
major and minor International AIDS Society (IAS) mutations was 3 (range, 0 to
7) and 9 (range, 0 to 14), respectively. Overall, 55% of patients achieved a virological
response.
Mutations at 6 codons were associated with a lower
proportion of to TPV/r: E35D/G/K/N, M36I/L/V, Q58E, Q61D/E/G/H/N/R, H69I/K/N/Q/R/Y,
L89I/M/R/T/V, and 1 mutation with a higher proportion of virological
response to TPV/r: F53L/W/Y. The Cochran-Armitage procedure did not retain mutations
at codons 35 and 61 and led to select the following genotypic score: 36 – 53 +
58 + 69 + 89, as providing the strongest association with virological
response (p = 1.47x10–7). In the 7 patients with a genotypic
score of –1 (viruses with only mutation at codon 53), the percentage of
responders was 100% and it was 79% (n
= 33), 56% (n = 63), 33% (n = 24), 21% (n = 14), and 0% (n = 2) in
those with a genotypic score of 0, 1, 2, 3, and 4, respectively.
Conclusions: This
study identified a set of mutations associated with virological
response in
a TPV/r-based regimen. Most of these mutations were not previously described to
be associated with PI resistance suggesting that TPV has a unique resistance
profile that helps to explain its activity against viruses harboring classical PI-resistance
mutations.
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