TY - JOUR
T1 - Two different patterns of mutations are involved in the genotypic resistance score for atazanavir boosted versus unboosted by ritonavir in multiple failing patients
AU - Santoro, M. M.
AU - Bertoli, A.
AU - Lorenzini, P.
AU - Ceccherini-Silberstein, F.
AU - Gianotti, N.
AU - Mussini, C.
AU - Torti, C.
AU - Di Perri, G.
AU - Barbarini, G.
AU - Bini, T.
AU - Melzi, S.
AU - Caramello, P.
AU - Maserati, R.
AU - Narciso, P.
AU - Micheli, V.
AU - Antinori, A.
AU - Perno, C. F.
PY - 2009/6
Y1 - 2009/6
N2 - Objectives: : The protease inhibitor atazanavir (ATV) can be used either boosted by ritonavir (ATV300/r) or unboosted (ATV400). To date, however, genotypic resistance scores (GRSs) have been developed only for boosted-ATV. We have determined GRS associated with virologic response (VR) for both ATV300/r and ATV400 in highly pre-treated HIV-1 infected patients. Patients and Methods: : We analyzed the results of genotypic tests available 0-3 months before the initiation of an ATV-containing regimen in 159 patients with HIV-RNA ≤ 500 copies/ml (ATV300/r group: 74; ATV400 group: 85) who were enrolled in the CARe study through an Early Access Program. The impact of baseline protease mutations on VR (≤ 1 log10copies/ml HIV-RNA decrease at 12-24 weeks) was analyzed using Fisher's exact test. Mutated protease amino acid positions (MPP) with p <0.20 were retained for further analysis. The GRSs were determined by a step-by-step analysis using the χ2 test for trend. Results: : The GRSs for ATV300/r and ATV400 revealed differing sets of mutations. For ATV300/r, 12 MPPs (10C/I/V + 32I + 34Q + 46I/L + 53L + 54A/M/V + 82A/F/I/T + 84V + 90M - 15E/G/L/V - 69K/M/N/Q/R/T/Y - 72M/ T/V; p = 1.38 × 10 -9) were the most strongly associated with VR (VR: 100%, 78.3%, 83.3%, 75% and 0% of patients with a score of -2/-1, 0, 1, 2, and ≤ 3, respectively); the last three MPPs (I15/H69/I72) were associated with a better VR. For ATV400, nine MPPs (16E + 20I/M/R/T/V + 32I + 33F/I/V + 53L/Y + 64L/M/ V + 71I/T/V + 85V + 93L/M; p = 9.42 × 10-8) were most strongly associated with VR (VR: 83.3%, 66.7%, 5.9%, 0% of patients with 0, 1/2, 3, and ≤ 4 MPP, respectively). Differences between GRSs for ATV300/r and ATV400 may be due to different ATV drug levels (boosted vs unboosted), favoring different pathways of escape from antiviral pressure. Conclusions: : Both GRSs were independent predictors of response in a multivariable logistic regression model. Nevertheless, cross-validation of these GRSs on different patient databases is required before their implementation in clinical practice.
AB - Objectives: : The protease inhibitor atazanavir (ATV) can be used either boosted by ritonavir (ATV300/r) or unboosted (ATV400). To date, however, genotypic resistance scores (GRSs) have been developed only for boosted-ATV. We have determined GRS associated with virologic response (VR) for both ATV300/r and ATV400 in highly pre-treated HIV-1 infected patients. Patients and Methods: : We analyzed the results of genotypic tests available 0-3 months before the initiation of an ATV-containing regimen in 159 patients with HIV-RNA ≤ 500 copies/ml (ATV300/r group: 74; ATV400 group: 85) who were enrolled in the CARe study through an Early Access Program. The impact of baseline protease mutations on VR (≤ 1 log10copies/ml HIV-RNA decrease at 12-24 weeks) was analyzed using Fisher's exact test. Mutated protease amino acid positions (MPP) with p <0.20 were retained for further analysis. The GRSs were determined by a step-by-step analysis using the χ2 test for trend. Results: : The GRSs for ATV300/r and ATV400 revealed differing sets of mutations. For ATV300/r, 12 MPPs (10C/I/V + 32I + 34Q + 46I/L + 53L + 54A/M/V + 82A/F/I/T + 84V + 90M - 15E/G/L/V - 69K/M/N/Q/R/T/Y - 72M/ T/V; p = 1.38 × 10 -9) were the most strongly associated with VR (VR: 100%, 78.3%, 83.3%, 75% and 0% of patients with a score of -2/-1, 0, 1, 2, and ≤ 3, respectively); the last three MPPs (I15/H69/I72) were associated with a better VR. For ATV400, nine MPPs (16E + 20I/M/R/T/V + 32I + 33F/I/V + 53L/Y + 64L/M/ V + 71I/T/V + 85V + 93L/M; p = 9.42 × 10-8) were most strongly associated with VR (VR: 83.3%, 66.7%, 5.9%, 0% of patients with 0, 1/2, 3, and ≤ 4 MPP, respectively). Differences between GRSs for ATV300/r and ATV400 may be due to different ATV drug levels (boosted vs unboosted), favoring different pathways of escape from antiviral pressure. Conclusions: : Both GRSs were independent predictors of response in a multivariable logistic regression model. Nevertheless, cross-validation of these GRSs on different patient databases is required before their implementation in clinical practice.
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U2 - 10.1007/s15010-008-8065-4
DO - 10.1007/s15010-008-8065-4
M3 - Article
C2 - 19169632
AN - SCOPUS:67650224695
VL - 37
SP - 233
EP - 243
JO - Infection
JF - Infection
SN - 0300-8126
IS - 3
ER -