TY - JOUR
T1 - Study of genotypic and phenotypic HIV-1 dynamics of integrase mutations during raltegravir treatment
T2 - A refined analysis by ultra-deep 454 pyrosequencing
AU - Armenia, Daniele
AU - Vandenbroucke, Ina
AU - Fabeni, Lavinia
AU - Van Marck, Herwig
AU - Cento, Valeria
AU - D'Arrigo, Roberta
AU - Van Wesenbeeck, Liesbeth
AU - Scopelliti, Fernanda
AU - Micheli, Valeria
AU - Bruzzone, Bianca
AU - Lo Caputo, Sergio
AU - Aerssens, Jeroen
AU - Rizzardini, Giuliano
AU - Tozzi, Valerio
AU - Narciso, Pasquale
AU - Antinori, Andrea
AU - Stuyver, Lieven
AU - Perno, Carlo Federico
AU - Ceccherini-Silberstein, Francesca
PY - 2012/2/15
Y1 - 2012/2/15
N2 - Background.The dynamics of raltegravir-resistant variants and their impact on virologic response in 23 HIV-1-infected patients, who started a salvage raltegravir-containing regimen, were investigated.Methods.Integrase population sequencing and Ultra-Deep-454 Pyrosequencing (UDPS) were performed on plasma samples at baseline and at raltegravir failure. All integrase mutations detected at a frequency ≥1% were considered to be reliable for the UDPS analyses. Phylogenetic and phenotypic resistance analyses were also performed.Results.At baseline, primary resistance mutations were not detected by both population and UDPS genotypic assays; few secondary mutations (T97A-V151I-G163R) were rarely detected and did not show any statistically association either with virologic response at 24-weeks or with the development of resistant variants at failure. At UDPS, not all resistant variants appearing early during treatment evolved as major populations during failure; only specific resistance pathways (Y143R-Q148H/R-N155H) associated with an increased rate of fitness and phenotypic resistance were selected.Conclusions.Resistance to raltegravir in integrase strand transfer inhibitor-naive patients remains today a rare event, which might be changed by future extensive use of such drugs. In our study, pathways of resistance at failure were not predicted by baseline mutations, suggesting that evolution plus stochastic selection plays a major role in the appearance of integrase-resistance mutations, whereas fitness and resistance are dominant factors acting for the late selection of resistant quasispecies.
AB - Background.The dynamics of raltegravir-resistant variants and their impact on virologic response in 23 HIV-1-infected patients, who started a salvage raltegravir-containing regimen, were investigated.Methods.Integrase population sequencing and Ultra-Deep-454 Pyrosequencing (UDPS) were performed on plasma samples at baseline and at raltegravir failure. All integrase mutations detected at a frequency ≥1% were considered to be reliable for the UDPS analyses. Phylogenetic and phenotypic resistance analyses were also performed.Results.At baseline, primary resistance mutations were not detected by both population and UDPS genotypic assays; few secondary mutations (T97A-V151I-G163R) were rarely detected and did not show any statistically association either with virologic response at 24-weeks or with the development of resistant variants at failure. At UDPS, not all resistant variants appearing early during treatment evolved as major populations during failure; only specific resistance pathways (Y143R-Q148H/R-N155H) associated with an increased rate of fitness and phenotypic resistance were selected.Conclusions.Resistance to raltegravir in integrase strand transfer inhibitor-naive patients remains today a rare event, which might be changed by future extensive use of such drugs. In our study, pathways of resistance at failure were not predicted by baseline mutations, suggesting that evolution plus stochastic selection plays a major role in the appearance of integrase-resistance mutations, whereas fitness and resistance are dominant factors acting for the late selection of resistant quasispecies.
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U2 - 10.1093/infdis/jir821
DO - 10.1093/infdis/jir821
M3 - Article
C2 - 22238474
AN - SCOPUS:84856247092
VL - 205
SP - 557
EP - 567
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
SN - 0022-1899
IS - 4
ER -