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Identification of new genotypic cut‐off levels to predict the efficacy of lopinavir/ritonavir and darunavir/ritonavir in the TITAN trial
Author(s) -
Hill A,
Marcelin AG,
Calvez V
Publication year - 2009
Publication title -
hiv medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 79
eISSN - 1468-1293
pISSN - 1464-2662
DOI - 10.1111/j.1468-1293.2009.00734.x
Subject(s) - darunavir , lopinavir , ritonavir , medicine , genotype , viral load , lopinavir/ritonavir , clinical endpoint , virology , clinical trial , human immunodeficiency virus (hiv) , genetics , biology , antiretroviral therapy , gene
Background Genotypic algorithms used to predict the clinical efficacy of lopinavir/ritonavir (LPV/r) have included a range of mutation lists and efficacy endpoints. Normally, HIV clinical trials are powered to detect a difference between treatment arms of 10–12% for the endpoint of viral load suppression <50 HIV‐1 RNA copies/mL. The TITAN trial evaluated LPV/r vs . darunavir/ritonavir (DRV/r) in treatment‐experienced patients with viral load >1000 copies/mL. This analysis aimed to re‐evaluate resistance algorithms for LPV/r in the TITAN trial. Methods Baseline genotype data were classified using seven genotypic resistance algorithms: International AIDS Society USA (IAS‐USA) LPV mutations (current cut‐off=6), Abbott 2007 mutation list (cut‐off=3), ANRS mutations (cut‐off=4), FDA mutations (cut‐off=3), Stanford, REGA and IAS‐USA major protease inhibitor (PI) mutations. Efficacy in the TITAN trial (HIV‐1 RNA <50 copies/mL at week 48) was correlated with the number of mutations from each list, to show the ‘efficacy advantage cut‐off level’: the number of mutations from each list associated with a difference in efficacy between treatment arms of at least 12%. Results Multivariate logistic regression analysis identified lower genotypic cut‐off levels than previously reported where there was at least 12% lower efficacy for LPV/r vs . DRV/r. These efficacy advantage cut‐off levels were: IAS‐USA LPV mutations, cut‐off=3; Abbott 2007, cut‐off=2; ANRS LPV, cut‐off=3; FDA LPV mutations, cut‐off=2; major IAS‐USA PI mutations, cut‐off=1; Stanford algorithm, cut‐off=low‐level LPV resistance; REGA algorithm, cut‐off=intermediate‐level LPV resistance. There were linear falls in HIV‐1 RNA suppression rates with rising mutation counts in the TITAN, French LPV ATU, BMS‐045 and RESIST trials. Conclusions The analysis identified more sensitive cut‐off levels for LPV genotypic algorithms, below those currently used.