TMC278, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), Active against Wild-Type and NNRTI-Resistant HIV-1

被引:241
作者
Azijn, Hilde [1 ]
Tirry, Ilse [1 ]
Vingerhoets, Johan [1 ]
de Bethune, Marie-Pierre [1 ]
Kraus, Guenter [1 ]
Boven, Katia [2 ]
Jochmans, Dirk [1 ]
Van Craenenbroeck, Elke [1 ]
Picchio, Gaston [2 ]
Rimsky, Laurence T. [1 ]
机构
[1] Tibotec BVBA, B-2800 Mechelen, Belgium
[2] Tibotec Inc, Yardley, PA USA
关键词
IMMUNODEFICIENCY-VIRUS TYPE-1; EXPERIENCED HIV-1-INFECTED PATIENTS; PLACEBO-CONTROLLED TRIAL; IN-VITRO; PHENOTYPIC RESISTANCE; ANTIVIRAL ACTIVITY; TMC125; ETRAVIRINE; CROSS-RESISTANCE; DOUBLE-BLIND; DRUG;
D O I
10.1128/AAC.00986-09
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz-and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
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收藏
页码:718 / 727
页数:10
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