Incidence of CXCR4 tropism and CCR5-tropic resistance intreatment-experienced participants receiving maraviroc in the 48-week MOTIVATE 1and 2 trials

摘要

Maraviroc blocks HIV-1 entry into CD4+ cells by interrupting the interactionbetween viral gp120 and cell-surface CCR5. Resistance to CCR5antagonist–mediated inhibition can develop by unmasking pre-existing CXCR4-usingvirus or through selection of CCR5-tropic resistant virus, characterized byplateaus in maximum percent inhibition <95%. Here, we examine viral escape inmaraviroc-treated participants during virologic failure through Week 48 in theMOTIVATE 1 and 2 trials. Resistance was assessed relative to number of activedrugs in participants’ optimized background therapy, pharmacokinetic adherencemarkers, Baseline demographic data, HIV-1 RNA and CD4+ counts. For participantswith R5 virus confirmed ( ) at Screening, Baselinegenotypic weighted optimized background therapy susceptibility scores (gwOBTSS)were assigned where possible. Through Week 48, 219/392 (56%) participants withan assigned gwOBTSS achieved a virologic response. Of those remaining, 48/392(12%) had CXCR4-using virus; 58/392 (15%) had R5 virus (maraviroc sensitive:  = 35/392, 9%; maraviroc resistant:  = 18/392, 5%; undeterminable:  = 5/392, 1%)and 67/392 (17%) had no failure tropism result. When optimized backgroundtherapy provided limited support to maraviroc (gwOBTSS <2), 143/286 (50%)responded to therapy, while 76/106 (72%) participants with gwOBTSS ≥2 responded(  n = 10) were exclusivelymaraviroc sensitive; five of these participants had pharmacokinetic and/orpill-count markers of non-adherence. When co-administered with a fully activebackground regimen, maraviroc did not readily generate resistance in theclinical setting.