Relationship between antiretroviral plasma concentration and emergence of HIV-1 resistance mutations at treatment failure

PURPOSE: The relationship between antiretroviral pharmacokinetic exposure and\r\nacquisition of human immunodeficency virus-1 (HIV-1) drug resistance mutations\r\n(DRM) is not fully understood. The aim of this study was to investigate whether\r\nantiretroviral plasma concentration could predict the emergence of DRM at\r\ntreatment failure.\r\nMETHODS: The study cohort comprised retrospectively selected patients with\r\nfailing antiretroviral regimens for whom a protease inhibitor (PI) or\r\nnon-nucleoside reverse transcriptase inhibitor (NNRTI) trough concentration\r\nmeasurement (TDM) had been obtained before failure, a genotypic resistance test\r\n(GRT1) had been performed before the TDM, and a genotypic resistance test (GRT2) \r\nhad been performed at therapeutic failure. Drug levels were classified as\r\nundetectable/detectable or subtherapeutic/therapeutic according to limits of\r\nquantification of a high-performance liquid chromatography-ultraviolet assay or\r\npre-defined efficacy thresholds, respectively. The number of DRM acquired at\r\ntreatment failure was evaluated by comparing the results of the GRT2 and GRT1.\r\nRESULTS: A total of ten and 57 failure episodes occurred among our patients on\r\nNNRTI-based and PI-based regimens, respectively, and included in the evaluation. \r\nPI concentration was subtherapeutic in 28.1% of patients, among which the levels \r\nwere undetectable in 21.1%. Twenty-five (43.9%) patients acquired at least one\r\nnew PI-DRM according to the GRT2. Patients with undetectable PI levels showed a\r\nlower emergence of PI-DRM (minor + major) than those with detectable levels (8.3 \r\nvs. 53.3%, p = 0.007). Multivariate analysis confirmed that undetectable PI\r\nlevels were independent negative predictors of DRM selection. NNRTI measurements \r\nwere subtherapeutic in 2/10 (20%) patients. NNRTI-DRM were acquired by all\r\npatients regardless of NNRTI levels.\r\nCONCLUSIONS: A PI measurement showing undetectable drug levels prior to treatment\r\nfailure predicted the lack of emergence of PI-DRM at failure. These results\r\nsuggest that PI levels can help clinicians interpret the reasons for treatment\r\nfailure and guide the type of interventions needed.