title: Relationship between antiretroviral plasma concentration and emergence of HIV-1 resistance mutations at treatment failure.
abstract: OBJECTIVE
  The relationship between antiretroviral pharmacokinetic exposure and acquisition of human immunodeficency virus-1 (HIV-1) drug resistance mutations (DRM) is not fully understood. The aim of this study was to investigate whether antiretroviral plasma concentration could predict the emergence of DRM at treatment failure.
  
  
  METHODS
  The study cohort comprised retrospectively selected patients with failing antiretroviral regimens for whom a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) trough concentration measurement (TDM) had been obtained before failure, a genotypic resistance test (GRT1) had been performed before the TDM, and a genotypic resistance test (GRT2) had been performed at therapeutic failure. Drug levels were classified as undetectable/detectable or subtherapeutic/therapeutic according to limits of quantification of a high-performance liquid chromatography-ultraviolet assay or pre-defined efficacy thresholds, respectively. The number of DRM acquired at treatment failure was evaluated by comparing the results of the GRT2 and GRT1.
  
  
  RESULTS
  A total of ten and 57 failure episodes occurred among our patients on NNRTI-based and PI-based regimens, respectively, and included in the evaluation. PI concentration was subtherapeutic in 28.1% of patients, among which the levels were undetectable in 21.1%. Twenty-five (43.9%) patients acquired at least one new PI-DRM according to the GRT2. Patients with undetectable PI levels showed a lower emergence of PI-DRM (minor + major) than those with detectable levels (8.3 vs. 53.3%, p = 0.007). Multivariate analysis confirmed that undetectable PI levels were independent negative predictors of DRM selection. NNRTI measurements were subtherapeutic in 2/10 (20%) patients. NNRTI-DRM were acquired by all patients regardless of NNRTI levels.
  
  
  CONCLUSIONS
  A PI measurement showing undetectable drug levels prior to treatment failure predicted the lack of emergence of PI-DRM at failure. These results suggest that PI levels can help clinicians interpret the reasons for treatment failure and guide the type of interventions needed.
authors.affiliation: Institute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Largo F. Vito 1, 00168 Rome, Italy. massifab@alice.it
authors.forename: M
authors.initials: M
authors.lastname: Fabbiani
authors.forename: L
authors.initials: L
authors.lastname: Bracciale
authors.forename: E
authors.initials: E
authors.lastname: Ragazzoni
authors.forename: R
authors.initials: R
authors.lastname: Santangelo
authors.forename: P
authors.initials: P
authors.lastname: Cattani
authors.forename: S
authors.initials: S
authors.lastname: Di Giambenedetto
authors.forename: G
authors.initials: G
authors.lastname: Fadda
authors.forename: P
authors.initials: P
authors.lastname: Navarra
authors.forename: R
authors.initials: R
authors.lastname: Cauda
authors.forename: A
authors.initials: A
authors.lastname: De Luca
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D015331:Cohort Studies; D016903:Drug Monitoring / Q000379:methods*; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010949:Plasma / Q000737:chemistry / Q000821:virology; D011379:Prognosis; D012189:Retrospective Studies; D017211:Treatment Failure
chemical_list: D019380:Anti-HIV Agents