title: Mutations in the protease gene associated with virological failure to lopinavir/ritonavir-containing regimens.
abstract: OBJECTIVE
  To assess the most frequent resistance-associated mutations (RAMs) to lopinavir/ritonavir in a cohort of patients attended in daily practice.
  
  
  METHODS
  We retrospectively identified 195 multitreated subjects with virological failure. Patients were classified as follows: (i) 71 (36.4%) never received lopinavir/ritonavir (lopinavir/ritonavir naive); (ii) 75 (38.5%) had previously failed on lopinavir/ritonavir; and (iii) 49 (25.1%) were on lopinavir/ritonavir at failure. RAM patterns were assessed. Medians, IQRs, percentages, Kruskal-Wallis, χ(2) or Fisher's exact test, and multinomial logistic regression were used whenever appropriate.
  
  
  RESULTS
  L10I/F, K20R, L24I, L33F, M36I, M46I/L, I47V, G48V, F53L, I54V, A71V, G73S, V82A, I84V and L90M (all with P ≤ 0.037) were protease RAMs overexpressed in patients with lopinavir/ritonavir failure. L10I, M36I, M46I, I54V, L63P, A71V, V82A, I84V and L90M were the most common in lopinavir/ritonavir-naive patients. Other IAS-USA RAMs for lopinavir/ritonavir (L10R/V, K20M, V32I, I47A, I50V, I54L/A/M/T/S, A71T, L76V and V82F/T/S) were not associated with previous or current failure to lopinavir/ritonavir. Lopinavir/ritonavir failure was associated with the number of protease RAMs (OR = 1.146, 95% CI = 1.287, 1.626), higher exposure to protease inhibitors, and the presence of E44D, L33F, I54V and I84V.
  
  
  CONCLUSIONS
  In multitreated patients with previous or current lopinavir/ritonavir failure, some protease mutations are selected at significantly greater rates. L10I, M36I, I54V, L63P, A71V, V82A and L90M were found in >50% of cases. Thus, their presence should be expected when genotypic testing results are not available. The number of protease RAMs and higher prior exposures to protease inhibitors were significantly associated with lopinavir/ritonavir failure.
authors.affiliation: Lluita contra la SIDA Foundation, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain. jrsantos@flsida.org
authors.forename: José R
authors.initials: JR
authors.lastname: Santos
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llibre
authors.forename: Arkaitz
authors.initials: A
authors.lastname: Imaz
authors.forename: Pere
authors.initials: P
authors.lastname: Domingo
authors.forename: José A
authors.initials: JA
authors.lastname: Iribarren
authors.forename: Ana
authors.initials: A
authors.lastname: Mariño
authors.forename: Celia
authors.initials: C
authors.lastname: Miralles
authors.forename: María J
authors.initials: MJ
authors.lastname: Galindo
authors.forename: Arelly
authors.initials: A
authors.lastname: Ornelas
authors.forename: Santiago
authors.initials: S
authors.lastname: Moreno
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schapiro
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000494:pharmacology; D015331:Cohort Studies; D005260:Female; D006678:HIV / Q000235:genetics / Q000302:isolation & purification*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D016333:HIV Protease / Q000235:genetics*; D006801:Humans; D061466:Lopinavir / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D020125:Mutation, Missense; D012189:Retrospective Studies; D019438:Ritonavir / Q000008:administration & dosage* / Q000494:pharmacology; D017211:Treatment Failure; D014481:United States
chemical_list: D019380:Anti-HIV Agents; D061466:Lopinavir; D016333:HIV Protease; D019438:Ritonavir