Mutations in the protease gene associated with virological failure to lopinavir/ritonavir-containing regimens

José R. Santos, Josep M. Llibre, Arkaitz Imaz, Pere Domingo, José A. Iribarren, Ana Mariño, Celia Miralles, María J. Galindo, Arelly Ornelas, Santiago Moreno, Jonathan M. Schapiro, Bonaventura Clotet, Piedad Arazo, Manel Crespo, Gracia Mateo, Miguel A. del Pozo, Teresa Puig, Melcior Riera

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4 Citations (Scopus)

Abstract

Objectives: 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 IASUSA 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.
Original languageEnglish
Article numberdks080
Pages (from-to)1462-1469
JournalJournal of Antimicrobial Chemotherapy
Volume67
Issue number6
DOIs
Publication statusPublished - 1 Jun 2012

Keywords

  • Genotypic resistance tests
  • Resistance-associated mutations
  • Salvage therapy

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