title: Protease inhibitor resistance analysis in the MONARK trial comparing first-line lopinavir-ritonavir monotherapy to lopinavir-ritonavir plus zidovudine and lamivudine triple therapy.
abstract: The MONARK study was a pilot randomized trial comparing the safety and efficacy of lopinavir-ritonavir (LPV/r) monotherapy to those of LPV/r-zidovudine-lamivudine triple therapy for antiretroviral-naïve human immunodeficiency virus type 1 (HIV-1)-infected patients. Resistance testing was performed at the time of initial screening and at the time of virological failure (defined to include low-level viremia with >50 and <400 HIV-1 virus RNA copies/ml of plasma). Changes from the baseline sequences, including mutations noted on the 2008 International AIDS Society-USA list of resistance-associated protease mutations, were considered. Drug resistance testing was performed for 38 patients (5 of 53 on triple therapy and 33 of 83 on monotherapy). By week 96 (W96), virus samples from 18 of 33 patients in the monotherapy arm showed changes from baseline sequences, and 5 of these patients had viruses with major protease inhibitor (PI) resistance-associated mutations (M46I at W40, L76V at W48, M46I and L76V at W48, L10F and V82A at W72, and L76V at W84). Data on virus phenotypes detected at the time of initial screening and the time of virological failure were available for four patients in whom major PI resistance mutations developed, and these data revealed a mean increase of 2.2-fold (range, 0.75- to 4.6-fold) in the LPV 50% inhibitory concentration. All three patients in whom the L76V PI resistance mutation developed were infected with HIV-1 subtype CRF02_AG. In the triple-therapy group, no major PI resistance mutation was selected among the three patients with protease changes by W48. No association between the baseline CD4 cell count and the viral load, the W4 and final viral loads, or the final LPV trough concentration and the emergence of a major PI resistance mutation was found. Major PI resistance-associated mutations were detected in 5 (6%) of 83 patients treated with LPV/r monotherapy, suggesting that LPV/r monotherapy is an inappropriate first option. The mutation L76V may be considered in further studies of lopinavir resistance.
authors.affiliation: University Paris Descartes, EA 3620, Virology Department, Necker Hospital AP-HP, Paris, France. constance.delaugerre@sls.aphp.fr
authors.forename: Constance
authors.initials: C
authors.lastname: Delaugerre
authors.forename: Philippe
authors.initials: P
authors.lastname: Flandre
authors.forename: Marie Laure
authors.initials: ML
authors.lastname: Chaix
authors.forename: Jade
authors.initials: J
authors.lastname: Ghosn
authors.forename: François
authors.initials: F
authors.lastname: Raffi
authors.forename: Pierre
authors.initials: P
authors.lastname: Dellamonica
authors.forename: H
authors.initials: H
authors.lastname: Jaeger
authors.forename: D
authors.initials: D
authors.lastname: Shürmann
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cohen-Codar
authors.forename: Philippe Ngo
authors.initials: PN
authors.lastname: Van
authors.forename: Michael
authors.initials: M
authors.lastname: Norton
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Taburet
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Delfraissy
authors.forename: Christine
authors.initials: C
authors.lastname: Rouzioux
mesh_terms: D024882:Drug Resistance, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D061466:Lopinavir; D011744:Pyrimidinones / Q000627:therapeutic use*; D019438:Ritonavir / Q000627:therapeutic use*; D016896:Treatment Outcome; D015215:Zidovudine / Q000627:therapeutic use*
chemical_list: D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D019259:Lamivudine; D015215:Zidovudine; D019438:Ritonavir