Failure of Treatment with First-Line Lopinavir Boosted with Ritonavir Can Be Explained by Novel Resistance Pathways with Protease Mutation 76V

• Published in: The Journal of infectious diseases Vol. 200; no. 5; pp. 698 - 709
• Main Authors: Nijhuis, Monique, Wensing, Annemarie M. J., Bierman, Wouter F. W., de Jong, Dorien, Kagan, Ron, Fun, Axel, Jaspers, Christian A. J. J., Schurink, Karin A. M., van Agtmael, Michael A., Boucher, Charles A. B.
• Format: Journal Article
• Language: English
• Published: Oxford The University of Chicago Press 01-09-2009; University of Chicago Press; Oxford University Press
• Subjects: Amino Acid Sequence; Amino Acid Substitution - genetics; Anti-HIV Agents - pharmacology; Anti-HIV Agents - therapeutic use; Antivirals; Biological and medical sciences; DNA Mutational Analysis; Drug resistance; Drug Resistance, Viral; Fundamental and applied biological sciences. Psychology; gag Gene Products, Human Immunodeficiency Virus - genetics; Genetic mutation; HIV; HIV - drug effects; HIV - genetics; HIV 1; HIV Infections - drug therapy; HIV Protease - genetics; HIV/AIDS; Human immunodeficiency virus; Humans; Infectious diseases; Longitudinal Studies; Lopinavir; Medical sciences; Memory interference; Microbiology; Molecular Sequence Data; Mutation, Missense; Phylogeny; Protease inhibitors; Pyrimidinones - pharmacology; Pyrimidinones - therapeutic use; Ritonavir - pharmacology; Ritonavir - therapeutic use; Sequence Analysis, DNA; Sequence Homology; Treatment Failure; Virology; Virus Replication - drug effects; Viruses; Antiretroviral agent; Microbiology; Enzyme; Ritonavir; Lopinavir; Enzyme inhibitor; Infection; Resistance; Peptidases; Treatment; Hydrolases; Antiviral; Mutation; Protease inhibitor; Failure
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/605329

BackgroundVirological failure of first-line antiretroviral therapy based on lopinavir boosted with ritonavir (lopinavir/r) has rarely been associated with resistance in protease. We identified a new genotypic resistance pathway in 3 patients who experienced failure of first-line lopinavir/r treatment MethodsViral protease and the C-term part of Gag were sequenced. The observed mutations were introduced in a reference strain to investigate impact on protease inhibitor susceptibility and replication capacity ResultsA detailed longitudinal analysis demonstrated the selection of the M46I+L76V protease mutations in all 3 patients. The L76V conferred a solitary 3.5-fold increase in one-half the maximal inhibitory concentration to lopinavir but severely hampered viral replication. Addition of M46I, which did not confer any lopinavir resistance on its own, had a dual effect. It partly compensated for the loss in replication capacity and increased the one-half maximal inhibitory concentration to above the lower clinical cutoff (11-fold). Analysis of a large clinical database (>180,000 human immunodeficiency virus [HIV] sequences) demonstrated a significant association (Spearman ρ, 0.93) between the increased presence of L76V in clinical samples (0.5% in 2000 to 3.4% in 2006) and lopinavir prescription over time ConclusionsThe HIV protease substitution L76V, in combination with M46I, confers clinically relevant levels of lopinavir resistance and represents a novel resistance pathway to first-line lopinavir/r therapy