In-vivo selection of the mutation F121Y in a patient failing raltegravir containing salvage regimen

► Three major pathways, G148H/R/K, N155H and Y143C/H/R are associated to resistance to raltegravir. ► The substitution F121Y is associated to resistance to raltegravir in vitro. ► The selection of F121Y in an patient failing raltegravir was followed by the emergence of Y143R. ► Changing regimen upon...

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Published in:	Antiviral research Vol. 95; no. 1; pp. 9 - 11
Main Authors:	Souza Cavalcanti, Jaqueline, Minhoto Lança, André, de Paula Ferreira, João Leandro, da Eira, Margareth, de Souza Dantas, Daniel Soares, de Macedo Brígido, Luís Fernando
Format:	Journal Article
Language:	English
Published:	Kidlington Elsevier B.V 01-07-2012 Elsevier
Subjects:	Adult Anti-HIV Agents - administration & dosage Anti-HIV Agents - pharmacology Antibiotics. Antiinfectious agents. Antiparasitic agents Antiretroviral Therapy, Highly Active - methods Antiviral agents Biological and medical sciences Brazil Developmental stages Drug Resistance, Viral Evolution Genetic resistance HIV Infections - drug therapy HIV Infections - virology HIV-1 HIV-1 - genetics HIV-1 - isolation & purification Human immunodeficiency virus 1 Human viral diseases Humans Immunodeficiencies Immunodeficiencies. Immunoglobulinopathies Immunopathology Infectious diseases Integrase Male Medical sciences Molecular Sequence Data Mutation Mutation, Missense Pharmacology. Drug treatments Polymerase chain reaction Pyrrolidinones - administration & dosage Pyrrolidinones - pharmacology Raltegravir Raltegravir Potassium Reverse Transcriptase Polymerase Chain Reaction Salvage Therapy - methods Selection, Genetic Sequence Analysis, DNA Time Factors Treatment Failure Viral diseases Viral diseases of the lymphoid tissue and the blood. Aids Viral Load Viremia South America Brazil America HIV-1 Integrase Brazil Genetic resistance Raltegravir Antiretroviral agent HIV-1 virus Selection Integrase inhibitor Antiviral Genetics Human Immunopathology Retroviridae Patient AIDS Immune deficiency Lentivirus Infection Virus Resistance In vivo Viral disease Human immunodeficiency virus Mutation Salvage treatment
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Summary:	► Three major pathways, G148H/R/K, N155H and Y143C/H/R are associated to resistance to raltegravir. ► The substitution F121Y is associated to resistance to raltegravir in vitro. ► The selection of F121Y in an patient failing raltegravir was followed by the emergence of Y143R. ► Changing regimen upon the identification of F121Y might avoid the evolution of raltegravir resistance. Raltegravir is an integrase inhibitor (INI) licensed for clinical use and other INI are in advanced stage of development. Different resistance mutations in HIV integrase from patients using these antiretroviral drugs have been described and G148H/R/K, N155H and less frequently Y143C/H/R are considered major resistant mutations to raltegravir. Both Stanford Database and Geno2Pheno list F121Y as conferring intermediate resistance “in vitro” both to raltegravir and elvitegravir. We report for the first time the “in vivo” selection F121Y and evolution to Y143R in a 31years old male clade B HIV-1 infected patient failing a raltegravir-containing salvage regimen. Plasma samples nine months prior to raltegravir (RAL-Naïve) and at weeks 32, 40 and 88 after RAL-containing regimen were analyzed. Antiretroviral susceptibility was evaluated at Stanford and Geno2Pheno from sequences obtained with RT-PCR. After a Viral load at week 12 below 50 copies/mL, viremia raised at week 20 to 4.5log10. The emergence of F121Y was observed at week 32 and 40, alongside with L74I, T97A, Q137H and V151I. At week 88 F121Y was no longer detected, L74I and T97A were maintained and Y143R emerged. F121Y might be an alternative pathway to Y143R. Changing of RAL-containing regimen upon the identification of F121Y might avoid the evolution of raltegravir resistance.
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ISSN:	0166-3542 1872-9096
DOI:	10.1016/j.antiviral.2012.04.007