期刊
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
卷 65, 期 6, 页码 1262-1269出版社
OXFORD UNIV PRESS
DOI: 10.1093/jac/dkq099
关键词
HIV drug resistance; integrase inhibitors; phenotype; genotype; pharmacokinetics; resistance mutations
资金
- French Ministry of Education and Research [EA2968]
- Sidaction [AI18-3-01354]
- European Community [FP7/2007-2013]
- project 'Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN)' [223131]
- Agence Nationale de Recherche sur le SIDA et les Hepatites virales (ANRS, France)
- European AIDS treatment network NEAT
Our aim was to study the in vivo viral genetic pathways for resistance to raltegravir, in antiretroviral-experienced patients with virological failure (VF) on raltegravir-containing regimens. We set up a prospective study including antiretroviral-experienced patients receiving raltegravir-based regimens. Integrase (IN) genotypic resistance analysis was performed at baseline. IN was also sequenced at follow-up points in the case of VF, i.e. plasma HIV-1 RNA > 400 copies/mL at month 3 and/or > 50 copies/mL at month 6. For phenotyping, the IN region was recombined with an IN-deleted HXB2-based HIV-1 backbone. A titrated amount of IN recombinant viruses was used for antiviral testing against raltegravir and elvitegravir. Among 51 patients, 11 (21.6%) had VF. Four different patterns of IN mutations were observed: (i) emergence of Q148H/R with secondary mutations (n = 5 patients); (ii) emergence of N155H, then replaced by a pattern including Y143C/H/R (n = 3); (iii) selection of S230N (n = 1); and (iv) no evidence of selection of IN mutations (n = 2). The median raltegravir and elvitegravir fold changes (FCs) were 244 (154-647) and 793 (339-892), respectively, for the Q148H/R pattern, while the median raltegravir and elvitegravir FCs were 21 (6-52) and 3 (2-3), respectively, with Y143C/H/R. The median plasma raltegravir C-min was lower in patients with selection of the N155H mutation followed by Y143C/H/R compared with patients with Q148H/R and with patients without emerging mutations or without VF. Diverse genetic profiles can be associated with VF on raltegravir-containing regimens, including the dynamics of replacement of mutational profiles. Pharmacokinetic parameters could be involved in this genetic evolution.
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