JAC Advance Access originally published online on May 14, 2009
Journal of Antimicrobial Chemotherapy 2009 64(1):25-32; doi:10.1093/jac/dkp153
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Original research |
Evolution of raltegravir resistance during therapy
1 Institute of Virology, University of Cologne, Germany 2 Institute of Immunology and Genetics, Kaiserslautern, Germany 3 Department of Gastroenterology, University of Düsseldorf, Germany 4 The Computational Biology and Applied Algorithmics Department, Max Planck Institute for Informatics, Saarbrücken, Germany 5 Department of Internal Medicine I, University of Cologne, Germany 6 Department of Virology, University of Duisburg Essen, Germany 7 Department of Dermatology, University of Duisburg Essen, Germany
Received 10 December 2008; returned 4 February 2009; revised 1 April 2009; accepted 3 April 2009
* Corresponding author. Tel: +49-221-478-7741; Fax: +49-221-478-3904; E-mail: rolf.kaiser{at}uk-koeln.de
Objectives: We investigated the prevalence of raltegravir resistance-associated mutations at baseline and their evolution during raltegravir therapy in patients infected with different HIV-1 subtypes.
Methods: At pre-treatment screening, the integrase gene from plasma samples from patients infected with subtype B and non-B viruses was analysed. Raltegravir resistance evolution was further evaluated in 10 heavily pre-treated patients.
Results: Two hundred and nine plasma samples from 94 subtype B and 115 non-B patients were sequenced. No signature/primary raltegravir resistance mutations were detected at baseline. The secondary mutations L74M, T97A, V151I and G163R were observed with a frequency of <4%. The primary mutations N155H, Q148R/H or Q143R were observed during raltegravir therapy. The Q148R/H was detected only in subtype B. A switch of the primary mutation during raltegravir treatment was not restricted to the subtype B viruses. The prevalence of each primary mutation varied depending on the length of the raltegravir therapy. The Q148R/H was mostly detected after short exposure to raltegravir, while the Y143R was observed only after prolonged raltegravir exposure. We detected an association between the presence of the T206S in the baseline genotype and the absence of the primary Q148R/H mutation or any secondary mutation accompanying the N155H following raltegravir failure.
Conclusions: A number of secondary and additional mutations were found in baseline genotypes. During therapy, when the virus was not optimally suppressed, resistance mutations developed, which were dependent on subtype and time on raltegravir.
Keywords: HIV-1 , integrase inhibitors , drug resistance , non-B subtypes , antiviral therapy