title: Evolution of raltegravir resistance during therapy.
abstract: OBJECTIVE
  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.
authors.affiliation: Institute of Virology, University of Cologne, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Sichtig
authors.forename: Saleta
authors.initials: S
authors.lastname: Sierra
authors.forename: Rolf
authors.initials: R
authors.lastname: Kaiser
authors.forename: Martin
authors.initials: M
authors.lastname: Däumer
authors.forename: Stefan
authors.initials: S
authors.lastname: Reuter
authors.forename: Eugen
authors.initials: E
authors.lastname: Schülter
authors.forename: Andre
authors.initials: A
authors.lastname: Altmann
authors.forename: Gerd
authors.initials: G
authors.lastname: Fätkenheuer
authors.forename: Ulf
authors.initials: U
authors.lastname: Dittmer
authors.forename: Herbert
authors.initials: H
authors.lastname: Pfister
authors.forename: Stefan
authors.initials: S
authors.lastname: Esser
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D019427:HIV Integrase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011760:Pyrrolidinones / Q000494:pharmacology* / Q000627:therapeutic use*; D000068898:Raltegravir Potassium; D017422:Sequence Analysis, DNA
chemical_list: D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1