title: Tipranavir-ritonavir genotypic resistance score in protease inhibitor-experienced patients.
abstract: To identify mutations associated with the virological response (VR) to a tipranavir-ritonavir (TPV/r)-based regimen, 143 patients previously treated with protease inhibitor (PI) were studied. VR was defined by a decrease of at least 1 log(10) in, or undetectable, human immunodeficiency virus (HIV) RNA at month 3. The effect of each mutation in the protease, considering all variants at a residue as a single variable, on the VR to TPV/r was investigated. Mutations at six residues were associated with a lower VR (E35D/G/K/N, M36I/L/V, Q58E, Q61D/E/G/H/N/R, H69I/K/N/Q/R/Y, and L89I/M/R/T/V), and one mutation was associated with a higher VR (F53L/W/Y). The genotypic score M36I/L/V-53L/W/Y + Q58E + H69I/K/N/Q/R/Y + L89I/M/R/T/V was selected as providing a strong association with VR. For the seven patients with a genotypic score of -1 (viruses with only mutation at codon 53), the percentage of responders was 100% and the percentages were 79%, 56%, 33%, 21%, and 0% for those with scores of 0, 1, 2, 3, and 4, respectively. The percentage of patients showing a response to TPV/r was lower for patients infected with non-clade B viruses (n = 16, all non-B subtypes considered together) than for those infected with clade B viruses (n = 127) (25% and 59%, respectively; P = 0.015). Most mutations associated with VR to TPV/r had not previously been associated with PI resistance. This is consistent with phenotypic analysis showing that TPV has a unique resistance profile. Mutations at five positions (35, 36, 61, 69, and 89) were observed significantly more frequently in patients infected with a non-B subtype than in those infected with the B subtype, probably explaining the lower VR observed in these patients.
authors.affiliation: Department of Virology, Pitié-Salpêtrière Hospital, 83 Boulevard de l'Hôpital, 75013 Paris, France. anne-genevieve.marcelin@psl.aphp.fr
authors.forename: Anne-Genevieve
authors.initials: AG
authors.lastname: Marcelin
authors.forename: Bernard
authors.initials: B
authors.lastname: Masquelier
authors.forename: Diane
authors.initials: D
authors.lastname: Descamps
authors.forename: Jacques
authors.initials: J
authors.lastname: Izopet
authors.forename: Charlotte
authors.initials: C
authors.lastname: Charpentier
authors.forename: Chakib
authors.initials: C
authors.lastname: Alloui
authors.forename: Magali
authors.initials: M
authors.lastname: Bouvier-Alias
authors.forename: Anne
authors.initials: A
authors.lastname: Signori-Schmuck
authors.forename: Brigitte
authors.initials: B
authors.lastname: Montes
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Chaix
authors.forename: Corinne
authors.initials: C
authors.lastname: Amiel
authors.forename: Georges Dos
authors.initials: GD
authors.lastname: Santos
authors.forename: Annick
authors.initials: A
authors.lastname: Ruffault
authors.forename: Francis
authors.initials: F
authors.lastname: Barin
authors.forename: Gilles
authors.initials: G
authors.lastname: Peytavin
authors.forename: Marc
authors.initials: M
authors.lastname: Lavignon
authors.forename: Philippe
authors.initials: P
authors.lastname: Flandre
authors.forename: Vincent
authors.initials: V
authors.lastname: Calvez
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics*; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D016333:HIV Protease / Q000187:drug effects / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D011725:Pyridines / Q000494:pharmacology*; D011753:Pyrones / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D019438:Ritonavir / Q000494:pharmacology*; D013449:Sulfonamides
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D011725:Pyridines; D011753:Pyrones; D018894:Reverse Transcriptase Inhibitors; D013449:Sulfonamides; D016333:HIV Protease; D019438:Ritonavir; C107201:tipranavir