title: Clinically relevant genotype interpretation of resistance to didanosine.
abstract: We analyzed the didanosine (ddI) arm of the randomized, placebo-controlled Jaguar trial in order to define a genotypic score for ddI associated with virologic response. In this arm, 111 patients experiencing virologic failure received ddI in addition to their current combination therapy for 4 weeks. The impact of mutations in the reverse transcriptase gene on the virologic response to ddI was studied in univariate analysis. Genotypic score was constructed using step-by-step analyses first including only mutations associated to poorer virologic response (scored as +1), while secondarily, mutations associated to a better response (scored as -1) were also eligible. Eight mutations were associated with a reduced response to ddI, M41L, D67N, T69D, L74V, V118I, L210W, T215Y/F, and K219Q/E, and two mutations were associated with a better response, K70R and M184V/I. The best prediction of the virologic response to ddI was obtained with a composite score comprising mutations added and subtracted (set II, M41L + T69D + L74V+ T215Y/F + K219Q/E - K70R - M184V/I; P = 4.5 x 10(-9)) and by comparing that to only mutations added (set I, M41L + T69D + L74V + L210W + T215Y/F + K219Q/E; P = 1.2 x 10(-7)). Patients had a human immunodeficiency virus RNA reduction of 1.24, 0.84, 0.61, 0.40, and 0.07 log(10) copies/ml when they were ranked as having a genotypic score II of -2, -1, or 0 or 1 and 2 mutations or more, respectively. In conclusion, we developed and validated a genotypic score, taking into account mutations negatively and positively impacting the virologic response to ddI.
authors.affiliation: Department of Virology, Pitié-Salpêtrière Hospital, 83 Boulevard de l'Hôpital, 75013 Paris, France. anne-genevieve.marcelin@psl.ap-hop-paris.fr
authors.forename: Anne-Geneviève
authors.initials: AG
authors.lastname: Marcelin
authors.forename: Philippe
authors.initials: P
authors.lastname: Flandre
authors.forename: Juliette
authors.initials: J
authors.lastname: Pavie
authors.forename: Nathalie
authors.initials: N
authors.lastname: Schmidely
authors.forename: Marc
authors.initials: M
authors.lastname: Wirden
authors.forename: Olivier
authors.initials: O
authors.lastname: Lada
authors.forename: Dan
authors.initials: D
authors.lastname: Chiche
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Molina
authors.forename: Vincent
authors.initials: V
authors.lastname: Calvez
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D003627:Data Interpretation, Statistical; D016049:Didanosine / Q000494:pharmacology* / Q000627:therapeutic use*; D004311:Double-Blind Method; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D019380:Anti-HIV Agents; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D016049:Didanosine