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Antimicrobial Agents and Chemotherapy, May 2005, p. 1739-1744, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1739-1744.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Clinically Relevant Genotype Interpretation of Resistance to Didanosine

Anne-Geneviève Marcelin,^1* Philippe Flandre,² Juliette Pavie,³ Nathalie Schmidely,⁴ Marc Wirden,¹ Olivier Lada,¹ Dan Chiche,⁴ Jean-Michel Molina,² Vincent Calvez,¹ the AI454-176 Jaguar Study Team,

Department of Virology, Pitié-Salpêtrière Hospital, Paris, France,¹ INSERM, Paul Brousse Hospital, Villejuif, France,² Department of Infectious Diseases, Saint Louis Hospital, Paris, France,³ BMS France Laboratory, Rueil, France⁴

Received 28 September 2004/ Returned for modification 12 November 2004/ Accepted 3 January 2005

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 log₁₀ 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.

Contributing members of the AI454-176 Jaguar Study Team are listed in Acknowledgments.

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