 |
|
|
| |
Predicting Response to ddI in Experienced Patients
|
| |
| |
"New genotypic score comprising mutations impacting negativelyand positively the virological response to didanosine intreatment-experienced patients from the randomized didanosineadd on Jaguar study"
ABSTRACT 132
Antiviral Therapy 2004; 9:S146.
AG Marcelin1, P Flandre2, J Pavie3, N Schmidely4, M Wirden1, O Lada1, D Chiche4, MC Bernard4, JM Molina3 and V Calvez1
1 Pitie-Salpetriere Hospital, Paris, France; 2 INSERM, Villejuif, France; 3 Saint Louis Hospital, Paris, France; and 4 BMS, Rueil, France
BACKGROUND: The antiviral efficacy of didanosine in antiretroviral experienced patients has not been fully investigated. The aim of this study was to define a genotypic score for didanosine associated to virologicalresponse based on data from the didanosine arm of the Jaguar study (AI454-176).
METHODS: 168 patients under stable antiretroviral regimen experiencing virological failure were randomized to receive either didanosine (n=110) or didanosine- placebo (n=58) in addition to their current combination therapy for 4 weeks. First, the impact of mutations (IAS-USA list) in the reverse transcriptase gene on the virological response to didanosine was studied inunivariate analysis. Mutations with a P-value below 0.20 were retained for further analysis. Then, two step-by-step analyses were done using a non-parametric test. In the first analysis, only mutations associated to poorer virological response were eligible while in the second, mutations associated to better virological response were also eligible.
RESULTS: Eight mutations were associated with a reduced virological response to didanosine: M41L, D67N, T69D, L74V, V118I, L210W, T215Y/F and the K219Q/E and two mutations with a better virological response: K70R and M184V/I. When only mutations associated to poorer virological response were considered, the procedure led to select M41L + L74V +T215Y/F + K219Q/E + L210W + T69D as a genotypic score (score I, P=1.19•10--7). When mutations associated to better virological response were also eligible, the procedure selected a composite score comprisingmutations added (M41L + L74V + D67N + K219Q/E + T215Y/F + T69D) and mutations subtracted (--K70R--M184V/I). This new approach led to astronger prediction of the virological response than the score I (score II, P=8.50 x10-9). Patients had an HIV-1 RNA reduction of 1.24, 0.85, 0.50 and 0.11 log10 copies/ml when they were ranked as having a genotypicscore II of --2, --1, 0 or 1 and 2 mutations or more, respectively.
CONCLUSION: Genotypic score (M41L + L74V + D67N + K219Q/E + T215Y/F + T69D -- K70R -- M184V/I) is a better predictor than a score including only mutations impacting negatively the virological response to didanosine.
|
| |
|
|
|
|
|
