Improving the prediction of virological response to tipranavir: the development and validation of a tipranavir-weighted mutation score.
BACKGROUND
The purpose of this study was to develop a tipranavir-weighted mutation score that provides guidance to treating physicians on the relative effect of specific protease mutations on tipranavir activity.


METHODS
Weights were developed using data from RESIST tipranavir-treated patients based on regressions of virological response at weeks 8 and 24, accounting for baseline CD4(+) T-cell count and background regimen activity. The resulting weighted score and cutoffs were validated using a set of cohort patients external to the tipranavir development programme. Response rates were tabulated for the new weighted score and compared with other tipranavir mutation scores used in clinical practice.


RESULTS
The final weights were 74P, 82L/T, 83D and 47V (+4), 58E and 84V (+3), 36I, 43T and 54A/M/V (+2), 10V, 33F and 46L (+1), 24I and 76V (-2), 50L/V (-4), and 54L (-6). Tipranavir-weighted score susceptibility categories were susceptible ≤3, partially susceptible >3 but ≤10, and resistant ≥11. Week 48 response rates for RESIST patients were 34.6%, 15.9% and 5.9%, respectively. Using the external cohort data (n=150), the weighted score was highly associated with week 8 viral load reduction (P=0.0027). Only one other score achieved statistical significance.


CONCLUSIONS
The tipranavir-weighted score developed and externally validated here, in three datasets representing a broad population of treatment-experienced patients, can be used to make clinical decisions about whether to consider tipranavir in a treatment-experienced patient who has limited treatment options.
National Hemophilia Center, Tel Hashomer, Israel.
Jonathan M
JM
Schapiro
Joseph
J
Scherer
Charles A
CA
Boucher
John D
JD
Baxter
Clemens
C
Tilke
Carlo F
CF
Perno
Franco
F
Maggiolo
Maria M
MM
Santoro
David B
DB
Hall
D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001835:Body Weight; D018791:CD4 Lymphocyte Count; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D011753:Pyrones / Q000494:pharmacology* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D019438:Ritonavir / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides; D019562:Viral Load
D019380:Anti-HIV Agents; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D019438:Ritonavir; C107201:tipranavir