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Title: Modelled in vivo HIV fitness under drug selective pressure and estimated genetic barrier towards resistance are predictive for virological response
Authors: Deforche, Koen ×
Cozzi-Lepri, Alessandro
Theys, Kristof
Clotet, Bonaventura
Camacho, Ricardo J
Kjaer, Jesper
Van Laethem, Kristel
Phillips, Andrew
Moreau, Yves
Lundgren, Jens D
Vandamme, Anne-Mieke #
Issue Date: 2008
Publisher: International Medical Press
Series Title: Antiviral Therapy vol:13 issue:3 pages:399-407
Abstract: BACKGROUND: A method has been developed to estimate a fitness landscape experienced by HIV-1 under treatment selective pressure as a function of the genotypic sequence thereby also estimating the genetic barrier to resistance. METHODS: We evaluated the performance of two estimated fitness landscapes (nelfinavir [NFV] and zidovudine [AZT] plus lamivudine [3TC]) to predict week 12 viral load (VL) change for 176 treatment change episodes (TCEs) and probability of week 48 virological failure for 90 TCEs, in treatment experienced patients starting these drugs in combination. RESULTS: A higher genetic barrier for AZT plus 3TC, (quantified per additional mutation required to develop resistance against these drugs) was associated with a 0.54 (95% confidence interval [CI] 0.30-0.77) larger log10 VL reduction at 12 weeks (P < 0.0001) and a 0.39 (95%/ CI 0.23-0.66) lower odds of virological failure at 48 weeks (P = 0.0005), in analyses adjusting for the pre-TCE VL and the exact time-lag between the TCE and the date of determining response VL. The strength of these associations was comparable with those seen with expert interpretation systems (Rega, ANRS and HIVDB). A higher genetic barrier to NFV resistance was the only genotypic predictor that tended to be associated with a 0.19 (95% CI 0-0.39) higher log10 VL reduction at 12 weeks (P = 0.05) and a 0.63 (95% CI 0.36-1.09) lower odds of virological failure at 48 weeks ( P = 0.10) per additional mutation. CONCLUSIONS: These results suggest that an estimated genetic barrier derived from fitness landscapes may contribute to an improvement of predicted treatment outcome for NFV and this approach should be explored for other drugs.
ISSN: 1359-6535
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Clinical and Epidemiological Virology (Rega Institute)
ESAT - STADIUS, Stadius Centre for Dynamical Systems, Signal Processing and Data Analytics
× corresponding author
# (joint) last author

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