Estimating the individualized HIV-1 genetic barrier to resistance using a nelfinavir fitness landscape.
BACKGROUND
Failure on Highly Active Anti-Retroviral Treatment is often accompanied with development of antiviral resistance to one or more drugs included in the treatment. In general, the virus is more likely to develop resistance to drugs with a lower genetic barrier. Previously, we developed a method to reverse engineer, from clinical sequence data, a fitness landscape experienced by HIV-1 under nelfinavir (NFV) treatment. By simulation of evolution over this landscape, the individualized genetic barrier to NFV resistance may be estimated for an isolate.


RESULTS
We investigated the association of estimated genetic barrier with risk of development of NFV resistance at virological failure, in 201 patients that were predicted fully susceptible to NFV at baseline, and found that a higher estimated genetic barrier was indeed associated with lower odds for development of resistance at failure (OR 0.62 (0.45 - 0.94), per additional mutation needed, p = .02).


CONCLUSIONS
Thus, variation in individualized genetic barrier to NFV resistance may impact effective treatment options available after treatment failure. If similar results apply for other drugs, then estimated genetic barrier may be a new clinical tool for choice of treatment regimen, which allows consideration of available treatment options after virological failure.
Theys
Kristof
K
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium. kristof.theys@uz.kuleuven.ac.be
Deforche
Koen
K
Beheydt
Gertjan
G
Moreau
Yves
Y
van Laethem
Kristel
K
Lemey
Philippe
P
Camacho
Ricardo J
RJ
Rhee
Soo-Yon
SY
Shafer
Robert W
RW
Van Wijngaerden
Eric
E
Vandamme
Anne-Mieke
AM
D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D016333:HIV Protease / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D009154:Mutation; D019888:Nelfinavir / Q000494:pharmacology / Q000627:therapeutic use; D017211:Treatment Failure
D019380:Anti-HIV Agents; D016333:HIV Protease; D019888:Nelfinavir