title: Estimating the individualized HIV-1 genetic barrier to resistance using a nelfinavir fitness landscape.
abstract: 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.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium. kristof.theys@uz.kuleuven.ac.be
authors.forename: Kristof
authors.initials: K
authors.lastname: Theys
authors.forename: Koen
authors.initials: K
authors.lastname: Deforche
authors.forename: Gertjan
authors.initials: G
authors.lastname: Beheydt
authors.forename: Yves
authors.initials: Y
authors.lastname: Moreau
authors.forename: Kristel
authors.initials: K
authors.lastname: van Laethem
authors.forename: Philippe
authors.initials: P
authors.lastname: Lemey
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Camacho
authors.forename: Soo-Yon
authors.initials: SY
authors.lastname: Rhee
authors.forename: Robert W
authors.initials: RW
authors.lastname: Shafer
authors.forename: Eric
authors.initials: E
authors.lastname: Van Wijngaerden
authors.forename: Anne-Mieke
authors.initials: AM
authors.lastname: Vandamme
mesh_terms: 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
chemical_list: D019380:Anti-HIV Agents; D016333:HIV Protease; D019888:Nelfinavir