Open Access Research article

Estimating the individualized HIV-1 genetic barrier to resistance using a nelfinavir fitness landscape

Kristof Theys1*, Koen Deforche1, Gertjan Beheydt1, Yves Moreau2, Kristel van Laethem1, Philippe Lemey1, Ricardo J Camacho3, Soo-Yon Rhee4, Robert W Shafer4, Eric Van Wijngaerden5 and Anne-Mieke Vandamme13

Author Affiliations

1 Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium

2 ESAT, Katholieke Universiteit Leuven, Leuven, Belgium

3 Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon, Portugal

4 Internal Medicine, University Hospitals Leuven, Leuven, Belgium

5 Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA, USA

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BMC Bioinformatics 2010, 11:409  doi:10.1186/1471-2105-11-409

Published: 3 August 2010

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.