Screening and selecting for optimized antiretroviral drugs: rising to the challenge of drug resistance

Abstract

Background: Resistance to antiretroviral (ARV) drugs constitutes one of the greatest limitations to effective long-term therapy for human immunodeficiency virus (HIV) infection – a problem alleviated, but by no means overcome, by the application of carefully selected, sequential combination regimens. The rational development of novel therapeutics with the ability to suppress viraemia effectively and also address the complex problems of resistance offers a useful way forward for HIV therapy. The investigational drug TMC114 (darunavir) was designed to be active against both wild-type HIV and strains that are resistant to currently available protease inhibitors. Scope: This review describes the challenges posed by HIV drug resistance and the novel approach taken in the design and selection of TMC114. Articles were identified by searching MEDLINE in September 2005 (search limits: 1995–2006) using the terms: TMC114, darunavir, resistance, screening, selection, ARV therapy, HIV and HAART. Additional data included bibliographies from identified articles. Findings: With the continuing problem of resistance, ARV drugs must be designed with broadspectrum activity forming a central part of their development and screening. Drugs must not only be able to treat existing resistant strains, but must also possess more intrinsic resilience to the development of resistance. TMC114 was designed and selected with strong emphasis on potent activity across a range of both wild-type and resistant HIV strains and high binding affinity to HIV protease. Conclusion: This review illustrates that future treatment strategies should include screening against multiple-resistant strains to optimize the identification of novel therapeutic agents for the treatment of HIV.