HIV-1 drug resistance is a major cause of treatment failure and there is evidence of increasing transmission of drug resistant virus. Resistance is caused by mutations in the HIV-1 genome coding for structural changes in the target enzymes that can affect the binding or activity of the inhibitors. We are, therefore, developing new compounds that are designed to bind more effectively to mutated virus enzymes and to be highly active against resistant viral strains. A new, accelerated drug screening strategy is being used to expedite the development of these new HIV drugs. Candidate compounds with anti-HIV activity in a primary screen are evaluated both for
antiviral activity against drug-resistant HIV strains and for suitable pharmacokinetic properties, in parallel. Compounds in the non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI) classes are under development and currently entering the Phase II and Phase I clinical trials, respectively. The two lead NNRTIs, TMC120 and TMC125, remain highly active in vitro against most site-directed mutant HIV-1 strains with the ‘classic’ mutations associated with NNRTI-resistance, as well as against most NNRTI-resistant recombinant clinical isolates. In vitro selection experiments show that these compounds are associated with reduced and delayed resistance development, involving more mutations, compared with the first
generation NNRTIs. Phase I monotherapy results with TMC 120/125 demonstrate a mean 1.5-2.0 log reduction in HIV-1 RNA in drug naïve patients. The PIs, TMC 114 and 126 bind very tightly and flexibly to protease and are highly active at sub-fentomolar concentrations. In vitro selection demonstrates that only low level resistance can be generated after very prolonged passage. HIV-1site-directed mutants with classical PI mutations exhibit reduced fitness in the presence of the compounds, raising the possibility that these inhibitors represent a new class of ‘resistant-repellent’ compounds that are able to prevent or delay the development of PI-resistance.
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