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In vitro resistance profile of the human immunodeficiency virus type 1 to two new HIV-1 protease inhibitors: CRS-074 and CRS-075
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Reported by Jules Levin
16th Intl HIV Drug Resistance Workshop, June 12-16, 2007, Barbados
A Calazans1, E Xavier2, R Debom2, O Pacheco2, A Tanuri1 and R Brindeiro1.
1Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil
2Cristália Farmoquímicos Ltda, São Paulo, Brasil
BACKGROUND: CRS-074 and CRS-075 are two new protease inhibitors with EC50 values of 0.5 and 50.0 nM, respectively. The aim of this study is to characterize the phenotypic antiretroviral activity against wild-type and protease inhibitor-resistant (PIr) HIV-1 strains from different subtypes, and to describe in vitro selection and characterization of HIV-1 variants having increased resistance to CRS-074 and CRS-075.
METHODS: Phenotyping assays were performed using a MT-4 cell-based MTT viability assay. A panel of 12 HIV-1 recombinant viruses was generated: seven viruses from subtypes B and F carrying PIr mutations, and five others PI-susceptible, from subtypes B, C and F. In vitro selection experiments were performed by passaging HIV-1 strain NL4-3 into MT-4 cells, in the presence of increasing concentrations of CRS-074 or CRS-075. Viral RNA was extracted from selected viruses and the cDNA subjected to sequencing and viral load determination by Q-PCR.
RESULTS: Both drugs presented the same EC50 for different subtypes WT viruses (B, C and F). The EC50 values of CRS-074 against resistant viruses varied from 2.5- to 510-fold higher than the EC50 for reference virus. For the CRS-075 these EC50 values varied from 1.8-9.3; while ritonavir (used as a reference drug) exhibited values from 3.5 to 21.2-fold. After 43 days, a viral variant carrying the mutation E34G was selected for the CRS-074. No mutations were found from the viruses under selective pressure of CRS-075, after 53 days in culture.
CONCLUSIONS: CRS-074 is one of most potent PI ever described (EC50=0.5 nM). Although CRS-074 presented high relative values of EC50 against resistant viruses, the absolute value of EC50 reached is still very low when compared to other PI against susceptible viruses. CRS-075 has an EC50 value comparable to the FDA-approved PI; moreover, CRS-075 highly effectiveness against resistant viruses demonstrated its potential as a future drug for second-line therapy.
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