Phenotypic and genotypic analysis of clinical HIV-1 isolates reveals extensive protease inhibitor cross-resistance: a survey of over 6000 samples

Objective: To evaluate in HIV-1 the extent of phenotypic and genotypic anti retroviral drug resistance and cross-resistance towards the protease inhibi tors (PIs) saquinavir, ritonavir, indinavir and nelfinavir among a set of p atient samples originating from European and US routine clinical practice a nd submitted for phenotypic drug resistance testing and/or genotypic analys is. The mutational pattern(s) underlying both resistance and cross-resistan ce to Pls was investigated. Method: Over 6000 patient isolates with plasma viral load greater than 1000 copies/ mi plasma were analysed. Phenotypic resistance was evaluated by a recombinant virus assay. Phenotypic resistance is expressed as the fold-inc rease of the 50% inhibitory concentration (IC50) value of a compound for a patient-derived recombinant virus isolate compared with that for a wild-typ e laboratory virus. Genotypic analysis is reported as amino acid changes at positions in the HIV-1 protease compared to a wild-type reference. Results: Phenotypic resistance to any single PI was observed in 17 to 25% o f the clinical isolates investigated. Phenotypic cross-resistance among Pls (> 10-fold increase in IC50 value) was detected in 59 to 80% of the sample s resistant (> 10-fold increase in IC50 value) to at least one PI. The prev alent mutations in PI-resistant isolates involved substitutions at codons 1 0, 36, 46, 54, 71, 77, 82 and 90. The most frequent mutational pattern in s amples with Pi cross-resistance involved combined substitutions at position s 10 and 90, extended with substitutions at positions 54, 71, 77, 82 or 84. Conclusions: Extensive use of first-generation Pls leads to the emergence o f HIV-1 isolates possessing cross-resistance to all members of this class. Identification of particular mutational profiles among these isolates may a ssist in the design of new generation inhibitors with specific activity aga inst protease-mutant HIV strains. (C) 2000 Lippincott Williams & Wilkins.