Patterns of resistance mutations to antiretroviral drugs in extensively treated HIV-1-infected patients with failure of highly active antiretroviral therapy

Summary: Resistance-mutation pattems in the reverse transcriptase (RT) and protease ' genes of HIV-1 were analyzed in 22 patients who had been extensively prekeated and who failed to respond to highly active antiretroviral therapy (HAART). The number of mutations ranged from 8 to 19 (median, 13): 4 to 12 (median, 6) mutations in the RT gene, and 4 to 8 (median, 7) mutations in the protease gene. In the RT gene, the most frequent resistance mutations were found at codons 215 (loo%), 41 (95%), 67 (91%), and 210 (77%). Multidrug-resistant mutation pattems including QI5 1M and insertion mutations at codon 69, which confer cross-resistance to the different nucleoside ana- Iogue RT inhibitors were detected in l and 3 patients, respectively; l patient with insertion mutation displayed a NGQCV sequence at codons 67 to 70. In the protease gene, the most frequent mutations were found at codons 63 (95%), 10 (86%), 90(86%), 71(77%), 46 @O%), 36 (45%), and 84 (45%). Genotypic resistance to zidovudine, saquinavir, and indinavir was found in 100% of the patients. All patients showed also resistance or possible resistance to stavudine, abacavir, ritonavir, and nelfiavir. Mu- tations conferring genotypic resistance to nonnucleoside analogue RT inhibitors ("RTIs) were found in 12 (80%) of the "RTI-experienced patients and 1 of 7 NNRTI-naive patients. Our results indicate that failure of HAART in the patients extensively pretreated results from the multiplicity of RT and protease mutations that confer genotypic resistance to almost all available antiretroviral drugs. In these pa- tients, genotypic resistance tests confirm the lack of altemative salvage therapy strat- egies based on the currently available antiretroviral drugs. Key Words: Mutations- Genotypic resistance-Highly active antiretroviral therapy-Treatment fdure.