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

Abstract

Resistance-mutation patterns in the reverse transcriptase (RT) and protease genes of HIV-1 were analyzed in 22 patients who had been extensively pretreated 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 (100%), 41 (95%), 67 (91%), and 210 (77%). Multidrug-resistant mutation patterns including Q151M and insertion mutations at codon 69, which confer cross-resistance to the different nucleoside analogue RT inhibitors were detected in 1 and 3 patients, respectively; 1 patient with insertion mutation displayed a NGQGV [corrected] 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 (50%), 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 nelfinavir. Mutations conferring genotypic resistance to nonnucleoside analogue RT inhibitors (NNRTIs) were found in 12 (80%) of the NNRTI-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 patients, genotypic resistance tests confirm the lack of alternative salvage therapy strategies based on the currently available antiretroviral drugs.