Drug resistance mutations and outcome of second-line treatment in patients with first-line protease inhibitor failure on nelfinavir-containing HAART.

OBJECTIVES:To determine resistance mutations emerging in HIV-1-infected patients experiencing their first protease inhibitor (PI)-failure on nelfinavir-containing highly active antiretroviral therapy (HAART), and to assess virological response to rescue regimens. METHODS:Plasma HIV-1 RNA from 24 patients failing nelfinavir-containing HAART was sequenced. Failure was defined as two consecutive measurements of viral load > 400 HIV-1 RNA copies/mL. Patients with previous failure on other PIs were excluded. Data on response to second-line treatment was extracted from patient files. RESULTS:At failure primary protease mutations were found in 14 patients (58%). Ten patients had D30N (38%), five patients had L90M (19%), two patients had V82A/F (8%) and two patients had M46I/L (8%). Two patients had both D30N and L90M. Pronounced increases of secondary protease mutations were seen at codon 88 (Delta: 33%), codon 36 (Delta: 30%) and codon 71 (Delta: 17%). Of eight patients with N88D, seven also harboured D30N (P < 0.01). Polymorphisms at codon 63 were detected at baseline in all patients who developed primary resistance mutations at failure (P < 0.01). On rescue regimens, 78% achieved viral loads below limit of detection (BLD). The presence of primary protease mutations was not associated with a higher risk of failure on second-line treatment. CONCLUSION:In patients failing nelfinavir-containing HAART, D30N was detected frequently and L90M occasionally. A pronounced accumulation of the secondary protease mutations N88D, M36I, and A71V/T was found, and D30N was strongly associated with N88D. A high proportion of patients became undetectable on second-line treatment and the presence of primary resistance mutations did not negatively affect the outcome of rescue regimens.