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

• Published in: HIV medicine Vol. 4; no. 1; pp. 38 - 47
• Main Authors: Røge, BT, Katzenstein, TL, Nielsen, HL, Gerstoft, J
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-01-2003
• Subjects: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; D30N; Drug Resistance, Viral - genetics; Genotype; HIV; HIV Infections - drug therapy; HIV Infections - immunology; HIV Infections - virology; HIV Protease - genetics; HIV Protease Inhibitors - therapeutic use; HIV Reverse Transcriptase - genetics; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 - isolation & purification; Humans; Molecular Sequence Data; Mutation; N88D; nelfinavir; Nelfinavir - therapeutic use; resistance mutation; RNA, Viral - genetics; Sequence Analysis, RNA; Treatment Failure; Viral Load
• ISSN: 1464-2662; 1468-1293
• DOI: 10.1046/j.1468-1293.2003.00133.x

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 (Δ: 33%), codon 36 (Δ: 30%) and codon 71 (Δ: 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.