Minor HIV-1 variants with the K103N resistance mutation during intermittent efavirenz-containing antiretroviral therapy and virological failure

• Published in: PloS one 2011-06, Vol.6 (6), p.e21655
• Main Authors: Delobel, Pierre, Saliou, Adrien, Nicot, Florence, Dubois, Martine, Trancart, Stéphanie, Tangre, Philippe, Aboulker, Jean-Pierre, Taburet, Anne-Marie, Molina, Jean-Michel, Massip, Patrice, Marchou, Bruno, Izopet, Jacques
• Format: Article
• Language: English
• Subjects: Adult; Alleles; Anti-HIV Agents - therapeutic use; Antiretroviral agents; Antiretroviral drugs; Antiretroviral therapy; Benzoxazines - therapeutic use; Biology; Correlation analysis; Drug resistance; Drug Resistance, Viral - genetics; Drug therapy; Efavirenz; Emergence; Failure; Female; Genetic aspects; Highly active antiretroviral therapy; HIV; HIV-1 - drug effects; HIV-1 - genetics; Human immunodeficiency virus; Humans; Impact resistance; Male; Medical research; Medicine; Microbial drug resistance; Middle Aged; Mutant frequency; Mutants; Mutation; Patients; Pharmacokinetics; Pharmacology; pol Gene Products, Human Immunodeficiency Virus - genetics; Populations; Protease inhibitors; Real time; Real-Time Polymerase Chain Reaction; Risk groups; Therapy; Viruses; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0021655

The impact of minor drug-resistant variants of the type 1 immunodeficiency virus (HIV-1) on the failure of antiretroviral therapy remains unclear. We have evaluated the importance of detecting minor populations of viruses resistant to non-nucleoside reverse-transcriptase inhibitors (NNRTI) during intermittent antiretroviral therapy, a high-risk context for the emergence of drug-resistant HIV-1. We carried out a longitudinal study on plasma samples taken from 21 patients given efavirenz and enrolled in the intermittent arm of the ANRS 106 trial. Allele-specific real-time PCR was used to detect and quantify minor K103N mutants during off-therapy periods. The concordance with ultra-deep pyrosequencing was assessed for 11 patients. The pharmacokinetics of efavirenz was assayed to determine whether its variability could influence the emergence of K103N mutants. Allele-specific real-time PCR detected K103N mutants in 15 of the 19 analyzable patients at the end of an off-therapy period while direct sequencing detected mutants in only 6 patients. The frequency of K103N mutants was 0.1% in 8. It was 0.1%-10% in 6 of these 8 patients. The mutated virus populations of 4 of these 6 patients underwent further selection and treatment failed for 2 of them. The K103N mutant frequency was >10% in the remaining 2, treatment failed for one. The copy numbers of K103N variants quantified by allele-specific real-time PCR and ultra-deep pyrosequencing agreed closely (ρ = 0.89 P0.1%) than in the 11 patients in whom it did not (32 hours) (P = 0.04). Thus ultrasensitive methods could prove more useful than direct sequencing for predicting treatment failure in some patients. However the presence of minor NNRTI-resistant viruses need not always result in virological escape. ClinicalTrials.gov NCT00122551.