Low-frequency drug-resistant HIV-1 and risk of virological failure to first-line NNRTI-based ART: A multicohort European case-control study using centralized ultrasensitive 454 pyrosequencing
Cozzi-Lepri, Alessandro; Noguera-Julian, Marc; Di Giallonardo, Francesca; Schuurman, Rob; Däumer, Martin; Aitken, Sue; Ceccherini-Silberstein, Francesca; Monforte, Antonella D Arminio; Geretti, Anna Maria; Booth, Clare L.; Kaiser, Rolf; Michalik, Claudia; Jansen, Klaus; Masquelier, Bernard; Bellecave, Pantxika; Kouyos, Roger D.; Castro, Erika; Furrer, Hansjakob; Schultze, Anna; Günthard, Huldrych F.; Brun-Vezinet, Francoise; Paredes, Roger; Metzner, Karin J.; Brockmeyer, Norbert H.; CHAIN Minority HIV-1 Variants Working Group
(2015) Journal of Antimicrobial Chemotherapy, volume 70, issue 3, pp. 930 - 940
(Article)
Abstract
Objectives: It is still debated if pre-existing minority drug-resistant HIV-1 variants (MVs) affect the virological outcomes of first-line NNRTI-containing ART. Methods: This Europe-wide case-control study included ART-naive subjects infected with drug-susceptible HIV-1 as revealed by population sequencing, who achieved virological suppression on first-line ART including one NNRTI. Cases experienced virological
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failure and controls were subjects from the same cohort whose viraemia remained suppressed at a matched time since initiation of ART. Blinded, centralized 454 pyrosequencing with parallel bioinformatic analysis in two laboratories was used to identify MVs in the 1%-25% frequency range. ORs of virological failure according to MV detection were estimated by logistic regression. Results: Two hundred and sixty samples (76 cases and 184 controls), mostly subtype B (73.5%),were used for the analysis. Identical MVs were detected in the two laboratories. 31.6% of cases and 16.8% of controls harboured pre-existing MVs. Detection of at least one MV versus no MVs was associated with an increased risk of virological failure (OR=2.75, 95% CI=1.35-5.60, P=0.005); similar associations were observed for at least one MV versus no NRTIMVs (OR=2.27, 95% CI=0.76-6.77, P=0.140) and at least oneMV versus no NNRTIMVs (OR=2.41, 95% CI=1.12-5.18, P=0.024). A dose-effect relationship between virological failure and mutational loadwas found. Conclusions: Pre-existing MVs more than double the risk of virological failure to first-line NNRTI-based ART.
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Keywords: Antiretroviral therapy, CHAIN, European multicentre study, Minority drug-resistant HIV-1 variants, Pharmacology, Pharmacology (medical), Infectious Diseases
ISSN: 0305-7453
Publisher: Oxford University Press
(Peer reviewed)