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 ; D'Arminio Monforte, Antonella ; 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. ; Paredes, Roger ; Metzner, Karin J. ; Cozzi-Lepri, Alessandro ; Schuurman, Rob ; Brun-Vezinet, Francoise ; Günthard, Huldrych ; Ceccherini-Silberstein, Francesca ; Kaiser, Rolf ; Geretti, Anna Maria ; Brockmeyer, Norbert ; Masquelier, Bernard ; Paredes, Roger ; Metzner, Karin J. ; Cozzi-Lepri, Alessandro ; Schuurman, Rob ; Brun-Vezinet, Francoise ; Günthard, Huldrych ; Ceccherini-Silberstein, Francesca ; Kaiser, Rolf ; Geretti, Anna Maria ; Brockmeyer, Norbert ; Masquelier, Bernard
In: Journal of Antimicrobial Chemotherapy, 2015, vol. 70, no. 3, p. 930-940
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- 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 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 NRTI MVs (OR = 2.27, 95% CI = 0.76-6.77, P = 0.140) and at least one MV versus no NNRTI MVs (OR = 2.41, 95% CI = 1.12-5.18, P = 0.024). A dose-effect relationship between virological failure and mutational load was found. Conclusions Pre-existing MVs more than double the risk of virological failure to first-line NNRTI-based ART