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Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial

Paton, NI; Kityo, C; Thompson, J; Nankya, I; Bagenda, L; Hoppe, A; Hakim, JG; ... Walker, AS; + view all (2017) Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial. The Lancet HIV , 4 (8) e341-e348. 10.1016/S2352-3018(17)30065-6. Green open access

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Abstract

BACKGROUND: Cross-resistance after first-line antiretroviral treatment (ART) failure is expected to impair activity of nucleoside-reverse-transcriptase-inhibitors (NRTIs) in second-line therapy, but evidence for effect on virological outcomes is limited. METHODS: We performed an observational analysis of a randomised-controlled trial of second-line ART (EARNEST) in sub-Saharan Africa. 1277 HIV-infected adults/adolescents failing first-line ART (WHO criteria, virological confirmation) were randomised to a boosted protease-inhibitor (PI; standardised to lopinavir/ritonavir) with either 2/3 NRTIs (clinician-selected, without resistance testing; PI/NRTI); raltegravir (PI/RAL); or as monotherapy (PI-mono; discontinued after week 96). Predicted activity of prescribed second-line NRTIs was determined by genotypic resistance testing on stored baseline samples in PI/NRTI. Viral load was measured on stored samples in all patients obtained every 12-16 weeks. FINDINGS: Baseline genotypes were available in 391 (92%) in PI/NRTI. For the 230 (59%) taking no predicted-active NRTIs, there was a high rate of VL suppression (89%(176/198) <400 copies per mL at week-144), superior to PI/RAL (81%(312/383) at week 144; P=0.02) and PI-mono (61%(233/280) at week-96; P<0.0001). VL suppression was no better with 1 predicted-active NRTI (85%(95/112), P=0.3 vs no active NRTIs) and appeared worse with 2-3 predicted active NRTIs (77%(20/26), P=0.08 vs no active NRTIs). Over all follow-up, greater predicted NRTI activity was associated with worse VL suppression (global p=0.0004). INTERPRETATION: Genotypic resistance testing may not accurately predict NRTI activity in PI-based second-line ART. Our results do not support the introduction of routine resistance testing in ART programmes in low-income settings for the purpose of selecting second-line NRTIs.

Type: Article
Title: Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/S2352-3018(17)30065-6
Publisher version: https://doi.org/10.1016/S2352-3018(17)30065-6
Language: English
Additional information: Copyright © The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute for Global Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute for Global Health > Infection and Population Health
URI: https://discovery.ucl.ac.uk/id/eprint/1545101
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