dc.contributor.author | Szubert, AJ | en_US |
dc.contributor.author | Prendergast, AJ | en_US |
dc.contributor.author | Spyer, MJ | en_US |
dc.contributor.author | Musiime, V | en_US |
dc.contributor.author | Musoke, P | en_US |
dc.contributor.author | Bwakura-Dangarembizi, M | en_US |
dc.contributor.author | Nahirya-Ntege, P | en_US |
dc.contributor.author | Thomason, MJ | en_US |
dc.contributor.author | Ndashimye, E | en_US |
dc.contributor.author | Nkanya, I | en_US |
dc.contributor.author | Senfuma, O | en_US |
dc.contributor.author | Mudenge, B | en_US |
dc.contributor.author | Klein, N | en_US |
dc.contributor.author | Gibb, DM | en_US |
dc.contributor.author | Walker, AS | en_US |
dc.contributor.author | ARROW Trial Team | en_US |
dc.date.accessioned | 2018-04-27T17:13:02Z | |
dc.date.available | 2017-10-09 | en_US |
dc.date.issued | 2017-11 | en_US |
dc.date.submitted | 2018-02-27T09:12:00.255Z | |
dc.identifier.uri | http://qmro.qmul.ac.uk/xmlui/handle/123456789/36563 | |
dc.description.abstract | BACKGROUND: Although WHO recommends viral load (VL) monitoring for those on antiretroviral therapy (ART), availability in low-income countries remains limited. We investigated long-term VL and resistance in HIV-infected children managed without real-time VL monitoring. METHODS AND FINDINGS: In the ARROW factorial trial, 1,206 children initiating ART in Uganda and Zimbabwe between 15 March 2007 and 18 November 2008, aged a median 6 years old, with median CD4% of 12%, were randomised to monitoring with or without 12-weekly CD4 counts and to receive 2 nucleoside reverse transcriptase inhibitors (2NRTI, mainly abacavir+lamivudine) with a non-nucleoside reverse transcriptase inhibitor (NNRTI) or 3 NRTIs as long-term ART. All children had VL assayed retrospectively after a median of 4 years on ART; those with >1,000 copies/ml were genotyped. Three hundred and sixteen children had VL and genotypes assayed longitudinally (at least every 24 weeks). Overall, 67 (6%) switched to second-line ART and 54 (4%) died. In children randomised to WHO-recommended 2NRTI+NNRTI long-term ART, 308/378 (81%) monitored with CD4 counts versus 297/375 (79%) without had VL <1,000 copies/ml at 4 years (difference = +2.3% [95% CI -3.4% to +8.0%]; P = 0.43), with no evidence of differences in intermediate/high-level resistance to 11 drugs. Among children with longitudinal VLs, only 5% of child-time post-week 24 was spent with persistent low-level viraemia (80-5,000 copies/ml) and 10% with VL rebound ≥5,000 copies/ml. No child resuppressed <80 copies/ml after confirmed VL rebound ≥5,000 copies/ml. A median of 1.0 (IQR 0.0,1.5) additional NRTI mutation accumulated over 2 years' rebound. Nineteen out of 48 (40%) VLs 1,000-5,000 copies/ml were immediately followed by resuppression <1,000 copies/ml, but only 17/155 (11%) VLs ≥5,000 copies/ml resuppressed (P < 0.0001). Main study limitations are that analyses were exploratory and treatment initiation used 2006 criteria, without pre-ART genotypes. CONCLUSIONS: In this study, children receiving first-line ART in sub-Saharan Africa without real-time VL monitoring had good virological and resistance outcomes over 4 years, regardless of CD4 monitoring strategy. Many children with detectable low-level viraemia spontaneously resuppressed, highlighting the importance of confirming virological failure before switching to second-line therapy. Children experiencing rebound ≥5,000 copies/ml were much less likely to resuppress, but NRTI resistance increased only slowly. These results are relevant to the increasing numbers of HIV-infected children receiving first-line ART in sub-Saharan Africa with limited access to virological monitoring. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN24791884. | en_US |
dc.description.sponsorship | The ARROW trial was jointly funded by the UK Medical Research Council (MRC, mrc.ac.uk) grant numbers G0300400 (AJP, VM, PM, MB-D, NK, DMG, ASW) and G1001190 (AJP, VM, PM, MB-D, NK, DMG, ASW) and the UK Department for International Development (DFID, gov.uk/dfid) (DMG) under the MRC/DFID Concordat agreement. It was also part of the EDCTP2 programme supported by the European Union; drugs were donated and viral load and genotyping assays were funded by ViiV Healthcare/GlaxoSmithKline. The MRC Clinical Trials Unit at UCL (AJS, MJS, MJT, DMG, ASW) is supported by funding from the MRC (MC_UU_12023/26). AJP is a Wellcome Trust Fellow (grant number 108065/Z/15/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. | en_US |
dc.format.extent | e1002432 - ? | en_US |
dc.language | eng | en_US |
dc.language.iso | en | en_US |
dc.relation.ispartof | PLoS Med | en_US |
dc.subject | Adolescent | en_US |
dc.subject | Anti-HIV Agents | en_US |
dc.subject | Antiretroviral Therapy, Highly Active | en_US |
dc.subject | Child | en_US |
dc.subject | Child, Preschool | en_US |
dc.subject | Drug Administration Schedule | en_US |
dc.subject | Drug Monitoring | en_US |
dc.subject | Drug Resistance, Viral | en_US |
dc.subject | Female | en_US |
dc.subject | HIV Infections | en_US |
dc.subject | HIV-1 | en_US |
dc.subject | Humans | en_US |
dc.subject | Infant | en_US |
dc.subject | Longitudinal Studies | en_US |
dc.subject | Male | en_US |
dc.subject | Time Factors | en_US |
dc.subject | Treatment Outcome | en_US |
dc.subject | Uganda | en_US |
dc.subject | Viral Load | en_US |
dc.subject | Zimbabwe | en_US |
dc.title | Virological response and resistance among HIV-infected children receiving long-term antiretroviral therapy without virological monitoring in Uganda and Zimbabwe: Observational analyses within the randomised ARROW trial. | en_US |
dc.type | Article | |
dc.identifier.doi | 10.1371/journal.pmed.1002432 | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/29136032 | en_US |
pubs.issue | 11 | en_US |
pubs.notes | No embargo | en_US |
pubs.notes | Published as open access article accessed via weblink provided | en_US |
pubs.publication-status | Published online | en_US |
pubs.volume | 14 | en_US |
dcterms.dateAccepted | 2017-10-09 | en_US |