Journal Article

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

Musiime, Victor, Mudenge, Boniface, Spyer, Moira J., Walker, A. Sarah, Nkanya, Immaculate, Klein, Nigel, Senfuma, Oscar, Bwakura-Dangarembizi, Mutsa, Thomason, Margaret J., Gibb, Diana M., Musoke, Philippa, Prendergast, Andrew J., Nahirya-Ntege, Patricia, Szubert, Alexander J., Ndashimye, Emmanuel

2017

Overview

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. 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. 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. ISRCTN Registry, ISRCTN24791884.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Abacavir / Acquired immune deficiency syndrome / Adolescent / AIDS / Anti-HIV Agents - administration & dosage / Antiretroviral agents / Antiretroviral drugs / Antiretroviral therapy / Antiretroviral Therapy, Highly Active - methods / Biology and Life Sciences / CD4 antigen / Child / Child, Preschool / Children / Drug Administration Schedule / Drug Monitoring - methods / Drug resistance / Drug Resistance, Viral - drug effects / Drug therapy / Female / Genotypes / HIV / HIV infections / HIV Infections - diagnosis / HIV Infections - drug therapy / HIV Infections - epidemiology / HIV-1 - drug effects / Human immunodeficiency virus / Humans / Infant / Lamivudine / Longitudinal Studies / Male / Medicine and Health Sciences / Microbial drug resistance / Monitoring / Nucleoside reverse transcriptase inhibitors / Nucleosides / Observations / People and Places / Protease inhibitors / Randomization / Randomized Controlled Trials as Topic / RNA-directed DNA polymerase / Studies / Testing / Time Factors / Treatment Outcome / Uganda - epidemiology / Viral load / Viral Load - drug effects / Viral Load - methods / Viremia / Zimbabwe - epidemiology