Research 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

Date Published: November 14, 2017

Publisher: Public Library of Science

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

Abstract: BackgroundAlthough 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 findingsIn 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.ConclusionsIn 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 registrationISRCTN Registry, ISRCTN24791884

Partial Text: The Joint United Nations Programme on HIV/AIDS (UNAIDS) has set an ambitious target for 2020: that 90% of people living with HIV know their status, 90% of those diagnosed receive antiretroviral therapy (ART), and 90% receiving ART have viral load (VL) suppression [1]. There are an estimated 1.8 million HIV-infected children worldwide, >80% of whom live in sub-Saharan Africa. Treating children is challenging, given their more limited access to antiretroviral drugs compared with adults; in 2015, only 49% of HIV-infected children globally were estimated to be receiving ART [2]. Current WHO guidelines recommend VL monitoring 6 and 12 months after initiating ART, and every 12 months thereafter [3]. A threshold of >1,000 copies/ml is used to define virological failure, which, if confirmed and adherence has been addressed, should be followed by the switch to second-line ART. Current guidelines also recommend stopping routine CD4 monitoring, provided patients are clinically stable and virologically suppressed. However, despite this push to increase VL monitoring and reduce reliance on immunological and clinical failure criteria, the availability of VL monitoring remains limited in low-income settings (estimated at 25% of people living with HIV in 2014 [4]), and VL is less frequently measured in low-income settings than in well-resourced ones (typically annually versus 3-monthly). Therefore, it is important to understand virological outcomes among children who are not managed using real-time VL monitoring, as this reflects the reality in most ART programmes in resource-limited settings.

The ARROW trial (ISRCTN24791884) recruited 1,206 previously untreated HIV-infected children and adolescents (aged 3 months to 17 years) eligible for ART using WHO 2006 criteria [8], between 15 March 2007 and 18 November 2008. Children were recruited from 3 centres in Uganda and 1 in Zimbabwe. Caregivers gave written informed consent for all children to enrol; if older children (8–17 years) were aware of their HIV status, they gave additional assent or consent following national guidelines. The ARROW trial and this current study were approved by Research Ethics Committees and Institutional Review Boards for Uganda (Joint Clinical Research Centre and Baylor College of Medicine and the Uganda National Council for Science and Technology [UNCST]), for Zimbabwe (Medical Research Council of Zimbabwe [MRCZ/A/1321]), and for the United Kingdom (University College London [0701/001]).

One thousand two hundred and six children initiated ART in ARROW, aged median 6.0 years (IQR 2.4,9.3) with median CD4% 12% (7%,17%) (Table 1). Over a median 4 years follow-up, 54 children (4%) died [9], 39/54 (72%) before week 48. Sixty-seven children (6%) switched to ritonavir-boosted protease-inhibitor-containing regimens (see S1 Appendix for details of VL in children who died or switched).

There are few long-term longitudinal data on virological and resistance outcomes among children initiating first-line ART in sub-Saharan Africa. In this study, we compared virological outcomes in a large cohort of children with moderately advanced HIV disease receiving first-line ART without real-time VL monitoring in Uganda and Zimbabwe. Overall, virological outcomes were good, with almost three-quarters of children on current WHO-recommended abacavir+lamivudine+NNRTI regimens fully suppressed after 4 years of ART and only 6% switching to second-line treatment. We found no evidence of a difference in VL suppression or drug susceptibility between children managed with or without CD4 monitoring. Virological blips were relatively common, but pLLVL and rebound ≥5,000 copies/ml occurred in a minority; only 15% of child-time after week 24 was spent with viraemia in children taking NNRTI+2NRTI regimens. Even among children with VL >1,000 copies/ml, intermediate/high-level drug resistance to key second-line NRTIs was found only in a minority. Children with virological rebound did have a small increase in genotypic NRTI resistance over 2 years. Overall, these results suggest that, where available, annual VL monitoring as recommended by WHO is a reasonable and pragmatic approach in low- and middle-income countries.



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