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

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

Virologic Response of Treatment Experienced HIV-Infected Ugandan Children and Adolescents on NNRTI Based First-Line Regimen, Previously Monitored Without Viral Load

“…Our ndings are in agreement with previous Sub-Saharan Africa studies which have shown that clinical and immunologic monitoring is not su cient to detect virologic failure in a timely manner [32][33][34], which further supports the need for viral load testing as a strategy to monitor response to treatment in children. This is similar to ndings from a study done in Uganda and Zimbabwe, the ARROW TRIAL which highlighted the importance of con rming virological failure before switching to second-line ART, since some children with detectable low-level viraemia spontaneously resuppressed [35].…”

Patterns of detectable viraemia among children and adults with HIV infection taking antiretroviral therapy in Zimbabwe

“…There appear to be limited data on the incidence of viral blips in children in the low-income setting (Jobanputra et al, 2015;Szubert et al, 2017). In a retrospective analysis of VL tests among children who initiated ART in Uganda and Zimbabwe, 46% of children experienced viral blips (Szubert et al, 2017).…”

“…There appear to be limited data on the incidence of viral blips in children in the low-income setting (Jobanputra et al, 2015;Szubert et al, 2017). In a retrospective analysis of VL tests among children who initiated ART in Uganda and Zimbabwe, 46% of children experienced viral blips (Szubert et al, 2017). This is considerably higher than the results of the present study, but may be explained by the use of WHO 2006 criteria for ART initiation, which relied on clinical and/or immunological assessment and not just the diagnosis of HIV infection.…”

Factors associated with high-risk low-level viremia leading to virologic failure: 16-year retrospective study of a Chinese antiretroviral therapy cohort

“…All subjects received first-line ART regimen according to Chinese guidelines for diagnosis and treatment of HIV/AIDS [26]. This included two nucleoside reverse transcriptase inhibitors (NRTIs) and a non-nucleoside reverse transcriptase inhibitor (NNRTI) that are widely used globally [27][28][29][30][31]. All participants were followed up every 3 to 6 months for evaluation of VL, CD4 + T cell counts, and other routine clinical parameters.…”