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Background: Although WHO recommends viral load (VL) monitoring 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, 1206 children initiating ART in Uganda and Zimbabwe between 15 March 2007 and 18 November 2008, aged median 6 years old, with median CD4% 12%, were randomised to monitoring with or without 12-weekly CD4 counts; and to receive two nucleoside-reverse-transcriptase-inhibitors (2NRTI, mainly abacavir+lamivudine) with a non-NRTI (NNRTI), or three NRTIs as long-term ART. All children had VL assayed retrospectively after median 4 years on ART; those >1000 copies/ml were genotyped. 316 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 VLConclusions: 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 re-suppressed, highlighting the importance of confirming virological failure before switching to second-line therapy. Children experiencing rebound ≥5000 copies/ml were much less likely to re-suppress, 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.

Background: Antiretroviral therapy (ART) adherence is critical for successful HIV treatment outcomes. Once-daily dosing could improve adherence. Plasma concentrations of once-daily vs twice-daily abacavir + lamivudine are bioequivalent in children, but no randomized trial has compared virological outcomes. Methods: Children taking abacavir + lamivudine-containing first-line regimens twice daily for more than 36 weeks in the ARROW trial (NCT02028676, ISRCTN24791884) were randomized to continue twice-daily vs move to once-daily abacavir + lamivudine (open-label). Co-primary outcomes were viral load suppression at week 48 (12% noninferiority margin, measured retrospectively) and lamivudine or abacavir-related grade 3/4 adverse events. Results: Six hundred and sixty-nine children (median 5 years, range 1–16) were randomized to twice daily (n = 333) vs once daily (n = 336) after median 1.8 years on twice-daily abacavir + lamivudine-containing first-line ART. Children were followed for median 114 weeks. At week 48, 242/331 (73%) twice daily vs 236/330 (72%) once daily had viral load less than 80 copies/ml [difference −1.6% (95% confidence interval −8.4,+5.2%) P = 0.65]; 79% twice daily vs 78% once daily had viral load less than 400 copies/ml (P = 0.76) (week 96 results similar). One grade 3/4 adverse event was judged uncertainly related to abacavir + lamivudine (hepatitis; once daily). At week 48, 9% twice daily vs 10% once daily reported missing one or more ART pills in the last 4 weeks (P = 0.74) and 8 vs 8% at week 96 (P = 0.90). Carers strongly preferred once-daily dosing. There was no difference between randomized groups in postbaseline drug-resistance mutations or drug-susceptibility; WHO 3/4 events; ART-modifying, grade 3/4 or serious adverse events; CD4% or weight-for-age/height-for-age (all P > 0.15). Conclusion: Once-daily abacavir + lamivudine was noninferior to twice daily in viral load suppression, with similar resistance, adherence, clinical, immunological and safety outcomes. Abacavir + lamivudine provides the first once-daily nucleoside backbone across childhood that can be used to simplify ART.

Background. Identifying determinants of morbidity and mortality may help target future interventions for human immunodeficiency virus (HIV)–infected children. Methods. CD4+ T-cell count, HIV viral load, and levels of biomarkers (C-reactive protein, tumor necrosis factor α [TNF-α], interleukin 6 [IL-6], and soluble CD14) and interleukin 7 were measured at antiretroviral therapy (ART) initiation in the ARROW trial (case-cohort design). Cases were individuals who died, had new or recurrent World Health Organization clinical stage 4 events, or had poor immunological response to ART. Results. There were 115 cases (54 died, 45 had World Health Organization clinical stage 4 events, and 49 had poor immunological response) and 485 controls. Before ART initiation, the median ages of cases and controls were 8.2 years (interquartile range [IQR], 4.4–11.4 years) and 5.8 years (IQR, 2.3–9.3 years), respectively, and the median percentages of lymphocytes expressing CD4 were 4% (IQR, 1%–9%) and 13% (IQR, 8%–18%), respectively. In multivariable logistic regression, cases had lower age-associated CD4+ T-cell count ratio (calculated as the ratio of the subject's CD4+ T-cell count to the count expected in healthy individuals of the same age; P < .0001) and higher IL-6 level (P = .002) than controls. Clustering biomarkers and age-associated CD4+ and CD8+ T-cell count ratios identified 4 groups of children. Group 1 had the highest frequency of cases (41% cases; 16% died) and profound immunosuppression; group 2 had similar mortality (23% cases; 15% died), but children were younger, with less profound immunosuppression and high levels of inflammatory biomarkers and malnutrition; group 3 comprised young children with moderate immunosuppression, high TNF-α levels, and high age-associated CD8+ T-cell count ratios but lower frequencies of events (12% cases; 7% died); and group 4 comprised older children with low inflammatory biomarker levels, lower HIV viral loads, and good clinical outcomes (11% cases; 5% died). Conclusions. While immunosuppression is the major determinant of poor outcomes during ART, baseline inflammation is an additional important factor, identifying a subgroup of young children with similar mortality. Antiinflammatory interventions may help improve outcomes.