Abstract
To determine the impact of virological control on inflammation and cluster of differentiation 4 depletion among HIV-infected children initiating antiretroviral therapy (ART) in sub-Saharan Africa. Longitudinal cohort study. In a sub-study of the ARROW trial (ISRCTN24791884), we measured longitudinal HIV viral loads, inflammatory biomarkers (C-reactive protein, tumour necrosis factor alpha, interleukin 6 (IL-6), soluble CD14) and (Uganda only) whole blood immunophenotype by flow cytometry in 311 Zimbabwean and Ugandan children followed for median 3.5 years on first-line ART. We classified each viral load measurement as consistent suppression, blip/post-blip, persistent low-level viral load or rebound. We used multi-level models to estimate rates of increase or decrease in laboratory markers, and Poisson regression to estimate the incidence of clinical events. Overall, 42% children experienced viral blips, but these had no significant impact on immune reconstitution or inflammation. Persistent detectable viraemia occurred in one-third of children and prevented further immune reconstitution, but had little impact on inflammatory biomarkers. Virological rebound to ≥5000 copies/ml was associated with arrested immune reconstitution, rising IL-6 and increased risk of clinical disease progression. As viral load testing becomes more available in sub-Saharan Africa, repeat testing algorithms will be required to identify those with virological rebound, who need switching to prevent disease progression, whilst preventing unnecessary second-line regimen initiation in the majority of children with detectable viraemia who remain at low risk of disease progression.
Highlights
Of the 1.8 million children living with HIV globally, over 80% live in sub-Saharan Africa
Cytokine measurements were available for 99.4% (n 1⁄4 309) children pre-antiretroviral therapy (ART) and for 83.6% of subsequent 24-weekly measurements [median (IQR) 7 (7, 8) timepoints per child]
Clinical events and growth by viral load dynamics After week 48, clinical events (WHO stage 3/4 events and deaths) were relatively rare (n 1⁄4 10) but occurred at a greater rate during rebound (53/1000 child-years [95% confidence interval (CI) 20–116]) than during suppression (5/1000 child-years [95% CI 1–17]) and after blips (9/1000 child-years [95% CI 1–34]; rebound vs. suppression: P 1⁄4 0.003); there were no events in children with LLVL
Summary
Of the 1.8 million children living with HIV globally, over 80% live in sub-Saharan Africa. Antiretroviral therapy (ART) has transformed clinical outcomes in HIV-infected children [1], only two-thirds were receiving treatment in 2019 [2]. HIV infection is characterized by inflammation and cluster of differentiation 4 (CD4þ) depletion, which underlie mortality in both children [4] and adults [5,6,7,8]. There has been considerable research in adults [9,10,11,12,13,14,15,16], much less is known about the relationships between CD4þ reconstitution, inflammation and viral load (VL) dynamics following ART initiation in children, in sub-Saharan Africa
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