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Objective: 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., Design: Longitudinal cohort study., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: A proportion of HIV-infected children with advanced disease develop severe malnutrition soon after antiretroviral therapy (ART) initiation. We tested the hypothesis that systemic inflammation underlies the pathogenesis of severe malnutrition in HIV-infected children., Design: Cross-sectional laboratory substudy in 613 HIV-infected children initiating ART in Uganda and Zimbabwe., Methods: We measured C-reactive protein (CRP), TNFα, IL-6 and soluble CD14 by ELISA in cryopreserved plasma at baseline (pre-ART) and week-4 (children with severe malnutrition only). Independent associations between baseline biomarkers and subsequent hospitalization for severe malnutrition were identified using multivariable fractional polynomial logistic regression., Results: Compared with children without severe malnutrition (n = 574, median age 6.3 years, median baseline weight-for-age Z-score -2.2), children hospitalized for severe malnutrition post-ART (n = 39, median age 2.3 years, median baseline weight-for-age Z-score -4.8) had higher baseline CRP [median 13.5 (interquartile range 5.5, 41.1) versus 4.1 (1.4, 14.4) mg/l; P = 0.003] and IL-6 [median 9.2 (6.7, 15.6) versus 5.9 (4.6, 9.3) pg/ml; P < 0.0001], but similar overall TNFα, soluble CD14 and HIV viral load (all P > 0.06). In a multivariable model, higher pre-ART IL-6, lower TNFα and lower weight-for-age were independently associated with subsequent hospitalization for severe malnutrition. Between weeks 0 and 4, there was a significant rise in CRP, IL-6 and soluble CD14, and fall in TNFα and HIV viral load in children hospitalized for severe malnutrition (all P < 0.02)., Conclusion: Pre-ART IL-6 and TNFα were more strongly associated with hospitalization for severe malnutrition than CD4 cell count or viral load, highlighting the importance of inflammation at the time of ART initiation in HIV-infected children.