Optimal timing of antiretroviral treatment initiation in HIV-positive children and adolescents: a multiregional analysis from Southern Africa, West Africa and Europe

Schomaker, Michael; Leroy, Valériane; Wolfs, Tom F. W.; Technau, Karl-Günter; Renner, Lorna; Judd, Ali; Sawry, Shobna; Amorissani‐Folquet, Madeleine; Noguera-Julián, Antoni; Tanser, Frank; Eboua, François Tanoh; Navarro, Marı́a Luisa; Chimbetete, Cleophas; Amani-Bossé, Clarisse; Warszawski, Josiane; Phiri, Sam; N’Gbeche, Sylvie; Cox, Vivian; Kouéta, Fla; Giddy, Janet; Sygnaté-Sy, Haby; Raben, Dorthe; Chêne, Geneviève; Davies, Mary‐Ann

doi:10.1093/ije/dyw097

Cited by 28 publications

(44 citation statements)

References 29 publications

(41 reference statements)

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“…Causal modelling analyses that adjust for time-dependent confounding affected by prior treatment showed no mortality benefit of immediate cART 1–5 year old children, possibly because few children in routine care presented with CD4 count >750 cells/μl or CD4% >25% (WHO 2010 cART initiation threshold) and a high proportion were lost to follow-up (LTFU) with likely mortality under-ascertainment [18,19]. For children 5–10 years old, causal modelling showed a small but significant mortality benefit of 0.4% (95% Confidence IntervaI [CI]: 0.02–0.6%) by 5 years of follow-up when starting cART immediately versus deferring until CD4 <500 cells/μl (Figure 2) [20]. …”

Section: Impact Of Cart On Survivalmentioning

confidence: 99%

Survival of HIV-1 vertically infected children

Davies

Gibb

Turkova

2016

Current Opinion in HIV and AIDS

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Purpose of review It is 20 years since the start of the combination antiretroviral therapy (cART) era and >10 years since cART scale-up began in resource-limited settings. We examined survival of vertically HIV-infected infants and children in the cART era. Recent findings Good survival has been achieved on cART in all settings with up to ten-fold mortality reductions compared to before cART availability. Although mortality risk remains high in the first few months after cART initiation in young children with severe disease, it drops rapidly thereafter even for those who started with advanced disease, and longer term mortality risk is low. However, suboptimal retention on cART in routine programs threatens good survival outcomes and even on treatment children continue to experience high comorbidity risk; infections remain the major cause of death. Interventions to address infection risk include co-trimoxazole prophylaxis, isoniazid preventive therapy, routine childhood and influenza immunization and improving maternal survival. Summary Pediatric survival has improved substantially with cART and HIV-infected children are aging into adulthood. It is important to ensure access to diagnosis and early cART, good program retention and optimal co-morbidity prophylaxis and treatment to achieve the best possible long-term survival and health outcomes for vertically infected children.

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Section: Impact Of Cart On Survivalmentioning

confidence: 99%

Survival of HIV-1 vertically infected children

Davies

Gibb

Turkova

2016

Current Opinion in HIV and AIDS

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“…The PREDICT trial showed significantly faster height gain and greater mean height-for-age z-score (HAZ) with immediate compared to deferred ART, with a mean difference in HAZ of 0.22 by 144 weeks of follow-up [9]. Similarly causal modelling studies in children age 1-10 years show consistently better height gain with immediate compared to deferred ART [10,11]. For example in children aged 5-10 years with initial CD4 > 500cells/µl, immediate ART was associated with a HAZ difference of 0.1(95% CI: 0.07-0.12) by 4 years of follow-up compared to deferring until CD4 < 500 cells/µl [10].…”

Section: Improved Growthmentioning

confidence: 99%

“…The causal-modelling Figure 1. Mortality among children in Southern Africa, West Africa, and Europe with ART initiated at different CD4 thresholds: a causal modelling study [10]. analysis from Southern Africa, West Africa and Europe showed no mortality benefit of immediate compared to deferred (CD4 < 500 cells/µl) among 10-15year old adolescents; however, only 14% of adolescents in the 10-15 year age group presented with CD4 > 500cells/µl, and the population was a mix of both vertically and horizontally infected children with likely different effects of immediate ART.…”

Section: Benefits Of Universal Art For Childrenmentioning

confidence: 99%

Universal antiretroviral therapy for HIV‐infected children: a review of the benefits and risks to consider during implementation

Barlow‐Mosha

Musiime

Davies

et al. 2017

Journal of the International AIDS Society

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Background: The 2016 World Health Organization (WHO) consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, recommended to start all HIV-infected children on antiretroviral therapy (ART). Here, we explore the possible benefits and risks of implementing universal ART for all HIV-infected children and adolescents and outline some of the key considerations that led to the 2016 revision of WHO guidelines.Methods: We conducted a review of the published data from 2000 to 2016, to ascertain the clinical and programmatic benefits, as well as the risks of implementing universal ART for all children.Results and discussion: Universal ART for all children has the potential to increase treatment coverage, which in 2015 was only 51% globally, as well as providing several biological benefits, by preventing: premature death/loss to follow-up, progressive destruction of the immune system, poor growth and pubertal delay, poor neuro-cognitive outcomes and future burden to the health care system with complications of untreated HIV-infection. However, the strategy could be associated with risks, notably development of HIV drug resistance, antiretroviral drug toxicities and increased costs to an already stretched health system.Conclusion: Overall, our findings suggest that the benefits could outweigh the risks and support universal ART for all HIV-infected children, but recognize that national programmes will need to put measures in place to minimize the risks if they choose to implement the strategy.

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“…For adolescents, early initiation of ART can potentially increase the risk of poor adherence, leading to development of drug resistance, while initiating too late increases mortality and morbidity associated with HIV. Evidence from both clinical trials (Luzuriaga et al , ; Violari et al , ) and observational studies (Berk et al , ; Schomaker et al , ) supports the immediate ART initiation rule recommended by the WHO for children under 10 years of age. Conclusive evidence is lacking for adolescents.…”

Section: Introductionmentioning

confidence: 95%

Causal Comparative Effectiveness Analysis of Dynamic Continuous-Time Treatment Initiation Rules With Sparsely Measured Outcomes and Death

Hogan

2019

Biometrics

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Evidence supporting the current World Health Organization recommendations of early antiretroviral therapy (ART) initiation for adolescents is inconclusive. We leverage a large observational data and compare, in terms of mortality and CD4 cell count, the dynamic treatment initiation rules for human immunodeficiency virus‐infected adolescents. Our approaches extend the marginal structural model for estimating outcome distributions under dynamic treatment regimes, developed in Robins et al. (2008), to allow the causal comparisons of both specific regimes and regimes along a continuum. Furthermore, we propose strategies to address three challenges posed by the complex data set: continuous‐time measurement of the treatment initiation process; sparse measurement of longitudinal outcomes of interest, leading to incomplete data; and censoring due to dropout and death. We derive a weighting strategy for continuous‐time treatment initiation, use imputation to deal with missingness caused by sparse measurements and dropout, and define a composite outcome that incorporates both death and CD4 count as a basis for comparing treatment regimes. Our analysis suggests that immediate ART initiation leads to lower mortality and higher median values of the composite outcome, relative to other initiation rules.

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Optimal timing of antiretroviral treatment initiation in HIV-positive children and adolescents: a multiregional analysis from Southern Africa, West Africa and Europe

Cited by 28 publications

References 29 publications

Survival of HIV-1 vertically infected children

Survival of HIV-1 vertically infected children

Universal antiretroviral therapy for HIV‐infected children: a review of the benefits and risks to consider during implementation

Causal Comparative Effectiveness Analysis of Dynamic Continuous-Time Treatment Initiation Rules With Sparsely Measured Outcomes and Death

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