Optimal time for initiating antiretroviral therapy (ART) in HIV-infected, treatment-naive children aged 2 to 5 years old
- PMID: 24114324
- PMCID: PMC3950819
- DOI: 10.1002/14651858.CD010309.pub2
Optimal time for initiating antiretroviral therapy (ART) in HIV-infected, treatment-naive children aged 2 to 5 years old
Abstract
Background: The use of combination antiretroviral therapy (cART) comprising three antiretroviral medications from at least two classes of drugs is the current standard treatment for HIV infection in adults and children. Current World Health Organization (WHO) guidelines for antiretroviral therapy recommend early treatment regardless of immunologic thresholds or the clinical condition for all infants (less than one years of age) and children under the age of two years. For children aged two to five years current WHO guidelines recommend (based on low quality evidence) that clinical and immunological thresholds be used to identify those who need to start cART (advanced clinical stage or CD4 counts ≤ 750 cells/mm(3) or per cent CD4 ≤ 25%). This Cochrane review will inform the current available evidence regarding the optimal time for treatment initiation in children aged two to five years with the goal of informing the revision of WHO 2013 recommendations on when to initiate cART in children.
Objectives: To assess the evidence for the optimal time to initiate cART in treatment-naive, HIV-infected children aged 2 to 5 years.
Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the AEGIS conference database, specific relevant conferences, www.clinicaltrials.gov, the World Health Organization International Clinical Trials Registry platform and reference lists of articles. The date of the most recent search was 30 September 2012.
Selection criteria: Randomised controlled trials (RCTs) that compared immediate with deferred initiation of cART, and prospective cohort studies which followed children from enrolment to start of cART and on cART.
Data collection and analysis: Two review authors considered studies for inclusion in the review, assessed the risk of bias, and extracted data on the primary outcome of death from all causes and several secondary outcomes, including incidence of CDC category C and B clinical events and per cent CD4 cells (CD4%) at study end. For RCTs we calculated relative risks (RR) or mean differences with 95% confidence intervals (95% CI). For cohort data, we extracted relative risks with 95% CI from adjusted analyses. We combined results from RCTs using a random effects model and examined statistical heterogeneity.
Main results: Two RCTs in HIV-positive children aged 1 to 12 years were identified. One trial was the pilot study for the larger second trial and both compared initiation of cART regardless of clinical-immunological conditions with deferred initiation until per cent CD4 dropped to <15%. The two trials were conducted in Thailand, and Thailand and Cambodia, respectively. Unpublished analyses of the 122 children enrolled at ages 2 to 5 years were included in this review. There was one death in the immediate cART group and no deaths in the deferred group (RR 2.9; 95% CI 0.12 to 68.9). In the subgroup analysis of children aged 24 to 59 months, there was one CDC C event in each group (RR 0.96; 95% CI 0.06 to 14.87) and 8 and 11 CDC B events in the immediate and deferred groups respectively (RR 0.95; 95% CI 0.24 to 3.73). In this subgroup, the mean difference in CD4 per cent at study end was 5.9% (95% CI 2.7 to 9.1). One cohort study from South Africa, which compared the effect of delaying cART for up to 60 days in 573 HIV-positive children starting tuberculosis treatment (median age 3.5 years), was also included. The adjusted hazard ratios for the effect on mortality of delaying ART for more than 60 days was 1.32 (95% CI 0.55 to 3.16).
Authors' conclusions: This systematic review shows that there is insufficient evidence from clinical trials in support of either early or CD4-guided initiation of ART in HIV-infected children aged 2 to 5 years. Programmatic issues such as the retention in care of children in ART programmes in resource-limited settings will need to be considered when formulating WHO 2013 recommendations.
Conflict of interest statement
NS has no conflict of interest. ME and MD are investigators in the collaborative IeDEA cohort studies which evaluate the effects of cART on outcomes in HIV-infected children. MP is a consultant for the WHO and LM is an employee of the WHO.
Figures
Similar articles
-
Folic acid supplementation and malaria susceptibility and severity among people taking antifolate antimalarial drugs in endemic areas.Cochrane Database Syst Rev. 2022 Feb 1;2(2022):CD014217. doi: 10.1002/14651858.CD014217. Cochrane Database Syst Rev. 2022. PMID: 36321557 Free PMC article.
-
Optimisation of antiretroviral therapy in HIV-infected children under 3 years of age.Cochrane Database Syst Rev. 2014 May 22;2014(5):CD004772. doi: 10.1002/14651858.CD004772.pub4. Cochrane Database Syst Rev. 2014. PMID: 24852077 Free PMC article. Review.
-
Optimal time for initiation of antiretroviral therapy in asymptomatic, HIV-infected, treatment-naive adults.Cochrane Database Syst Rev. 2010 Mar 17;2010(3):CD008272. doi: 10.1002/14651858.CD008272.pub2. Cochrane Database Syst Rev. 2010. PMID: 20238364 Free PMC article. Review.
-
Effectiveness of antiretroviral therapy in HIV-infected children under 2 years of age.Cochrane Database Syst Rev. 2012 Jul 11;(7):CD004772. doi: 10.1002/14651858.CD004772.pub3. Cochrane Database Syst Rev. 2012. Update in: Cochrane Database Syst Rev. 2014 May 22;(5):CD004772. doi: 10.1002/14651858.CD004772.pub4. PMID: 22786492 Updated. Review.
-
Efavirenz or nevirapine in three-drug combination therapy with two nucleoside or nucleotide-reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral-naïve individuals.Cochrane Database Syst Rev. 2016 Dec 10;12(12):CD004246. doi: 10.1002/14651858.CD004246.pub4. Cochrane Database Syst Rev. 2016. PMID: 27943261 Free PMC article. Review.
Cited by
-
Early Initiation of Antiretroviral Therapy is Protective Against Seizures in Children With HIV in Zambia: A Prospective Case-Control Study.J Acquir Immune Defic Syndr. 2024 Mar 1;95(3):291-296. doi: 10.1097/QAI.0000000000003357. J Acquir Immune Defic Syndr. 2024. PMID: 38032746
-
Older age at initiation of antiretroviral therapy predicts low bone mineral density in children with perinatally-infected HIV in Zimbabwe.Bone. 2019 Aug;125:96-102. doi: 10.1016/j.bone.2019.05.012. Epub 2019 May 10. Bone. 2019. PMID: 31082498 Free PMC article.
-
Better Outcomes Among HIV-Infected Rwandan Children 18-60 Months of Age After the Implementation of "Treat All".J Acquir Immune Defic Syndr. 2019 Mar 1;80(3):e74-e83. doi: 10.1097/QAI.0000000000001907. J Acquir Immune Defic Syndr. 2019. PMID: 30422899 Free PMC article.
-
Optimal timing of antiretroviral treatment initiation in HIV-positive children and adolescents: a multiregional analysis from Southern Africa, West Africa and Europe.Int J Epidemiol. 2017 Apr 1;46(2):453-465. doi: 10.1093/ije/dyw097. Int J Epidemiol. 2017. PMID: 27342220 Free PMC article.
-
Chronic Morbidity Among Older Children and Adolescents at Diagnosis of HIV Infection.J Acquir Immune Defic Syndr. 2016 Nov 1;73(3):275-281. doi: 10.1097/QAI.0000000000001073. J Acquir Immune Defic Syndr. 2016. PMID: 27171738 Free PMC article.
References
References to studies included in this review
References to studies excluded from this review
-
- Munyagwa M, Baisley K, Levin J, Brian M, Grosskurth H, Maher D. Mortality of HIV-infected and uninfected children in a longitudinal cohort in rural south-west Uganda during 8 years of follow-up. Tropical medicine & international health : TM & IH. 2012;17(7):836–43. - PubMed
-
- Patel K, Hernán MA, Williams PL, Seeger JD, McIntosh K, Van Dyke RB, Seage GR, 3rd Pediatric AIDS Clinical Trials Group 219/219C Study Team. Long-term effects of highly active antiretroviral therapy on CD4+ cell evolution among children and adolescents infected with HIV: 5 years and counting. Clin Infect Dis. 2008;46(11):1751–60. - PMC - PubMed
Additional references
-
- Division of AIDS. [Accessed 28 October 2009];Table for grading the severity of Adult and Pediatric Adverse Events. http://rcc.tech-res.com/Document/safetyandpharmacovigilance/DAIDS.AE.Gra....
-
- Fenner L, Brinkhof MW, Keiser O, Weigel R, Cornell M, Moultrie H, Prozesky H, Technau K, Eley B, Vaz P, Pascoe M, Giddy J, Van Cutsem G, Wood R, Egger M, Davies MA. Early mortality and loss to follow-up in HIV-infected children starting antiretroviral therapy in Southern Africa. J Acquir Immune Defic Syndr. 2010;54(5):542–532. - PMC - PubMed
-
- Bozek Jan, Oxman Andrew, Schunemann Olger. GradePro 2008. 3.2 for Windows. GRADE Working Group; 2008.
-
- Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. Journal of clinical epidemiology. 2011;64(4):383–94. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials