The majority of excess deaths observed in the deferred treatment arm was among untreated children who died before meeting the clinical/immune criteria for ART. Following the interim result of this trial, the WHO, United States and PENTA guidelines were all revised in 2008 to recommend immediate ART in all HIV-infected infants under 12 months, irrespective of clinical or immune status . In the WHO 2010 guidelines, this was extended to all children under 24 months , for programmatic reasons and also in recognizing that observational data indicate the higher risk of AIDS and death extend to young children below 2 years [22,23]. Importantly, final results of the CHER trial showed that very few children in the early ART arms switched to second line (4 of 252), although this may have been partly because of the treatment-sparing strategy in which infants on early ART were randomized to treatment interruption after 40 or 96 weeks of ART (see later section) [25▪▪].
The Paediatric Randomized Early vs. Deferred Initiation in Cambodia and Thailand (PREDICT) study, randomized 284 children, aged 1–12 years with CD4 of 15–24% and no AIDS-defining illness to immediate ART or deferred treatment until CD4 less than 15% or Centres for Disease Control and Prevention (CDC) stage C. At 3 years of follow-up, there was no difference in the AIDS-free survival: 97.9% (95% CI, 93.7–99.3) and 98.7% (95%CI, 94.7–99.7, P = 0.6) in the early and deferred arms, respectively [28▪▪]. The rate of events was very low (one death and five CDC C events), and the authors concluded that the study was underpowered to detect a difference between the two strategies. However, there were also no differences between the two arms in any secondary outcomes: rate of hospitalization, CDC stage B or C events, virological suppression, immunological response or neurodevelopmental outcomes, suggesting no significant benefit of earlier treatment in asymptomatic children above 1 year. However, it is important to note that children in the deferred treatment arm received CD4 assessments every 3 months and prompt ART initiation at higher median CD4% as compared to other studies in comparable routine care settings [30,31]. Furthermore, this trial included mainly older surviving children, with a median age of 6.4 years at randomization (only 26% were aged <3 years and 6% aged 1–2 years); therefore, the findings may not be generalizable to all children below 5 years.
In the absence of clinical trial data, the South Africa International Epidemiologic Database to Evaluate AIDS collaboration conducted a causal modelling analysis, using data from the their large cohort of approximately 3000 children aged 2 to below 5 years at first presentation [32▪]. The model estimated mortality over 3 years if the 2013 guidelines for immediate ART was implemented as compared to starting ART when CD4 declined to less than 25% or less than 750 cell counts as per routine practice within the cohort. The model showed no significant benefit in mortality from the immediate treatment strategy, most likely because of the relatively low risk of mortality in children aged 2–5 years with CD4 more than 25%.
In summary, there is limited evidence to support immediate ART in children aged 2–5 years in terms of survival or AIDS-free survival. This is partly reflected in the WHO recommendations, which state that priority for immediate ART should be given to children aged less than 2 years or those aged 2–5 years with advanced disease stage .
As most children on ART are now surviving into adolescence and young adulthood, there is a need to study the impact of earlier treatment initiation on long-term response and morbidity. Numerous studies have shown that children who initiate ART at low CD4 or older age are less likely to achieve immune reconstitution to near normal levels, often defined as CD4 at least 25% [33–35] or at least 30% , which represents the upper threshold for start of treatment in children above 2 years. Children who fail to reach this threshold may be vulnerable to disease progression. However, most studies have been limited to follow-up of 2–5 years on ART, and the long-term trajectory of immune response is unclear.
These findings are consistent with recent results from an observational study in Thailand. Among 507 children followed up for a median of 7 years, 22% failed to achieve immune reconstitution defined as confirmed CD4 of at least 25%, of whom over half had sustained viral suppression less than 400 copies throughout their follow-up time . Age above 7 years and very low CD4 less than 5% at start of ART were associated with poor immune reconstitution, although the impact on clinical events was not assessed. In contrast, in the PREDICT trial, composed of similarly older children, there were no differences in long-term immune response in the immediate versus deferred ART arms, and it was unclear if there was an effect of age at start of therapy [28▪▪].
In summary, observational studies suggest that delayed initiation of ART until age above 7 years or when severely immunosuppressed significantly reduces the probability of immune reconstitution, although the clinical implications of this remains unclear. In adult studies, nonimmune response despite viral suppression has been associated with increased risk of severe clinical events  and death , whereas prolonged periods of immune reconstitution (defined as CD4 ≥ 500 cells/mm3) have been associated with improved life expectancy, comparable to the general population [42,43]. No equivalent study has yet been conducted in perinatally infected patients, mainly because of lack of data on long-term clinical outcomes; this highlights the need for continued follow-up after children transfer to adolescent and adult clinics.
There were two recent reviews on neurodevelopmental outcomes in perinatally HIV-infected children and adolescents [44▪▪,45]. AIDS-defining illness and low CD4 have been associated with poorer neurodevelopmental outcomes in resource-rich and resource-limited settings [46▪,47▪]. However, the debate on whether earlier treatment initiation improves neurodevelopmental outcomes among children without advanced disease stage continues. In the CHER trial's neurological sub-study, children in the early ART group had significantly higher General and Locomotor scores at 11 months of age as compared to the deferred ART group, and were comparable to HIV-uninfected controls [27▪]. However, differences between the groups were relatively small, and the mean General and Locomotor score in the deferred arm remained within the normal developmental range.
In the PREDICT trial sub-study, with a median age 9 years at last examination, there was no difference in the neurocognitive performance in the early versus deferred ART groups, despite repeat measurements throughout the study. Both groups had poorer outcomes as compared to HIV-exposed uninfected controls on key measures [29▪]. However, it is important to note that these measures were based on the methods developed in the USA or Europe and have not been standardized for these other settings. Also comparisons with HIV-exposed uninfected controls may be subject to unmeasured confounders, such as differences in the family settings and access to care, which may affect outcomes. Also the magnitude of differences in outcomes and their impact on daily function, learning capabilities and quality of life are unknown.
As with adults, earlier initiation of lifelong ART poses potential risks of long-term toxicities, increased risk of virological failure and limited treatment options. A fuller discussion of potential toxicities is beyond the scope of this review. Briefly, concerns have been raised regarding prolonged exposure to tenofovir (recommended first line for children >3 years) and protease inhibitors (lopinavir is recommended first line for children <3 years) among children and adolescents because of their impact on bone mineral density/kidney function and metabolic disease respectively, during critical periods of growth and development [48▪,49,50]. Such concerns are particularly important in resource-constrained settings wherein there is limited monitoring of such toxicities.
Recent results from the CHER and PREDICT trials show very good long-term virological suppression and low rates of switch to second line among children on immediate ART [25▪▪,26]. However, data from observational studies in routine care settings suggest much higher rates of virological failure in Asia and Africa (range from 19 to 25% at 3–5 years of ART in settings with routine virological monitoring) [51,52▪,53]. Also a recent meta-analysis reported higher levels of triple-class virological failure in European adolescents starting ART compared with 5–9-year olds . In countries, where only first line and second-line treatment options are available, this presents a critical dilemma and has resulted in trials exploring treatment-sparing strategies.
The first is the Nevirapine Resistance Study (NEVEREST) trial, wherein children aged below 3 years started ART with lopinavir-based therapy and continued on this regimen or switched to nevirapine-based regimen after a prolonged period of virological suppression with the aim of preserving lopinavir for second line. Results suggested that those who switched to nevirapine had poorer virological outcomes but better growth and CD4 responses [55▪▪]. The other strategy was within the CHER trial, in which children on early ART had a treatment interruption at 40 or 96 weeks with CD4 and clinical-guided criteria for reinitiation of ART [25▪▪]. Up to a third of children in the 96 weeks arm remained off treatment at the end of the study with good CD4 profiles. The study showed that this strategy was well tolerated and superior when compared with deferred ART. However, the study was not powered to detect a difference in outcomes between the two treatment interruption arms, and there was no early ART continuous arm to compare with. These findings suggest that there may be a future role for early intensive treatment followed by periods of interruption, but, critically, rely on close clinical and laboratory monitoring, which is not available everywhere. Nonetheless, the findings confirm conclusions from previous studies that, unlike in adults, treatment interruption in children appears well tolerated without higher risk of mortality, serious clinical events  or negative impact on long-term immune/virological response after reinitiation of ART [57▪], although further study is needed.
With an estimated 300 000 children newly infected with HIV in 2012 alone, questions concerning when to start lifelong ART remain extremely relevant to paediatrics. Although there is strong evidence of wide ranging benefits of immediate ART in infants, there remains conflicting evidence on the benefits of early ART in asymptomatic children above 1 year. Modelling studies suggest that delayed ART initiation at older ages and lower CD4 reduces the probability of immune reconstitution with unknown implications for long-term disease progression, highlighting the need for continued follow-up of perinatally infected patients as they transfer to adolescent and adult clinics. Lastly, recent trial results suggest that treatment interruption following early intensive ART during infancy may be a well tolerated alternative strategy but requires close monitoring, which is not available in most of the affected regions.
Papers of particular interest, published within the annual period of review, have been highlighted as:
4. Newell M-L, Coovadia H, Cortina-Borja M, et al. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet 2004; 364:1236–1243.
5▪. Becquet R, Marston M, Dabis F, et al. Children who acquire HIV infection perinatally are at higher risk of early death than those acquiring infection through breastmilk: a meta-analysis. PLoS One 2012; 7:e28510.
A large pooled analysis of over 12 000 children, which showed poorer survival in perinatally infected as compared to postnatally infected children without ART.
12. Dunn D, Woodburn P, Duong T, et al. Current CD4 cell count and the short-term risk of AIDS and death before the availability of effective antiretroviral therapy in HIV-infected children and adults. J Infect Dis 2008; 197:398–404.
13. Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children: Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection Edited by; 2012. Centres of Disease Control and Prevention. Developed by the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children—A Working Group of the Office of AIDS Research Advisory Council (OARAC) http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf
[Accessed 3 March 2013]
14. Welch S, Sharland M, Lyall EG, et al. PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection. HIV Med 2009; 10:591–613.
15. Okomo U, Togun T, Oko F, et al. Mortality and loss to programme before antiretroviral therapy among HIV-infected children eligible for treatment in The Gambia, West Africa. AIDS Res Ther 2012; 9:28.
16. Sutcliffe C, van Dijk J, Munsanje B, et al. Risk factors for pretreatment mortality among HIV-infected children in rural Zambia: a cohort study. PLoS One 2011; 6:e29294.
17▪. Mugglin C, Wandeler G, Estill J, et al. Retention in care of HIV-infected children from HIV test to start of antiretroviral therapy: systematic review. PLoS One 2013; 8:e56446.
A systematic review including 10 studies from Africa and Asia with more than 10 000 children showed that 63.2–90.7% of children met the eligibility criteria for ART and 39.5–99.4% of the eligible children started ART.
18. Avila D, Patel K, Chi B, Wools-Kaloustian K, Leroy V, Sohn A, Chimbetete C, Hazra R, Egger M, Davies MA. Severe Immunodeficiency in Children Starting ART in Low-, Middle- and High-income Countries (Poster #940). In 20th Conference on Retroviruses and Opportunistic Infections. Edited by. Georgia, USA; 2013.
19. Leroy V, Malateste K, Rabie H, et al. Outcomes of antiretroviral therapy in children in Asia and Africa: a comparative analysis of the IeDEA pediatric multiregional collaboration. J Acquir Immune Defic Syndr 2013; 62:208–219.210.1097/QAI.1090b1013e31827b31870bf.
20. Kabue MM, Buck WC, Wanless SR, et al. Mortality and clinical outcomes in HIV-infected children on antiretroviral therapy in Malawi, Lesotho, and Swaziland. Pediatrics 2012; 130:e591–e599.
21. TREAT Asia Pediatric Observational Cohort (TApHOD) International Epidemiologic Databases to Evaluate AIDS (IeDEA) Southern Africa Paediatric Group A biregional survey and review of first-line treatment failure and second-line paediatric antiretroviral access and use in Asia and southern Africa. J Int AIDS Soc 2011; 14:7.
22. HIV Paediatric Prognostic Markers Collaborative Study Group (HPPMCS) Short-term risk of disease progression in HIV-1-infected children receiving no antiretroviral therapy or zidovudine monotherapy: a meta-analysis. Lancet 2003; 362:1605–1611.
23. Cross Continents Collaboration for Kids (3Cs4kids) Analysis and Writing Committee Markers for predicting mortality in untreated HIV-infected children in resource-limited settings: a meta-analysis. AIDS 2008; 22:97–105.
24. Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med 2008; 359:2233–2244.
Final results of the CHER trial, demonstrated better clinical and immunological outcomes in children initiated early time-limited ART as compared to deferred ART. Treatment interruption appeared well tolerated but needed close monitoring.
26. Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med 2008; 359:2233–2244.
27▪. Laughton B, Cornell M, Grove D, et al. Early antiretroviral therapy improves neurodevelopmental outcomes in infants. AIDS 2012; 26:1685–1690.
Sub-study of the CHER trial: cross-sectional study, which showed that infants on early ART had better neurodevelopmental outcomes as compared to deferred ART arm at 11 months of age, with comparable outcomes to uninfected controls.
28▪▪. Puthanakit T, Saphonn V, Ananworanich J, et al. Early versus deferred antiretroviral therapy for children older than 1 year infected with HIV (PREDICT): a multicentre, randomised, open-label trial. Lancet Infect Dis 2012; 12:933–941.
Trial in Cambodia and Thailand with 300 children aged 1–12 years with CD4 15–24% randomized to immediate versus deferred ART showed no difference in AIDS-free survival at 144 weeks.
29▪. Puthanakit T, Ananworanich J, Vonthanak S, et al. Cognitive function and neurodevelopmental outcomes in HIV-infected children older than 1 year of age randomized to early versus deferred antiretroviral therapy: the PREDICT neurodevelopmental study. Pediatr Infect Dis J 2013; 32:501–508.
Sub-study of the PREDICT trial, which showed no difference in neurodevelopmental outcomes in children (median age 9 years at last examination) who received early versus deferred ART, despite repeat measurements over 144 weeks of follow-up.
30. McConnell MS, Chasombat S, Siangphoe U, et al. National program scale-up and patient outcomes in a pediatric antiretroviral treatment program, Thailand 2000-2007. J Acquir Immune Defic Syndr 2010; 54:423–429.
31. Collins IJ, Jourdain G, Hansudewechakul R, et al. Long-term survival of HIV-infected children receiving antiretroviral therapy in Thailand: a 5-year observational cohort study. Clin Infect Dis 2010; 51:1449–1457.
32▪. M-A Davies, M Schomaker, T Gsponer, J Ndirangu, S Phiri, H Moultrie, K Technau, V Cox, J Giddy, C Chimbetete, et al. When to start ART in children aged 2-5 years? Causal modeling analysis of IeDEA southern Africa (TUPE313). In 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Edited by Kuala Lumpur, Malaysia; 2013.
Modelling study showed no benefit in survival with the application of immediate ART in children aged 2–5 years irrespective of immunological or clinical status.
33. Patel K, Hernan MA, Williams PL, et al. 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; 46:1751–1760.
34. Puthanakit T, Kerr SJ, Ananworanich J, et al. Pattern and predictors of immunologic recovery in human immunodeficiency virus-infected children receiving non-nucleoside reverse transcriptase inhibitor-based highly active antiretroviral therapy. Pediatr Infect Dis J 2009; 28:488–492.
35. Soh CH, Oleske JM, Brady MT, et al. Long-term effects of protease-inhibitor-based combination therapy on CD4 T-cell recovery in HIV-1-infected children and adolescents. Lancet 2003; 362:2045–2051.
36. Walker AS, Doerholt K, Sharland M, Gibb DM. Collaborative HIV Paediatric Study CHIPS Steering Committee Response to highly active antiretroviral therapy varies with age: the UK and Ireland Collaborative HIV Paediatric Study. AIDS 2004; 18:1915–1924.
37▪▪. Lewis J, Walker AS, Castro H, et al. Age and CD4 count at initiation of antiretroviral therapy in HIV-infected children: effects on long-term T-cell reconstitution. J Infect Dis 2012; 205:548–556.
Novel modelling study using data from 127 children in a European trial to model the long-term CD4 trajectory of children, by age and CD4 at start of therapy, showing that children initiating ART at older ages and with low CD4 are less likely to achieve immune reconstitution.
38▪. ARROW Trial team Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial. Lancet 2013; 381:1391–1403.
A large trial of 1206 Ugandan and Zimbabwean children randomized to clinically driven monitoring or clinical and laboratory driven monitoring, which reported no difference in new WHO stage 4 event or death at 5 years of ART.
39. Collins I, Ngo-Giang-Huong N, Jourdain G, Chanta C, Puangsombat A, Kwanchaipanich R, Bunjongpak S, Cressey T, Le-Coeur S, Jaffar S, et al. Long-term immune response in HIV-infected children receiving highly active antiretroviral therapy in Thailand: outcomes at 7-years. In 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Kuala Lumpur, Malaysia Edited by (#TUPE314).; 2013.
40. Lapadula G, Cozzi-Lepri A, Marchetti G, et al. Risk of clinical progression among patients with immunological nonresponse despite virological suppression after combination antiretroviral treatment. AIDS 2013; 27:769–779.710.1097/QAD.1090b1013e32835cb32747.
41. Gilson R, Man SL, Copas A, et al. Discordant responses on starting highly active antiretroviral therapy: suboptimal CD4 increases despite early viral suppression in the UK Collaborative HIV Cohort (UK CHIC) Study*. HIV Med 2010; 11:152–160.
42. The Collaboration of Observational HIV Epidemiological Research Europe in EuroCoord All-cause mortality in treated HIV-infected adults with CD4 ≥500/mm3 compared with the general population: evidence from a large European observational cohort collaboration. Int J Epidemiol 2012; 41:433–445.
43. Lewden C, Chêne G, Morlat P, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr 2007; 46:72–77.10.1097/QAI.1090b1013e318134257a.
44▪▪. Laughton B, Cornell M, Boivin M, Van Rie A. Neurodevelopment in perinatally HIV-infected children: a concern for adolescence. J Int AIDS Soc 2013; 16:18603.
Insightful review of studies on neurodevelopment in HIV-infected children and adolescents in randomized trials and observational studies.
45. Le Doaré K, Bland R, Newell M-L. Neurodevelopment in children born to HIV-infected mothers by infection and treatment status. Pediatrics 2012; 130:e1326–e1344.
46▪. Ruel TD, Boivin MJ, Boal HE, et al. Neurocognitive and motor deficits in HIV-infected Ugandan children with high CD4 cell counts. Clin Infect Dis 2012; 54:1001–1009.
Cross-sectional study showed that HIV-infected ART-naive children in Uganda with CD4 more than 350 cells had poorer neurocognitive and motor scores as compared to uninfected controls despite having high CD4 (median >655 cells).
47▪. Smith R, Chernoff M, Williams PL, et al. Impact of HIV severity on cognitive and adaptive functioning during childhood and adolescence. Pediatr Infect Dis J 2012; 31:592–598.510.1097/INF.1090b1013e318253844b.
Cross-sectional study of HIV-infected youth (aged 7–16 years) in the USA, showed children with previous CDC C event had poorer cognitive performance, whereas children without CDC C events performed comparably to HIV-uninfected controls.
48▪. Barlow-Mosha L, Eckard AR, McComsey GA, Musoke PM. Metabolic complications and treatment of perinatally HIV-infected children and adolescents. J Int AIDS Soc 2013; 16:18600.
Comprehensive review of long-term treatment complications and toxicities of children and adolescents on ART as part of a special issue on perinatally HIV-infected adolescents.
49. Bhimma R, Purswani MU, Kala U. Kidney disease in children and adolescents with perinatal HIV-1 infection. J Int AIDS Soc 2013; 16:18596.
50. Puthanakit T, Siberry GK. Bone health in children and adolescents with perinatal HIV infection. J Int AIDS Soc 2013; 16:18575.
51. Davies MA, Moultrie H, Eley B, et al. Virologic failure and second-line antiretroviral therapy in children in South Africa: the IeDEA Southern Africa collaboration. J Acquir Immune Defic Syndr 2011; 56:270–278.
52▪. Lowenthal ED, Ellenberg JH, Machine E, et al. Association between efavirenz-based compared with nevirapine-based antiretroviral regimens and virological failure in HIV-infected children. JAMA 2013; 309:1803–1809.
Observational cohort of 804 children aged 3–16 years on ART and followed for median of 69 months in Botswana, showed higher rates of virological failure in those initiated on nevirapine versus efavirenz-based first-line regimens.
53. Collins I, Cairns J, Le Coeur S, et al. Five-year trends in antiretroviral usage and drug costs in HIV-infected children in Thailand. J Acquir Immune Defic Syndr 2013; 64:95–102.110.1097/QAI.1090b1013e318298a318309.
54. Castro H, Judd A, Gibb DM, et al. Risk of triple-class virological failure in children with HIV: a retrospective cohort study. Lancet 2011; 377:1580–1587.
55▪▪. Kuhn L, Coovadia A, Strehlau R, et al. Switching children previously exposed to nevirapine to nevirapine-based treatment after initial suppression with a protease-inhibitor-based regimen: long-term follow-up of a randomised, open-label trial. Lancet Infect Dis 2012; 12:521–530.
Final results of the NEVEREST trial showing children on continuous lopinavir-based regimens were more likely to achieve virological suppression as compared to those switched to nevirapine-based regimen after suppression on lopinavir. Most failures in the nevirapine arm were detected within 52 weeks after switch.
56. Paediatric European Network for Treatment of AIDS Response to planned treatment interruptions in HIV infection varies across childhood. AIDS 2010; 24:231–241.210.1097/QAD.1090b1013e328333d328343.
57▪. Bunupuradah T, Duong T, Compagnucci A, et al. Outcomes after reinitiating antiretroviral therapy in children randomized to planned treatment interruptions. AIDS 2013; 27:579–589.510.1097/QAD.1090b1013e32835c31181.