To our knowledge, this is the largest reported cohort of children on ART across multiple African countries, which reflects the scale-up of HIV care and treatment across sub-Saharan Africa. At 12 and 24 months, 80% and 72% of children were retained in care, 16% and 22% were LTF, and 5% and 7% were known to have died. The true proportion of children who have died is likely much higher than reported values, given some children who are categorized as LTF are undocumented deaths.18,33 Although the outcomes of this study are similar to other cohorts,7,11,14,15,17–19,22,34,35 there was substantial variation within specific populations of children, particularly the youngest (<1 year) and those with advanced disease, and across country programs.
One of the most striking findings of this study is the outcomes seen among the youngest children initiating ART (<1 year of age). Although young age, and advanced disease, has been associated with increased risk of LTF and death,4,7,13–15,17,36–39 the fact that only half of children who initiated ART during infancy were retained in care at 24 months and 18% have died is sobering (Table 2). Although these estimates can be considered an improvement from the reports in the pre-ART era (50% mortality at 24 months), the mortality rates remain unacceptably high in the context of ART.40
From 2005 through 2011, we observed an increase in the proportion of young children (both infants younger than 1 year and young children aged 1–2 years) initiating ART (Fig. 1) and a concomitant decrease in the severity of illness among infants (see Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A362). These findings reflect improved access to early diagnostic testing in the 4 countries41 and implementation of the WHO guidelines recommending treatment of all children younger than 1 year, later revised to younger than 2 years. However, despite a decrease in the proportion of infants categorized as severely ill at the time of ART initiation from 2005 to 2011, as noted, there was no concurrent improvement in retention or mortality over time (see Table S2, Supplemental Digital Content, http://links.lww.com/QAI/A362). We would anticipate improved outcomes with the enrollment of healthier children and the accrual of benefits from early treatment.5,6,10 Although it is encouraging to see greater numbers of young children initiating earlier treatment, further research is needed to identify other factors impacting health outcomes among this highly vulnerable group of children. These findings also underscore the ongoing need for special attention for infants to be promptly diagnosed, initiated on treatment, and retained in care.
Another striking finding of this study is the fact that country programs contributing to this analysis achieved vastly different outcomes, with retention at 24 months ranging from 62% to 93%. Moreover, within countries, we observed substantial heterogeneity in both retention and mortality. All facilities received technical support through ICAP and implemented the same general model of care, which emphasizes early infant diagnosis, family-focused care, involvement of peer-educators, and active follow-up. Possible reasons explaining such differences in country outcomes likely include a combination of national influences, such as national leadership, access to health services, and requirements for medical record documentation, and epidemiological and program factors, such as HIV seroprevalence (ranging from 2.9% in Rwanda to 11.5% in Mozambique42), patient caseload, provider–patient ratios, and decentralization of services. Because the proportion of documented transfers is fairly similar across programs, variability in quality of documentation of transfers may explain some but not all the variation seen in retention.
There are a number of strengths to this analysis. The first is that it is the largest, single program multicountry analysis reporting outcomes of children on ART over the period of PEPFAR scale-up beginning in 2005. The results are likely generalizable to other PEPFAR-supported pediatric HIV programs and reflect the diversity in outcomes from rapid scale-up of ART for children across SSA. The use of patient-level data allows analysis within age categories and links patient-level data to facility data. Finally, we were able to assess retention, LTF, and death across a relatively long follow-up period of 24 months.
An important limitation of this analysis is the amount of missing data for patient characteristics at the time of ART initiation, which may be because of poor documentation, lack of clinical staging, and limited access to CD4 testing. The large amount of missing data prevented the use of imputation techniques. Instead, we chose to include “missing” as a separate category in our regression analyses to investigate whether children with missing information differed from children with complete information in outcomes of interest, and indeed, children with missing data seem to be at increased risk for LTF or death. This is not surprising as clinicians report that some children entering HIV care programs attend only one clinic visit and do not return to complete full enrollment evaluation including CD4 assessment. Second, this study only includes ICAP-supported pediatric HIV facilities that have capacity for electronic patient-level database, which may represent higher-resourced facilities compared with others. A total of 192 facilities were included representing 31% of ICAP-supported care and treatment facilities in Kenya (24%), Rwanda (88%), Mozambique (47%), and Tanzania (39%), and regional differences within countries were not analyzed. Finally, this analysis does not include HIV-exposed infants, HIV-infected children who have not enrolled in care, or those who have enrolled in care but have not initiated ART—all groups that have lower estimated retention rates.12,22,34,52–54
It is established that the benefits of ART on children in resource-limited settings are comparable with those in developed countries3–9; yet, these benefits are not currently realized in many pediatric HIV programs, such as those presented in this analysis. This study builds upon the evidence that overall retention, LTF, and death are suboptimal, and young children and those with advanced disease are at highest risk for LTF and death. Despite encouraging results suggesting enrollment of a larger proportion of younger children and a smaller proportion of those with severe illness, we do not yet see substantial improvement in reported retention, LTF, or death of young children. The vast differences across country programs illustrate that improved retention is achievable. However, additional attention to prompt diagnosis, early ART initiation, active follow-up of children who miss appointments, and improved documentation of known transfers and deaths are urgent priorities for pediatric HIV programs.
3. Ciaranello AL, Chang Y, Margulis AV, et al.. Effectiveness of pediatric
antiretroviral therapy in resource-limited settings: a systematic review and meta-analysis. Clin Infect Dis. 2009;49:1915–1927.
4. Sutcliffe CG, van Dijk JH, Bolton C, et al.. Effectiveness of antiretroviral therapy among HIV
-infected children in sub-Saharan Africa. Lancet Infect Dis. 2008;8:477–489.
5. Edmonds A, Yotebieng M, Lusiama J, et al.. The effect of highly active antiretroviral therapy on the survival of HIV
-infected children in a resource-deprived setting: a cohort study. PLoS Med. 2011;8:e1001044.
6. Desmonde S, Coffie P, Aka E, et al.. Severe morbidity and mortality in untreated HIV
-infected children in a paediatric care programme in Abidjan, Cote d'Ivoire, 2004-2009. BMC Infect Dis. 2011;11:182.
7. Rouet F, Fassinou P, Inwoley A, et al.. Long-term survival and immuno-virological response of African HIV
-1-infected children to highly active antiretroviral therapy regimens. AIDS. 2006;20:2315–2319.
8. Fassinou P, Elenga N, Rouet F, et al.. Highly active antiretroviral therapies among HIV
-1-infected children in Abidjan, Cote d'Ivoire. AIDS. 2004;18:1905–1913.
9. O'Brien DP, Sauvageot D, Olson D, et al.. Treatment outcomes stratified by baseline immunological status among young children receiving nonnucleoside reverse-transcriptase inhibitor-based antiretroviral therapy in resource-limited settings. Clin Infect Dis. 2007;44:1245–1248.
10. 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.
11. KIDS-ART-LINC. Low risk of death, but substantial program attrition, in pediatric HIV
treatment cohorts in Sub-Saharan Africa. J Acquir Immune Defic Syndr. 2008;49:523–531.
12. Anaky MF, Duvignac J, Wemin L, et al.. Scaling up antiretroviral therapy for HIV
-infected children in Cote d'Ivoire: determinants of survival and loss to programme. Bull World Health Organ. 2010;88:490–499.
13. Bolton-Moore C, Mubiana-Mbewe M, Cantrell RA, et al.. Clinical outcomes and CD4 cell response in children receiving antiretroviral therapy at primary health care facilities in Zambia. JAMA. 2007;298:1888–1899.
14. Davies MA, Keiser O, Technau K, et al.. Outcomes of the South African National Antiretroviral Treatment Programme for children: the IeDEA Southern Africa collaboration. S Afr Med J. 2009;99:730–737.
15. Sauvageot D, Schaefer M, Olson D, et al.. Antiretroviral therapy outcomes in resource-limited settings for HIV
-infected children <5 years of age. Pediatrics. 2010;125:e1039–e1047.
16. Peacock-Villada E, Richardson BA, John-Stewart GC. Post-HAART outcomes in pediatric
populations: comparison of resource-limited and developed countries. Pediatrics. 2011;127:e423–e441.
17. Ekouevi DK, Azondekon A, Dicko F, et al.. 12-month mortality and loss-to-program in antiretroviral-treated children: the IeDEA pediatric
West African Database to evaluate AIDS (pWADA), 2000-2008. BMC Public Health. 2011;11:519.
18. Fenner L, Brinkhof MW, Keiser O, et al.. Early mortality and loss to follow-up in HIV
-infected children starting antiretroviral therapy in Southern Africa. J Acquir Immune Defic Syndr. 2010;54:524–532.
19. Ellis J, Molyneux EM. Experience of anti-retroviral treatment for HIV
-infected children in Malawi: the 1st 12 months. Ann Trop Paediatr. 2007;27:261–267.
20. Mugavero MJ, Amico KR, Westfall AO, et al.. Early retention
care and viral load suppression: implications for a test and treat approach to HIV
prevention. J Acquir Immune Defic Syndr. 2012;59:86–93.
22. Lahuerta M, Lima J, Elul B, et al.. Patients enrolled in HIV
care in Mozambique: baseline characteristics and follow-up outcomes. J Acquir Immune Defic Syndr. 2011;58:e75–e86.
25. WHO. Report of the WHO Technical Reference Group, Paediatric HIV
/ART Care Guideline Group Meeting. Geneva, Switzerland; 2008.
26. Vaz P, Macassa E, Santos P, et al.. National Guideline on Treatment for HIV
-Infected Children, Mozambique. Maputo, Mozambique; 2008.
27. The United Republic of Tanzania MoHaSW-NACP. National Guideline for the Management of HIV
and AIDS, Third Edition. Dar es Salaam, Tanzania; 2008.
28. National AIDS/STI Control Program K. Guidelines for Antiretroviral Therapy in Kenya, 4th edn. Nairobi, Kenya: Ministry of Medical Services; 2011.
29. Vaz P, Macassa E, Santos P, et al.. National Guideline on Treatment for HIV
-Infected Children, Mozambique. Maputo, Mozambique; 2011.
30. The United Republic of Tanzania MoHaSW-NACP. National Guideline for the Management of HIV
and AIDS, Fourth Edition. Dar es Salam, Tanzania; 2012.
31. Chi BH, Yiannoutsos CT, Westfall AO, et al.. Universal definition of loss to follow-up in HIV
treatment programs: a statistical analysis of 111 facilities in Africa, Asia, and Latin America. PLoS Med. 2011;8:e1001111.
32. Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, et al.. CDC growth charts: United States. Adv Data. 2000:1–27.
33. McGuire M, Munyenyembe T, Szumilin E, et al.. Vital status of pre-ART and ART patients defaulting from care in rural Malawi. Trop Med Int Health. 2010;15(Suppl 1):55–62.
34. Braitstein P, Katshcke A, Shen C, et al.. Retention
-infected and HIV
-exposed children in a comprehensive HIV
clinical care programme in Western Kenya. Trop Med Int Health. 2010;15:833–841.
35. Asfawesen GY, Solomie J, Bisirat T, et al.. Outcome in a paediatric cohort receiving ART in Addis Abeba, Ethiopia. Acta Paediatr. 2011;100:1164–1167.
36. Wamalwa DC, Obimbo EM, Farquhar C, et al.. Predictors of mortality in HIV
-1 infected children on antiretroviral therapy in Kenya: a prospective cohort. BMC Pediatr. 2010;10:33.
37. Markers for predicting mortality in untreated HIV
-infected children in resource-limited settings: a meta-analysis. AIDS. 2008;22:97–105.
38. Fetzer BC, Hosseinipour MC, Kamthuzi P, et al.. Predictors for mortality and loss to follow-up among children receiving anti-retroviral therapy in Lilongwe, Malawi. Trop Med Int Health. 2009;14:862–869.
39. Bong CN, Yu JK, Chiang HC, et al.. Risk factors for early mortality in children on adult fixed-dose combination antiretroviral treatment in a central hospital in Malawi. AIDS. 2007;21:1805–1810.
40. Newell ML, 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.
41. Chatterjee A, Tripathi S, Gass R, et al.. Implementing services for Early Infant Diagnosis (EID) of HIV
: a comparative descriptive analysis of national programs in four countries. BMC Public Health. 2011;11:553.
43. Lowrance DW, Ndamage F, Kayirangwa E, et al.. Adult clinical and immunologic outcomes of the national antiretroviral treatment program in Rwanda during 2004-2005. J Acquir Immune Defic Syndr. 2009;52:49–55.
44. Franke MF, Stulac SN, Rugira IH, et al.. High human immunodeficiency virus-free survival of infants born to human immunodeficiency virus-positive mothers in an integrated program to decrease child mortality in rural Rwanda. Pediatr Infect Dis J. 2011;30:614–616.
45. van Griensven J, De Naeyer L, Uwera J, et al.. Success with antiretroviral treatment for children in Kigali, Rwanda: experience with health center/nurse-based care. BMC Pediatr. 2008;8:39.
46. Rich ML, Miller AC, Niyigena P, et al.. Excellent clinical outcomes and high retention
in care among adults in a community-based HIV
treatment program in rural Rwanda. J Acquir Immune Defic Syndr. 2012;59:e35–e42.
47. Fatti G, Grimwood A, Mothibi E, et al.. The effect of patient load on antiretroviral treatment programmatic outcomes at primary health care facilities in South Africa: a multicohort study. J Acquir Immune Defic Syndr. 2011;58:e17–e19.
48. Lambdin BH, Micek MA, Koepsell TD, et al.. Patient volume, human resource levels, and attrition from HIV
Treatment programs in central Mozambique. J Acquir Immune Defic Syndr. 2011;57:e33–e39.
49. Thomson KA, Cheti EO, Reid T. Implementation and outcomes of an active defaulter tracing system for HIV
, prevention of mother to child transmission of HIV
(PMTCT), and TB patients in Kibera, Nairobi, Kenya. Trans R Soc Trop Med Hyg. 2011;105:320–326.
50. Tweya H, Gareta D, Chagwera F, et al.. Early active follow-up of patients on antiretroviral therapy (ART) who are lost to follow-up: the ‘Back-to-Care' project in Lilongwe, Malawi. Trop Med Int Health. 2010;15(Suppl 1):82–89.
51. Nash D, Wu Y, Elul B, et al.. Program-level and contextual-level determinants of low-median CD4+ cell count in cohorts of persons initiating ART in eight sub-Saharan African countries. AIDS. 2011;25:1523–1533.
52. Nyandiko WM, Otieno-Nyunya B, Musick B, et al.. Outcomes of HIV
-exposed children in western Kenya: efficacy of prevention of mother to child transmission in a resource-constrained setting. J Acquir Immune Defic Syndr. 2010;54:42–50.
53. Ioannidis JP, Taha TE, Kumwenda N, et al.. Predictors and impact of losses to follow-up in an HIV
-1 perinatal transmission cohort in Malawi. Int J Epidemiol. 1999;28:769–775.
54. van Kooten Niekerk NK, Knies MM, Howard J, et al.. The first 5 years of the family clinic for HIV
at Tygerberg Hospital: family demographics, survival of children and early impact of antiretroviral therapy. J Trop Pediatr. 2006;52:3–11.