The HIV/AIDS epidemic has taken a tremendous toll on children worldwide. As of 2005, in Uganda, 110,000 of the 1,000,000 people living with HIV were children younger than 14 years.1 Without treatment, approximately 20% of children in wealthier countries progress to severe immunodeficiency or death within the first year of life, followed by 5% per year thereafter.2,3 A pooled analysis of mortality from studies of HIV-infected African infants and children identified mortality rates of 35% at year 1 and 53% at 2 years of age.4 Antiretroviral therapy (ART) can positively influence these outcomes. However, the optimal timing of ART initiation for HIV-infected infants and children is still a matter of debate.5
HIV disease progression in children perinatally infected varies based on a number of maternal and child factors.3 One factor potentially diminishing HIV outcomes is the influence of orphanhood on HIV outcome.6 The loss of one or both parents can lead to a situation of vulnerability for children leading to negative health, educational, and psychosocial consequences.7 Using data from a prospective pediatric cohort in Mbale, Uganda, we aimed to determine treatment differences by orphanhood status and evaluate adherence.
The Mbale region contains the largest number of medical facilities in Eastern Uganda. There are approximately 700,000 residents in the region. The main providers of care in the region are The AIDS Support Organization (TASO) and the Joint Clinical Research Centre (JCRC). JCRC provides the majority of pediatric care. Antenatal clinic testing is offered to all women, but uptake is comparatively low, with fewer than 50% of antenatal patients receiving HIV testing.
The JCRC began providing cART to children in 2002. Before this, there was no public cART and limited private provision of care. Since 2002, JCRC has initiated 101 children on cART in this setting. Children testing seropositive are followed clinically until cART eligible. The primary initiation regimen is non-nucleoside reverse transcription inhibitor (NNRTI) based. Criteria used for initiation of cART are similar to adults and include WHO stage 3 or 4 or a CD4 cell count below 200 cells/mm3. HIV-1-RNA levels were not used in this setting, as no viral load facilities existed in the region at the time of this study.
In the setting of Mbale, many orphans are received and adopted by next of kin or communities that assist in maintaining children with education, food, and health. These children do not often receive the same attention as a parent might provide, but may be considerably better off than street children, an underserved population. All children in our cohort had caregivers.
We maintain a prospective cohort of all patients attending JCRC facilities in Uganda. We abstracted data from the 101 pediatric HIV-infected patients who initiated cART at Mbale JCRC between August 8, 2002 and January 2008. Informed consent was obtained from the child's caregiver upon enrollment at the JCRC. All children younger than 14 years at the time of ART initiation were eligible for inclusion. Orphans were defined as children age 14 or younger who had lost one or both parents. We used WHO clinical staging of HIV/AIDS and the WHO immunologic classification guidelines to determine when children were eligible for cART.
We collected data on patient age, orphan status, absolute CD4 cell count and CD4% (%CD4+), WHO clinical stage of infection, the presence of tuberculosis, and cART regimen chosen, all at cART initiation. For the duration of cART, variables of interest included the development of tuberculosis (TB), the need for cART regimen switch, and if applicable, the second-line regimen. We assessed adherence to cART using caregiver 3-day prior report and pharmacy monitored drug possession ratio. We considered adherence clinically adequate if they were consistently >95% adherent.
We used descriptive statistics on the overall cohort and Pearson's χ2 test to determine differences between orphan status and covariates including age at initiation, WHO clinical stage at initiation, therapy switch, and adherence level. The Mann-Whitney-Wilcoxon test was used to determine if the distribution of absolute CD4 counts, %CD+, and months of follow-up differed based on orphan status. All P values are 2-sided. The significance level for this study was set at <0.05. The ethics review board at Mbale Regional Referral Hospital approved this study.
This cohort of 101 pediatric patients with HIV-1 infection (56 girls and 45 boys) contributed 180.4 person-years of follow-up. The median age of the cohort at cART initiation was 6 years [interquartile range (IQR): 3–10]. Forty-seven were orphans [median age of 7 years (IQR: 5–11)]. Table 1 displays differing characteristics between orphans and nonorphans. Nonorphans had a median age of 4 years (IQR: 2–7) at cART initiation. Orphans were older at cART initiation than nonorphans (P = 0.0008) and were more likely (P = 0.03) to be WHO clinical stage 4 than nonorphans. The median absolute CD4 count and the median %CD4+ at initiation were not different between orphans and nonorphans.
Our composite measurement of cART adherence was high for both orphans and nonorphans, with almost all patients [(93% (93/101)] consistently achieving adherence of 95% or greater. This did not differ by orphanhood status. Reasons for poor adherence in the other 8 patients included advanced illness, privacy issues, travel difficulties, and inability to pay for treatment. After initiation of therapy, 7 children were lost to follow-up, and 3 children died post-cART initiation, resulting in a mortality rate of 1.66 per 100 person-years. Therapy switches were required for 28 children. The children who required a regimen switch trended towards longer periods of follow-up (P = 0.06). No other variables predicted regimen changes.
Orphanhood is one of many negative consequences of the HIV epidemic in Africa. There are an estimated 12,000,000 orphans in Africa, many of whom are HIV infected.8 There are several potential outcomes for children who have lost both patients. In some cases, they are able to find a stable environment within the household of a community member or relative. Others remain within households where the eldest child acts as the head. In the worst-case scenario, these children become street children and are at greatest risk for abuse, malnutrition, and disease.
In our cohort, the comparison of orphans to nonorphans revealed 2 important differences. The median age of orphans at cART initiation was significantly older than that of nonorphans. Furthermore, despite median CD4 counts and %CD4+ that were not significantly different at initiation, orphans were more likely to be WHO clinical stage 4. A recent study from Kenya revealed similar results, finding that orphans were older than nonorphans at cART initiation and that there were no differences in CD4 counts and percentages at initiation.9 Although age alone does not serve as an indicator for treatment initiation according to current staging and immunologic classification WHO guidelines, there is evidence suggesting a benefit to earlier ART initiation.5,10 As our understanding of the timing of ART initiation in pediatric populations continues to develop, it remains vitally important that all children are equally supported to access treatment according to current recommendations.
Strengths of this analysis include the novelty of this cohort as there are few studies examining pediatric outcomes in Africa. Loss to follow-up was minimal as a consequence of active follow-up. Even so, we were unable to identify the status of 7 children, and it is possible that they did not survive or moved to another provider. Our cohort study was carried out at 1 HIV treatment center located in Eastern Uganda, potentially limiting the generalizability of our findings. Although 2 methods of estimating adherence were used, there is the potential that adherence was overestimated in some cases. Indeed, there is a lack of consensus on the measurement of adherence in children. Although median CD4% and CD4 T cells were considerably lower in the orphan group, we were unable to detect a statistically significant difference. This may be due to our small sample size and large variance of these factors at initiation. Given our resource-limited setting, we were unable to determine viral load of patients. There is important selection bias of orphans fortunate enough to be placed with guardians. In Eastern Uganda orphans are often received by next of kin or communities as guardians, although rarely receiving as much direct attention as a parent might provide. There were no street children in our cohort, despite the large numbers of street children in Mbale. We recognize that a large-proportion of street children likely require cART and are unable to access it.
Ensuring that all children with HIV/AIDS are able to receive timely access to cART remains a challenge. Our findings that orphans present at an older age and with more advanced disease suggest that the orphaned children of Africa are at particular risk. Even so, these children can be engaged with HIV treatment centers and achieve superb therapeutic outcomes assuming the appropriate resources are dedicated to their care. There is an important need to provide care to orphans without caregivers and to very young children regardless of socioeconomic situations.
1. UNAIDS. 2007 Update on the Global HIV/AIDS Epidemic.
Geneva: UNAIDS; 2007.
2. Rich K, Fowler MG, Mofenson LM, et al. Maternal and infant factors predicting disease progression in human immunodeficiency virus type 1-infected infants. Pediatrics
3. The European Collaborative Study. Fluctuations in symptoms in human immunodeficiency virus-infected children: the first 10 years of life. Pediatrics
4. Newell M, Coovadia H, Cortina-Borja M, et al. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet
5. World Health Organization. Report of the WHO Technical Reference Group, Paediatric HIV/ART Care Guideline Group Meeting, Geneva, Switzerland, WHO Headquarters, April 10–11, 2008.
6. Miller CM, Gruskin S, Subramanian SV, et al. Emerging health disparities in Botswana: examining the situation of orphans during the AIDS epidemic. Soc Sci Med
7. Andrews G, Skinner D, Zuma K. Epidemiology of health and vulnerability among children orphaned and made vulnerable by HIV/AIDS in sub-Saharan Africa. AIDS Care
8. UNAIDS, UNICEF, USAID. Children on the brink: a joint report of new orphans estimates and a framework for action, 2004.
9. Nyandiko WM, Ayaya S, Nabakwe E, et al. Outcomes of HIV-infected orphaned and non-orphaned children on antiretroviral therapy in Western Kenya. J Acquir Immune Defic Syndr
10. The European Collaborative Study. CD4 cell response to antiretroviral therapy in children with vertically acquired HIV infection: is it associated with age at initiation? J Infect Dis.