Scale-up of pediatric HIV care and treatment across sub-Saharan Africa (SSA), where over 90% of children living with HIV reside,1 has been substantial with more than 387,000 children reported as initiating antiretroviral treatment (ART) by December 2010.2 Treatment responses of children on ART in resource-limited settings have been robust,3–9 with high rates of viral suppression and immune reconstitution, and improved survival.10–15 However, the mortality rate of children on ART in resource-limited settings is considerably higher than that of children in developed countries, 8.0 versus 0.9 deaths per 100 child-years (P < 0.001), respectively.16 Reasons for this disparity include both biomedical and programmatic factors, such as advanced disease at the time of presentation, fragility of infants and younger children, other infectious comorbidities and malnutrition, delays in ART initiation, and suboptimal retention in care.4,13
Retention of HIV-infected children in care is essential for prevention of HIV-related morbidity and mortality through timely ART initiation, monitoring and management of disease progression and treatment failure, and provision of medications and supportive care. Pediatric programs in SSA report retention ranging from 77% to 89% at 12 and 24 months,11,14,15,17–19 which may jeopardize long-term health outcomes.20 Both patient and programmatic factors influencing retention need to be identified to improve outcomes and inform future interventions.
We examined retention, lost to follow-up (LTF), and death among 17,712 children, younger than 15 years, initiating ART at 192 health facilities in Kenya, Mozambique, Rwanda, and Tanzania from January 2005 through June 2011. The objectives of this analysis were to determine the proportion of children who were retained, LTF, and died at 12 and 24 months, to assess variation in retention outcomes by country, and to identify patient- and facility-level factors associated with these outcomes.
We conducted a retrospective cohort analysis of all children, younger than 15 years, initiating ART at 192 HIV care facilities in Kenya, Mozambique, Rwanda, and Tanzania from January 2005 to June 2011. All facilities received support from ICAP, a President’s Emergency Plan for AIDS Relief (PEPFAR) implementing partner that has been supporting HIV care and treatment in SSA since 2005. ICAP is a nongovernmental organization at the Mailman School of Public Health at the Columbia University that supports scale-up of HIV care and treatment through facility mentorship of facility staff, renovation of laboratory and health facilities, creation and support of monitoring and evaluation tools and practices, and other technical assistance.21 All health facilities included in this analysis participate in the Identifying Optimal Models of HIV Care and Treatment Study (5U2GPS001537-03),22 which uses routinely collected patient- and facility-level data to measure patient and program outcomes. All facilities had electronic patient-level databases, which are password protected, and encrypted deidentified databases are transferred to ICAP offices every quarter where they are aggregated for analysis. Clinical and laboratory data were recorded by facility staff onto paper records and later transferred into an electronic patient database by data clerks. Data quality assessments were performed every 6 months to assess for completeness and accuracy of data entry.
Eligibility criteria for ART initiation followed each country’s national guidelines, which reflect the World Health Organization (WHO) recommendations.23,24 As per the WHO 2006 guidelines, children younger than 5 years were eligible for ART if they had the WHO stage III/IV, CD4 percent <25% (<12 months), CD4 percent <20% (12–35 months), or CD4 percent <15% (36–59 months). For children older than 5 years, ART eligibility included (1) the WHO stage IV, 2) the WHO stage III and CD4 <350 cells per microliter, or (3) CD4 <200 cells per microliter irrespective of the WHO stage.23 From 2006 to 2011, all 4 countries began adopting the revised WHO guidelines, including recommendations of ART for all HIV-infected children younger than 1 year,25–28 later updated to younger than 2 years regardless of CD4 measurement.24,29,30 Standard of care for HIV care and ART regimens followed national guidelines, which recommended ART for eligible children beginning in 2006.23 Recommended facility follow-up was a minimum of every 3 months with semiannual CD4 testing. Access to CD4 testing was not always available but improved over time with increased access to CD4 analyzers and decentralization of laboratories.
Definitions and Outcomes
Follow-up time on ART was estimated as the time between date of ART initiation and documented transfer, death, LTF, or completion of the observation period. Children were considered retained if they were known to be alive and continuing ART at their initiation facility. Mortality was passively ascertained from documentation of death in patient records. LTF was defined as having no recorded visit for 6 months with no visits after the last missed visit, as per by Chi et al,31 and nonretention was defined as either death or LTF. Children who were LTF were censored 15 days after their last recorded visit. Children documented to have transferred to another facility were censored at their recorded date of transfer.
Individual-level factors were chosen based on available data across all country data sets and factors known or suspected through previous research to influence retention and survival. The CD4 percent or cell count and the WHO stage taken closest to the date of ART initiation, within a window of 3 months before or up to 1 month after ART initiation, was used to determine disease severity at ART initiation. Clinical stage and immunologic category were defined according to the WHO 2006 guidelines: severe immunodeficiency is defined as CD4 percent <25% or <1500 cells per microliter in children aged 11 months and younger, CD4 percent <20% or <750 cells per microliter in children aged 12–35 months, CD4 percent <15% or <350 cells per microliter in children aged 36–59 months, and CD4 percent <15% or <200 cells per microliter in children older than 5 years.23 To investigate the potential influence of malnourishment in our population, we constructed weight-for-age z-scores and categorized children as z-score ≤ or > −2SDs.32 No reliable data were available for tuberculosis status or treatment at the time of ART initiation. A new category of “severe illness” was created to include any child with severe immunodeficiency, defined above, or the WHO stage IV at the time of ART initiation because of the high proportion of missing CD4 measurements and the WHO stage.
Facilities were defined as primary or secondary/tertiary. A primary facility is any health center; secondary and tertiary facilities are district, regional, or national hospitals. Facility location was categorized into urban (capital and other large cities with city administration and political bodies), semiurban (big and small towns, periurban areas, growth areas, and mining communities), and rural (small towns and farming areas).
Cumulative incidence of nonretention, LTF, and reported death through 24 months after ART initiation were estimated using Kaplan–Meier techniques. In the primary analysis, Cox proportional hazard models accounting for within-clinic correlation between patients with robust sandwich error terms were used to assess the association between measured patient- and facility-level characteristics and LTF and documented death after ART initiation. Individual-level factors include age, point of entry, weight-for-age z-scores at ART initiation, CD4 measure at ART initiation, the WHO stage at ART initiation, and year of ART initiation; facility-level factors include country, facility type, and setting.
This study is part of the Identifying Optimal Models of HIV Care and Treatment, which was approved by the Columbia University Medical Center Institutional Review Board, the US Centers for Disease Control and Prevention, the PEPFAR’s Office of the Global AIDS Coordinator, and each participating country’s national ethics committee.
Characteristics of HIV Care Programs
From January 2005 through June 2011, a total of 37,154 children were enrolled in HIV services at 192 facilities in Kenya, Rwanda, Tanzania, and Mozambique (Table 1). A total of 17,712 children initiated ART with the largest cohort in Mozambique (7226) and the smallest in Rwanda (2170). The number of children initiated on ART increased annually from 585 in 2005 to 3653 in 2010, the last full year of observation, with the number of facilities increasing from 75 to 192. Half of the facilities (54%) were in primary-level health centers compared with secondary- (district/regional hospitals) or tertiary-level facilities (teaching or national referral hospitals). Half of facilities (49%) were in rural locations (Table 1), and the majority of facilities were government-supported.
Median follow-up time for children initiated on ART was 598 days [interquartile ratio (IQR), 245–1106]. The median age at ART initiation was 4.6 years (IQR, 1.9–8.3), with a similar distribution of females (51%) and males. Forty-eight percent of children had the WHO stage III/IV disease, and 32% of children had severe immunodeficiency (67% of children younger than 5 years and 38% of children aged 5 years or older). Thirty-three percent of children had a weight-for-age z-score of −2 or less. Among the 8263 children with recorded CD4 measurements (33% for children younger than 5 years and 62% of children aged 5 years or older) at ART initiation, the median CD4 was 15% (IQR, 10–20) for children younger than 5 years and 265 cells per microliter (IQR, 111–461) for children aged 5 years or older (Table 1). Overall, 34.5% of children were classified with severe illness at the time of ART initiation (Table 1) and the proportion of children younger than 1 year classified with severe illness decreased from 56% in 2006 to 18% in 2011 (see Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A362). Over time, the proportion of children younger than 2 years initiated on ART increased from 12% of all children in 2005 to 33% in 2011 (Fig. 1). The majority of all children reported entry into HIV care through voluntary counseling and testing or provider-initiated counseling and testing (Table 1). First-line ART regimens for 95% of children included 2 nucleoside reverse transcriptase inhibitors plus 1 nonnucleoside reverse transcriptase inhibitor.
Country programs varied in the proportion of young (<2 years) and severely ill children. Rwanda reported the smallest proportion of young children, 15.6% compared with 38.7% in Mozambique. Rwanda also reported the smallest proportion of children with severe illness at 18.6% compared with 44.5% in Mozambique, 36.5% in Tanzania, and 26.9% in Kenya. Tanzania had the largest proportion of children with the documented WHO stage IV, 26.2%, compared with Kenya (4.5%); however, over 30% of children in Mozambique did not have the WHO stage recorded.
Retention, LTF, and Mortality at 12 and 24 Months
Among those initiated on ART, 80% and 72% of children were retained at 12 and 24 months (Table 2, Fig. 2A). At 12 and 24 months, 16% and 22% of children were LTF, whereas 5% and 7% had documented deaths (Table 2). LTF and mortality rates were highest in the first 6 months after ART initiation (26.3 and 9.1 per 100 person-years, respectively), declining through 12 months (18.4 and 6.3 per 100 person-years) and 24 months (14.2 and 4.5 per 100 person-years). Retention varied substantially across countries, ranging from 71% to 95% at 12 months and from 62% to 93% at 24 months (Table 2, Fig. 2B). Compared with children in Rwanda, children in Mozambique had 16-fold higher rate of LTF [adjusted hazard ratio (HR), 16.8; 95% confidence interval (CI): 8.9 to 32.0] and children in Tanzania had over 2 times higher death rate (adjusted HR, 2.6; 95% CI: 1.8 to 3.6). All country programs experienced the largest drop in retention during the first 6 months after ART initiation. Across all age groups and time periods, the proportion of children who were LTF was higher than the proportion of known deaths, except for Rwanda. The overall proportion of documented transfers was similar across programs: 18% Kenya, 12% Mozambique, 19% Rwanda, and 15% Tanzania.
Retention was lowest among children younger than 1 year, 61% and 51% at 12 and 24 months, and highest in children aged 5 to <10 years, 87% and 80%, respectively (Table 2, Fig. 2C). There was no consistent improvement in retention, LTF, or death in children younger than 1 year over time by calendar year, although LTF appeared to be marginally lower in later years (see Table S2, Supplemental Digital Content, http://links.lww.com/QAI/A362).
Factors Associated With LTF and Death
Multivariable analysis was performed to assess factors associated with LTF and death, including country, age at ART initiation, severe illness at ART initiation, weight-for-age z-score at ART initiation, year of ART initiation, point of entry into HIV care, and facility type and location. The adjusted HR for LTF and death were highest in children younger than 1 year (HRLTF = 2.0, 95% CI: 1.7 to 2.4; HRDeath = 3.4, 95% CI: 2.6 to 4.6) (Table 3). Compared with children with less advanced disease, children with severe illness had higher rate of death (HRDeath = 1.6, 95% CI: 1.4 to 1.9) but similar rate of LTF (HRLTF = 0.99, 95% CI: 0.86 to 1.13) (Table 3). Among older children, CD4 count was a strong predictor of LTF and death; children aged 5 years or older with CD4 <100 cells per microliter had nearly 3 times higher death rates compared with children initiating ART at CD4 >350 cells per microliter. Children with missing CD4 counts had 2.3 times the rate of death compared with children with a CD4 count >350 cells per microliter; and children missing the WHO stage or severe illness information were also more likely than other children to be LTF or to be documented deaths. There was no evidence of differences in LTF, or death by point of entry or facility type (Table 3). There was no consistent evidence for reduced LTF or death by year of ART initiation. No facility-level factors were found to have a significant impact on the risk of LTF or death.
Results were also stratified by country (see Table S3, Supplemental Digital Content, http://links.lww.com/QAI/A362), and similar factors are associated with increased risk of LTF and death across all countries. Sensitivity analyses using random-effects multilevel Cox proportional hazard models, in addition to the fixed-effects model presented, yielded no substantial differences in the magnitude of the HRs presented in Table 3.
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.
The high retention observed in Rwanda is consistent with other studies investigating retention in HIV programs in this country.43–46 The ICAP-supported program in Rwanda, in comparison to the other country programs included in this study, had a smaller proportion of young (age <2 years) and severely ill children at the time of ART initiation. Also, the Rwanda program is smaller with a lower patient caseload, 2170 children in Rwanda compared with 7226 children in ICAP-Mozambique (Table 1), that has been associated with lower LTF in resource-limited settings.47,48 Smaller programs may have higher staff to patient ratios, shorter wait times, and more staff and time for active patient follow-up, which has been shown to significantly decrease LTF.49–51 Finally, better documentation may explain some of the differences seen among countries. In Rwanda, the proportion of children who are LTF is lower than the proportion of known deaths, for which the reverse is true in other country programs. The category of LTF serves as a combination category of children who have been truly LTF and others who have undocumented deaths or transfers. Rwanda’s results are encouraging as they illustrate what is achievable in public programs and suggest that improvement is obtainable. Additional evaluation of program- and facility-level factors, not available in this data set, to explain variations seen across countries is clearly warranted.
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.
The authors thank all children and staff at the HIV care and treatment facilities included in this analysis. We also thank the Optimal Model Country team member in Kenya (Mark Hawkens, Davies Kimanga, Emily Koech, William Reidy, John Elijah Thiongo, Lucy Wanjiku), Mozambique (Maria Fernanda Sardella Alvim, Américo Rafi Assan, Amy L. Boore, Kebba M. Jobarteh, Jose Mizela, Antonio Mussa, Carla Xavier), Rwanda (Maria Lahuerta, David Lowrance, Emmanuel Manzi, Njeri Micheu, Fernando Morales, Jules Mugabo, Veronicah Mugisha, William Nagaba, John Pierre Nyemazi, Pratima Raghunathan, Sabin Nsanzimana, Ruben Sahabo), and Tanzania (Annette Almeida, Gretchen Antelman, Gilly Arthur, Ahmed Khatib, Bonita Kilama, Redempta Mbatia, Mohammed Mfaume, Harriet Nuwabaga-Biribonwoha, Geoffrey Somi Ayele Zewde Woldehana).
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