HIV continues to take a heavy toll on children in low-income countries, despite global strategies to scale up access to interventions preventing mother-to-child transmission and pediatric antiretroviral therapy (ART).1,2 Children aged younger than 15 years account for an estimated 10% of the 34 million people living with HIV worldwide and represent 14% of both new HIV infections and AIDS-related deaths.3 Progress has been made over the past 5 years. The number of children receiving ART increased 6-fold to an all-time high of 456,000 children in 2011, and preventing mother-to-child transmission services now cover 48% of HIV-infected pregnant women globally. Together, these interventions contributed to greater than 20% reductions in both pediatric AIDS-related mortality and new pediatric HIV infections.3 However, a treatment gap remains. Less than 1 in 4 children eligible for ART are receiving therapy.3 The obstacles to scaling up pediatric HIV care in the context of stifling resource constraints have been well documented.4,5 Along with prevention, among the most important strategies to circumvent these obstacles is identification of HIV-infected children early in life, to initiate ART, and thus reduce the infectious, metabolic, and neurocognitive complications of HIV and enhance survival.6
In Malawi, a southern African nation with an adult HIV prevalence of 11%, an estimated 120,000 children are currently living with HIV, more than half of whom are eligible for ART.1 Located on the campus of Kamuzu Central Hospital (KCH) in Lilongwe, the Baylor College of Medicine-Abbott Fund Children’s Clinical Centre of Excellence (COE) is the largest provider of pediatric ART in Malawi.7 The clinic initially offered comprehensive HIV care for children identified primarily through community-based client-initiated HIV testing and counseling (CITC) modalities and non-routine HIV testing in the hospital. But in 2008, KCH added routine pediatric inpatient provider-initiated HIV testing and counseling (PITC), which identified and linked an entirely new cohort of children into outpatient HIV care.8,9 However, it is not yet known whether identification of HIV-infected children by PITC, compared with traditional CITC modalities, has any impact on retention, mortality, or other outcomes of outpatient HIV care.
To answer these questions, we prospectively enrolled every newly identified HIV-infected child referred for outpatient care at the COE over a 12-month period and sought to determine whether children identified as HIV-infected by PITC differed at baseline from HIV-infected children identified by CITC. We then sought to determine factors, including HIV testing strategy, which predict mortality within the first year of enrollment in outpatient HIV care.
The Malawi Ministry of Health began scaling up access to ART for adults in 2004,10 but access to ART for children lagged before the establishment of the COE in 2006.7 The COE currently provides comprehensive HIV care to more than 5,000 HIV-infected children in central Malawi. Routine inpatient PITC is performed at KCH, which records more than 13,000 pediatric admissions per year, and has an inpatient pediatric HIV prevalence of 8.8%, as determined by routine inpatient HIV testing.9 Certified HIV counselors from community-based CITC programs or from the hospital test children using HIV antibody and/or DNA-polymerase chain reaction (PCR) testing.8,9 HIV-exposed and infected children are then referred to the COE for registration. Notably, few community programs had access to DNA-PCR testing during the study period.11
This prospective study enrolled every newly identified HIV-infected child that presented for an initial COE visit between January 1 and December 31, 2008. These patients were separated into 2 cohorts based on the location of their HIV test: within various CITC programs in the community vs PITC on the pediatric ward at KCH. At the initial COE visit, baseline clinical data were obtained for every child, including height, weight, World Health Organization (WHO) clinical stage, and ART eligibility status. Laboratory values included absolute CD4 for children aged 5 years and older, CD4 percent for children aged younger than 5 years, and hemoglobin, whenever available. Any child who returned to the clinic 12 months later (range 11–13 months after the initial visit date) was considered to be an active patient in the program. Thus, 1-year follow-up data were collected through January 31, 2009. Changes in WHO stage, anthropomorphic measurements, CD4 values, and hemoglobin levels were calculated for individual patients; thus, children who died, transferred out of the program, were lost-to-follow-up, or had either baseline or 1-year laboratory values missing were not included in these change-over-time calculations.
PITC at KCH has been described in depth elsewhere.8,9 Briefly, mothers of all hospitalized children are offered an HIV test. Inpatient testing rates during the study period were 80% to 85%, because of lack of certified HIV counselors on the weekends; thus, this group is representative of all hospitalized children. All children aged younger than 18 months whose mothers tested antibody-positive were offered a DNA-PCR test, although not all children receiving a DNA-PCR test received their results. Infants of mothers found to be antibody negative were considered to be HIV uninfected.8,9 Lost to follow-up was defined as any child enrolled in the program who failed to present for a clinic visit within a period of 11 to 13 months after program enrollment; children who failed to present during this 2-month window but subsequently returned to care were still considered lost to follow-up in this study. In contrast, children transferred out are defined as newly identified children whose outpatient treatment was confirmed to be continued elsewhere; in most cases, these children were deemed stable enough to be treated in facilities closer to their homes. ART eligibility is defined as any HIV-infected child aged younger than 1 year, any child aged younger than 3 years with <20% CD4%, any child aged between 3 and 5 years with <25% CD4%, any child older than 5 years with absolute CD4 cell count <200, and any child with WHO clinical stage III or IV disease. Of note, Malawi guidelines changed to include universal ART for all infants aged younger than or equal to 12 months in April 2008, which corresponds to the time at which the first newly identified infants in our study were initiated on ART; guidelines were subsequently revised to recommend universal ART for all children aged younger than 24 months in July 2011, after the conclusion of this study. ART adherence is defined as the percent of clinic visits during the 1-year follow-up period for which the caregivers brought the child’s pills to the visit as instructed and for which the number of remaining pills were determined by counting to be 95% to 105% what was expected.
The collection and use of this clinical data was approved by the Malawi National Health Sciences Research Committee and Baylor College of Medicine institutional review boards. De-identified data were extracted from electronic medical records and analyzed.
Weight-for-age z, height-for-age z, and weight-for-height z (WHZ) scores were calculated for all children aged younger than 5 years using the Child Growth Standards macro distributed by the WHO.12 Subsequently, all children were assigned a wasting status; those with WHZ scores <−2 and <−3 were classified as moderately and severely wasted, respectively, whereas children aged 5 years and older were assigned a wasting status by manually plotting their height and weight on childhood growth charts published by the Malawi Ministry of Health.13
Normally distributed data were reported using mean and standard deviation, and comparisons between 2 groups were made by independent-samples t test. Nonparametric continuous data were reported with median and interquartile range and compared by Mann–Whitney U test. Proportions were compared using Pearson χ2 or Fisher exact test. For categorical variables with multiple levels, a global χ2 test was performed; if this test indicated a significant difference somewhere among the data, individual post hoc pair-wise comparisons were made using χ2 or exact tests, with Bonferroni correction applied to adjust alpha for multiple comparisons. Only P values less than the corrected alpha were considered significant.
Cox proportional hazards analysis was used to identify predictors of mortality. Univariate hazard ratios with 95% confidence intervals were calculated. For multivariate analysis, laboratory values (CD4 percent, absolute CD4, and hemoglobin) were excluded a priori, given their large number of missing values and colinearity with other covariates, and a regression model was constructed using a 2-step approach. First, site of HIV testing (PITC vs CITC) was entered into the equation because this was the main covariate of interest. Next, the remaining covariates were tested for entry with a forward stepwise approach, with conditional entry based on the significance of the Wald statistic and removal testing based on the change in log likelihood ratio. For multilevel categorical variables, a simple contrast method was used, in which each category of the predictor variable was compared with the reference category. The final multivariate model included age, nutritional status, WHO clinical stage, and testing modality. All calculations were performed using IBM SPSS Statistics 20 (IBM, Corp., Chicago, IL).
We first sought to determine whether children identified as HIV-infected through routine inpatient HIV testing were clinically similar at baseline to the children identified by community-based testing. In a 12-month period, the 2 testing modalities identified a total of 742 HIV-infected children that subsequently enrolled into care at the COE, the majority (79.1%) of whom were identified by CITC (Table 1). The median age of PITC-identified children was 28.5 months younger than children identified through CITC. Children identified in the hospital had poorer nutritional status based on weight-for-age and weight-for-height criteria, and a 2.8-fold greater proportion of HIV-infected children identified by PITC had advanced WHO stage disease (7.8% of CITC vs 22.2% of PITC with WHO stage IV disease). There were no differences between the 2 groups with respect to gender, CD4+ cell levels, or hemoglobin levels.
After 1 year of outpatient HIV care, there were no differences between the 2 cohorts with respect to the proportion of children either lost to follow-up or transferred out of the program. However, the mortality rate for hospital-identified children, 15.5%, was double the 7.8% mortality rate for community-identified children (Table 1). Up to 2 causes of death were recorded in the hospital register by clinicians. Malnutrition was implicated in 21% of deaths, followed by sepsis and malaria in 16%, and pneumonia in 13% of deaths (data not shown).
Among the barriers to scaling up routine pediatric hospital-based PITC is the perception that hospital-identified HIV-infected children are less likely to follow-up and sustain good outcomes.8,14–16 To determine whether clinical outcomes of surviving HIV-infected children identified by CITC and PITC were similar, we examined medical records of the 396 HIV-infected children who remained in outpatient care at the COE 1 year after enrollment (Table 2). Overall, 80.3% of children were eligible for ART, although a higher proportion of ART-eligible children identified in the hospital, compared with those identified as HIV-infected in the community, were receiving ART 1 year after identification (91.4% vs 75.0%, p = 0.005). The median time from identification of HIV infection to initiation of ART for all children was just over 2 months, with a median duration of therapy of 9.7 months at the 12-month appointment.
After 1 year of enrollment in the COE outpatient care program, both cohorts showed profound improvements in both nutritional status and CD4 laboratory values. No differences were detected between the 2 groups with respect to ART adherence, nutritional status, WHO clinical stage, CD4 values, or hemoglobin levels. Thus, after 1 year of outpatient pediatric HIV care, children identified by routine inpatient HIV testing were less distinguishable from children identified as HIV-infected by community-based testing than they were at baseline. Furthermore, although early mortality was higher among PITC-identified children, survivors demonstrated similar rates of adherence, follow-up, and response to treatment as CITC-identified children.
Finally, we sought to identify baseline clinical features among the 742 children with new HIV-infected diagnoses that could predict early mortality after enrollment in outpatient HIV care. Univariate survival analyses revealed that age younger than 24 months, moderate or severe wasting, WHO stage IV, lower absolute CD4, lower hemoglobin, and identification by routine inpatient HIV testing as factors were associated with increased mortality within the first year of HIV care (Table 3). Multivariate logistic regression analysis revealed that moderate or severe wasting, WHO stage IV, and age younger than 24 months were each independent predictors of early death. Although CITC-identified children who died had a longer median survival time than those in the PITC-identified cohort (15.0 vs 6.0 weeks, P < 0.001; Fig. 1), after controlling for age, nutritional status, and WHO stage, testing modality did not independently predict mortality at 1 year (Table 3). These data indicate that hospital-based PITC preferentially identifies the children at highest risk of early mortality but that the site of testing does not by itself predict poor outcomes for HIV-infected children.
Routine hospital-based PITC has recently been shown to be a critical portal of entry into HIV care for children in regions facing high prevalence of HIV and resource limitations.8,9,14–18 However, outcomes of PITC-identified children are thought to be less favorable compared with children identified by traditional CITC systems. By prospectively enrolling newly identified children from both CITC and PITC testing modalities and monitoring their outcomes over 1 year, we found that, despite PITC-identified children being younger, more malnourished, with more advanced HIV disease and a higher early mortality rate compared with CITC-identified HIV-infected children, there were no differences with respect to the default or lost-to-follow-up rate, in the time to ART initiation, or in ART adherence rates. Furthermore, clinical characteristics and 1-year outcomes among the survivors were strikingly similar between the 2 cohorts. Thus, routine inpatient PITC identifies a subset of younger HIV-infected children with more severe, rapidly progressing disease that CITC-based testing is currently missing.
Our analyses reveal that age younger than 24 months, moderate or severe wasting, and WHO clinical stage IV, but not HIV testing strategy, independently predict mortality within the first year of HIV care. Two smaller studies from Lilongwe, Malawi, revealed WHO stage IV, poor nutritional status, and severe immunodeficiency to be predictive of mortality at 3 and 6 months after ART initiation among 439 children,19 and age younger than 18 months and WHO stage IV to be predictive of early death or defaulting among 258 children,20 respectively. These earlier studies were undertaken before the recommendation of initiating universal ART for all HIV-infected Malawian infants and before the introduction of routine inpatient HIV testing at KCH in 2008. More recently, hemoglobin < 9 g/dL was found to be the sole independent predictor of mortality among a cohort of 135 HIV-infected children in Nairobi, Kenya, although WHZ <−2 and WHO clinical stage IV were both associated with increased mortality on univariate analysis.21 Among the strengths of our study, therefore, was a large sample size that allowed us to fully probe independent predictors of mortality in the context of newer national guidelines for ART initiation and novel pediatric HIV testing modalities in the hospital setting.
Identification of younger children with more advanced HIV disease provides evidence that inpatient PITC identifies high-risk children known as “fast progressors,” a poorly understood biological phenomenon that appears to be related to a combination of host and viral factors.22–27 These younger, more severely ill children are critical targets for ART scale-up programs, but our data reveal that they are not being identified by traditional community-based testing approaches. When unidentified, many of these children likely die at home or in hospitals before their HIV status becomes known. Given the strong evidence that ART initiation very early in life dramatically reduces both mortality and HIV disease progression,28 we recommend routine inpatient HIV testing as an integral adjunct to the identification of HIV-infected children, including those younger and at higher risk. This subpopulation is being missed by initial HIV testing modalities including immunization clinics and early infant diagnosis programs and would likely benefit most from early identification and access to HIV care.
Children identified by either testing approach demonstrated dramatic improvements in CD4 laboratory values, hemoglobin levels, and nutritional status after 1 year of HIV care at the COE. Among the few differences between the 2 cohorts after 1 year was the proportion of ART-eligible children on therapy. Reasons for lower rates of ART initiation among community-identified children warrant further investigation but may include our finding that a greater proportion of HIV-infected infants identified in the hospital met the relatively straightforward criteria for age-based ART initiation (47% of hospitalized ART-eligible children were eligible because of age < 12 months), compared with the community-identified children (just 23% of ART-eligible were eligible because of age < 12 months). For older children, more complicated WHO clinical staging or laboratory-based criteria, which are often not immediately available in resource-constrained settings, must be used to determine ART eligibility. Alternatively, clinicians might perceive ART initiation to be more urgently needed in the group with visibly more clinically advanced (or faster-progressing) disease, despite equal ART eligibility by standard criteria. Other reasons for not starting ART may include the rigorous initiation criteria used at the COE, which includes identification of 2 caregivers per child, both of whom need to complete multiple ART training sessions. Anecdotally, very few caregivers declined starting therapy. It should be noted that 1-year outcomes were known for just 53% of children, primarily because of the large number of patients transferring to lower-acuity outpatient centers closer to their homes and to our study’s strict definition of lost to follow-up (patients returning to clinic more than 4 weeks after a missed 12-month appointment were still considered lost to follow-up). Nonetheless, these data reinforce the finding that favorable outcomes can be achieved in pediatric HIV care programs, even among subgroups of HIV-infected children shown to be at the highest risk of dying.
Among the weaknesses of our study, laboratory values including CD4 and hemoglobin were not routinely available in this resource-constrained setting. Having baseline and 1-year values for every child likely would have enhanced our ability to identify the highest-risk patients at their baseline clinic visit. However, these laboratory indicators are unavailable in many low-income regions29; thus, addition of these laboratory parameters would limit the utility of more complex predictive models in similar settings in Africa. Our study also revealed aspects of the HIV care program that could be improved. For example, the 11.1% rate of HIV-infected children lost to follow-up, similar to rates reported in multiple settings in sub-Saharan Africa,30 was higher than attrition rates more recently reported in western31 and South Africa.32 In addition, an unknown number of infants aged younger than 18 months who had a DNA-PCR test never received their test results; this delay in PCR test reporting likely disproportionately affected the younger hospital-identified cohort and highlights the need to develop new point-of-care HIV testing strategies for infants in similar settings. In addition, reducing the median duration, currently more than 2 months, between HIV care enrollment and ART initiation should be explored as another strategy to improve outcomes in all HIV-infected children. Given our finding that HIV-infected children identified in the hospital are at highest risk of early mortality, novel strategies to initiate ART earlier might explore the possibility, for example, of point-of-care HIV testing33 coupled to inpatient ART initiation. Finally, future studies could examine characteristics of newly identified HIV-infected children not presenting to outpatient care. We have shown previously that 67% to 78% of HIV-infected children identified at KCH subsequently enrolled in the COE clinic9; however, these rates are unknown for the multiple community-based testing centers referring new patients to the COE. A thorough understanding of the reasons for not presenting for follow-up would strengthen this and other HIV care programs throughout Africa.
In summary, this study reveals that the community-based CITC strategies currently being used throughout sub-Saharan Africa are failing to identify a critical subset of younger HIV-infected children who are in urgent need of immediate access to HIV care including ART. Thus, HIV testing in the pediatric hospital will be an important component of comprehensive HIV testing programs in areas of high HIV prevalence and, along with novel community-based approaches such as door-to-door household testing and integration of HIV testing with childhood immunization schedules,34,35 will likely play a central role in a successful scale-up of access to pediatric HIV care worldwide.
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
Africa; antiretroviral therapy; HIV testing; Malawi; pediatric HIV; pediatric hospitals