articlePredictors of mortality in HIV-1 infected children on antiretroviral therapy in Kenya : a prospective cohort

Background: Among children, early mortality following highly active antiretroviral therapy (HAART) remains high. It is important to define correlates of mortality in order to improve outcome. Methods: HIV-1-infected children aged 18 months-12 years were followed up at Kenyatta National Hospital, Nairobi after initiating NNRTI-based HAART. Cofactors for mortality were determined using multivariate Cox regression models. Results: Between August 2004 and November 2008, 149 children were initiated on HAART of whom 135 were followed for a total of 238 child-years (median 21 months) after HAART initiation. Baseline median CD4% was 6.8% and median HIV-1-RNA was 5.98-log10 copies/ml. Twenty children (13.4%) died at a median of 35 days post-HAART initiation. Mortality during the entire follow-up period was 8.4 deaths per 100 child-years (46 deaths/100 child-years in first 4 months and 1.0 deaths/100 child-years after 4 months post-HAART initiation). On univariate Cox regression, baseline hemoglobin (Hb) <9 g/dl, weight-for-height z-score (WHZ) < -2, and WHO clinical stage 4 were associated with increased risk of death (Hb <9 g/dl HR 3.00 [95% C.I. 1.21-7.39], p = 0.02, WHZ < -2 HR 3.41 [95% C.I. 1.28-9.08], p = 0.01, and WHO clinical stage 4, HR 3.08 [1.17-8.12], p = 0.02). On multivariate analysis Hb < 9 g/dl remained predictive of mortality after controlling for age, baseline CD4%, WHO clinical stage and weight-for-height z-score (HR 2.95 (95% C.I. 1.04-8.35) p = 0.04). Conclusion: High early mortality was observed in this cohort of Kenyan children receiving HAART, and low baseline hemoglobin was an independent risk factor for death. Background Sub-Saharan Africa carries the highest burden of paediatric HIV-1 with an estimated 1.8 million children < 15 years infected which represents 90% of all children living with HIV worldwide [1]. In Kenya there are approximately 150,000 HIV-1 infected children, out of whom nearly 60,000 are in need of antiretroviral therapy and about 25,000 are currently accessing treatment [2]. There is a concerted effort to raise the number of children on antiretroviral therapy through increased availability of early infant diagnosis and strengthening provider-initiated counseling and testing in health facilities. As a result, survival of HIV-1 infected children in Kenya and similar settings has dramatically improved as more children access highly active antiretroviral therapy [3-7]. However, mortality within the first few months of starting antiretroviral therapy remains high with various studies reporting between 8% and 15% and most deaths attributable to infections and failure to thrive [3-9]. This level of mortality is substantially higher than what is observed for children initiating HAART in developed nations [10-13]. There is limited but increasing published literature on predictors of early mortality following initiation of HAART and few studies have involved African children. Children with advanced HIV disease manifesting as low weight-for-height, as well as those with very low CD4% have been found to be at highest risk of early mortality following HAART initiation in Cote d'Ivoire, Malawi, and * Correspondence: dalton@africaonline.co.ke 1 Department of Paediatrics, University of Nairobi, Box 19676 Nairobi 00202, Kenya Full list of author information is available at the end of the article © 2010 Wamalwa et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Wamalwa et al. BMC Pediatrics 2010, 10:33 http://www.biomedcentral. com/1471-2431/10/33 Page 2 of 8 Zambia [4,8,9]. In a large Zambian cohort of children followed up for a limited period of time, younger age and low hemoglobin levels were additional factors associated with higher likelihood of early death following HAARTinitiation [8]. Following the results of the Children with HIV Early Antiretroviral Therapy (CHER) Trial in which early treatment reduced early infant mortality by 76%, international guidelines were modified to recommend initiation of HAART for infants below 18 months of age upon HIV diagnosis [14-16]. Initiation of antiretroviral therapy for older children is still dependent on clinical and immunologic staging [15]. Ideally, a child would be diagnosed and treated early, however, in spite of increased efforts to diagnose children early, some don't present for care till they are older. Therefore it remains important to better define factors that impact survival of such children in local settings with a view to maximize benefits by addressing any modifiable cofactors. We describe mortality in a cohort of HIV-1 infected children receiving antiretroviral therapy who have been followed up prospectively since 2004. Methods The Paediatric Adherence Study is a 5-year prospective observational study which started enrolling children in August 2004 as previously described [6]. Children were drawn from the Paediatric wards and HIV-1 Clinic of the Kenyatta National Hospital (KNH) in Nairobi Kenya. The study enrolled children aged 18 months 12 years who had advanced clinical and/or immunological HIV disease (WHO clinical stage 3-4 or WHO clinical stage 2 with CD4 <15%) and were antiretroviral drug-naïve. After counseling and informed consent, sociodemographic information was obtained and a physical examination performed. Samples were taken for baseline laboratory investigations including full haemogram, T-cell lymphocyte subsets (CD4), plasma HIV-1 RNA, and liver function tests, and a return appointment given for initiation of antiretroviral therapy. Children were initiated on a firstline antiretroviral drug combination recommended by the Kenya national guidelines which consists of two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) [16]. Follow-up visits were scheduled after 2 weeks, monthly for the first year, and quarterly thereafter. At each follow-up visit, children had a physical examination and information regarding adherence, adverse drug effects, and intercurrent illness was obtained. Hematologic and biochemical tests for toxicity monitoring and plasma HIV-1 RNA were performed 3-monthly during the first year and 6-monthly thereafter, while CD4 counts were obtained every 6 months. Information on the cause of death was abstracted from medical records for children who died in hospital, while for those who died at home, verbal autopsy was used. The caregiver was invited to the clinic to give details of the conditions preceding the child's death and a presumptive diagnosis was reached. In cases where the caregiver was unable to come to the research clinic, the study staff paid a home visit to conduct the verbal autopsy. Written informed consent was obtained from all study participants. Verbal assent was obtained from children between ages 7 and 12 years. This study received ethical approval from the Institutional Review Boards of the University of Washington and the Kenyatta National Hospital. Statistical methods Stata version 8 (Stata Corp, College Station Texas) was used for all analyses. The probability of survival was estimated using the Kaplan-Meier method. Cox proportional hazards models were used to determine baseline characteristics associated with mortality. Factors found to be significant predictors of mortality on univariate Cox proportional Hazards model (p value < 0.05) were entered into a multivariate model. We computed z-scores for anthropometric measures (weight-for-age, height-forage, and weight-for-height) using the Epi-Info (version 3.2, Centers for Disease Control, Atlanta Georgia) using CDC 2000 reference population. We analyzed weight-forheight z-score as a categorical variable with a cut off value of -2 which is the WHO upper limit for children with moderate protein energy malnutrition [17]. Similarly we categorized hemoglobin at a cut off value of 9 g/dl, below which children in low income countries are considered to have significant iron deficiency anemia [18].