Dissertations & Theses (Open Access)

Date of Award

Spring 5-2019

Degree Name

Doctor of Philosophy (PhD)

Advisor(s)

Lu-Yu Hwang, Md

Second Advisor

Ruosha Li, Phd

Third Advisor

Christine Markham, Phd

Abstract

Despite the over 10-years’ experience providing pediatric antiretroviral therapy(ART) and implementing different WHO guidelines, data on updated trends (after 2010) in advanced disease at ART start, and on long-term survival of children receiving ART are scarce. Without these data, the impact of recent WHO guidelines on early treatment initiation and long-term survival remains unclear. First, we examined trends in advanced disease at ART start, then described 10-year survival and investigated risk factors of early mortality in children treated with ART and lastly examined the association between rapid ART initiation and outcomes (mortality and loss to follow-up) of HIV infected. We studied children (0-14 years) with HIV who initiated ART at seven Baylor International Pediatric AIDS initiative supported clinics in Botswana, Lesotho, Malawi, Swaziland, Tanzania, and Uganda. For the first aim, we conducted a pooled cross sectional study of children (N=20,605) who initiated ART between 2003 and 2017. We examined the linear trends in the proportion of children with advanced disease (over seven periods of ART initiation 8 corresponding to WHO guideline implementation period) using the Cochran-Armitage test for trend. For the second aim, we conducted a retrospective cohort study of children (N=18,010) who initiated ART between 2003 and 2017. We estimated 10-year survival using the Kaplan Meier approach and assessed risk factors of early mortality using Cox proportional hazard regression. For the third aim, we conducted a retrospective cohort study of children (N=3,299) who initiated ART between 2014 and 2017. We examined the association between rapid ART initiation and outcomes of children using sub-distribution hazard regression for competing risks, treating death and loss to follow-up as competing risks. Between 2003-2017, the proportion of children initiating ART with advanced disease declined among ages 5-9 years (58.3% to 39.9%; p<0.01) and 10-14 years (61.9% to 38.1%; p<0.01), remained the same for ages <2 years (72.7% to 70.6%; p=0.1), and increased for ages 2 4 years (59.4% to 62.3%; p<0.01). 10-year survival probability %( 95%CI) was 88.9 (88.3-89.5) overall, 83.7 (82.5-84.8) in children aged <2 years, 91.9 (90.7-93.0) in those 2-4 years, 92.6 (91.5-93.6) in 5-9 years and 88.8 (9 87.2-90.2) in 10-14 years. Half of the deaths occurred within 6–months of therapy. The risk factors of mortality were: baseline age <2 years (aHR 1.41(95% CI: 1.11-1.79) compared to 10-14 years; WHO stage 4 (aHR 2.95(95% CI 2.33-2.72) and stage 3 (aHR 1.36(95% CI: 1.06-1.73) compared to stage 1 and 2 disease; severe (aHR=6.71, 95% CI 5.29-8.52) and moderate (aHR=2.64, 95% CI 1.90-3.66) immune suppression compared to no/mild immune suppression; and severe underweight (aHR 1.84 (95% CI 1.48-2.29) compared to normal weight-for-age. The risk of mortality was similar between children who initiated ART on the same-day [adjusted sub distributional hazard risk (aSHR) =1.10, 95% CI 0.79, 1.75] and those who initiated within 2-7 days (aSHR=1.05, 95% CI 0.77, 1.43) compared to those who initiated within 8-90 days. The risk of LTFU was higher in children who initiated ART on the 9 same day (aSHR=1.86, 95% CI 1.39, 2.49) and those who initiated within 2-7 days (aSHR=1.83, 95% CI 1.38, 2.43) compared to those who initiated within 8-90 days. The proportion of children with HIV aged 5-14 years who initiate ART with advanced disease has reduced, and long-term survival in those treated with ART is good. However, nearly two-thirds of children aged <5 years are still initiating ART with advanced disease, early mortality is high, and disease severity characteristics were associated with a higher risk of early mortality. A significant proportion of those who initiate ART rapidly is lost to follow-up. While programs can use the good survival outcome to motivate caretaker to test and initiate ART early in children, more work is required to diagnose, initiate and keep children with HIV in care.

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