Journal
PLOS ONE
Volume 8, Issue 12, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0083389
Keywords
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Categories
Funding
- National Institutes of Health (International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT)
- National Institute of Allergy and Infectious Diseases [K01 AI078754, K24 AI062476, R01 AI058736, R01 AI093269, U01 AI069911, U01AI09919]
- Harvard Center for AIDS Research
- Elizabeth Glaser Pediatric AIDS Foundation
- March of Dimes Foundation
- Massachusetts General Hospital Executive Committee on Research
- National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- National Institute of Mental Health (NIMH) [AI068632]
- Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases [5 U01 AI41110, 1 U01 AI068616]
- National Institute of Allergy and Infectious Diseases (NIAID)
- NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network
- NICHD [N01-DK-9-001/HHSN267200800001C]
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Background: Computer simulation models can project long-term patient outcomes and inform health policy. We internally validated and then calibrated a model of HIV disease in children before initiation of antiretroviral therapy to provide a framework against which to compare the impact of pediatric HIV treatment strategies. Methods: We developed a patient-level (Monte Carlo) model of HIV progression among untreated children <5 years of age, using the Cost-Effectiveness of Preventing AIDS Complications model framework: the CEPAC-Pediatric model. We populated the model with data on opportunistic infection and mortality risks from the International Epidemiologic Database to Evaluate AIDS (IeDEA), with mean CD4% at birth (42%) and mean CD4% decline (1.4%/month) from the Women and Infants' Transmission Study (WITS). We internally validated the model by varying WITS-derived CD4% data, comparing the corresponding model-generated survival curves to empirical survival curves from IeDEA, and identifying best-fitting parameter sets as those with a root-mean square error (RMSE) <0.01. We then calibrated the model to other African settings by systematically varying immunologic and HIV mortality-related input parameters. Model-generated survival curves for children aged 0-60 months were compared, again using RMSE, to UNAIDS data from >1,300 untreated, HIV-infected African children. Results: In internal validation analyses, model-generated survival curves fit IeDEA data well; modeled and observed survival at 16 months of age were 91.2% and 91.1%, respectively. RMSE varied widely with variations in CD4% parameters; the best fitting parameter set (RMSE = 0.00423) resulted when CD4% was 45% at birth and declined by 6%/month (ages 0-3 months) and 0.3%/month (ages > 3 months). In calibration analyses, increases in IeDEA-derived mortality risks were necessary to fit UNAIDS survival data. Conclusions: The CEPAC-Pediatric model performed well in internal validation analyses. Increases in modeled mortality risks required to match UNAIDS data highlight the importance of pre-enrollment mortality in many pediatric cohort studies.
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