Children hospitalized with severe illness in sub-Saharan Africa are at high risk of morbidity and mortality following discharge from hospital. This risk appears particularly elevated among HIV-infected (HIV+) and HIV-exposed uninfected (HEU) children, a risk that is compounded by the frequency of hospitalizations in these populations. Targeted interventions at hospital discharge could improve recovery, prevent new infections, and reduce rates of re-hospitalization and death. However, identifying effective interventions for HIV+ and HEU children requires a better understanding of the unique mechanisms underlying post-discharge vulnerability in these populations, including the role of dysregulated immune responses to pathogens, persistent immune activation and inflammation, and exposure to and carriage of specific pathogens or antibiotic resistance in those pathogens. The ongoing Toto Bora Trial (R01HD079695) randomizes children aged 1-59 months who have been hospitalized and subsequently discharged from two Western Kenya hospitals to a 5-day course of azithromycin or placebo, and examines risk of morbidity and mortality in the subsequent 6-month period. The trial sites are located in Homa Bay and Kisii counties, which have some of the highest rates of new pediatric HIV infections in the country. A rich data and specimen set is being collected, which includes clinical and sociodemographic data as well as blood, stool, and nasopharyngeal swabs at each study visit. Supplemental funds will be used for new laboratory assays and associated analyses investigating the mechanisms of post-discharge infectious morbidity in HIV+ and HEU children, and to determine whether azithromycin prophylaxis provides differential benefit in these groups. Outcomes from this supplement will directly inform the development of novel management strategies for children affected by HIV.
Rates of child mortality rates in sub-Saharan Africa are higher than any other region. A substantial proportion of child deaths in this region are due to infectious causes, including diarrhea, pneumonia, and malaria, diseases that are often more common and more deadly amongst HIV-infected (HIV+) and HIV-exposed uninfected (HEU) children. HIV+/HEU children are more likely to be hospitalized than HIV-unexposed children and these children represent an accessible high-risk population in which targeted interventions to prevent morbidity and mortality could have dramatic impact. The proposed mechanistic study leverages and expands upon the existing data and samples being collected in an ongoing clinical trial testing the efficacy of azithromycin given to children at hospital discharge, aiming to identify novel mechanisms of morbidity and mortality in HIV+/HEU children. The results of this study may benefit thousands of HIV-affected children in sub-Saharan Africa and will directly impact treatment guidelines for HIV+ and HEU hospitalized children in low-resource settings.
| Pavlinac, Patricia B; Singa, Benson O; John-Stewart, Grace C et al. (2017) Azithromycin to prevent post-discharge morbidity and mortality in Kenyan children: a protocol for a randomised, double-blind, placebo-controlled trial (the Toto Bora trial). BMJ Open 7:e019170 |
| Pavlinac, P B; Denno, D M; John-Stewart, G C et al. (2016) Failure of Syndrome-Based Diarrhea Management Guidelines to Detect Shigella Infections in Kenyan Children. J Pediatric Infect Dis Soc 5:366-374 |
