Identifying the long-term metabolic complications of in-utero and lactational antiretroviral exposure - Project Summary / Abstract
The increased use of combination antiretroviral therapy (cART) has significantly reduced the perinatal
transmission of HIV. However, as more HIV-infected women take cART, there is an increasing population of
children exposed to cART in-utero and while nursing. The World Health Organization (WHO) now recommends
dolutegravir (DTG)-based cART as first-line treatment for all people living with HIV, including pregnant women.
Although early exposure to non-DTG based cART has been associated with bone and fat-related
complications, the long-term consequences of in-utero and lactational exposure to DTG are completely
unknown and will take decades to determine. The current proposal aims to address this gap in knowledge
by leveraging banked bone and fat samples from an 18-month rat experiment to test the hypothesis that
developmental exposure to DTG-based cART will cause lasting deleterious effects on bone and fat tissues. To
test this hypothesis, we will determine the effects of in-utero and lactational exposure to DTG-based cART on
(1) bone mass and quality using micro-computed tomography, Raman microspectroscopy, and mechanical
testing and (2) fat tissue using RNAsequencing, RT-qPCR, and western blot analysis. The current proposal is
significant because it addresses a critical clinical concern. The research question is timely, as DTG-based
cART has become the recommended first line cART for all people living with HIV, including pregnant women.
The hypothesis is conceptually innovative, as the metabolic consequences of early DTG exposure are
unknown. Finally, the proposed aims are well-matched to the R03 programmatic goals as they represent a
secondary analysis of an existing dataset. Results from this proposal will begin to establish the long-term
effects of developmental exposure to DTG on bone and fat tissues and begin to determine the driving
mechanisms.
