A request for applications (RFA) with set aside is proposed, entitled “Pediatric HIV-AIDS Cohort Study (PHACS)” using the U01 Research Project – Cooperative Agreements grant mechanism.
The proposed RFA is a competing renewal, using the U01 mechanism, to provide support for continuing the observational cohorts developed during the first two competitive funding cycles. These cohorts address two critical issues in HIV research: 1) the long-term safety of in utero exposure to multiple antiretroviral drugs in HIV-exposed but uninfected infants, children, and adolescents, and 2) the interactive effects of HIV and its treatment on perinatally HIV-infected children, adolescents, and young adults. This mechanism has operated very well during the first two funding cycles, and recompetition under the same mechanism affords the most efficient means of continuation.
PHACS includes 2 distinct cohorts in the United States – 1) HIV-exposed but uninfected infants, children and adolescents, and 2) perinatally HIV-infected children, adolescents, and young adults.
The study of an open cohort of HIV-uninfected children exposed to antiretrovirals during pregnancy and early infancy to identify potential consequences continues to be a critical need as new drugs and more complex antiretroviral regimens are increasingly being used, often much earlier in pregnancy, by HIV-infected pregnant women to prevent mother to child transmission and/or for treatment for maternal health reasons. The importance of this effort is illustrated by recent data from PHACS that in utero exposure to the antiretroviral drug tenofovir – a drug with renal and bone toxicity when used for therapy - may be associated with diminished bone mineral density in exposed infants at birth compared those exposed to other drugs. Continuation of this effort will allow for ongoing evaluations of new antiretroviral exposures in the HIV-uninfected cohort in utero and postnatally and further work to identify specific adverse events and potential etiologic factors. Over 3000 HIV-exposed uninfected children have been enrolled in PHACS to date and are under active follow-up.
Perinatally-infected youth are now routinely surviving to young adulthood but face the consequences of prolonged HIV infection and long-term antiretroviral therapy on multiple organs and systems in the body. Given the great increase in the number of available antiretrovirals but the limited data on the long term safety of these agents in growing and developing youth, a cohort study such as this also continues to have critical importance. Over 400 children and adolescents with perinatal HIV infection and over 200 uninfected control subjects have been enrolled and are under intensive evaluation in PHACS to date; a high prevalence of abnormalities has already been detected. Recent findings from this PHACS cohort have demonstrated that youth starting therapy at very young ages appear to have a significantly diminished viral reservoir compared to those starting later, data critical to evaluating the potential for functional cure of HIV in children.
As of December 2013, work in PHACS has resulted in over 30 manuscripts and over 50 abstracts, including the reports mentioned above. Since this initiative represents the extension of funding for an established set of cohorts, Program expects that competition will be limited to applicant institutions that were funded in the initial competitive segment. Awards made to new institutions would not serve the interests of efficiently and seamlessly maintaining PHACS activities.
The goals of the PHACS network: (1) Acquire more definitive information regarding long-term safety of antiretroviral drugs used during pregnancy and in infancy on HIV-exposed but uninfected infants, children, and adolescents and to estimate the upper bounds of risk to children associated with in utero exposure to antiretroviral drugs and (2) Understand the effect of HIV and its treatment on various domains including cardiovascular risk, bone health, sexual maturation, pubertal development, and mental health, in perinatally HIV-infected children, adolescents, and young adults.
Denise Russo, PhD
Maternal and Pediatric Infectious Disease Branch
Back to Concept Review by Council