The long-lasting viral reservoir in resting CD4 memory cells and other anatomic sanctuaries requires that antiretroviral therapy (ART) be continued life-long. The recent report of the infant in Mississippi who started treatment within 30 hours of birth and who has been able to maintain viral suppression off treatment raises the tantalizing possibility that establishment of the viral reservoir may be avoidable in some infants. Limitations of this single case report necessitate urgent replication as the potential public healt benefits of the intervention are profound. We propose a single-arm clinical trial in Johannesburg, South Africa, to replicate the Mississippi case in a more robust number of infants. Our trial is designed to test whether initiation of ART within 48 hours of birth has the potential to allow the majority of HIV-infected infants to safely discontinue ART without viral rebound. The context of starting ART within hours of birth and stopping it 18 months later provides an unprecedented opportunity to elucidate mechanisms involved in the establishment and maintenance of viral reservoir. In the context of this unique trial, we will collect samples before, during and after AR cessation to investigate potential mechanisms driving the establishment of the viral reservoir. Following the exciting new findings from the Mississippi child, we hypothesize that infant immunological developmental maturity is one of the critical parameters influencing the success of early treatment. ART given at birth is not only close in time to acquisition of infection but is given during a developmentally-critical time period when the immune system is transitioning to its mature form and is at its most quiescent. We will also recruit a carefully-selected observational cohort of infants 4-12 weeks of age initiating and continuing ART in the standard way from routine clinical services. We will investigate whether lesser CCR5 and CD2 expression on T-cells, a smaller pool of CD4 memory cells, reduced markers of T-cell activation, and larger proportions of regulatory (suppressive) T-cells (T-regs) relative to Th17 cells will be associated with more limited seeding and greater decay of the viral reservoir when ART is started at a young age. We will also investigate whether markers in infant stool samples can be used as a non-invasive method of defining relevant immune and HIV-specific parameters associated with smaller viral reservoirs.

Public Health Relevance

Our study will evaluate whether initiation of antiretroviral therapy (ART) within 48 hours of birth has the potential to allow the majority of HIV-infected infants to safely discontinue ART without viral rebound and to investigate the role of neonatal immune quiescence in limiting the establishment of the viral reservoir in early-treated infants.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HD080441-04
Application #
9260039
Study Section
Special Emphasis Panel (ZHD1-DSR-A (50)R)
Program Officer
Russo, Denise
Project Start
2014-05-15
Project End
2019-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
4
Fiscal Year
2017
Total Cost
$955,755
Indirect Cost
$85,948
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Shiau, Stephanie; Abrams, Elaine J; Arpadi, Stephen M et al. (2018) Early antiretroviral therapy in HIV-infected infants: can it lead to HIV remission? Lancet HIV 5:e250-e258
Technau, Karl-Günter; Strehlau, Renate; Patel, Faeezah et al. (2018) 12-month outcomes of HIV-infected infants identified at birth at one maternity site in Johannesburg, South Africa: an observational cohort study. Lancet HIV 5:e706-e714
Technau, Karl-Günter; Kuhn, Louise; Coovadia, Ashraf et al. (2017) Xpert HIV-1 point-of-care test for neonatal diagnosis of HIV in the birth testing programme of a maternity hospital: a field evaluation study. Lancet HIV 4:e442-e448
Shiau, Stephanie; Strehlau, Renate; Technau, Karl-Günter et al. (2017) Early age at start of antiretroviral therapy associated with better virologic control after initial suppression in HIV-infected infants. AIDS 31:355-364
Technau, Karl-Günter; Mazanderani, Ahmad Haeri; Kuhn, Louise et al. (2017) Prevalence and outcomes of HIV-1 diagnostic challenges during universal birth testing - an urban South African observational cohort. J Int AIDS Soc 20:21761
Technau, Karl-Günter; Kuhn, Louise; Coovadia, Ashraf et al. (2017) Improving early identification of HIV-infected neonates with birth PCR testing in a large urban hospital in Johannesburg, South Africa: successes and challenges. J Int AIDS Soc 20:21436
Kuhn, Louise; Shiau, Stephanie (2017) The pharmacological treatment of acute HIV infections in neonates. Expert Rev Clin Pharmacol 10:1353-1361
Shiau, Stephanie; Kuhn, Louise (2014) Antiretroviral treatment in HIV-infected infants and young children: novel issues raised by the Mississippi baby. Expert Rev Anti Infect Ther 12:307-18