A Clinical Trial of Three Broadly Neutralizing Antibodies and Analytic Treatment Interruption in Early-Treated Children in Botswana - Project Summary/Abstract Novel HIV-1 treatment strategies that maintain viral suppression while allowing time off small molecule antiretroviral treatment (ART) are of high priority. An ART-sparing treatment intervention using potent and long- acting broadly neutralizing antibodies (bNAbs) may reduce direct ART toxicities during critical periods of growth and development for children with HIV, will ensure adherence, and may have benefits over ART for viral reservoir reduction and post-treatment control. bNAbs have been associated with reduction in viral reservoirs, and recent studies support a potential vaccine-like effect that may train immune responses and improve long-term outcomes. Like early-treated adults, early-treated children may have the best chance to become post-treatment controllers, but further studies are needed -- including studies that utilize an analytic treatment interruption (ATI). We recently completed the Tatelo Study, a proof-of-concept trial demonstrating that monthly treatment with dual bNAbs could maintain viral suppression for 24 weeks without ART in 44% of early-ART treated children. We also showed that specific markers for success were identifiable, and that interruption of standard ART could be safely performed in our study setting. In the proposed study (Tatelo Plus), we will perform a multi-step interventional clinical trial that advances the field farther. Using a novel step-wise design and an innovative bNAb rotation strategy, we will first determine the safety, pharmacokinetics, dosing, and reservoir impact of long-acting triple bNAb immunotherapy with VRC07-523LS, PGDM1400LS and PGT121-414LS when added to existing effective ART. In selected participants with favorable markers for success, we will next measure triple-bNAb treatment success following ART discontinuation. Finally, we will test for the maintenance of virologic control during an ATI in an even more highly selected group of participants -- those with extremely low viral reservoir or evidence of HIV integration in non-encoding regions of the genome. The specific aims of this study are (1) to determine the safety, pharmacokinetics and dosing of up to 24 weeks of concomitant use of triple bNAb immunotherapy when added to ART in 35 early-treated children living with HIV-1 in Botswana; (2) to determine the safety, maintenance of virologic suppression, and CD4 cell count preservation of 24 weeks of maintenance triple bNAb treatment following the discontinuation of standard ART in selected early-treated children; and (3) to determine the safety, maintenance of virologic suppression, and CD4 cell count preservation of a 24 week ATI among two groups: a) those with markers for the lowest viral reservoir, and b) those with evidence of HIV-1 integration in predominantly non-encoding regions of the genome. At each study step, we will measure the size and cellular composition of residual viral reservoirs, and the magnitude and quality of antiviral innate and adaptive immune responses. This study will represent a leap forward for combination bNAb treatment in children, and will advance the pediatric cure agenda through a carefully conducted ATI.
