Clinical Project

Johns Hopkins University, Baltimore MD

Investigators

Abstract

Abstract – Clinical Project The chief objective of the Clinical Project is to advance a hepatitis B virus (HBV) cure by detailed investigation of the dynamics of virus replication and host response in the plasma of well-characterized persons living with HIV or HBV. Our premise is that the net abundance of HBV replication and host response is evident in plasma. By detailed study of the forms and quantities of virus-specific proteins, DNA, and replicative RNA intermediates, we will reveal novel insights into an HBV cure, specifically in persons with HIV and HBV (PWHHB). Using a comprehensive panel of serologic and molecular markers, we will characterize longitudinal dynamics of HBV replication and host immune response and evaluate those responses in light of established markers of liver disease. Given the focus on a functional cure, we will also evaluate the impact of HIV and antiviral therapy on the quantity, composition, and source of HBsAg. We will test the hypothesis that HBsAg from iDNA is responsible for delayed HBsAg clearance, using pregenomic RNA to reveal cccDNA transcription. We will then extend those findings by developing mechanistic mathematical models, including HBsAg source and dynamics. Fitting these models to the data will provide detailed insights into the parameters governing HBV DNA and HBsAg decay. The models will quantify the effect of treatment on those rates, including differences due to clinical and biological variables (e.g., HBeAg status, HIV, or sex). To accomplish these aims in the Hepatitis B HIV Cure Consortium (BICC), we will respond to key objectives of RFA-AI-23-057 by characterizing clinically relevant noninvasive biomarkers and elucidating mechanisms of persistence and pathogenesis. This project works closely with the Translational Project, connecting intrahepatic events with serologic findings. It also works with the Immunology Project to understand HBV clearance dynamics, and it works with all cores. Therefore, we anticipate an extremely high likelihood of clinically significant and scientifically conclusive findings that substantially advance the HBV cure agenda.