Abstract Hepatitis B virus (HBV) is a serious global health concern. In those with HIV it is associated with increased risk of chronicity after acute infection, and increased rates of liver-associated mortality. The field of HBV treatment is undergoing evolution, changing focus from HBV DNA suppression to functional and complete HBV cure. Biomarkers that provide clear guidance regarding prediction, treatment outcome and accurate information regarding liver injury are limited. Though research use of newer HBV biomarkers including pgRNA, quantitative surface antigen and HBV core-related antigen has accelerated in the last year, very limited data exists with regard to their use and utility among persons living with HIV (PLWH). In this Exploratory R21 application we propose to evaluate the potential role of several biomarkers that have not been previously characterized in those with HBV/HIV coinfection. HBV pgRNA represents a transcript of the cccDNA minichromosome that is central to development and perpetuation of HBV chronicity. Using 3 complementary cohorts of PLWH, we will evaluate the association of these biomarkers with CD4 count, HIV viral load and other demographic and serologic HBV markers stratified by categorical natural history replicative stages of HBV disease. In one AIDS Clinical Trials Group (ACTG) cohort, we will examine longitudinal changes in these biomarkers associated with initiation of nucleoside therapy. Our laboratory has recently implemented use of a new blood-based cccDNA assay which will be utilized in conjunction with the pgRNA assays to determine the frequency and proportion of gene silencing. Using novel liver-derived exosome markers of liver injury we will explore whether gene silencing is associated with lower levels of liver injury than are identified with more traditional markers of response such as serum ALT. This characterization will provide key information that may inform future cure strategies for HBV, in PLWH which are being studied within the ACTG and elsewhere.