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Hepatitis B virus (HBV) infection remains a major public health concern. The interaction between HBV and the host inflammatory response is an important contributing factor driving liver damage and diseases outcomes. Here, we performed a retrospective analysis employing an adapted molecular degree of perturbation (MDP) score system to assess the overall inflammatory imbalance related to persistent HBV infection. Plasma levels of several cytokines, chemokines, and other inflammatory markers were measured in Brazilian individuals diagnosed with either chronic HBV or previous HBV infection, as well as in uninfected controls between 2006 and 2007. Multidimensional analyses were used to depict and compare the overall expression profile of inflammatory markers between distinct clinical groups. Chronic HBV patients exhibited a marked inflammatory imbalance, characterized by heightened MDP scores and a distinct profile of correlation networks inputting plasma concentrations of the biomarkers, compared with either individuals with previous HBV or controls. Furthermore, in participants with chronic HBV infection, the viral loads in peripheral blood were directly proportional to overall molecular perturbation as well as to specific perturbations of interleukin (IL)-4 and interferon (IFN)-γ concentrations. These findings highlight additional nuances about systemic inflammation related to persistent HBV infection. [ABSTRACT FROM AUTHOR]