Large-scale profile study on hepatitis B surface antigen levels in chronic hepatitis B: Implications for drug development targeting functional cure

Quantifying the interplay between hepatitis B virus and antiviral immunity: The ALT/qHBsAg ratio

Quantitative measurement of hepatitis B surface antigen (HBsAg) has gained substantial importance in recent years. Although quantitative HBsAg levels (qHBsAg) do not directly correlate with the number of hepatitis B virus (HBV)-infected hepatocytes, several studies have demonstrated that low HBsAg levels are predictive of spontaneous HBsAg loss or HBsAg seroconversion, which is commonly defined as a functional cure. These findings have now been convincingly confirmed in a large Asian cohort study conducted by Hui et al.
Functional cure of chronic HBV infection is an immune-mediated event. A substantial body of evidence, including data from studies evaluating nucleos(t)ide analogue (NUC) discontinuation, indicates that a certain degree of immune activation is required to achieve this outcome. This activation is often reflected by an increase in serum transaminases, particularly alanine aminotransferase (ALT), commonly referred to as “HBV flares.” In their study, the authors introduce a novel integrative marker that captures the interaction between viral burden and host immune response: the ALT/qHBsAg ratio. This ratio relates biochemical inflammatory activity, with ALT serving as a surrogate marker of immune-mediated hepatocyte injury, to the viral antigen load as reflected by quantitative HBsAg. In doing so, it provides an estimate of immune activation relative to the amount of viral antigen. The ALT/qHBsAg ratio specifically addresses an important limitation of conventional prognostic markers such as age, HBeAg status, or HBV DNA levels, which insufficiently capture the dynamic virus–host equilibrium. It also complements other virological markers that are less widely available in clinical practice. By integrating ALT activity and qHBsAg levels, the ratio allows a functional interpretation of whether ALT activity is sufficiently high relative to the existing HBsAg level to indicate meaningful immunological control. The data presented demonstrate that the ALT/qHBsAg ratio is a significant predictor of long-term HBsAg seroclearance and favorable qHBsAg trajectories in both treatment-naïve and treated patients, with consistent performance across different subgroups. Because both parameters are routinely measured, the ratio is also well suited for longitudinal monitoring of immunovirological dynamics.
Beyond the natural course of disease, the ALT/qHBsAg ratio may also play an important role for emerging antiviral therapies currently under development. Indeed, the efficacy of almost all compounds in clinical testing with HBsAg loss as a primary end point, efficacy appears to be greatest in patients with low baseline qHBsAg levels. However, selecting patients solely on the basis of qHBsAg levels may exclude potentially “immunoactive” patients with high qHBsAg values. In contrast to isolated qHBsAg measurement, the ratio therefore allows a more nuanced assessment of immune activity, including whether changes in HBsAg levels are accompanied by evidence of immune response. This aspect may become particularly relevant for future personalized combination therapies with immunomodulators, such as RNA interference–based strategies or therapeutic vaccination.
In summary, the ALT/qHBsAg ratio appears to be a simple, biologically plausible, and clinically relevant tool for estimating immune activity over the course of chronic HBV infection. Nevertheless, further validation and standardization in prospective studies are required.