Quantitative HBsAg monitoring in hepatitis B virus treatment

Nov. 21, 2017

There is a lot of excitement in the infectious disease community about the robust late-stage hepatitis B virus (HBV) pipeline of potential new drug therapies. Like today’s hepatitis C treatments, these new treatments offer new hope for a functional cure, and possibly a complete cure, for people living with HBV. While true curative therapy is the ideal, HBV is a complicated disease and there is debate about what constitutes a true cure. The current drug pipeline aims for a functional cure, which requires sustained HBsAg clearance, HBV DNA negativity, and reduction or clearance of other disease markers in the blood even after an HBV drug is stopped.

The serological course of chronic HBV has greatly been debated. Hepatitis B e antigen (HBeAg) typically develops after infection with the HBV virus. The majority of carriers eventually stop making HBeAg and develop antibody to HBeAg either through viral mutations, immune control, or immune clearance. In most of these persons undergoing seroconversion from HBeAg to antibody to HBeAg (anti-HBe), levels of HBV DNA decrease and chronic hepatitis improves or is functionally cured when HBsAg is cleared. A more ambitious (but less likely) goal for some patients is loss of HBV surface antigen (HBsAg), appearance of HBV surface antibody (anti-HBs), HBV DNA negative, and silencing or eliminating cccDNA (covalently closed circular DNA), a DNA structure that arises during the propagation of some viruses in the cell nucleus and remains there permanently with all current therapies and even with natural HBsAg clearance.

HBsAg as a biomarker

Hepatitis B serologic testing involves measurement of several HBV-specific antigens and antibodies. Different serologic markers are used to identify different phases of HBV infection and to determine whether a patient has acute or chronic HBV infection, is immune to HBV as a result of prior infection or vaccination, or is susceptible to infection.

One such marker, HBsAg, can be detected in low, moderate, or high levels in serum during acute or chronic hepatitis B virus infection. The presence of HBsAg indicates that the person is infectious, and chronic infection is characterized by the persistence of HBsAg for at least six months (with or without concurrent HBeAg). Hepatitis B surface antigens are an early sign of an acute infection, and they are also present during chronic, or long-term, infection. HBsAg level may reflect the transcriptional activity of cccDNA as well as integrated HBV DNA mRNA production and translation to HBsAg (truncated) rather than the absolute amount of cccDNA. The serum HBsAg level tends to be higher in hepatitis B e antigen (HBeAg)-positive than HBeAg-negative patients.

While HBsAg has been suggested to be helpful in the management of HBV, until recently, this assay was not available through any commercial labs in the U.S. Its recent availability through one commercial lab has energized interest in using it as a biomarker to aid prognosis and treatment response in patients with chronic HBV.

Patients on interferon-based antiviral therapies

For patients who are on currently available treatments for HBV and who have not been functionally cured, HBsAG is essential to monitoring whether or not there is hope for a functional cure, such as would be evident by clearance of HBsAg and the development of antibodies to HBsAg. The majority of carriers of HBV are HBsAg-positive for life, although some carriers eventually clear HBsAg and may develop antibody to HBsAg. Those tested with levels equal to or greater than 1000 IU/mL will not clear; those with levels of 100-1000 have a low probability; and those with levels below 100 (especially if less than 10) have a high probability of functional cure.

The response to antiviral therapy in chronic HBV patients can vary significantly among patients. qHBsAg in combination with HBV DNA detection may aid clinicians in creating a specific therapeutic regimen for individual patients. With new treatments on the horizon, for patients who are on current, interferon-based antiviral therapies, close monitoring of quantitative HBsAg values during treatment can help predict treatment response. Twelve weeks is typically an appropriate time period to determine whether or not therapy is working. In clinical practice, during this time, changes in HBsAg levels can be observed in combination with indicators such as HBeAg, HBV DNA, and ALT to determine likelihood of viral clearance and cure.1

Patients who have been functionally cured

While some patients may achieve functional cure on currently available anti-viral therapies, they still may be at risk from co-morbidities associated with the virus. That is why in addition to continued qHBsAg testing, it is important to determine whether or not other testing, such as HBeAg status, liver enzymes (AST, ALT), liver function (ALB, INR, Bili), elastography, and portal vein and spleen size analysis, among others, may be appropriate. So may APRI and FIB4 scoring with online tools.

For example, it is important in functionally cured patients to monitor for hepatocellular carcinoma (HCC), the most common type of primary liver cancer, if cirrhosis is present. In patients with chronic HBV infection or chronic hepatitis B, a Gastroenterology study found that high levels of qHBsAg increase risk of hepatocellular carcinoma in patients with low HBV load.2 Additionally, functionally cured patients who are not on treatment may be at risk for cirrhosis. HBsAg in combination with alanine aminotransferase (ALT) testing can assist in determining the risk of progression to cirrhosis.

How we monitor our patients with HBV

Outside of the United States, HBsAg monitoring is utilized widely for patients who are being treated for HBV and for those who have been functionally cured but are receiving ongoing monitoring for comorbidities.

Now that a test is broadly available in the U.S. for monitoring qHBsAg, clinicians have the option of incorporating it more broadly into their treatment protocol for patients with HBV. By doing so, physicians can better predict a patient’s prognosis for a functional cure as well as assess risk or progression to liver disease. For patients who have been functionally cured, qHBsAg testing allows them to be placed in a matrix of appropriate lab tests and imaging to determine long term health. HBsAg provides a window into a patient’s health that HBV DNA alone cannot. qHBsAg and this matrix of tests offer the best change at understanding prognosis, determining a treatment protocol, and monitoring a patient for long-term health and wellness.


  1. European Association for the Study of the Liver (EASL). EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. https://www.easl.eu/medias/cpg/management-of-hepatitis-B-virus-infection/English-report.pdf.
  2. T. Tseng, Liu CJ, Yang HC, et al. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology. 2012;142(5):1140-1149.

Robert Gish, MD, FAASLD, is the medical director of the Hepatitis B Foundation and an Adjunct Professor of Medicine at Stanford University.