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Hepatitis B Surface Antigen, Quantitative, Monitoring

Hepatitis B Surface Antigen, Quantitative, Monitoring

Test Summary

Hepatitis B Surface Antigen, Quantitative, Monitoring


Clinical Use

  • Confirm ongoing hepatitis B virus (HBV) replication

  • Differentiate phases of HBV infection

  • Evaluate prognosis of hepatitis B envelope antigen (HBeAg)-negative (genotype B or C) patients

  • Monitor response to treatment with pegylated interferon (peg-IFN) or nucleos(t)ide analogs (NAs)

Clinical Background

Hepatitis B surface antigen (HBsAg) is often used as a marker of HBV replication. Clearance of HBsAg indicates "immunological cure." Available HBsAg assays in the United States report the presence or absence of the antigen. However, assays that measure HBsAg levels can be used in conjunction with guideline-approved1 assays (HBV DNA quantitation, HBeAg, and alanine aminotransferase [ALT]) to differentiate phases of infection, establish prognosis, and guide treatment.

HBsAg levels fluctuate during the phases of HBV infection, which include: 1) immune-tolerant, 2) immune-clearance, 3) low replication (inactive carrier), and 4) reactivation (HBeAg-negative chronic hepatitis B). Towards the end of the immune-clearance phase, conversion from HBeAg-positive to HBeAg-negative occurs, which usually indicates a good outcome. Both HBsAg and HBV DNA levels are highest in the immune-tolerant phase, decrease during the immune-clearance phase, and are lowest during the inactive carrier phase. During the reactivation phase, HBV DNA and ALT levels may fluctuate, which can lead to a false conclusion that the infection is inactive. Thus, serial measurements of HBV DNA or ALT have been used to differentiate HBeAg-negative phases (ie, inactive vs reactivation).

In contrast, a single measurement of HBV DNA and HBsAg levels may be able to help differentiate the HBeAg-negative phases. HBsAg levels are higher in the reactivation phase than in the inactive carrier phase.2,3 Thus, use of quantitative HBsAg along with HBV DNA improves the ability to differentiate the phases in HBeAg-negative patients and results in a diagnostic accuracy of 70% to 94%, a sensitivity of 71% to 91%, a specificity of 85% to 95%, a positive predictive value of 83% to 88%, and a negative predictive value (NPV) of 74% to 97%.2,3

Quantitative HBsAg and HBV DNA testing can also be used together to assess the prognosis of HBeAg-negative patients. In patients with low HBV DNA levels (<2,000 IU/mL) and HBV genotype B or C, HBsAg levels <1,000 IU/mL are associated with lower rates of liver cirrhosis and hepatocellular carcinoma (HCC)3,4; levels <100 IU/mL are associated with higher rates of HBsAg clearance.2,5

HBsAg levels can also indicate the likelihood of success of HBV therapy. Depending on HBV genotype, response to peg-IFN therapy is unlikely in HBeAg-positive patients if HBsAg levels do not decline or are >20,000 IU/mL after 12 weeks of therapy (NPV, 92% to 100%); if levels are ≤20,000 at 12 weeks, response is more likely (22% to 45% of patients).6 Response is unlikely in HBeAg-negative patients who have a decline of <2 log HBV DNA and no HBsAg decline at week 12: in a study that included 7 such patients, none achieved sustained response.7

Similar to peg-IFN, the likelihood of response to NA therapy can also be assessed based on HBsAg levels. Many studies have examined different NAs and different outcomes (see reference 8). In HBeAg-positive patients, steep declines during treatment or low levels at baseline or the end of treatment are associated with virologic response. In HBeAg-negative patients, low levels at the end of treatment are associated with sustained virologic response.

Individuals Suitable for Testing

  • Individuals diagnosed with hepatitis B infection by qualitative HBsAg or PCR testing

  • Individuals with hepatitis B who are being considered for, or are being treated with, peg-IFN or an NA


  • Immunometric immunoassay: HBsAg in the specimen binds anti-HBs antibody conjugated to horseradish peroxidase (HRP); unbound antibody is washed away; a reagent that interacts with HRP to produce light is added; the amount of light is proportional to quantity of HBsAg

  • Reportable range: 0.05 IU/mL to 25,000 IU/mL

Interpretive Information

For HBeAg-positive patients, high levels of HBsAg are consistent with the immune-tolerant phase. For HBeAg-negative patients, high levels of HBsAg are consistent with the reactivation (active) phase.

For HBeAg-negative patients with B or C genotype, low HBsAg levels (<100 IU/mL) in patients with low HBV DNA levels (<2,000 IU/mL) are consistent with a higher likelihood of HBsAg clearance and lower risk of liver cirrhosis and HCC.

HBsAg levels can indicate the likelihood of response to peg-IFN and NAs (Table).

Table. Likelihood of HBV Therapy Response Based on HBsAg Levels6-8


Serum HBeAg

Quantitative HBsAg Levels
(HBV genotype)


Therapy Response



No decline (A or D) or >20,000 IU/mL
(B or C) after 12 weeks of therapy

≤20,000 IU/mL after 12 weeks of therapy



More likelya



No decline and <2 log HBV DNA
decline after 12 weeks of therapy



Nucleos(t)ide analogs


Low baseline

Steep decline during therapy

Low at end of therapy




Likely (sustained)


Low at end of therapy


Likely (sustained)

HBV indicates hepatitis B virus; HBeAg, hepatitis B envelope antigen; HBsAg, hepatitis B surface antigen; Peg-IFN, pegylated interferon.
a 22% to 45% of patients vs only 6% of patients with >20,000 IU/mL6


  1. Terrault NA, Bzowej NH, Chang KM, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63:261-283.

  2. Brunetto MR, Oliveri F, Colombatto P, et al. Hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers. Gastroenterology. 2010;139:483-490.

  3. Liu J, Yang HI, Lee MH, et al. Serum Levels of Hepatitis B Surface Antigen and DNA Can Predict Inactive Carriers With Low Risk of Disease Progression. Hepatology. 2016;64:381-389.

  4. Tseng TC, 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;142:1140-1149.

  5. Liu J, Lee MH, Batrla-Utermann R, et al. A predictive scoring system for the seroclearance of HBsAg in HBeAg-seronegative chronic hepatitis B patients with genotype B or C infection. J Hepatol. 2013;58:853-860.

  6. Sonneveld MJ, Hansen BE, Piratvisuth T, et al. Response-guided peginterferon therapy in hepatitis B e antigen-positive chronic hepatitis B using serum hepatitis B surface antigen levels. Hepatology. 2013;58:872-880.

  7. Rijckborst V, Hansen BE, Ferenci P, et al. Validation of a stopping rule at week 12 using HBsAg and HBV DNA for HBeAg-negative patients treated with peginterferon alfa-2a. J Hepatol. 2012;56:1006-1011.

  8. Chen CH, Chiu YC, Lu SN, et al. Serum hepatitis B surface antigen levels predict treatment response to nucleos(t)ide analogues. World J Gastroenterol. 2014;20:7686-7695.

Content reviewed 11/2016


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