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Noninvasive Testing in HBV Management: When to Use Quantitative HBsAg and Elastography

Anna Christina L. dela Cruz, MD

Assistant Professor
Division of Digestive Diseases and Nutrition
Department of Internal Medicine
University of Kentucky
Lexington, Kentucky


Anna Christina L. dela Cruz, MD, has disclosed that she has received funds for research support from Novo Nordisk.


View ClinicalThoughts from this Author

Released: August 18, 2020

In general, an HBV DNA level < 2000 IU/mL, a negative hepatitis B e antigen (HBeAg), and a normal alanine aminotransferase (ALT) defines inactive chronic hepatitis B (CHB) infection. However, patients with immune-active HBeAg-negative CHB can have fluctuating liver enzymes and DNA levels that mimic the results seen in patients with inactive chronic hepatitis B infection. Therefore, distinguishing between inactive infection and immune-active HBeAg-negative CHB is essential in the decision to treat or monitor and in predicting the risk for hepatocellular carcinoma (HCC) and progression. Patients who are true inactive carriers do not require treatment, and quantitative hepatitis B surface antigen (qHBsAg) can be a valuable tool in identifying true inactive carrier status.

Quantitative HBsAg
qHBsAg can be a marker for the amount and activity of covalently closed circular DNA inside hepatocytes. In one study, an HBV DNA level < 2000 IU/mL and an HBsAg level < 1000 IU/mL identified inactive carriers with a diagnostic accuracy of 94.3%. These HBV DNA and qHBsAg cutoffs have also been associated with a lower risk for HCC and liver disease progression. In addition, patients with very low HBsAg (< 100 IU/mL) in combination with an HBV DNA < 2000 IU/mL have a high probability of spontaneous HBsAg clearance. The AASLD guidelines also note that HBeAg-negative patients in the “gray zone”—those who have HBV DNA or ALT levels that are borderline between inactive infection and immune-active HBeAg-negative CHB—may be differentiated with a 1-time qHBsAg test assessed in combination with their HBV DNA level.

qHBsAg levels have been explored in both HBeAg-negative and HBeAg-positive CHB for its roles in the natural course of HBV infection, in predicting response to pegIFN or nucleos(t)ide analogue therapy, and in coinfections with HCV, HDV, and HIV.

Liver Biopsy and Elastography in Patients With CHB and Inactive Carriers
For patients in the “gray zone,” the AASLD guidelines recommend liver biopsy to determine the degree of fibrosis and inflammation. Although an inactive carrier will have absent/minimal necroinflammation on biopsy, AASLD guidelines note that these patients may have variable degrees of fibrosis both on liver biopsy and noninvasive fibrosis testing.

However, some patients are hesitant to have a biopsy, and there is the potential for sampling error. The preferred noninvasive fibrosis test is elastography. If HBV DNA is < 2000 IU/mL and ALT is elevated, other causes of liver enzyme elevation should be examined. Transient elastography (TE) has demonstrated very good diagnostic accuracy in patients with CHB (AUROC > 0.88 for stages F2-F4). Although more costly, magnetic resonance elastography (MRE) more accurately distinguished fibrosis stage in patients with CHB (AUROC > 0.96 for stages F1-F4). MRE may be valuable in patients with a BMI > 40, in whom TE has variable reliability. EASL guidelines recommend a liver biopsy for either patients who have a normal ALT and a liver stiffness measurement (LSM) of 6-9 kPa on TE or patients with an elevated ALT up to 5 times the upper limit of normal and an LSM of 6-12 kPa.

What I Do in My Practice
In my practice, I do not routinely order qHBsAg for all patients with CHB, but I have found qHBsAg to be very helpful in differentiating between inactive carrier status and immune-active HBeAg-negative CHB in certain scenarios. These include:

  1. Patients with normal ALT, an HBV DNA maintaining or fluctuating slightly > 2000 IU/mL (eg, 2200-5000 IU/mL), conflicting information such as a low LSM but slightly coarse liver on imaging, and hesitation to have a liver biopsy
  2. Patients who have borderline elevated ALT and/or HBV DNA and intermediate LSM on TE
  3. Patients who have other causes of elevated ALT such as nonalcoholic steatohepatitis with borderline or fluctuating HBV DNA
  4. Or any patient whose HBV DNA or ALT levels are borderline between inactive infection and immune-active HBeAg-negative CHB who are hesitant to have liver biopsy

If a patient in any of the above scenarios has an HBsAg > 1000 IU/mL, this suggests to me that the patient is likely not an inactive carrier but rather has immune-active HBeAg-negative CHB and may be at higher risk for HCC and liver disease progression. This will push my decision toward starting antiviral treatment and initiating HCC screening.

Your thoughts
Do you use qHBsAg in your clinical practice? In what situations have you obtained a qHBsAg?

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