Chronic Hepatitis B: The Role of HBsAg Quantitative Testing in Patient Management
In the United States, it is estimated that 850,000 to 2.2 million people are living with HBV infection1,2, with many unaware of their infection status.3 Those with chronic HBV infection may have no symptoms of liver disease, or they may have a range of diseases, including chronic liver disease, cirrhosis, and liver cancer. The Centers for Disease Control and Prevention (CDC) recommend hepatitis B virus (HBV) testing for at-risk populations and public health management of persons living with chronic HBV infection.4
In this newsletter, Robert Gish MD, Clinical Professor of Medicine, University of Nevada, Las Vegas, Nevada, reviews the diagnostic approach to evaluating HBV patients. He discusses the role of the hepatitis B surface antigen (HBsAg) quantitative test to stratify patients and guide patient management, and explains how this test, together with HBV DNA, helps predict outcomes for chronic HBV patients.
Dr. Gish outlines the initial approach for diagnosing HBV infection. “To diagnose acute HBV disease, two tests should be ordered: HBV surface antigen and HBV core antibody IgM. These are the initial tests, which can then be supplemented if the surface antigen is positive.”
“To determine if somebody has chronic disease, has cleared HBV, been exposed to HBV, or is immune to HBV, you need to order HBV surface antigen, HBV core antibody total, and HBV surface antibody total, with a titer, if available. Each of these will lead down one of three pathways: HBV surface antigen determines infection; HBV core antibody determines exposure; HBV surface antibody determines vaccine induced immunity if the core antibody is negative.”
“HBV is incurable, so once somebody has been exposed to HBV it remains in his or her body for a lifetime. Like herpes, HBV is a DNA virus, which the body is unable to clear.”
As in all diagnostic testing, any diagnosis or treatment plan must be made by the physician based on test results, individual patient history, the physician’s knowledge of the patient, and the physician’s clinical judgment.
Evaluation of Chronic HBV Patients
After initial diagnosis of chronic HBV, Dr. Gish performs a comprehensive assessment to gain a better understanding of the patient’s disease and liver status. “The introductory tests to order include those for liver enzymes (AST and ALT), liver function (bilirubin, albumin, and an INR coagulation test) and liver cancer biomarkers, including AFP, AFP-L3 and DCP.”
“I have the patient undergo a special abdominal ultrasound to determine liver size, spleen size, and portal vein diameter. I review any family history of HBV, cirrhosis, or liver cancer, and order tests for HBV e-antigen (HBeAg), HBV e-antibody (anti-HBe), and a HBV DNA quantification. I also verify whether there is infection with HIV, hepatitis C (HCV), and hepatitis delta virus (HDV), or if there is immunity to hepatitis A (HAV). I look at the platelet count and use an online score calculator—APRI or FIB4—to calculate fibrosis without performing a liver biopsy. If HBV DNA is positive, I order a pre-core and core mutation test and HBV genotype. In addition, I order HBsAg quantification (as discussed below).
“All this information is needed to develop a patient profile to establish a prognosis for death, cirrhosis, transplant or cancer and to determine whether or not to treat.”
HBsAg Test, Quantitative—A New Tool
“In addition to the above, a very important test has recently become available to us: the quantitative HBsAg test,” notes Dr. Gish. “In combination with the HBV DNA level, this test helps to stratify patients: if the quantitative HBsAg level is under 100 IU/mL, patients are very likely to clear HBsAg on their own; if it’s over 2000 IU/mL, they are very unlikely to clear spontaneously, and it and needs to be combined with HBV DNA quantitative. HBsAg levels also relate to future risk of liver cancer, particularly in combination with other factors like DNA level, ALT, cirrhosis, and family history.”
Dr. Gish goes on to explain how the quantitative HBsAg test helps physicians to gain a better understanding of patients whose status is unclear. “There are some patients who are in a gray zone,” he explains. “In such cases, the DNA level may not be very high and ALT is marginally elevated. Quantitative HBsAg plays a role in distinguishing whether they have active or inactive disease, and sequential tests over time reveal the trajectory of the disease and chance of immune clearance. If HBsAg is increasing, it’s more important to intervene with treatment. If it is going down, especially in people who are DNA negative or have very low DNA levels, it’s very possible that they’re going to clear HBsAg on their own without any intervention. Essentially you’re dealing with a matrix—you have to look across all the different laboratory tests, and their trends, and then make a judgment.”
Once patients move to therapy, the HBsAg quantitative test is used to predict and monitor treatment response. “The standard of care to treat HBV is one of the nucleotide polymerase inhibitors—either tenofovir or entecavir,” says Dr. Gish. “The quantitative HBsAg test predicts who will respond to each drug and then serves to monitor on treatment response, usually at in interval of every 6 months, though it could be as short as every 3 months. Patients remain on these drugs indefinitely until they lose surface antigen. 90% of people will be on therapy for more than 5 years.”
“In all of our patients, we check DNA levels every 3-6 months, either during monitoring or on therapy. This period is critical to determine the trajectory of their disease, or the trajectory of their treatment response. You would expect the DNA level in a patient on a nucleotide polymerase inhibitor to decrease to an undetectable level within 2 years of initiating therapy.”
“HBeAg testing is only valuable in HBeAg positive patients. Half of patients will lose e antigen over time. If they’re DNA negative and if they lose HBeAg, they have a much more stable course and can clear HBsAg, especially if quantitative HBsAg is low. You can even take them off treatment before they’ve cleared the s antigen and discuss whether they want to stop based on e loss and DNA negativity, as opposed to waiting for HBsAg loss.”
Quantitative HBsAg—Role in Drug Development
The measurement of quantitative HBsAg has become an important factor in assessing the efficacy of new drugs in clinical trials. “Every single drug in development is monitoring quantitative HBsAg, over as short a period as 1 to 3 days, then weekly and monthly,” notes Dr. Gish. “Quantitative HBsAg is the first and most important test for drug development if the patient with HBV is DNA negative. With a DNA positive patient there will be monitoring of DNA and quantitative HBsAg. HBeAg positive patients will need to be monitored for HBeAg. Those tests tend to move in parallel and they’re co-monitored as early co-primary endpoints. For a new drug to be successful, it will have to be able to truncate therapy and have a higher rate of HBsAg loss.”
1. Roberts H, Kruszon-Moran D, Ly KN, Hughes E, Iqbal K et al. Prevalence of chronic hepatitis B virus (HBV) infection in U.S. households: National Health and Nutrition Examination Survey (NHANES), 1988-2002. Hepatology. 2016; 63:388-97.
2. Kowdley KV, Wang CC, Welch S, Roberts H, Brosgart CL. Prevalence of chronic hepatitis B among foreign-born persons living in the United States by country of origin. Hepatology. 2012;56:422-33.
3. Spradling PR, Rupp LB, Moorman AC, Lu M, Teshale EH, Gordon SC, et al. Hepatitis B and C virus infection among 1.2 million persons with access to care: factors associated with testing and infection prevalence. Clin Infect Dis. 2012;55:1047-55.
4. Centers for Disease Control and Prevention. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR. 2008;57:1-18.
Robert G. Gish Consultants, LLC
Clinical Professor of Medicine, University of Nevada, Las Vegas, Nevada
Senior Consultant, St. Joseph’s Medical Center, Phoenix, Arizona
Professor Consultant, Stanford University, Stanford, California
Released on Tuesday, March 21, 2017