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Interpreting Hepatitis B Surface Antigen Levels: Useful Clinical Test or Just Another Confusing Assay?
Interpreting Hepatitis B Surface Antigen Levels: Useful Clinical Test or Just Another Confusing Assay?
M
ore than 350 million persons worldwide have chronic hepatitis B virus (HBV)1 infection, and without intervention, an estimated 15%–25% will develop the serious sequelae of hepatocellular carcinoma (HCC) or cirrhosis.2 Patients with this chronic infection can have a very complicated and often unpredictable course. Individuals with HBV can progress from having high viral loads with no demonstrable disease to active liver disease and later to inactive liver disease and can reverse course, going from inactive back to active liver disease.3 In individuals during this confusing course of events, liver biopsy findings can show active inflammation and fibrosis during periods of disease activity that can improve when the disease is inactive, only to reappear again if the infection reactivates. Likewise, liver fibrosis can progress or regress, depending on disease activity. A variety of laboratory tests are used to define the phase of disease a patient is in at a given moment as well as to attempt to predict future outcome. These primarily include aminotransferase levels, especially alanine aminotransferase (ALT), hepatitis B e antigen (HBeAg) and its corresponding antibody (anti-HBe), and HBV DNA levels. Recently, immune-based assays to measure the level of hepatitis B surface antigen (HBsAg) have been developed and are now commercially available in Europe, where 3 companies have marketed these tests. In this month’s issue of Clinical Gastroenterology and Hepatology, an article by Chen et al4 from Taiwan illustrates trends in HBsAg titer that can be useful in predicting HBsAg loss in persons with chronic HBV infection. Four phases of chronic hepatitis B have been defined by a National Institutes of Health workshop on chronic HBV infection (Figure 1).5 The immune tolerant phase is characterized by high levels of HBV DNA, the presence of HBeAg, normal levels of ALT, and no or minimal inflammation or fibrosis found on liver biopsy. In the immune active phase, patients can be HBeAg positive or negative and have elevated levels of HBV DNA but lower than those in the immune tolerant phase, because the patient’s immune system has an active T-cell response to the virus. This results in the elevation of ALT and lowering of HBV DNA levels over time. Most patients eventually progress to an inactive phase characterized by normal levels of ALT, levels of HBV DNA that are low (⬍1000 –2000 IU/mL) or nonmeasurable, and healing of liver histology including eventual decrease in liver fibrosis. A small portion of persons in the inactive phase, about 0.5%–1% per year, will lose HBsAg. The National Institutes of Health workshop defined the loss of HBsAg as the “recovery phase.” Although risk of progressing to cirrhosis in those who have cleared HBsAg is minimal, HBV DNA can still be detectable in approximately 20% and is likely present below the level of detection of current commercial assays in most of the others. The presence of replicating HBV DNA in low levels plus the presence of integrated HBV DNA into host hepatocyte genomes in persons with chronic HBV infection still place these persons at an increased risk of developing HCC. In our ongoing population-based study in Alaska, the annual incidence of HCC
in persons who lost HBsAg after years of chronic HBV infection was 35 per 100,000 versus 150 per 100,000 in those who were still HBsAg-positive, but this was still higher than in the general U.S. population, which is under 10 per 100,000.6 In this issue of Clinical Gastroenterology and Hepatology, Chen et al4 retrospectively examined levels of HBsAg in persons with chronic HBV infection who underwent spontaneous clearance of HBsAg. By using stored sera from 3 time points, 1 year, 3 years, and 5 years before the date HBsAg was first found to be negative, they found that HBsAg levels significantly declined during the 3 years before clearance when compared with age-, sex-, and genotype-matched controls that did not clear HBsAg. They also examined the positive predictive value of several different HBsAg cutoff levels. They found that when coupled with a 1-log decline in HBsAg level during the preceding 2– 4 years before time of HBsAg loss, levels less than 200 IU/mL were highly predictive of HBsAg loss. In both groups HBsAg levels declined during the study period. It would be interesting to continue following both groups over time and perhaps develop a model of HBsAg loss rate that could be applicable to all patients at any time point. Several studies have found that although levels of HBsAg are significantly lower in persons in the inactive phase than in those in the immune tolerant and immune active phases of chronic HBV infection, considerable variation in individual levels occur.7,8 A study from Italy examining persons predominantly infected with HBV genotype D, a different genotype than those found in Taiwan, which are genotypes B and C, reported that HBV DNA levels less than 2000 IU/mL and HBsAg levels less than 1000 IU/mL in HBV infected persons in the inactive phase were highly predictive of remaining in the inactive phase during a 36-month follow-up period.9 Antiviral therapy with oral nucleoside or nucleotide inhibitors given to patients in the immune active phase of chronic HBV has been shown to be very effective at suppressing HBV DNA and improving liver inflammation and fibrosis. In persons receiving interferon, declining levels of HBsAg are associated with a higher probability of clearing HBeAg and HBsAg. However, measuring HBsAg levels shows the most promise in predicting who will not respond to interferon, so that treatment can be stopped earlier and patients still needing therapy can be switched to oral agents.10,11 The usefulness of measuring HBsAg levels in patients on nucleoside/nucleotide therapy is less certain, but the rate of antigen decline over time and baseline levels might be predictive of HBeAg seroconversion.12 Some studies have found that HBsAg levels might also be helpful in predicting when antiviral therapy can be stopped after HBeAg seroconversion occurs in patients with undetectable HBV DNA. It is hoped that following HBsAg levels might not only predict when loss of HBeAg will occur but also which patients will remain HBeAg-negative and perhaps predict risk for reversion back to HBeAg-positive, thus alerting the clinician to not stop therapy. Moreover, it would be beneficial if HBsAg levels could predict when HBsAg loss will occur in persons who are HBeAg-negative on nucleoside/nucleotide therapy, because the ultimate goal in antiviral therapy is the loss of HBsAg, at which point antiviral therapy might conceivably be stopped. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10:218 –219
March 2012
INTERPRETING HBsAg LEVELS
219
Figure 1. The evolution of progression through the phases of chronic hepatitis B virus infection.
For now, HBsAg levels appear promising to predict which patients will remain in the inactive phase and to predict clearance of HBsAg. However, HBsAg levels have not shown promise in predicting when and if patients will go from the more active phases of HBV infection, immune tolerant or immune active, to the inactive phase or which patients in the inactive phase will reactivate. Further studies are needed to examine large cohorts of both treated and untreated persons with chronic HBV infection, which would include all HBV genotypes, followed prospectively over time to determine the true usefulness of measuring HBsAg levels and how to combine this test with HBV DNA levels to predict outcome. Until then, measuring these levels has limited usefulness in individual patients.
BRIAN J. MCMAHON, MD BRENNA C. SIMONS, PhD Liver Disease and Hepatitis Program Alaska Native Tribal Health Consortium Anchorage, Alaska References 1. Liu J, Yang HL, Lee MH, et al. Group ftREVEAL-HS: incidence and determinants of spontaneous hepatitis B surface antigen seroclearance—a community-based follow-up study. Gastroenterology 2010;139:474 – 482. 2. McMahon BJ. Natural history of chronic hepatitis B. Clin Liver Dis 2010;14:381–396. 3. McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology 2009;49:S45–S55. 4. Chen YC, Jeng WJ, Chu CM, et al. Decreasing levels of HBsAg predict HBsAg seroclearance in patients with inactive chronic hepatitis B virus infection. Clin Gastroenterol Hepatol 2012;10: 297–302.
5. Hoofnagle JH, Doo E, Liang TJ, et al. Management of hepatitis B: summary of a clinical research workshop. Hepatology 2007;45: 1056 –1075. 6. Simonetti J, Bulkow L, McMahon BJ, et al. Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus. Hepatology 2010;51: 1531–1537. 7. Liaw YF. Clinical utility of hepatitis B surface antigen quantitation in patients with chronic hepatitis B: a review. Hepatology 2011; 54:E1–E9. 8. Chan HL, Wong VW, Wong GL, et al. A longitudinal study on the natural history of serum hepatitis B surface antigen changes in chronic hepatitis B. Hepatology 2010;52:1232–1241. 9. 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. 10. Ma H, Yang RF, Wei L. Quantitative serum HBsAg and HBeAg are strong predictors of sustained HBeAg seroconversion to pegylated interferon alfa-2b in HBeAg-positive patients. J Gastroenterol Hepatol 2010;25:1498 –1506. 11. Sonneveld MJ, Rijckborst V, Boucher CA, et al. Prediction of sustained response to peginterferon alfa-2b for HBeAg-positive chronic hepatitis B using on-treatment HBsAg decline. Hepatology 2010;52:530A. 12. Lee JM, Ahn SH, Kim HS, et al. Quantitative hepatitis B surface antigen and hepatitis B e antigen titers in prediction of treatment response to entecavir. Hepatology 2011;53:1486 –1493.
Conflicts of interest The authors disclose the following: Alaska Native Tribal Health Consortium has received financial support from Gilead Sciences, Inc. doi:10.1016/j.cgh.2011.11.017
M
ore than 350 million persons worldwide have chronic hepatitis B virus (HBV)1 infection, and without intervention, an estimated 15%–25% will develop the serious sequelae of hepatocellular carcinoma (HCC) or cirrhosis.2 Patients with this chronic infection can have a very complicated and often unpredictable course. Individuals with HBV can progress from having high viral loads with no demonstrable disease to active liver disease and later to inactive liver disease and can reverse course, going from inactive back to active liver disease.3 In individuals during this confusing course of events, liver biopsy findings can show active inflammation and fibrosis during periods of disease activity that can improve when the disease is inactive, only to reappear again if the infection reactivates. Likewise, liver fibrosis can progress or regress, depending on disease activity. A variety of laboratory tests are used to define the phase of disease a patient is in at a given moment as well as to attempt to predict future outcome. These primarily include aminotransferase levels, especially alanine aminotransferase (ALT), hepatitis B e antigen (HBeAg) and its corresponding antibody (anti-HBe), and HBV DNA levels. Recently, immune-based assays to measure the level of hepatitis B surface antigen (HBsAg) have been developed and are now commercially available in Europe, where 3 companies have marketed these tests. In this month’s issue of Clinical Gastroenterology and Hepatology, an article by Chen et al4 from Taiwan illustrates trends in HBsAg titer that can be useful in predicting HBsAg loss in persons with chronic HBV infection. Four phases of chronic hepatitis B have been defined by a National Institutes of Health workshop on chronic HBV infection (Figure 1).5 The immune tolerant phase is characterized by high levels of HBV DNA, the presence of HBeAg, normal levels of ALT, and no or minimal inflammation or fibrosis found on liver biopsy. In the immune active phase, patients can be HBeAg positive or negative and have elevated levels of HBV DNA but lower than those in the immune tolerant phase, because the patient’s immune system has an active T-cell response to the virus. This results in the elevation of ALT and lowering of HBV DNA levels over time. Most patients eventually progress to an inactive phase characterized by normal levels of ALT, levels of HBV DNA that are low (⬍1000 –2000 IU/mL) or nonmeasurable, and healing of liver histology including eventual decrease in liver fibrosis. A small portion of persons in the inactive phase, about 0.5%–1% per year, will lose HBsAg. The National Institutes of Health workshop defined the loss of HBsAg as the “recovery phase.” Although risk of progressing to cirrhosis in those who have cleared HBsAg is minimal, HBV DNA can still be detectable in approximately 20% and is likely present below the level of detection of current commercial assays in most of the others. The presence of replicating HBV DNA in low levels plus the presence of integrated HBV DNA into host hepatocyte genomes in persons with chronic HBV infection still place these persons at an increased risk of developing HCC. In our ongoing population-based study in Alaska, the annual incidence of HCC
in persons who lost HBsAg after years of chronic HBV infection was 35 per 100,000 versus 150 per 100,000 in those who were still HBsAg-positive, but this was still higher than in the general U.S. population, which is under 10 per 100,000.6 In this issue of Clinical Gastroenterology and Hepatology, Chen et al4 retrospectively examined levels of HBsAg in persons with chronic HBV infection who underwent spontaneous clearance of HBsAg. By using stored sera from 3 time points, 1 year, 3 years, and 5 years before the date HBsAg was first found to be negative, they found that HBsAg levels significantly declined during the 3 years before clearance when compared with age-, sex-, and genotype-matched controls that did not clear HBsAg. They also examined the positive predictive value of several different HBsAg cutoff levels. They found that when coupled with a 1-log decline in HBsAg level during the preceding 2– 4 years before time of HBsAg loss, levels less than 200 IU/mL were highly predictive of HBsAg loss. In both groups HBsAg levels declined during the study period. It would be interesting to continue following both groups over time and perhaps develop a model of HBsAg loss rate that could be applicable to all patients at any time point. Several studies have found that although levels of HBsAg are significantly lower in persons in the inactive phase than in those in the immune tolerant and immune active phases of chronic HBV infection, considerable variation in individual levels occur.7,8 A study from Italy examining persons predominantly infected with HBV genotype D, a different genotype than those found in Taiwan, which are genotypes B and C, reported that HBV DNA levels less than 2000 IU/mL and HBsAg levels less than 1000 IU/mL in HBV infected persons in the inactive phase were highly predictive of remaining in the inactive phase during a 36-month follow-up period.9 Antiviral therapy with oral nucleoside or nucleotide inhibitors given to patients in the immune active phase of chronic HBV has been shown to be very effective at suppressing HBV DNA and improving liver inflammation and fibrosis. In persons receiving interferon, declining levels of HBsAg are associated with a higher probability of clearing HBeAg and HBsAg. However, measuring HBsAg levels shows the most promise in predicting who will not respond to interferon, so that treatment can be stopped earlier and patients still needing therapy can be switched to oral agents.10,11 The usefulness of measuring HBsAg levels in patients on nucleoside/nucleotide therapy is less certain, but the rate of antigen decline over time and baseline levels might be predictive of HBeAg seroconversion.12 Some studies have found that HBsAg levels might also be helpful in predicting when antiviral therapy can be stopped after HBeAg seroconversion occurs in patients with undetectable HBV DNA. It is hoped that following HBsAg levels might not only predict when loss of HBeAg will occur but also which patients will remain HBeAg-negative and perhaps predict risk for reversion back to HBeAg-positive, thus alerting the clinician to not stop therapy. Moreover, it would be beneficial if HBsAg levels could predict when HBsAg loss will occur in persons who are HBeAg-negative on nucleoside/nucleotide therapy, because the ultimate goal in antiviral therapy is the loss of HBsAg, at which point antiviral therapy might conceivably be stopped. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10:218 –219
March 2012
INTERPRETING HBsAg LEVELS
219
Figure 1. The evolution of progression through the phases of chronic hepatitis B virus infection.
For now, HBsAg levels appear promising to predict which patients will remain in the inactive phase and to predict clearance of HBsAg. However, HBsAg levels have not shown promise in predicting when and if patients will go from the more active phases of HBV infection, immune tolerant or immune active, to the inactive phase or which patients in the inactive phase will reactivate. Further studies are needed to examine large cohorts of both treated and untreated persons with chronic HBV infection, which would include all HBV genotypes, followed prospectively over time to determine the true usefulness of measuring HBsAg levels and how to combine this test with HBV DNA levels to predict outcome. Until then, measuring these levels has limited usefulness in individual patients.
BRIAN J. MCMAHON, MD BRENNA C. SIMONS, PhD Liver Disease and Hepatitis Program Alaska Native Tribal Health Consortium Anchorage, Alaska References 1. Liu J, Yang HL, Lee MH, et al. Group ftREVEAL-HS: incidence and determinants of spontaneous hepatitis B surface antigen seroclearance—a community-based follow-up study. Gastroenterology 2010;139:474 – 482. 2. McMahon BJ. Natural history of chronic hepatitis B. Clin Liver Dis 2010;14:381–396. 3. McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology 2009;49:S45–S55. 4. Chen YC, Jeng WJ, Chu CM, et al. Decreasing levels of HBsAg predict HBsAg seroclearance in patients with inactive chronic hepatitis B virus infection. Clin Gastroenterol Hepatol 2012;10: 297–302.
5. Hoofnagle JH, Doo E, Liang TJ, et al. Management of hepatitis B: summary of a clinical research workshop. Hepatology 2007;45: 1056 –1075. 6. Simonetti J, Bulkow L, McMahon BJ, et al. Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus. Hepatology 2010;51: 1531–1537. 7. Liaw YF. Clinical utility of hepatitis B surface antigen quantitation in patients with chronic hepatitis B: a review. Hepatology 2011; 54:E1–E9. 8. Chan HL, Wong VW, Wong GL, et al. A longitudinal study on the natural history of serum hepatitis B surface antigen changes in chronic hepatitis B. Hepatology 2010;52:1232–1241. 9. 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. 10. Ma H, Yang RF, Wei L. Quantitative serum HBsAg and HBeAg are strong predictors of sustained HBeAg seroconversion to pegylated interferon alfa-2b in HBeAg-positive patients. J Gastroenterol Hepatol 2010;25:1498 –1506. 11. Sonneveld MJ, Rijckborst V, Boucher CA, et al. Prediction of sustained response to peginterferon alfa-2b for HBeAg-positive chronic hepatitis B using on-treatment HBsAg decline. Hepatology 2010;52:530A. 12. Lee JM, Ahn SH, Kim HS, et al. Quantitative hepatitis B surface antigen and hepatitis B e antigen titers in prediction of treatment response to entecavir. Hepatology 2011;53:1486 –1493.
Conflicts of interest The authors disclose the following: Alaska Native Tribal Health Consortium has received financial support from Gilead Sciences, Inc. doi:10.1016/j.cgh.2011.11.017