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Hepatitis B Surface Antigen (HBsAg): A 40-Year-Old Hepatitis B Virus Seromarker Gets New Life
Editorials continued
Hepatitis B Surface Antigen (HBsAg): A 40-Year-Old Hepatitis B Virus Seromarker Gets New Life
See “Incidence and determinants of spontaneous hepatitis B surface antigen seroclearance: a community-based follow-up study,” Liu J, Yang H–L, Lee M–H, et al, on page 474; and “Hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers,” by Brunetto MR, Oliveri F, Colombatto P, et al, on page 483.
T
here are an estimated 350 to 400 million persons in the world with chronic hepatitis B virus (HBV) infection. Approximately 15% to 25% may die prematurely of either hepatocellular carcinoma (HCC) or end-stage liver disease from cirrhosis.1 Hepatitis B surface antigen (HBsAg) was identified ⬎40 years ago. Over the years, it has proven to be a steady, reliable but unspectacular marker of active HBV infection. Two papers in this month’s edition of Gastroenterology will revive the interest in this HBV seromarker. Most persons with chronic HBV are infected either at birth or in the first few years of life.1 Four phases of chronic HBV infection have been identified by the National Institutes of Health at Workshops of Hepatitis B Virus.2 Children infected at birth from mothers who are positive for HBsAg and hepatitis B e antigen (HBeAg) commonly develop what has been called the “immune tolerant phase” of chronic HBV. In this phase, HBV is not recognized by the immune system and liver disease is mild or not present. Later in life, when the immune system recognizes HBV as a foreign invader, most evolve into the immune active phase active and liver inflammation and fibrosis are present in various degrees. Eventually, most persons lose HBeAg and seroconvert to antiHBe, at which time the majority go into an inactive phase of chronic HBV infection, in previous times called a healthy carrier state. However, some persons after HBeAg seroconversion develop HBeAg-negative immune active disease, whereas others who achieved the inactive phase of HBV may experience a reversion to HBeAg-positive immune active disease or develop HBeAg-negative immune active hepatitis.1 A minority, 0.5% to 1.0% of persons per year have a more favorable event occur, clearance of HBsAg, often accompanied by the emergence of antibody to HBsAg.3 The paper by Liu et al4 from Taiwan involved in the REVEAL study, a population-based cohort study that followed 3087 HBsAg-positive persons for 8 years, exam380
ined the incidence and determinants of spontaneous clearance of HBsAg. This study found a much higher incidence of HBsAg clearance of 2.26% per year than in 3 previously reported studies from Taiwan, Korea, and Alaska, which found that clearance ranged between 0.5% and 0.7% per year. One possibility for this higher clearance rate may be because the mean age of the cohort at enrollment was in the mid 40s, and older persons have been found to clear HBsAg at a higher rate.3,5,6 The authors found that, on multivariate analysis, older age, lower baseline levels of HBV DNA, and, surprisingly, the presence of obesity, were positively correlated with HBsAg seroclearance. They also found the persons with a rapid drop in HBV DNA of ⬎3 log copies/mL and persons who became HBV DNA negative had a higher probability of losing HBsAg. There have been 7 previous papers examining the clearance of HBsAg in large untreated cohort studies (Table 1).3,5–10 Follow-up in these studies has ranged from ⬍3 months to 20 years. Three studies, as mentioned, calculated clearance of HBsAg. In none of these studies did decompensated cirrhosis occur after clearance in those without cirrhosis at time of HBsAg clearance. However, what has been found in all previous reports, but not mentioned in the study by Liu et al in this issue, was that HCC did occur in some persons after loss of HBsAg. For example, in the population-based study from our group in Alaska Native peoples, we found that out of 1271 HBsAg-positive persons followed for almost 20 years, 158 cleared HBsAg at a rate of 0.7%/year. Six persons developed HCC a mean of 7.3 years after clearance of HBsAg.3 Four of those 6 did not have cirrhosis at time of HCC diagnosis. The annual incidence of HCC was 36.8/100,000 from the time of HBsAg clearance in those who cleared versus 195.7/100,000 in those who remained HBsAg positive. This rate in those who cleared is still substantially higher than the US population as a whole of ⬍5/100,000. Older age was the only factor that was associated with HBsAg clearance; neither gender nor HBV genotype (A2, B6, C2, D2, D3, and F1) were associated. If clearance of HBsAg clearance is associated with no risk of liver decompensation in those without cirrhosis, why does HCC still occur, even if the risk is lower than those who remain HBsAg positive? It is likely that this may be due to low levels of replicating HBV DNA found in up to 20% of those who clear HBsAg,3,10 coupled with the fact that HBV DNA has been found to integrate into the genome of hepatocytes throughout the duration of
Editorials continued
Table 1. HBsAg Clearance in Persons With Chronic HBV Infection: Incidence, Associated Factors, and Subsequent Development of HCC Geographic Region
Type of Study
Taiwan Japan Taiwan South Korea
Clinic Clinic Clinic Clinic
based based based based
Taiwan Hong Kong
Clinic based Clinic based
Alaska Taiwan*
Population based Population based
Size of Cohort 1355 5055 NA 432 inactive carriers 1965 NA 1271 3087
Median/Mean Follow-up (mos)
Factors Associated With HBsAg Clearance
No. HBsAg Clearance
Rate/yr HBsAg Clearance
33 48 NA 223
55 156 218 49
NA NA NA 0.5%/yr
NA NA NA Older age
11 patients 2 patient 2 patients 5 patients
128 NA
245 285
0.8%/yr NA
4 patients 7 patients
235.2 96.6
158 562
0.7%/yr 2.26%
Older age HBV genotype B ⬎ genotype C Older age Older age, BMI ⱖ 30 (males), lower baseline HBV DNA level
No. HCC
6 patients Not reported
NA, not available. *Current study.
infection. Thus, persons who lose HBsAg are not off the HBV “hook.” Although this is a desirable goal to achieve naturally or via antiviral therapy, this event should not be called the “recovered phase,” but rather perhaps the “HBsAg seroclearance phase.” Thus, persons who clear HBsAg after years of chronic HBV infection should still be followed for the development of HCC.11 Recently, there has been much interest in measuring levels of HBsAg as a possible predictor of HBsAg loss after antiviral therapy with interferon. Decreases in HBsAg levels have been found to be associated with both sustained virologic response and clearance of HBsAg.12,13 In a second paper by Brunetto et al14 from Milan and Pisa, the authors examined actual HBsAg levels to determine if there was a cutoff below which predicted that persons chronically infected with HBV genotype D would remain in the inactive HBV phase. Two interesting findings emerged from this study. First, the authors found that in persons with an HBsAg level of ⬍1000 IU/mL and an HBV DNA level of ⱕ2000 IU/mL followed prospectively for a mean of 29 months, the sensitivity, specificity, and positive predictive value of remaining in the inactive phase was extremely high, 91.1%, 95.4%, and 87.9%, respectively, with a negative predictive value of 96.7%. Second, the authors found that in those persons who had HBV DNA levels ⬎2000 IU/mL that did not exceed 20,000 IU/mL over the entire follow-up period, all had hepatic activity index inflammation scores of no more than 4/18 and Ishak fibrosis scores of 1/6 or lower. In contrast, in those with an HBV DNA level that exceeded 20,000 IU/mL at any time point during the follow-up period, all had hepatic activity index scores higher than 4/18 and fibrosis scores of 2/6 or greater. Current Liver Society Practice Guidelines recommends that persons with HBV DNA levels above 2000 are potential candi-
dates for treatment. The American Association for the Study of Liver Diseases Practice Guideline for Hepatitis B recommends that liver biopsy be considered before treatment in persons with HBV DNA levels between 2000 and 20,000 IU/mL to gage the level of inflammation and fibrosis.15 The guideline recommends that only those with either moderate inflammation (hepatic activity index ⬎7) or moderate fibrosis (Ishak fibrosis score ⬎1) are candidates for treatment. However, other consensus statements recommend treating persons with HBV DNA ⬎2000 IU/mL and an elevated alanine aminotransferase without obtaining a liver biopsy first.16 This study provides strong prospective cohort evidence that persons with persistent HBV DNA levels between 2000 and 20,000 IU/mL are likely to have milder disease and should not ordinarily be treated without a liver biopsy to determine if they have more than mild inflammation and/or fibrosis. The severity of HBV-related liver disease has been found to differ by HBV genotype.17 If future studies confirm in persons infected with other HBV genotypes, that these 2 tests, HBV DNA and HBsAg levels, have high accuracy in distinguishing mild from moderate/severe histologic liver disease, using these 2 tests could be a valuable noninvasive tool for clinicians to use to follow persons with chronic HBV infection, along with the use of periodic liver biopsies in those with elevated alanine aminotransferase levels and HBV DNA levels ⬎2000 IU/mL but ⬍20,000 IU/mL, to identify persons more accurately who might need antiviral therapy. In summary, HBsAg is a very important clinical test that not only indicates active HBV infection, but also can be used to predict clinical outcome. Clearance of HBsAg in persons with chronic HBV infection is associated with a much better clinical outcome, although surveillance for 381
Editorials continued
early detection of HCC should continue. HBsAg titering may be a useful tool to manage persons with chronic HBV, more clearly defining who may, and more important, who may not, benefit from treatment and possibly even decrease the need for liver biopsy in those with mildly elevated alanine aminotransferase levels who concurrently have low HBsAg titers and HBV DNA levels.
BRIAN J. McMAHON Hepatitis and Liver Disease Program Alaska Native Tribal Health Consortium Anchorage, Alaska References 1. McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology 2009;49:S45–S55. 2. Hoofnagle JH, Doo E, Liang TJ, et al. Management of hepatitis B: summary of a clinical research workshop. Hepatology 2007;45: 1056 –1075. 3. 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. 4. Liu J, Yang H–L, Lee M–H, et al. Incidence and determinants of spontaneous hepatitis B surface antigen seroclearance: a community-based follow-up study. Gastroenterology 2010;139:474 – 482. 5. Ahn SH, Park YN, Park JY, et al. Long-term clinical and histological outcomes in patients with spontaneous hepatitis B surface antigen seroclearance. J Hepatol 2005;42:188 –194. 6. Chen YC, Sheen IS, Chu CM, et al. Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection. Gastroenterology 2002;123: 1084 –1089. 7. Chu CM, Liaw YF. HBsAg seroclearance in asymptomatic carriers of high endemic areas: appreciably high rates during a long-term follow-up. Hepatology 2007;45:1187–1192. 8. Huo TI, Wu JC, Lee PC, et al. Sero-clearance of hepatitis B surface antigen in chronic carriers does not necessarily imply a good prognosis. [see comments]. Hepatology 1998;28:231–236.
382
9. Yuen MF, Wong DKH, Fung J, et al. HBsAg seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology 2008;135:1192–1199. 10. Arase Y, Suzuki F, Suzuki Y, et al. Long-term presence of HBV in the sera of chronic hepatitis B patients with HBsAg seroclearance. Intervirology 2007;50:161–165. 11. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208 –1236. 12. Brunetto MR, Moriconi F, Bonino F, et al. Hepatitis B Virus surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. Hepatology 2009;49:1141–1150. 13. Moucari R, Mackiewicz V, Lada O, et al. Early serum HBsAg drop: a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients. Hepatology 2009; 49:1151–1157. 14. Brunetto MR, Olivari F, Colombatto P, et al. Use of hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers. Gastroenterology 2010;139:483– 490. 15. Lok ASF, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009;50:661– 662. 16. Keeffe EB, Dieterich DT, Han SHB, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol 2008; 6:1315–1341. 17. McMahon BJ. The influence of hepatitis B virus genotype and subgenotype on the natural history of chronic hepatitis B. Hepatol Intl 2009;3:334 –342.
Reprint requests Address requests for reprints to: Brian J. McMahon, MD, MACP, Liver Disease and Hepatitis Program, Alaska Native Medical Center, 4315 Diplomacy Drive, Anchorage, Alaska 99508. e-mail: [email protected]; fax: (907) 729-1570. Conflicts of interest The author discloses no conflicts. © 2010 by the AGA Institute 0016-5085/$36.00 doi:10.1053/j.gastro.2010.06.026
Hepatitis B Surface Antigen (HBsAg): A 40-Year-Old Hepatitis B Virus Seromarker Gets New Life
See “Incidence and determinants of spontaneous hepatitis B surface antigen seroclearance: a community-based follow-up study,” Liu J, Yang H–L, Lee M–H, et al, on page 474; and “Hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers,” by Brunetto MR, Oliveri F, Colombatto P, et al, on page 483.
T
here are an estimated 350 to 400 million persons in the world with chronic hepatitis B virus (HBV) infection. Approximately 15% to 25% may die prematurely of either hepatocellular carcinoma (HCC) or end-stage liver disease from cirrhosis.1 Hepatitis B surface antigen (HBsAg) was identified ⬎40 years ago. Over the years, it has proven to be a steady, reliable but unspectacular marker of active HBV infection. Two papers in this month’s edition of Gastroenterology will revive the interest in this HBV seromarker. Most persons with chronic HBV are infected either at birth or in the first few years of life.1 Four phases of chronic HBV infection have been identified by the National Institutes of Health at Workshops of Hepatitis B Virus.2 Children infected at birth from mothers who are positive for HBsAg and hepatitis B e antigen (HBeAg) commonly develop what has been called the “immune tolerant phase” of chronic HBV. In this phase, HBV is not recognized by the immune system and liver disease is mild or not present. Later in life, when the immune system recognizes HBV as a foreign invader, most evolve into the immune active phase active and liver inflammation and fibrosis are present in various degrees. Eventually, most persons lose HBeAg and seroconvert to antiHBe, at which time the majority go into an inactive phase of chronic HBV infection, in previous times called a healthy carrier state. However, some persons after HBeAg seroconversion develop HBeAg-negative immune active disease, whereas others who achieved the inactive phase of HBV may experience a reversion to HBeAg-positive immune active disease or develop HBeAg-negative immune active hepatitis.1 A minority, 0.5% to 1.0% of persons per year have a more favorable event occur, clearance of HBsAg, often accompanied by the emergence of antibody to HBsAg.3 The paper by Liu et al4 from Taiwan involved in the REVEAL study, a population-based cohort study that followed 3087 HBsAg-positive persons for 8 years, exam380
ined the incidence and determinants of spontaneous clearance of HBsAg. This study found a much higher incidence of HBsAg clearance of 2.26% per year than in 3 previously reported studies from Taiwan, Korea, and Alaska, which found that clearance ranged between 0.5% and 0.7% per year. One possibility for this higher clearance rate may be because the mean age of the cohort at enrollment was in the mid 40s, and older persons have been found to clear HBsAg at a higher rate.3,5,6 The authors found that, on multivariate analysis, older age, lower baseline levels of HBV DNA, and, surprisingly, the presence of obesity, were positively correlated with HBsAg seroclearance. They also found the persons with a rapid drop in HBV DNA of ⬎3 log copies/mL and persons who became HBV DNA negative had a higher probability of losing HBsAg. There have been 7 previous papers examining the clearance of HBsAg in large untreated cohort studies (Table 1).3,5–10 Follow-up in these studies has ranged from ⬍3 months to 20 years. Three studies, as mentioned, calculated clearance of HBsAg. In none of these studies did decompensated cirrhosis occur after clearance in those without cirrhosis at time of HBsAg clearance. However, what has been found in all previous reports, but not mentioned in the study by Liu et al in this issue, was that HCC did occur in some persons after loss of HBsAg. For example, in the population-based study from our group in Alaska Native peoples, we found that out of 1271 HBsAg-positive persons followed for almost 20 years, 158 cleared HBsAg at a rate of 0.7%/year. Six persons developed HCC a mean of 7.3 years after clearance of HBsAg.3 Four of those 6 did not have cirrhosis at time of HCC diagnosis. The annual incidence of HCC was 36.8/100,000 from the time of HBsAg clearance in those who cleared versus 195.7/100,000 in those who remained HBsAg positive. This rate in those who cleared is still substantially higher than the US population as a whole of ⬍5/100,000. Older age was the only factor that was associated with HBsAg clearance; neither gender nor HBV genotype (A2, B6, C2, D2, D3, and F1) were associated. If clearance of HBsAg clearance is associated with no risk of liver decompensation in those without cirrhosis, why does HCC still occur, even if the risk is lower than those who remain HBsAg positive? It is likely that this may be due to low levels of replicating HBV DNA found in up to 20% of those who clear HBsAg,3,10 coupled with the fact that HBV DNA has been found to integrate into the genome of hepatocytes throughout the duration of
Editorials continued
Table 1. HBsAg Clearance in Persons With Chronic HBV Infection: Incidence, Associated Factors, and Subsequent Development of HCC Geographic Region
Type of Study
Taiwan Japan Taiwan South Korea
Clinic Clinic Clinic Clinic
based based based based
Taiwan Hong Kong
Clinic based Clinic based
Alaska Taiwan*
Population based Population based
Size of Cohort 1355 5055 NA 432 inactive carriers 1965 NA 1271 3087
Median/Mean Follow-up (mos)
Factors Associated With HBsAg Clearance
No. HBsAg Clearance
Rate/yr HBsAg Clearance
33 48 NA 223
55 156 218 49
NA NA NA 0.5%/yr
NA NA NA Older age
11 patients 2 patient 2 patients 5 patients
128 NA
245 285
0.8%/yr NA
4 patients 7 patients
235.2 96.6
158 562
0.7%/yr 2.26%
Older age HBV genotype B ⬎ genotype C Older age Older age, BMI ⱖ 30 (males), lower baseline HBV DNA level
No. HCC
6 patients Not reported
NA, not available. *Current study.
infection. Thus, persons who lose HBsAg are not off the HBV “hook.” Although this is a desirable goal to achieve naturally or via antiviral therapy, this event should not be called the “recovered phase,” but rather perhaps the “HBsAg seroclearance phase.” Thus, persons who clear HBsAg after years of chronic HBV infection should still be followed for the development of HCC.11 Recently, there has been much interest in measuring levels of HBsAg as a possible predictor of HBsAg loss after antiviral therapy with interferon. Decreases in HBsAg levels have been found to be associated with both sustained virologic response and clearance of HBsAg.12,13 In a second paper by Brunetto et al14 from Milan and Pisa, the authors examined actual HBsAg levels to determine if there was a cutoff below which predicted that persons chronically infected with HBV genotype D would remain in the inactive HBV phase. Two interesting findings emerged from this study. First, the authors found that in persons with an HBsAg level of ⬍1000 IU/mL and an HBV DNA level of ⱕ2000 IU/mL followed prospectively for a mean of 29 months, the sensitivity, specificity, and positive predictive value of remaining in the inactive phase was extremely high, 91.1%, 95.4%, and 87.9%, respectively, with a negative predictive value of 96.7%. Second, the authors found that in those persons who had HBV DNA levels ⬎2000 IU/mL that did not exceed 20,000 IU/mL over the entire follow-up period, all had hepatic activity index inflammation scores of no more than 4/18 and Ishak fibrosis scores of 1/6 or lower. In contrast, in those with an HBV DNA level that exceeded 20,000 IU/mL at any time point during the follow-up period, all had hepatic activity index scores higher than 4/18 and fibrosis scores of 2/6 or greater. Current Liver Society Practice Guidelines recommends that persons with HBV DNA levels above 2000 are potential candi-
dates for treatment. The American Association for the Study of Liver Diseases Practice Guideline for Hepatitis B recommends that liver biopsy be considered before treatment in persons with HBV DNA levels between 2000 and 20,000 IU/mL to gage the level of inflammation and fibrosis.15 The guideline recommends that only those with either moderate inflammation (hepatic activity index ⬎7) or moderate fibrosis (Ishak fibrosis score ⬎1) are candidates for treatment. However, other consensus statements recommend treating persons with HBV DNA ⬎2000 IU/mL and an elevated alanine aminotransferase without obtaining a liver biopsy first.16 This study provides strong prospective cohort evidence that persons with persistent HBV DNA levels between 2000 and 20,000 IU/mL are likely to have milder disease and should not ordinarily be treated without a liver biopsy to determine if they have more than mild inflammation and/or fibrosis. The severity of HBV-related liver disease has been found to differ by HBV genotype.17 If future studies confirm in persons infected with other HBV genotypes, that these 2 tests, HBV DNA and HBsAg levels, have high accuracy in distinguishing mild from moderate/severe histologic liver disease, using these 2 tests could be a valuable noninvasive tool for clinicians to use to follow persons with chronic HBV infection, along with the use of periodic liver biopsies in those with elevated alanine aminotransferase levels and HBV DNA levels ⬎2000 IU/mL but ⬍20,000 IU/mL, to identify persons more accurately who might need antiviral therapy. In summary, HBsAg is a very important clinical test that not only indicates active HBV infection, but also can be used to predict clinical outcome. Clearance of HBsAg in persons with chronic HBV infection is associated with a much better clinical outcome, although surveillance for 381
Editorials continued
early detection of HCC should continue. HBsAg titering may be a useful tool to manage persons with chronic HBV, more clearly defining who may, and more important, who may not, benefit from treatment and possibly even decrease the need for liver biopsy in those with mildly elevated alanine aminotransferase levels who concurrently have low HBsAg titers and HBV DNA levels.
BRIAN J. McMAHON Hepatitis and Liver Disease Program Alaska Native Tribal Health Consortium Anchorage, Alaska References 1. McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology 2009;49:S45–S55. 2. Hoofnagle JH, Doo E, Liang TJ, et al. Management of hepatitis B: summary of a clinical research workshop. Hepatology 2007;45: 1056 –1075. 3. 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. 4. Liu J, Yang H–L, Lee M–H, et al. Incidence and determinants of spontaneous hepatitis B surface antigen seroclearance: a community-based follow-up study. Gastroenterology 2010;139:474 – 482. 5. Ahn SH, Park YN, Park JY, et al. Long-term clinical and histological outcomes in patients with spontaneous hepatitis B surface antigen seroclearance. J Hepatol 2005;42:188 –194. 6. Chen YC, Sheen IS, Chu CM, et al. Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection. Gastroenterology 2002;123: 1084 –1089. 7. Chu CM, Liaw YF. HBsAg seroclearance in asymptomatic carriers of high endemic areas: appreciably high rates during a long-term follow-up. Hepatology 2007;45:1187–1192. 8. Huo TI, Wu JC, Lee PC, et al. Sero-clearance of hepatitis B surface antigen in chronic carriers does not necessarily imply a good prognosis. [see comments]. Hepatology 1998;28:231–236.
382
9. Yuen MF, Wong DKH, Fung J, et al. HBsAg seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology 2008;135:1192–1199. 10. Arase Y, Suzuki F, Suzuki Y, et al. Long-term presence of HBV in the sera of chronic hepatitis B patients with HBsAg seroclearance. Intervirology 2007;50:161–165. 11. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208 –1236. 12. Brunetto MR, Moriconi F, Bonino F, et al. Hepatitis B Virus surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. Hepatology 2009;49:1141–1150. 13. Moucari R, Mackiewicz V, Lada O, et al. Early serum HBsAg drop: a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients. Hepatology 2009; 49:1151–1157. 14. Brunetto MR, Olivari F, Colombatto P, et al. Use of hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers. Gastroenterology 2010;139:483– 490. 15. Lok ASF, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009;50:661– 662. 16. Keeffe EB, Dieterich DT, Han SHB, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol 2008; 6:1315–1341. 17. McMahon BJ. The influence of hepatitis B virus genotype and subgenotype on the natural history of chronic hepatitis B. Hepatol Intl 2009;3:334 –342.
Reprint requests Address requests for reprints to: Brian J. McMahon, MD, MACP, Liver Disease and Hepatitis Program, Alaska Native Medical Center, 4315 Diplomacy Drive, Anchorage, Alaska 99508. e-mail: [email protected]; fax: (907) 729-1570. Conflicts of interest The author discloses no conflicts. © 2010 by the AGA Institute 0016-5085/$36.00 doi:10.1053/j.gastro.2010.06.026