Chronic hepatitis B virus (HBV) infection affects

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1 GASTROENTEROLOGY 2009;136: Predictive Factors for Early HBeAg Seroconversion in Acute Exacerbation of Patients With HBeAg-Positive Chronic Hepatitis B HYOUNG SU KIM,* HA JUNG KIM, WOON GEON SHIN,* KYUNG HO KIM,* JIN HEON LEE,* HAK YANG KIM,* and MYOUNG KUK JANG* *Department of Internal Medicine and Laboratory of Gastroenterology and Hepatology, Kangdong Sacred Heart Hospital of Hallym University Medical Center, Seoul, Republic of Korea See Wong GL H et al on page 227 in CGH. Background & Aims: This study aimed to identify the predictors for early hepatitis B e antigen (HBeAg) seroconversion following acute exacerbation (AE) in patients with HBeAg-positive chronic hepatitis B (CHB). Methods: A total of 151 patients with HBeAgpositive CHB and AE were consecutively enrolled. AE was defined as an elevation of alanine aminotransferase level to more than 5 times the upper limit of normal and more than twice the patients baseline value. Early HBeAg seroconversion was defined as HBeAg loss and the appearance of hepatitis B e antibody within 6 months of AE. Clinical and laboratory data were compared between an early HBeAg seroconversion group and a nonearly HBeAg seroconversion group. Results: All patients had genotype C hepatitis B virus (HBV). Early HBeAg seroconversion occurred in 35.5% (39/110). Under univariate analysis, age, transmission mode, disease status, and serum HBV DNA level were associated with early HBeAg seroconversion. Multivariate analysis showed that nonvertical transmission mode (RR, 3.681; 95% CI, ; P.016) and low serum HBV DNA levels (< log [copies/ml]; RR, 6.891; 95% CI, ; P.001) were independent predictors. Conclusions: Patients with CHB with genotype C may have a higher chance of early HBeAg seroconversion after AE in the context of nonvertical transmission and/or had low serum HBV DNA levels (<7 log [copies/ml]) at AE. Therefore, we should take into account transmission modes and serum HBV DNA levels when choosing appropriate management strategies for patients who exhibit AE of HBeAg-positive CHB with genotype C. Chronic hepatitis B virus (HBV) infection affects more than 400 million people globally, 1 of which 25% 40% will develop cirrhosis-related complications and/or hepatocellular carcinoma. 2 Acute exacerbation occurs frequently during the natural course of chronic HBV infection, particularly in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB). 3 5 The clinical manifestations of acute exacerbation in patients with CHB vary from asymptomatic to typical symptoms of acute hepatitis, rarely hepatic decompensation or hepatic failure. 4 6 Patients with HBeAg-positive CHB usually do not experience HBeAg seroconversion following acute exacerbation, whereas approximately two thirds of cases of spontaneous HBeAg seroconversion are preceded by acute exacerbation. 7 Consequently, acute exacerbation is regarded as a preceding event, not a prerequisite for HBeAg seroconversion. 3,7 Recently, it has been reported that serum HBV DNA level is one of the most important factors in determining both the risk of disease progression and the responsiveness to antiviral therapy in patients with CHB. However, HBeAg seroconversion to its antibody (anti-hbe) remains important because it is associated with loss of serum HBV DNA, clinical remission, and improvement of hepatic inflammatory activity HBeAg seroconversion, combined with appropriate serum HBV DNA levels, is commonly used to define the short-term end point of antiviral therapy in patients with HBeAg-positive CHB. Given that HBeAg may spontaneously seroconvert to anti-hbe, identification of those patients who may be prone to spontaneous HBeAg seroconversion is very important in constructing the treatment strategies for CHB with or without acute exacerbation. To date, researchers have identified older age, high serum alanine aminotransferase (ALT) level, and genotype B instead of genotype C as factors that may predispose a patient to spontaneous HBeAg seroconversion. 3,11 17 In particular, it is well known that the higher the serum ALT level, the greater the chance of HBeAg seroconversion during an acute flare. 12,13 However, little has been known about factors that may predispose early HBeAg seroconversion among patients with CHB who have genotype C under acute exacerbation. Therefore, our study aimed to identify predictive factors for early HBeAg seroconversion during acute ex- Abbreviations used in this paper: CHB, chronic hepatitis B; ULN, upper limit of normal by the AGA Institute /09/$36.00 doi: /j.gastro

2 506 KIM ET AL GASTROENTEROLOGY Vol. 136, No. 2 acerbation in patients with HBeAg-positive CHB who have genotype C and to evaluate the clinical consequences of these results. Patients and Methods Patients and Study Design A total of 151 patients with HBeAg-positive CHB who experienced an acute exacerbation during follow-up were consecutively enrolled at Kangdong Sacred Heart Hospital of Hallym University Medical Center (Seoul, Korea) between January 2000 and February Patients were all hepatitis B surface antigen (HBsAg) positive for at least 6 months and were HBeAg positive at the time of acute exacerbation. A detailed medical history was documented for all patients enrolled in the study. This included age, gender, family and personal history of liver diseases, alcohol consumption, and details of any significant systemic diseases. Serum samples were obtained for liver biochemistry and to identify HBV serologic markers including HBsAg, HBeAg, anti-hbe, and serum HBV DNA levels at the time of acute exacerbation and subsequently at intervals of 3 6 months or more frequently if appropriate. Antiviral therapy commenced immediately in the patients who presented with the following: (1) clinical features of cirrhosis at acute exacerbation; (2) evidence of decompensation such as ascites, varices, and hepatic encephalopathy; or (3) deteriorating liver function (as determined by serum albumin level, prothrombin time, total bilirubin level, and serum ALT level) within 2 weeks of acute exacerbation or no improvement in liver function within 1 month of acute exacerbation. To identify the predictors of early HBeAg seroconversion, clinical and laboratory data such as age, gender, transmission modes (vertical vs nonvertical), the existence of cirrhosis, serum HBV DNA levels, and other biochemical profiles were compared between an early HBeAg seroconversion group and a nonearly HBeAg seroconversion group using univariate and multivariate analyses. We also compared the cumulative occurrence rates of active hepatitis between 2 groups using the Kaplan Meier method to evaluate the clinical consequences in patients with early HBeAg seroconversion. The study was approved by the Investigation and Ethics Committee for Human Research at the Hallym University Medical Center (Seoul, Korea). Definitions and Exclusion Criteria Acute exacerbation and severe acute exacerbation were defined as an elevation of serum ALT level to more than 5 times the upper limit of normal (ULN, 40 IU/L) and 10 times the ULN, respectively, in the context of a doubling of patients baseline value after excluding other common causes of elevated ALT levels, such as viral coinfection, alcohol consumption, and drug-induced hepatotoxicity. Early HBeAg seroconversion and HBeAg reversion were defined as the loss of HBeAg accompanied by development of anti-hbe within 6 months of acute exacerbation and the reappearance of HBeAg following HBeAg seroconversion, respectively. Active hepatitis after acute exacerbation was defined as an elevation of ALT level to more than twice the ULN accompanied by a serum HBV DNA level that was 10 5 copies/ml, regardless of HBeAg positivity. Liver cirrhosis was diagnosed based on the imaging features supplemented with clinical features such as ascites, varices, and encephalopathy. Vertical transmission was clinically defined according to the following criteria 18 : (1) having tested positive for HBsAg at any point in the patient s lifetime, (2) patient s mother tested positive for HBsAg before delivery, (3) patient s father tested negative for HBsAg, and (4) no history of blood transfusion, operation, parenteral drug abuse, needlestick injury, or any other risk factors for HBV infection such as undergoing hemodialysis or having multiple sexual partners. If the patients did not meet the criteria of vertical transmission completely, they were considered to exhibit a nonvertical transmission route. Of the patients with nonvertical transmission, if they had only one attributable risk factor without any other known risk factors, we considered this in determining transmission route designation. If they had multiple risk factors or denied having other risk factors despite a careful review of their medical records, they were regarded as having an indeterminate route of transmission. To exclude the combined etiologies of other forms of hepatitis, all patients were tested for anti hepatitis C virus antibody, anti hepatitis delta antibody, and anti human immunodeficiency virus antibody. Exclusion criteria for patients were as follows: (1) tested positive for the other markers of viral hepatitis mentioned previously, (2) consumed more than 40 g of ethanol daily, (3) had a history of recent exposure to hepatotoxic drugs (including herbal medication), (4) had a history of using antiviral agents for HBV before their acute exacerbation, (5) were previously diagnosed with hepatocellular carcinoma, and (6) had not been followed up for at least 6 months following acute exacerbation. HBV DNA Extraction and HBV Genotyping Using Polymerase Chain Reaction HBV DNA was extracted from serum samples using commercial kits (QIAamp DNA Blood Mini Kit; Qiagen, Hilden, Germany) according to the manufacturer s protocol. All serum samples were stored at 70 C until use. To confirm the HBV genotype, we performed polymerase chain reaction with type-specific primers using a procedure originally reported by Naito et al, 19 with minor modifications. This assay was designed to take advantage of the fact that nucleotide sequences in the region of the pres1 through S genes are conserved and that there are

3 February 2009 PREDICTORS OF EARLY HBeAg SEROCONVERSION 507 Table 1. Primer Sequences Used for HBV Genotyping Specificity Polarity Sequences a Position Types A to E specific Sense 5=GGCTCMAGTTCMGGAACAGT-3= nucleotide Type C specific Antisense 5=-GGTCCTAGGAATCCTGATGTTG-3= nucleotide a An M represents a nucleotide that could be either an A or a C. differences in the sizes of the genotype-specific bands. Polymerase chain reaction could be performed with only 2 primers, because the HBV genotype is genotype C in 99% of patients with CHB in Korea. 20 Consequently, we used a common universal primer (types A to E specific, sense) and a type C specific primer (antisense) (Table 1). We undertook all necessary precautions to prevent crosscontamination, and negative controls were included at each step. Measurement of Serologic Markers of HBV HBsAg, antibody to HBsAg, HBeAg, and anti-hbe were measured using a microparticle enzyme immunoassay (Abbott Laboratories, North Chicago, IL). Serum HBV DNA levels were measured using the Digene Hybrid Capture II assay (Digene Corp, Gaithersburg, MD; lower limit of detection, 140,000 copies/ml) or VERANT 3.0 assay (Bayer Healthcare, Tarrytown, NY; lower limit of detection, 2000 copies/ml). The results of the Digene Hybrid Capture II assay were expressed in picograms per milliliter according to the plot of standards and were converted to copies per milliliter (1 pg/ml copies/ml). In cases where the results of the Digene Hybrid Capture II assay suggested more than 10 8 copies/ ml, they were recorded as 10 8 copies/ml. Statistics The Mann Whitney U test for continuous variables and the 2 test for categorical variables were used in our analyses as appropriate. Cumulative incidences of active hepatitis were calculated using the Kaplan Meier method, and the difference was determined using a logrank test. Multiple logistic regression analysis was used to identify the independent factors that were significantly associated with early HBeAg seroconversion. Candidate variables with a P value of.1 on univariate analysis were entered into the regression analysis. A P value of.05 was considered significant. Statistical analyses were performed using SPSS version 10 (SPSS, Inc, Chicago, IL). Results Baseline Characteristics of Patients A total of 110 patients who met the inclusion criteria were analyzed. The median age was 35 years (range, 18 76), and 79% of the cohort was male (87/110). Thirty-four patients (30.9%) were determined to have vertical transmission modes, while the remainder was considered to have nonvertical transmission modes (father, n 4; transfusion, n 1; indeterminate, n 71). All cases of HBV were genotype C. Demographic and laboratory characteristics at the time of diagnosis are shown in Table 2. Early HBeAg seroconversion was observed in 35.5% (39/110; median, 3 months; range, 1 6 months). All patients but one had normal serum ALT levels and serum HBV DNA levels 10 5 copies/ml at the time of HBeAg seroconversion. The patient whose serum ALT level did not return to normal developed HBeAg reversion 1 month following HBeAg seroconversion. Comparison of Clinical Features Between the Early HBeAg Seroconversion Group and the Nonearly HBeAg Seroconversion Group Age, disease status (CHB vs liver cirrhosis), transmission mode (vertical vs nonvertical), and serum HBV DNA level were candidate variables for multivariate analysis (P.1). Of the clinical features, older age, the existence of liver cirrhosis, nonvertical transmission mode, and low serum HBV DNA level were considered as favorable factors for early HBeAg seroconversion. Other factors such as gender, serum ALT level at acute exacerbation, application of treatment within 6 months following acute exacerbation, type of antiviral agents, and mean time from acute exacerbation to therapy were not significantly associated with early HBeAg seroconversion (Table 3). Independent Predictors for Early HBeAg Seroconversion A multivariate logistic regression analysis was performed to determine the independent predictors that affected early HBeAg seroconversion using variables that were significant in the univariate analysis. Serum HBV DNA levels were dichotomized at the level of 10 7 cop- Table 2. Baseline Characteristics of Patients Variables Total (n 110) Median age, range (y) 35 (18 76) Gender (M/F), n 87/23 Disease status (CHB/liver cirrhosis), n 92/18 Transmission mode (vertical/nonvertical), n 34/76 Median HBV DNA level, range (log [copies/ml]) 8.0 ( ) Median ALT level, range (IU/L) 358 ( ) Severity (severe acute exacerbation/acute 50/60 exacerbation), n Median duration of follow-up, range (mo) 40 (6 100)

4 508 KIM ET AL GASTROENTEROLOGY Vol. 136, No. 2 Table 3. Comparison of Clinical Features Between the Early HBeAg Seroconversion Group and the Nonearly HBeAg Seroconversion Group Early HBeAg seroconversion (n 39) Nonearly HBeAg seroconversion (n 71) P value Median age, range (y) 41 (20 57) 34 (18 76).082 Gender (M/F), n 31/8 56/15 1 Disease status (CHB/liver cirrhosis), n 29/10 63/8.063 Transmission mode (vertical/nonvertical), n 7/32 27/ Median HBV DNA level, range (log[copies/ml]) 7.6 ( ) 8.0 ( ).001 Medial ALT level, range (IU/L) 408 ( ) 332 ( ).178 Severity (severe acute exacerbation/acute exacerbation), n 22/17 28/ Treatment (yes/no), n 25/14 51/ Antiviral agents, n (1/2/3/4/5/6) a 19/5/0/1/0/0 37/7/1/0/1/5.272 Mean time from acute exacerbation to therapy, mean SD (mo) Median duration of follow-up, range (mo) 58 (6 99) 29 (6 100).018 a Antiviral agents were as follows: (1) lamivudine, (2) interferon alfa, (3) clevudine, (4) entecavir, (5) lamivudine plus interferon alfa, and (6) lamivudine plus pegylated interferon alfa. ies/ml using the receiver operating characteristic curve (data not shown). Under multivariate analysis, nonvertical transmission mode and low serum HBV DNA level ( 7 log [copies/ml]) were identified as independent factors for early HBeAg seroconversion (Table 4). Predictability To determine how well the final model predicted early HBeAg seroconversion, we developed risk groups based on the numbers of relevant clinical predictors. Only 11% (3/27) of the patients without favorable predictors (vertical transmission and high HBV DNA level group) experienced early HBeAg seroconversion, whereas 38% (27/71) of the patients with only one predictor did. Intriguingly, the patients with 2 favorable predictors in combination achieved early HBeAg seroconversion in 75% of cases (9/12) (Table 5). Long-term Clinical Outcomes Twenty-two patients additionally exhibited HBeAg seroconversion during the median follow-up period of 21 months (range, 8 61 months) (Figure 1). Two patients were newly diagnosed with hepatocellular carcinoma and 2 patients developed fulminant hepatic failure during the follow-up period. HBeAg reversion occurred in 51% (20/ 39) of the early HBeAg seroconversion group. Of these, 11 patients reexperienced HBeAg seroconversion, and ultimately HBeAg seroconversion was achieved in 77% (30/39) of the early HBeAg seroconversion group during the follow-up period. In the nonearly HBeAg seroconversion group, 36% (8/22) of the additional seroconverters experienced HBeAg reversion. Of these, 3 patients reexperienced HBeAg seroconversion and 24% (17/71) of the nonearly HBeAg seroconversion group ultimately exhibited HBeAg seroconversion (Figure 1). Cumulative HBeAg reversion rates at 1, 3, 5, and 7 years were 14%, 42%, 52%, and 67%, respectively, during the follow-up period (Figure 2). During a median period of 58 months (range, 6 99 months) in early HBeAg seroconverters, 31 episodes of active hepatitis were observed across 49% (19/39) of the patients. Of these, 8 episodes in 8 patients were HBeAgnegative hepatitis. During a median period of 35 months (range, months) in nonearly HBeAg seroconverters, 84 episodes of active hepatitis were observed in 62% (44/71) of the patients. Of these, 3 episodes in 2 patients were HBeAg-negative hepatitis. Interestingly, the median time to present active hepatitis in the early HBeAg seroconversion group was longer than in the nonearly HBeAg seroconversion group (55 months [range, 6 86 months] vs 24 months [range, 5 96 months]; P.08) (Figure 3). Discussion It is well known that seroconversion of HBeAg to its antibody is associated with a decrease in serum HBV DNA to low or undetectable levels, clinical remission, and an improvement in hepatic inflammatory activity Therefore, it is commonly considered as a clinical target in the management of patients with CHB. HBeAg seroconversion may occur spontaneously at a rate of 5% 10% per year. 21 However, most studies conducted to date have Table 4. Multivariate Analysis of Risk Factors Affecting Early HBeAg Seroconversion Relative risk 95% confidence interval P value Age (y) Disease status (liver cirrhosis/chb) Transmission mode (nonvertical/vertical) HBV DNA level ( 7/ 7 log [copies/ml])

5 February 2009 PREDICTORS OF EARLY HBeAg SEROCONVERSION 509 Table 5. Theoretical Prediction of Early HBeAg Seroconversion According to the Number of Relevant Clinical Factors Number of favorable predictors a Early HBeAg seroconversion (%) 0 3/27 (11) 1 27/71 (38) 2 9/12 (75) NOTE. Data are expressed as numbers of instances. a Favorable predictors: nonvertical transmission and low serum HBV DNA level ( 7 log copies/ml). included not only those patients with high ALT levels but also those who present low ALT levels that are within normal ranges. This can explain why HBeAg seroconversion rates in other studies were lower than the results in our study, which included only patients with acute exacerbation (ALT levels more than 5 times the ULN). In our study, cumulative HBeAg seroconversion rates were 41%, 57%, 65%, and 72% at 1, 3, 5, and 7 years, respectively. This was consistent with the HBeAg seroconversion rates of a subgroup with acute exacerbation in another study that recorded rates of 31.5%, 63.7%, and 78.1% at 1, 3, and 5 years, respectively. 13 Considering that HBV is not cytopathic and that hepatic injuries in patients with CHB are usually caused by cytotoxic T-cell mediated immune hepatolysis, 22,23 higher ALT levels may reflect a stronger immune response of the host against HBV. Although early HBeAg seroconversion occurred more frequently in patients with severe acute exacerbation (ALT levels more than 10 times the ULN; 44%) than in those with acute exacerbation (ALT levels more than 5 times the ULN; 28%), there was no significant difference between the groups (P.11). Therefore, we suppose that an ALT level more than 5 times the ULN may indicate an adequate strength of the host immune response against HBV for early HBeAg seroconversion in the context of acute exacerbation. To date, many factors have been shown to be related to HBeAg seroconversion, including older age, high ALT level, genotype B, the Knodell s index of histologic activity and the amount of HBV core antigen in the liver, low HBV DNA level, high serum -fetoprotein level, increased immunoglobulin M anti-hbc titer, increased serum 2 -microglobulin concentration, and enhanced expression of HLA-I antigens in the membrane of hepatocytes. 3,11 17,24 26 However, most of these determinants are not clinically useful because liver biopsy is additionally required or because they have not yet been approved for clinical use. In our study, we used only clinical information such as patients medical history and routine laboratory tests to evaluate the predictors of HBeAg seroconversion. We are confident that physicians are readily able to evaluate the course of CHB in clinical settings using the identified predictors in our study. In our study, age (P.082), disease status (P.063), transmission mode (P.033), and serum HBV DNA level (P.001) were significantly different or at least marginally significant under univariate analysis between the early HBeAg seroconversion group and the nonearly HBeAg seroconversion group. Interestingly, the early HBeAg seroconversion rate in patients who did not receive antiviral therapy at acute exacerbation (14/34; 41%) was no lower than that of patients who started antiviral therapy within 6 months of acute exacerbation (25/76; 33%) (P.518). This result may suggest that it is more important to find those patients who are prone to spontaneous early HBeAg seroconversion than to immediately provide antiviral therapy for acute exacerbation in patients with HBeAg-positive CHB. Figure 1. Patient flow diagram.

6 510 KIM ET AL GASTROENTEROLOGY Vol. 136, No. 2 Figure 2. (A) Cumulative occurrence rates of HBeAg seroconversion were 41%, 57%, 65%, and 72% at 1, 3, 5, and 7 years, respectively. (B) Cumulative occurrence rates of HBeAg reversion were 14%, 42%, 52%, and 67% at 1, 3, 5, and 7 years, respectively. In the Far East, the mother-to-child mode of HBV transmission is the main route of HBV spread. Although vertical transmission has been shown to be one of several unfavorable factors in respect to responsiveness to antiviral treatment, there are no reports about the association between the transmission modes and the probability of early HBeAg seroconversion following acute exacerbation. In this study, we determined the definition of vertical transmission using the clinical criteria, taking the patients history into account. It is very challenging to exactly classify the transmission modes of patients with CHB in clinical settings. Therefore, classification of patients according to our strict criteria might be the best practical approach to determine the route of HBV infection. It is likely that a small percentage of those patients who were actually vertically infected were classified as being part of the nonvertical transmission group in our study. Considering that the early HBeAg seroconversion rate was much lower in our vertical transmission group than in our nonvertical group, the differences in HBeAg seroconversion rates between the 2 groups would decrease if a subset of the vertical transmission group had indeed been misallocated into the nonvertical transmission group. Nevertheless, vertical transmission, as clinically defined, remained a significant, unfavorable factor for early HBeAg seroconversion under multivariate analysis. This suggests that vertical transmission is actually an unfavorable factor for early HBeAg seroconversion if the clinical criteria are strictly defined. Accordingly, we suggest that our clinical criteria are useful for clinicians to differentiate patients with vertical infection from patients with other risk factors, although there are limitations. Another significant finding from our study is the predictability of early HBeAg seroconversion in combination with the identified clinical factors. Patients without any predisposing factors have a minimal chance of exhibiting HBeAg seroconversion following acute exacerbation (11%; 3/27), while a high proportion of those patients with both favorable predictors did exhibit early HBeAg seroconversion (75%; 9/12). Of course, when patients present with acute exacerbation of HBeAg-positive CHB, we should take into account laboratory abnormalities (elevation of bilirubin level, prolongation of prothrombin time, and so on), clinical features of decompensation and the status of liver disease (such as cirrhosis), as well as the likelihood of spontaneous HBeAg seroconversion to determine whether or not to commence antiviral treatment. To date, the effects of antiviral agents on morbidity and mortality during the severe acute exacerbation of CHB or fulminant hepatic failure remain unclear. However, immediate antiviral therapy is usually recommended by most hepatologists in such situations because antiviral agents such as lamivudine do not pose a significant risk to patients. Therefore, a large-scale randomized study will be necessary to investigate the actual benefits of immediate antiviral therapy during severe acute exacerbation of CHB. As we have shown in our study, it may be very useful to identify the favorable predictors of early Figure 3. Cumulative occurrence rates of active hepatitis at 1, 3, 5, and 7 years were 22%, 49%, 53%, and 60% in the early HBeAg seroconversion group and 29%, 68%, 80%, and 87% in the nonearly HBeAg seroconversion group, respectively. The median time during which patients presented active hepatitis tended to be longer in the early HBeAg seroconversion group than in the nonearly HBeAg seroconversion group (55 months [range, 6 86 months] vs 24 months [range, 5 96 months]; P.08).

7 February 2009 PREDICTORS OF EARLY HBeAg SEROCONVERSION 511 HBeAg seroconversion when the clinicians have to decide whether or not to administer antiviral therapy to patients with acute exacerbation of HBeAg-positive CHB. We believe that such an approach may prevent patients who are prone to spontaneous HBeAg seroconversion from having to undergo unnecessary antiviral therapy. In addition, such a strategy may avoid further liver inflammation in patients who would not experience spontaneous HBeAg seroconversion in the context of early antiviral therapy being administered to nonearly seroconverters. In our study, the cumulative occurrence rates of active hepatitis at 1, 3, 5, and 7 years were higher in the nonearly HBeAg seroconversion group than in the early HBeAg seroconversion group (29%, 68%, 80%, and 87% vs 22%, 49%, 53%, and 60%; P.08). Cumulative occurrence rates of active hepatitis in this study were much higher than in the previous studies, in which active hepatitis after HBeAg seroconversion was reported in only 20% 33% of patients However, genotype C and high ALT level ( 5 times the ULN) during the HBeAg-positive phase are considered the risk factors for active hepatitis following HBeAg seroconversion. Overall, our results were similar to those from a previous study in which the cumulative probability of active hepatitis at 12 years after HBeAg seroconversion was 70% in patients with genotype C CHB. 29 Consequently, the differences in the cumulative occurrence rates of active hepatitis between the previous data and our results may result from the different baseline serum ALT levels and genotypes in our study population. A previous study showed that viral and biochemical responses are not durable in South Korean populations, even after successful HBeAg seroconversion by the nucleoside analogue. 30 Our results also revealed high cumulative rates of HBeAg reversion and frequent episodes of active hepatitis even following HBeAg seroconversion during long-term follow-up. This may suggest that patients with CHB, especially those in the nonearly HBeAg seroconversion group, should undergo regular long-term follow-up even after exhibiting HBeAg seroconversion. Although the results of our study cannot be generalized to all patients with CHB because this study was conducted only across a relatively small number of patients with genotype C HBV infection, our results may nonetheless be useful to clinicians in deciding whether to administer antiviral agents to patients with HBeAg-positive CHB with acute exacerbation, at least in genotype C cases. In conclusion, nonvertical transmission mode and low serum HBV DNA level of 10 7 copies/ml were independent factors that predisposed patients to early HBeAg seroconversion following acute exacerbation in genotype C CHB. Therefore, we recommend that transmission mode and HBV DNA level should be taken into account when choosing patient management strategies that may include antiviral therapies to treat such patients. References 1. Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337: Yuen MF, Lai CL. Natural history of chronic hepatitis B virus infection. J Gastroenterol Hepatol 2000;15(Suppl):E20 E Liaw YF, Chu CM, Huang MJ, et al. Determinants for hepatitis B e antigen clearance in chronic type B hepatitis. Liver 1984;4: Liaw YF, Yang SS, Chen TJ, et al. Acute exacerbation in hepatitis B e antigen positive chronic type B hepatitis. A clinicopathological study. J Hepatol 1985;1: Liaw YF, Tai DI, Chu CM, et al. Acute exacerbation in chronic type B hepatitis: comparison between HBeAg and antibody-positive patients. Hepatology 1987;7: Sheen IS, Liaw YF, Tai DI, et al. Hepatic decompensation associated with hepatitis B e antigen clearance in chronic type B hepatitis. Gastroenterology 1985;89: Liaw YF, Chu CM, Su IJ, et al. Clinical and histological events preceding hepatitis B e antigen seroconversion in chronic type B hepatitis. Gastroenterology 1983;84: Realdi G, Alberti A, Rugge M, et al. Seroconversion from hepatitis B e antigen to anti-hbe in chronic hepatitis B virus infection. Gastroenterology 1980;79: Hoofnagle JH, Dusheiko GM, Seeff LB, et al. Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis. Ann Intern Med 1981;94: Fattovich G, Rugge M, Brollo L, et al. Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti- HBe in chronic hepatitis type B. Hepatology 1986;6: Lok AS, Lai CL, Wu PC, et al. Spontaneous hepatitis B e antigen to antibody seroconversion and reversion in Chinese patients with chronic hepatitis B virus infection. Gastroenterology 1987; 92: Sánchez-Tapias JM, Costa J, Mas A, et al. Analysis of factors predicting early seroconversion to anti-hbe in HBeAg-positive chronic hepatitis B. J Hepatol 1988;6: Yuen MF, Yuan HJ, Hui CK, et al. A large population study of spontaneous HBeAg seroconversion and acute exacerbation of chronic hepatitis B infection: implications for antiviral therapy. Gut 2003;52: Yuen MF, Sablon E, Yuan HJ, et al. Significance of hepatitis B genotype in acute exacerbation, HBeAg seroconversion, cirrhosisrelated complications, and hepatocellular carcinoma. Hepatology 2003;37: Kao JH, Chen PJ, Lai MY, et al. Hepatitis B virus genotypes and spontaneous hepatitis B e antigen seroconversion in Taiwanese hepatitis B carriers. J Med Virol 2004;72: Livingston SE, Simonetti JP, Bulkow LR, et al. Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F. Gastroenterology 2007;133: Yuen MF, Fung SK, Tanaka Y, et al. Longitudinal study of hepatitis activity and viral replication before and after HBeAg seroconversion in chronic hepatitis B patients infected with genotypes B and C. J Clin Microbiol 2004;42: Jang MK, Choi DR, Lee JY, et al. Responsiveness to interferon alpha in chronic hepatitis B by presumed vertical transmission. J Infect 2005;51: Naito H, Hayashi S, Abe K. Rapid and specific genotyping system for hepatitis B virus corresponding to six major genotypes by PCR using type-specific primers. J Clin Microbiol 2001;39: Song BC, Cui XJ, Kim H. Hepatitis B virus genotypes in Korea: an endemic area of hepatitis B virus infection. Intervirology 2005; 48: Hui CK, Leung N, Shek TW, et al. Sustained disease remission after spontaneous HBeAg seroconversion is associated with re-

8 512 KIM ET AL GASTROENTEROLOGY Vol. 136, No. 2 duction in fibrosis progression in chronic hepatitis B Chinese patients. Hepatology 2007;46: Tsai SL, Chen PJ, Lai MY, et al. Acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to hepatitis B core and e antigens. Implications for hepatitis B e antigen seroconversion. J Clin Invest 1992;89: Liaw YF, Tsai SL. Pathogenesis and clinical significance of acute exacerbations and remissions in patients with chronic hepatitis B virus infection. Viral Hepat Rev 1997;3: Chu CM, Karayannis P, Fowler MJF, et al. Natural history of chronic hepatitis B virus infection m Taiwan: studies of hepatitis B virus DNA in serum. Hepatology 1985;5: Sjogren M, Hoofnagle JH. Immunoglobulin M antibody to hepatitis B core antigen in patients with chronic type B hepatitis. Gastroenterology 1985;89: Pignatelli M, Waters J, Brown D, et al. HLA class I antigens on the hepatocyte membrane during recovery from acute hepatitis B virus infection and during interferon therapy in chronic hepatitis B virus infection. Hepatology 1986;6: Hsu YS, Chien RN, Yeh CT, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology 2002;35: Yuan HJ, Yuen MF, Wong DK, et al. Determinants for the occurrence of acute exacerbation of hepatitis B virus infection in Chinese patients after HBeAg seroclearance. J Clin Microbiol 2005;43: Chu CM, Liaw YF. Predictive factors for reactivation of hepatitis B following hepatitis B e antigen seroconversion in chronic hepatitis B. Gastroenterology 2007;133: Song BC, Suh DJ, Lee HC, et al. Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea. Hepatology 2000;32: Received August 11, Accepted October 30, Address requests for reprints to: Myoung Kuk Jang, MD, Department of Internal Medicine, Kangdong Sacred Heart Hospital of Hallym University Medical Center, 445, Gildong, Kangdong-gu, Seoul, Republic of Korea, mkjang2@medimail.co.kr; fax: (82) The authors disclose no conflicts.