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Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection
GASTROENTEROLOGY 2002;123:1084 –1089
Prognosis Following Spontaneous HBsAg Seroclearance in Chronic Hepatitis B Patients With or Without Concurrent Infection YI–CHENG CHEN, I.–SHYAN SHEEN, CHIA–MING CHU, and YUN–FAN LIAW Liver Research Unit, Chang Gung Memorial Hospital and University, Taipei, Taiwan
Background & Aims: Spontaneous hepatitis B surface antigen (HBsAg) seroclearance is a rare event in patients with chronic hepatitis B virus infection. The aim of this study was to clarify the controversy on long-term prognosis following spontaneous HBsAg seroclearance using a large series of patients. Methods: A total of 218 patients (172 men and 46 women) who had undergone spontaneous HBsAg seroclearance were followed up for 12–179 months (median, 61.7 months; mean, 63.4 ⴞ 38.5 months) with liver biochemistry, serology, measurement of ␣-fetoprotein level, and abdominal ultrasonography every 6 months or every 3 months for the 29 patients who had developed cirrhosis at the time of HBsAg seroclearance. Results: Of the 189 patients who were noncirrhotic at the time of HBsAg clearance, 3 (1.6%) developed cirrhosis, 2 (1.1%) developed hepatocellular carcinoma (HCC), and 1 died of HCC. These complications all developed in patients with concurrent hepatitis C virus or hepatitis delta virus infection (P < 0.001). The prognosis of the noncirrhotic patients without concurrent infection was significantly better than that of the matched control group (elevation of alanine aminotransferase level, 11.6% vs. 0%, P < 0.001; development of cirrhosis/HCC, 4% vs. 0%, P ⴝ 0.004). In contrast, of the 29 patients who had developed liver cirrhosis, 4 (13.8%) had hepatic decompensation and one died of HCC. Conclusions: The prognosis following spontaneous HBsAg seroclearance is excellent, except in patients with cirrhosis or those with concurrent hepatitis C virus or hepatitis delta virus infection.
t has been generally recognized that the presence of hepatitis B surface antigen (HBsAg) in serum for more than 6 months establishes the status of chronic hepatitis B virus (HBV) infection, which usually remains indefinitely. Chronic HBV infection may be associated with untoward sequelae, such as cirrhosis and hepatocellular carcinoma (HCC), at an annual incidence of up to 1% and 2%, respectively.1– 6 Spontaneous HBsAg seroclearance may also occur during the course of chronic HBV infection, with an estimated annual incidence of 1%–2% in Western patients7–10 that is even lower (0.1%– 0.8%)
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in patients from Taiwan,11,12 an endemic area of HBV where infection is usually acquired perinatally or in early childhood. In general, HBsAg seroclearance has been associated with a good prognosis, including histologic and liver function improvement,13 and even prolonged survival in decompensated cirrhotic patients.14 A recent European study on compensated cirrhosis B patients with HBsAg seroclearance has also shown a much better prognosis compared with patients with persistent HBsAg antigenemia.15 However, Huo et al.16 reported from Taiwan that 33% of their 55 patients developed serious complications, including 11 (20%) with HCC and 6 with cirrhosis, in a mean follow-up period of 23 months after HBsAg seroclearance. Seven of the patients with HCC already had cirrhosis on operation, making a 24% incidence of cirrhosis in 2 years. Thus, the annual incidence of cirrhosis and HCC after HBsAg seroclearance was 12% and 10%, respectively, in the study by Huo et al. These figures were much higher than those of patients with persistent HBV antigenemia.1– 6 This extraordinarily high incidence of complications contradicts the general belief as well as our own preliminary data about the prognosis of patients with chronic hepatitis B after HBsAg seroclearance.17 We were therefore prompted to examine this phenomenon by reviewing a large series of patients with chronic hepatitis B who had undergone spontaneous HBsAg seroclearance and remained on longterm follow-up.
Materials and Methods Patients In a 21-year period, spontaneous HBsAg seroclearance was documented in 218 patients among thousands with chronic HBV infection who were HBsAg positive for more than 6 months and were followed up periodically in our unit as previously described.2,3,12,17 HBsAg seroclearance was de© 2002 by the American Gastroenterological Association
0016-5085/02/$35.00 doi:10.1053/gast.2002.36026
October 2002
PROGNOSIS AFTER SPONTANEOUS HBsAg SEROCLEARANCE
fined as persistent absence of HBsAg antigenemia for at least 12 months and until the last visit.12 The patients included 172 men (79%) and 46 women (21%) 18 –74 years of age (mean, 44.8 ⫾ 11.1 years; median, 44.0 years). All of the patients were seronegative for hepatitis B e antigen/seropositive for antibody to hepatitis B e antigen, and 189 (86.7%) were noncirrhotic at the time of HBsAg clearance. Fifty-five (25%) of these patients had had concurrent hepatitis C virus (HCV) and/or hepatitis delta virus (HDV) infection before HBsAg seroclearance. The demographic data for these subjects are shown in Table 1. There were 146 patients who had no evidence of cirrhosis and concurrent HCV and/or HDV infection at the time of HBsAg seroclearance. A control group of similar patients with chronic hepatitis B who did not undergo spontaneous HBsAg seroclearance (1:1 matched according to age at HBsAg seroclearance, sex, antibody to hepatitis B e antigen, and follow-up duration) was identified from our computer file of asymptomatic HBsAg carriers for comparison.
Follow-up The patients were followed up for a minimum of 1 year after HBsAg seroclearance. Routine follow-up examinations included clinical evaluations, conventional liver biochemistry, and serologic tests for hepatitis viral infection as well as ␣-fetoprotein assay on each visit. The interval between each clinical visit was set at 6 months, but the interval was shortened according to clinical changes, such as elevation of serum transaminase or ␣-fetoprotein levels. Real-time ultrasonography was routinely performed for the detection of cirrhosis and/or HCC every 3 months for those with cirrhosis and every 6 months for those without cirrhosis. The follow-up period following HBsAg seroclearance was 12.1–179.5 months (median, 61.7 months; mean, 63.4 ⫾ 38.5 months).
Methods Routine conventional liver biochemistry was assayed by a sequential multiple autoanalyzer. Elevation of serum alanine aminotransferase (ALT) levels more than 2 times the upper limit of normal was considered a significant ALT elevation. Serum hepatitis markers, including HBsAg, antibody to HBsAg (anti-HBs), hepatitis B e antigen, antibody to Table 1. Demographic Data of the Patients at the Time of HBsAg Seroclearance Status at HBsAg clearance
Cirrhotic
Noncirrhotic
P
No. of cases Age (yr)a Range Male (%) Age older than 45 yr (%) Positive anti-HBe (%) Hepatitis B alone (%)
29 53.8 ⫾ 9.3 37–74 23 (79.3) 26 (89.6) 29 (100) 17 (58.6)
189 43.4 ⫾ 10.7 18–74 149 (78.8) 79 (41.8) 189 (100) 146 (77.2)
— 0.124
anti-HBe, antibody to hepatitis B e antigen. ⫾ SD.
aMean
— ⬍0.0001 — 0.032
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hepatitis e antigen, and antibody to HDV, were assayed by commercially available radioimmunoassay kits (Ausria II, HBeAg-RIA, anti-delta; Abbott Laboratories, North Chicago, IL). ␣-Fetoprotein level was measured by ␣-feto-RIA-II (Dainabot, Tokyo, Japan). Serum antibody to HCV was tested by a commercially available second- or third-generation enzyme immunoassay kit (HCV EIA II and III; Abbott Laboratories). Serum specimens were stored at ⫺70°C until used for further assessment. Serum HBV DNA was measured by polymerase chain reaction as described earlier.12 Status of cirrhosis was determined on the basis of biopsy and/or ultrasonographic findings complemented with clinical features such as esophageal varices, ascites, and encephalopathy.2,4 Ultrasonography was performed with a high-resolution, real-time scanner (model SSD-1200, SSD-630, SSD-650; Aloka Co., Ltd., Tokyo, Japan) equipped with 3.5- and 5.0MHz rectilinear array or convex scan probes. Subjects in this study were scored quantitatively for liver surface, liver parenchyma, hepatic vessel, and spleen size according to the scoring system, in which a score ⱖ8 correlates well with laparoscopic liver biopsy findings of cirrhosis at a sensitivity of 74.1% and a specificity of 84%.18 The diagnosis of HCC was made histologically or was based on the image findings (including ultrasonography, computed tomography, and arteriography) consistent with HCC plus an ␣-fetoprotein level ⬎400 ng/ mL.3,4 Hepatic decompensation was defined as at least one appearance of ascites, clinical jaundice, hepatic encephalopathy, or variceal bleeding.2,15 Statistical analysis was performed using the Student t test, 2 test, Fisher exact test, Kaplan–Meier estimate, and log-rank test where appropriate.
Results During a follow-up period of 12–179 months (median, 61.7 months; mean, 63.4 ⫾ 38.5 months) after HBsAg seroclearance, 3 (1.6%) of the 189 noncirrhotic patients developed cirrhosis. Together with the 29 patients who had developed cirrhosis before HBsAg seroclearance, there were a total of 32 patients showing evidence of liver cirrhosis. Histologic evidence of cirrhosis was seen in 16 patients (50%), and ultrasonography complemented with surrogate markers of cirrhosis provided evidence in the remaining 16 patients (ascites in 2, esophageal varices in 6, splenomegaly and thrombocytopenia in 8). HCC developed in 1 (3.4%) of the 29 cirrhotic patients and in 2 (1.1%) of the 189 noncirrhotic patients. These 3 patients were all seropositive for antibody to HCV and were cirrhotic before the detection of HCC (the 2 noncirrhotic patients had progressed to cirrhosis). Hepatic decompensation developed in 4 (13.8%, 2 with esophageal varices bleeding and 2 with ascites) of the 29 cirrhotic patients but in none of the 189 noncirrhotic patients (P ⬍ 0.0001). There was one HCCrelated death in each of the above 2 groups (Table 2). Of
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Table 2. Outcomes After HBsAg Clearance in Chronic Hepatitis B Carriers Cirrhotic
Noncirrhotic
Outcomes/status at clearance
Age older than 45 yr (n ⫽ 26)
All (n ⫽ 29)
Age older than 45 yr (n ⫽ 79)
All (n ⫽ 189)
Follow-up, mo (mean) Liver cirrhosis (%) Decompensation (%) HCC (%) Death (%) Any (%)
50.0 — 3 (11.5)a 1 (3.8) 1 (3.8) 4 (15.4)c
50.8 — 4 (13.8)b 1 (3.4) 1 (3.4) 5 (17.2)d
64.1 3 (3.8) 0 (0)a 2 (2.5) 1 (1.3) 4 (5.1)c
65.4 3 (1.6) 0 (0)b 2 (1.1) 1 (0.5) 4 (2.1)d
NOTE. P ⬎ 0.05 unless otherwise noted. aP ⫽ 0.0007. bP ⬍ 0.0001. cP ⫽ 0.0159. dP ⬍ 0.0001.
the 32 patients with cirrhosis (including the 3 who became cirrhotic after HBsAg seroclearance), 12 had been followed up for more than 5 years after HBsAg seroclearance. Two of these 12 died of HCC, and one died of hepatic decompensation and HCC. In contrast, none of the remaining 20 patients with shorter follow-up developed HCC, but 3 (15%) became decompensated. All of these complications occurred in patients older than 45 years of age except one 37-year-old cirrhotic patient with decompensation. The patients in this study were divided into 4 groups according to hepatitis members: HBV group, 163 patients with HBV infection alone; HBV ⫹ HCV group, 42 patients with concurrent HCV infection; HBV ⫹ HDV group, 8 patients with concurrent HDV infection; and HBV ⫹ HCV ⫹ HDV group, 5 patients with concurrent HCV and HDV infection. These 4 groups
were further divided to cirrhotic or noncirrhotic at the time of HBsAg seroclearance as compared with the matched control group in Table 3. Of the 146 matched controls who did not undergo HBsAg seroclearance, 17 (11.6%) experienced significant elevation of serum ALT levels, 5 (3%) developed cirrhosis (2 decompensated), and one was found to develop HCC, whereas none of the 146 noncirrhotic patients in the HBV group experienced elevation of ALT levels (0% vs. 11.6%; P ⬍ 0.001) or developed cirrhosis and/or HCC (0% vs. 4%; P ⫽ 0.04) after HBsAg seroclearance. In contrast, 3 (9%) of 33 noncirrhotic patients in the HBV ⫹ HCV group developed cirrhosis (P ⫽ 0.0007). Similarly, none of the 146 noncirrhotic patients in the HBV group compared with 2 (6%) of 33 HBV ⫹ HCV group counterparts developed HCC after HBsAg clearance (P ⫽ 0.0093). In total, 4 (12%) of the 33 noncirrhotic patients in the HBV ⫹
Table 3. Outcomes After HBsAg Clearance in 4 Subgroups of Chronic Hepatitis B Outcomes Group HBV alone
HBV ⫹ HCV HBV ⫹ HDV HBV ⫹ HCV ⫹ HDV
Status at clearance
No. of cases
Follow-up (mo)
LC
HCC
Death
Decom
Any (%)
LC Non-LC Controlf LC Non-LC LC Non-LC LC Non-LC
17 146 146 9 33 1 7 2 3
49.8 63.6 63.3 59.5 72.4 29.9 54.5 30.0 101.2
— 0a,b 5a — 3b — 0 — 0
0 0c 1 1 2c 0 0 0 0
0 0 0 1 1 0 0 0 0
2 0 2 1 0 1 0 0 0
2 (12) 0d,e 6 (4)d 2 (22) 4 (12)e 1 0 0 0
NOTE. P ⬎ 0.05 unless otherwise noted. LC, liver cirrhosis; Decom, hepatic decompensation. aP ⫽ 0.074. bP ⫽ 0.0007. cP ⫽ 0.0093. dP ⫽ 0.041. eP ⫽ 0.0001. f Patients with persistent HBsAg antigenemia matched according to age at clearance, sex, and duration of follow-up of “B alone, non-LC.”
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HCV group, compared with none of the 146 noncirrhotic patients in the HBV group, developed untoward sequelae (P ⫽ 0.0001) (Table 3). The cumulative probability of cirrhosis and HCC in the HBV ⫹ HCV group was significantly (P ⫽ 0.0007 and P ⫽ 0.0093, respectively) higher than that of the HBV group (Figure 1). The number of patients in the HBV ⫹ HDV group and the HBV ⫹ HCV ⫹ HDV group is small, but the single cirrhotic patient in the HBV ⫹ HDV group also developed hepatic decompensation. Compared with the combined data of any concurrent infection (HBV ⫹ HCV, HBV ⫹ HDV, and HBV ⫹ HCV ⫹ HDV), the prognosis of noncirrhotic patients in the HBV-alone group was still much better. After a mean period of 31.4 months (0 –123.3 months) following HBsAg seroclearance, anti-HBs became detectable in 101 (46%) of the 218 patients, but only 62 patients had detectable anti-HBs with a serum to cutoff ratio ⬎10. HBV DNA was undetectable in 94.3% (100 of 106), 96.9% (124 of 128), and 98.7% (156 of 158) of the available serum specimens collected at the time of HBsAg seroclearance as well as 6 months and 1 year after HBsAg seroclearance, respectively. Of the 156 specimens with undetectable HBV DNA 1 year after HBsAg seroclearance, 88 (56%) were anti-HBs negative and only 68 (44%) were anti-HBs positive. In contrast, 3 of 6, 2 of 4, and 2 of 2 patients with polymerase chain reaction detectable HBV DNA at the respective time point were seronegative for anti-HBs.
Figure 1. Cumulative incidence of liver cirrhosis (LC) and HCC development following HBsAg seroclearance in noncirrhotic patients with or without concurrent HCV infection (B ⫹ C vs. B).
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Discussion The results of this long-term follow-up study in a large series of Taiwanese patients clearly show that noncirrhotic patients without concurrent HCV and/or HDV infection have an excellent prognosis after spontaneous HBsAg seroclearance in terms of HBV clearance and liver disease progression compared with a persistently HBsAg-positive control patients who experienced more significant elevation of ALT levels and cirrhosis/HCC development (P ⬍ 0.001 and P ⬍ 0.04, respectively). This supports the conclusion of several short-term studies12,13,15,17 and a long-term study in cirrhotic patients14 but is in sharp contrast to a recent study also from this geographic area,16 as compared in Table 4. Because our patients were 10 years younger than the patients of Huo et al.16 and all complications occurred in our patients older than 45 years, age may have been a factor for the extraordinarily grave prognosis of the patients in the study by Huo et al. However, even in our patients older than 45 years, only 4 (5%) developed untoward sequelae compared with 18 (46%) of 39 patients in the study by Huo et al. (P ⬍ 0.0001; Table 4). It seems that the age factor cannot be the sole explanation for the discrepancy between these 2 studies, and another possible explanation is that the number of patients in the study by Huo et al. may have been too small. Of note, our patients who had concurrent HCV and/or HDV infection before spontaneous HBsAg seroclearance showed a significantly higher incidence of untoward sequelae and a less favorable prognosis (Table 3 and Figure 1). Because the numbers of patients with concurrent HCV and/or HDV were relatively small, the data should be interpreted with caution. However, progression of liver disease following HBsAg seroclearance in patients with concurrent HCV infection is conceivable because HCV may displace HBV to cause ongoing hepatitis activities,19,20 and patients may thereby develop subsequent complications of chronic HCV infection.21,22 Our results in this regard are consistent with the observation of Huo et al. (Table 4). Consistent with our earlier observation that cirrhosis is a factor for spontaneous HBsAg seroclearance,12 29 of our patients (13.3%) already had evidence of cirrhosis at the time of spontaneous HBsAg seroclearance. The prognosis of these patients, whether they had concurrent infection or not (Table 3), was similar to the natural history of HBV-related cirrhosis in that HCC or decompensation may occur,23 as was observed in a recent European study.15 Because HCC was only detected in cirrhotic patients followed up for more than 5 years (as shown in
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Table 4. Recent Studies on the Outcomes Following HBsAg Seroclearance Outcomes Status at clearance
No. of cases
Mean age (yr)
LC LC Non-LC Age older than 45 yr HBV alone ⫹C/D Non-LC Age older than 45 yr HBV ⫹C/D
32 29 189 79 146 43 55 39 35 20
44 54 43
Source Fattovich et Present
Huo et al.16
al.15
LC
HCC
Death
Decom
Any (%)
— —
1 1
1 1
6 4
7 (22) 5 (17)
3 0 3
2 0 2
1 0 1
0 0 0
4 (5)a 0 (0)b 4 (9)c
54 18 (46)a 12 (34)b 6 (30)c
LC, liver cirrhosis; Decom, hepatic decompensation; ⫹C/D, concurrent HCV and/or HDV infection. aP ⬍ 0.0001. bP ⬍ 0.0001. cP ⫽ 0.061.
Figure 1), it seems the rate of untoward sequelae is likely to increase with a longer follow-up period. Previous studies have shown that HBV DNA was trace in amount or undetectable by polymerase chain reaction in serum after HBsAg seroclearance,14,24 –26 but HBV DNA was still detectable in most liver biopsy specimens.25 In the present study, HBV DNA was undetectable in 98.7% of the available serum specimens collected 1 year after HBsAg seroclearance. HBV DNA was not detectable in liver tissue obtained from a few of our patients after HBsAg seroclearance.12,20 Studies in HBsAg seroclearance following interferon therapy have shown that HBV DNA will disappear after longer follow-up.27 Even the cirrhotic patients who had lost serum HBsAg showed clinical improvement and prolonged survival despite the persistent detection of serum HBV DNA using polymerase chain reaction, which suggests that the small amount of residual HBV after HBsAg seroclearance may have no pathogenic significance.14 In conclusion, the prognosis following HBsAg seroclearance is excellent except in patients with cirrhosis or those with concurrent HCV and/or HDV infection before HBsAg seroclearance. Obviously, patients with cirrhosis or concurrent infection should be closely monitored for predictable complications. Considering cost-effectiveness, however, it seems reasonable to increase the interval of follow-up after HBsAg seroclearance for those with chronic HBV infection alone.
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Schalm SW. Delayed clearance of serum HBsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis. Am J Gastroenterol 1998;93:896 –900. Huo TI, Wu JC, Lee PC, Chau GY, Lui WY, Tsay SH, Ting LT, Chang FY, Lee SD. Sero-clearance of hepatitis B surface antigen in chronic carriers does not necessarily imply a good prognosis. Hepatology 1998;28:231–236. Liaw YF, Chen YC, Sheen IS. Spontaneous clearance of hepatitis B surface antigen in chronic hepatitis B virus infection confers a favorable response (letter). Hepatology 1999;29:296 –297. Lin DY, Sheen IS, Chiu CT, Lin SM, Kuo YC, Liaw YF. Ultrasonographic changes of early liver cirrhosis in chronic hepatitis B: a longitudinal study. J Clin Ultrasound 1993;21:303–308. Pontisso P, Ruvoletto MG, Fattovich G, Chemello L, Gallorini A, Ruol A, Alberti A. Clinical and virological profiles in patients with multiple hepatitis virus infections. Gastroenterology 1993;105: 1529 –1533. Liaw YF, Tsai SL, Chang JJ, Sheen IS, Chien RN, Lin DY, Chu CM. Displacement of hepatitis B virus by hepatitis C virus as the cause of continuing chronic hepatitis. Gastroenterology 1994; 106:1048 –1053. Sheen IS, Liaw YF, Lin DY, Chu CM. Role of hepatitis C and delta viruses in the termination of chronic hepatitis B surface antigen carrier state: a multivariate analysis in a longitudinal follow-up study. J Infect Dis 1994;170:358 –361. Liaw YF, Tsai SL, Sheen IS, Chao M, Yeh CT, Hsieh SY, Chu CM. Clinical and virological course of chronic hepatitis B virus infection with hepatitis C and D virus markers. Am J Gastroenterol 1998;93:354 –359. Liaw YF, Lin DY, Chen TJ, Chu CM. Natural course after the
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development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Liver 1989;9:235–241. Marcellin P, Martino-Peignoux M, Loriot MA, Giostra E, Boyer N, Thiers V, Benhamou JP. Persistence of hepatitis B virus DNA demonstrated by polymerase chain reaction in serum and liver after loss of HBsAg induced by antiviral therapy. Ann Intern Med 1990;112:227–228. Kuhns M, Mason A, McNamara A, Campbell C, Perrillo R. Polymerase chain reaction in the detection of HBV DNA after HBsAg clearance in chronic B (abstr). Hepatology 1990;12:904. Da Silva LC, Madruga CL, Carrilho FJ, Pinho JR, Saez-Alquezar A, Santos C, Bassit L, Barreto C, Fonseca LE, Alves VA, Leitao R, Vianna R, Cardoso RA, Franca AV, Gayotto LC. Spontaneous hepatitis B surface antigen clearance in a long-term follow-up study of patients with chronic type B hepatitis. Lack of correlation with hepatitis C and D virus superinfection. J Gastroenterol 1996;31:696 –701. Lau DTY, Everhart J, Kleiner DE, Park Y, Vergalla J, Schmid P, Hoofnagle JH. Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa. Gastroenterology 1997;113: 1660 –1667.
Received August 11, 2001. Accepted June 21, 2002. Address requests for reprints to: Yun-Fan Liaw, M.D., Liver Research Unit, Chang Gung Memorial Hospital and University, 199, Tung Hwa North Road, Taipei, Taiwan 105. e-mail: liveryfl@so-net.net.tw; fax: (886) 3-3282824. Supported by grants from Chang Gung Memorial Hospital (CMRP800) and the Prosperous Foundation (Taipei, Taiwan).
Prognosis Following Spontaneous HBsAg Seroclearance in Chronic Hepatitis B Patients With or Without Concurrent Infection YI–CHENG CHEN, I.–SHYAN SHEEN, CHIA–MING CHU, and YUN–FAN LIAW Liver Research Unit, Chang Gung Memorial Hospital and University, Taipei, Taiwan
Background & Aims: Spontaneous hepatitis B surface antigen (HBsAg) seroclearance is a rare event in patients with chronic hepatitis B virus infection. The aim of this study was to clarify the controversy on long-term prognosis following spontaneous HBsAg seroclearance using a large series of patients. Methods: A total of 218 patients (172 men and 46 women) who had undergone spontaneous HBsAg seroclearance were followed up for 12–179 months (median, 61.7 months; mean, 63.4 ⴞ 38.5 months) with liver biochemistry, serology, measurement of ␣-fetoprotein level, and abdominal ultrasonography every 6 months or every 3 months for the 29 patients who had developed cirrhosis at the time of HBsAg seroclearance. Results: Of the 189 patients who were noncirrhotic at the time of HBsAg clearance, 3 (1.6%) developed cirrhosis, 2 (1.1%) developed hepatocellular carcinoma (HCC), and 1 died of HCC. These complications all developed in patients with concurrent hepatitis C virus or hepatitis delta virus infection (P < 0.001). The prognosis of the noncirrhotic patients without concurrent infection was significantly better than that of the matched control group (elevation of alanine aminotransferase level, 11.6% vs. 0%, P < 0.001; development of cirrhosis/HCC, 4% vs. 0%, P ⴝ 0.004). In contrast, of the 29 patients who had developed liver cirrhosis, 4 (13.8%) had hepatic decompensation and one died of HCC. Conclusions: The prognosis following spontaneous HBsAg seroclearance is excellent, except in patients with cirrhosis or those with concurrent hepatitis C virus or hepatitis delta virus infection.
t has been generally recognized that the presence of hepatitis B surface antigen (HBsAg) in serum for more than 6 months establishes the status of chronic hepatitis B virus (HBV) infection, which usually remains indefinitely. Chronic HBV infection may be associated with untoward sequelae, such as cirrhosis and hepatocellular carcinoma (HCC), at an annual incidence of up to 1% and 2%, respectively.1– 6 Spontaneous HBsAg seroclearance may also occur during the course of chronic HBV infection, with an estimated annual incidence of 1%–2% in Western patients7–10 that is even lower (0.1%– 0.8%)
I
in patients from Taiwan,11,12 an endemic area of HBV where infection is usually acquired perinatally or in early childhood. In general, HBsAg seroclearance has been associated with a good prognosis, including histologic and liver function improvement,13 and even prolonged survival in decompensated cirrhotic patients.14 A recent European study on compensated cirrhosis B patients with HBsAg seroclearance has also shown a much better prognosis compared with patients with persistent HBsAg antigenemia.15 However, Huo et al.16 reported from Taiwan that 33% of their 55 patients developed serious complications, including 11 (20%) with HCC and 6 with cirrhosis, in a mean follow-up period of 23 months after HBsAg seroclearance. Seven of the patients with HCC already had cirrhosis on operation, making a 24% incidence of cirrhosis in 2 years. Thus, the annual incidence of cirrhosis and HCC after HBsAg seroclearance was 12% and 10%, respectively, in the study by Huo et al. These figures were much higher than those of patients with persistent HBV antigenemia.1– 6 This extraordinarily high incidence of complications contradicts the general belief as well as our own preliminary data about the prognosis of patients with chronic hepatitis B after HBsAg seroclearance.17 We were therefore prompted to examine this phenomenon by reviewing a large series of patients with chronic hepatitis B who had undergone spontaneous HBsAg seroclearance and remained on longterm follow-up.
Materials and Methods Patients In a 21-year period, spontaneous HBsAg seroclearance was documented in 218 patients among thousands with chronic HBV infection who were HBsAg positive for more than 6 months and were followed up periodically in our unit as previously described.2,3,12,17 HBsAg seroclearance was de© 2002 by the American Gastroenterological Association
0016-5085/02/$35.00 doi:10.1053/gast.2002.36026
October 2002
PROGNOSIS AFTER SPONTANEOUS HBsAg SEROCLEARANCE
fined as persistent absence of HBsAg antigenemia for at least 12 months and until the last visit.12 The patients included 172 men (79%) and 46 women (21%) 18 –74 years of age (mean, 44.8 ⫾ 11.1 years; median, 44.0 years). All of the patients were seronegative for hepatitis B e antigen/seropositive for antibody to hepatitis B e antigen, and 189 (86.7%) were noncirrhotic at the time of HBsAg clearance. Fifty-five (25%) of these patients had had concurrent hepatitis C virus (HCV) and/or hepatitis delta virus (HDV) infection before HBsAg seroclearance. The demographic data for these subjects are shown in Table 1. There were 146 patients who had no evidence of cirrhosis and concurrent HCV and/or HDV infection at the time of HBsAg seroclearance. A control group of similar patients with chronic hepatitis B who did not undergo spontaneous HBsAg seroclearance (1:1 matched according to age at HBsAg seroclearance, sex, antibody to hepatitis B e antigen, and follow-up duration) was identified from our computer file of asymptomatic HBsAg carriers for comparison.
Follow-up The patients were followed up for a minimum of 1 year after HBsAg seroclearance. Routine follow-up examinations included clinical evaluations, conventional liver biochemistry, and serologic tests for hepatitis viral infection as well as ␣-fetoprotein assay on each visit. The interval between each clinical visit was set at 6 months, but the interval was shortened according to clinical changes, such as elevation of serum transaminase or ␣-fetoprotein levels. Real-time ultrasonography was routinely performed for the detection of cirrhosis and/or HCC every 3 months for those with cirrhosis and every 6 months for those without cirrhosis. The follow-up period following HBsAg seroclearance was 12.1–179.5 months (median, 61.7 months; mean, 63.4 ⫾ 38.5 months).
Methods Routine conventional liver biochemistry was assayed by a sequential multiple autoanalyzer. Elevation of serum alanine aminotransferase (ALT) levels more than 2 times the upper limit of normal was considered a significant ALT elevation. Serum hepatitis markers, including HBsAg, antibody to HBsAg (anti-HBs), hepatitis B e antigen, antibody to Table 1. Demographic Data of the Patients at the Time of HBsAg Seroclearance Status at HBsAg clearance
Cirrhotic
Noncirrhotic
P
No. of cases Age (yr)a Range Male (%) Age older than 45 yr (%) Positive anti-HBe (%) Hepatitis B alone (%)
29 53.8 ⫾ 9.3 37–74 23 (79.3) 26 (89.6) 29 (100) 17 (58.6)
189 43.4 ⫾ 10.7 18–74 149 (78.8) 79 (41.8) 189 (100) 146 (77.2)
— 0.124
anti-HBe, antibody to hepatitis B e antigen. ⫾ SD.
aMean
— ⬍0.0001 — 0.032
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hepatitis e antigen, and antibody to HDV, were assayed by commercially available radioimmunoassay kits (Ausria II, HBeAg-RIA, anti-delta; Abbott Laboratories, North Chicago, IL). ␣-Fetoprotein level was measured by ␣-feto-RIA-II (Dainabot, Tokyo, Japan). Serum antibody to HCV was tested by a commercially available second- or third-generation enzyme immunoassay kit (HCV EIA II and III; Abbott Laboratories). Serum specimens were stored at ⫺70°C until used for further assessment. Serum HBV DNA was measured by polymerase chain reaction as described earlier.12 Status of cirrhosis was determined on the basis of biopsy and/or ultrasonographic findings complemented with clinical features such as esophageal varices, ascites, and encephalopathy.2,4 Ultrasonography was performed with a high-resolution, real-time scanner (model SSD-1200, SSD-630, SSD-650; Aloka Co., Ltd., Tokyo, Japan) equipped with 3.5- and 5.0MHz rectilinear array or convex scan probes. Subjects in this study were scored quantitatively for liver surface, liver parenchyma, hepatic vessel, and spleen size according to the scoring system, in which a score ⱖ8 correlates well with laparoscopic liver biopsy findings of cirrhosis at a sensitivity of 74.1% and a specificity of 84%.18 The diagnosis of HCC was made histologically or was based on the image findings (including ultrasonography, computed tomography, and arteriography) consistent with HCC plus an ␣-fetoprotein level ⬎400 ng/ mL.3,4 Hepatic decompensation was defined as at least one appearance of ascites, clinical jaundice, hepatic encephalopathy, or variceal bleeding.2,15 Statistical analysis was performed using the Student t test, 2 test, Fisher exact test, Kaplan–Meier estimate, and log-rank test where appropriate.
Results During a follow-up period of 12–179 months (median, 61.7 months; mean, 63.4 ⫾ 38.5 months) after HBsAg seroclearance, 3 (1.6%) of the 189 noncirrhotic patients developed cirrhosis. Together with the 29 patients who had developed cirrhosis before HBsAg seroclearance, there were a total of 32 patients showing evidence of liver cirrhosis. Histologic evidence of cirrhosis was seen in 16 patients (50%), and ultrasonography complemented with surrogate markers of cirrhosis provided evidence in the remaining 16 patients (ascites in 2, esophageal varices in 6, splenomegaly and thrombocytopenia in 8). HCC developed in 1 (3.4%) of the 29 cirrhotic patients and in 2 (1.1%) of the 189 noncirrhotic patients. These 3 patients were all seropositive for antibody to HCV and were cirrhotic before the detection of HCC (the 2 noncirrhotic patients had progressed to cirrhosis). Hepatic decompensation developed in 4 (13.8%, 2 with esophageal varices bleeding and 2 with ascites) of the 29 cirrhotic patients but in none of the 189 noncirrhotic patients (P ⬍ 0.0001). There was one HCCrelated death in each of the above 2 groups (Table 2). Of
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Table 2. Outcomes After HBsAg Clearance in Chronic Hepatitis B Carriers Cirrhotic
Noncirrhotic
Outcomes/status at clearance
Age older than 45 yr (n ⫽ 26)
All (n ⫽ 29)
Age older than 45 yr (n ⫽ 79)
All (n ⫽ 189)
Follow-up, mo (mean) Liver cirrhosis (%) Decompensation (%) HCC (%) Death (%) Any (%)
50.0 — 3 (11.5)a 1 (3.8) 1 (3.8) 4 (15.4)c
50.8 — 4 (13.8)b 1 (3.4) 1 (3.4) 5 (17.2)d
64.1 3 (3.8) 0 (0)a 2 (2.5) 1 (1.3) 4 (5.1)c
65.4 3 (1.6) 0 (0)b 2 (1.1) 1 (0.5) 4 (2.1)d
NOTE. P ⬎ 0.05 unless otherwise noted. aP ⫽ 0.0007. bP ⬍ 0.0001. cP ⫽ 0.0159. dP ⬍ 0.0001.
the 32 patients with cirrhosis (including the 3 who became cirrhotic after HBsAg seroclearance), 12 had been followed up for more than 5 years after HBsAg seroclearance. Two of these 12 died of HCC, and one died of hepatic decompensation and HCC. In contrast, none of the remaining 20 patients with shorter follow-up developed HCC, but 3 (15%) became decompensated. All of these complications occurred in patients older than 45 years of age except one 37-year-old cirrhotic patient with decompensation. The patients in this study were divided into 4 groups according to hepatitis members: HBV group, 163 patients with HBV infection alone; HBV ⫹ HCV group, 42 patients with concurrent HCV infection; HBV ⫹ HDV group, 8 patients with concurrent HDV infection; and HBV ⫹ HCV ⫹ HDV group, 5 patients with concurrent HCV and HDV infection. These 4 groups
were further divided to cirrhotic or noncirrhotic at the time of HBsAg seroclearance as compared with the matched control group in Table 3. Of the 146 matched controls who did not undergo HBsAg seroclearance, 17 (11.6%) experienced significant elevation of serum ALT levels, 5 (3%) developed cirrhosis (2 decompensated), and one was found to develop HCC, whereas none of the 146 noncirrhotic patients in the HBV group experienced elevation of ALT levels (0% vs. 11.6%; P ⬍ 0.001) or developed cirrhosis and/or HCC (0% vs. 4%; P ⫽ 0.04) after HBsAg seroclearance. In contrast, 3 (9%) of 33 noncirrhotic patients in the HBV ⫹ HCV group developed cirrhosis (P ⫽ 0.0007). Similarly, none of the 146 noncirrhotic patients in the HBV group compared with 2 (6%) of 33 HBV ⫹ HCV group counterparts developed HCC after HBsAg clearance (P ⫽ 0.0093). In total, 4 (12%) of the 33 noncirrhotic patients in the HBV ⫹
Table 3. Outcomes After HBsAg Clearance in 4 Subgroups of Chronic Hepatitis B Outcomes Group HBV alone
HBV ⫹ HCV HBV ⫹ HDV HBV ⫹ HCV ⫹ HDV
Status at clearance
No. of cases
Follow-up (mo)
LC
HCC
Death
Decom
Any (%)
LC Non-LC Controlf LC Non-LC LC Non-LC LC Non-LC
17 146 146 9 33 1 7 2 3
49.8 63.6 63.3 59.5 72.4 29.9 54.5 30.0 101.2
— 0a,b 5a — 3b — 0 — 0
0 0c 1 1 2c 0 0 0 0
0 0 0 1 1 0 0 0 0
2 0 2 1 0 1 0 0 0
2 (12) 0d,e 6 (4)d 2 (22) 4 (12)e 1 0 0 0
NOTE. P ⬎ 0.05 unless otherwise noted. LC, liver cirrhosis; Decom, hepatic decompensation. aP ⫽ 0.074. bP ⫽ 0.0007. cP ⫽ 0.0093. dP ⫽ 0.041. eP ⫽ 0.0001. f Patients with persistent HBsAg antigenemia matched according to age at clearance, sex, and duration of follow-up of “B alone, non-LC.”
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HCV group, compared with none of the 146 noncirrhotic patients in the HBV group, developed untoward sequelae (P ⫽ 0.0001) (Table 3). The cumulative probability of cirrhosis and HCC in the HBV ⫹ HCV group was significantly (P ⫽ 0.0007 and P ⫽ 0.0093, respectively) higher than that of the HBV group (Figure 1). The number of patients in the HBV ⫹ HDV group and the HBV ⫹ HCV ⫹ HDV group is small, but the single cirrhotic patient in the HBV ⫹ HDV group also developed hepatic decompensation. Compared with the combined data of any concurrent infection (HBV ⫹ HCV, HBV ⫹ HDV, and HBV ⫹ HCV ⫹ HDV), the prognosis of noncirrhotic patients in the HBV-alone group was still much better. After a mean period of 31.4 months (0 –123.3 months) following HBsAg seroclearance, anti-HBs became detectable in 101 (46%) of the 218 patients, but only 62 patients had detectable anti-HBs with a serum to cutoff ratio ⬎10. HBV DNA was undetectable in 94.3% (100 of 106), 96.9% (124 of 128), and 98.7% (156 of 158) of the available serum specimens collected at the time of HBsAg seroclearance as well as 6 months and 1 year after HBsAg seroclearance, respectively. Of the 156 specimens with undetectable HBV DNA 1 year after HBsAg seroclearance, 88 (56%) were anti-HBs negative and only 68 (44%) were anti-HBs positive. In contrast, 3 of 6, 2 of 4, and 2 of 2 patients with polymerase chain reaction detectable HBV DNA at the respective time point were seronegative for anti-HBs.
Figure 1. Cumulative incidence of liver cirrhosis (LC) and HCC development following HBsAg seroclearance in noncirrhotic patients with or without concurrent HCV infection (B ⫹ C vs. B).
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Discussion The results of this long-term follow-up study in a large series of Taiwanese patients clearly show that noncirrhotic patients without concurrent HCV and/or HDV infection have an excellent prognosis after spontaneous HBsAg seroclearance in terms of HBV clearance and liver disease progression compared with a persistently HBsAg-positive control patients who experienced more significant elevation of ALT levels and cirrhosis/HCC development (P ⬍ 0.001 and P ⬍ 0.04, respectively). This supports the conclusion of several short-term studies12,13,15,17 and a long-term study in cirrhotic patients14 but is in sharp contrast to a recent study also from this geographic area,16 as compared in Table 4. Because our patients were 10 years younger than the patients of Huo et al.16 and all complications occurred in our patients older than 45 years, age may have been a factor for the extraordinarily grave prognosis of the patients in the study by Huo et al. However, even in our patients older than 45 years, only 4 (5%) developed untoward sequelae compared with 18 (46%) of 39 patients in the study by Huo et al. (P ⬍ 0.0001; Table 4). It seems that the age factor cannot be the sole explanation for the discrepancy between these 2 studies, and another possible explanation is that the number of patients in the study by Huo et al. may have been too small. Of note, our patients who had concurrent HCV and/or HDV infection before spontaneous HBsAg seroclearance showed a significantly higher incidence of untoward sequelae and a less favorable prognosis (Table 3 and Figure 1). Because the numbers of patients with concurrent HCV and/or HDV were relatively small, the data should be interpreted with caution. However, progression of liver disease following HBsAg seroclearance in patients with concurrent HCV infection is conceivable because HCV may displace HBV to cause ongoing hepatitis activities,19,20 and patients may thereby develop subsequent complications of chronic HCV infection.21,22 Our results in this regard are consistent with the observation of Huo et al. (Table 4). Consistent with our earlier observation that cirrhosis is a factor for spontaneous HBsAg seroclearance,12 29 of our patients (13.3%) already had evidence of cirrhosis at the time of spontaneous HBsAg seroclearance. The prognosis of these patients, whether they had concurrent infection or not (Table 3), was similar to the natural history of HBV-related cirrhosis in that HCC or decompensation may occur,23 as was observed in a recent European study.15 Because HCC was only detected in cirrhotic patients followed up for more than 5 years (as shown in
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Table 4. Recent Studies on the Outcomes Following HBsAg Seroclearance Outcomes Status at clearance
No. of cases
Mean age (yr)
LC LC Non-LC Age older than 45 yr HBV alone ⫹C/D Non-LC Age older than 45 yr HBV ⫹C/D
32 29 189 79 146 43 55 39 35 20
44 54 43
Source Fattovich et Present
Huo et al.16
al.15
LC
HCC
Death
Decom
Any (%)
— —
1 1
1 1
6 4
7 (22) 5 (17)
3 0 3
2 0 2
1 0 1
0 0 0
4 (5)a 0 (0)b 4 (9)c
54 18 (46)a 12 (34)b 6 (30)c
LC, liver cirrhosis; Decom, hepatic decompensation; ⫹C/D, concurrent HCV and/or HDV infection. aP ⬍ 0.0001. bP ⬍ 0.0001. cP ⫽ 0.061.
Figure 1), it seems the rate of untoward sequelae is likely to increase with a longer follow-up period. Previous studies have shown that HBV DNA was trace in amount or undetectable by polymerase chain reaction in serum after HBsAg seroclearance,14,24 –26 but HBV DNA was still detectable in most liver biopsy specimens.25 In the present study, HBV DNA was undetectable in 98.7% of the available serum specimens collected 1 year after HBsAg seroclearance. HBV DNA was not detectable in liver tissue obtained from a few of our patients after HBsAg seroclearance.12,20 Studies in HBsAg seroclearance following interferon therapy have shown that HBV DNA will disappear after longer follow-up.27 Even the cirrhotic patients who had lost serum HBsAg showed clinical improvement and prolonged survival despite the persistent detection of serum HBV DNA using polymerase chain reaction, which suggests that the small amount of residual HBV after HBsAg seroclearance may have no pathogenic significance.14 In conclusion, the prognosis following HBsAg seroclearance is excellent except in patients with cirrhosis or those with concurrent HCV and/or HDV infection before HBsAg seroclearance. Obviously, patients with cirrhosis or concurrent infection should be closely monitored for predictable complications. Considering cost-effectiveness, however, it seems reasonable to increase the interval of follow-up after HBsAg seroclearance for those with chronic HBV infection alone.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
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Received August 11, 2001. Accepted June 21, 2002. Address requests for reprints to: Yun-Fan Liaw, M.D., Liver Research Unit, Chang Gung Memorial Hospital and University, 199, Tung Hwa North Road, Taipei, Taiwan 105. e-mail: liveryfl@so-net.net.tw; fax: (886) 3-3282824. Supported by grants from Chang Gung Memorial Hospital (CMRP800) and the Prosperous Foundation (Taipei, Taiwan).