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Hepatology Research 2014

doi: 10.1111/hepr.12444

Original Article

Effect of serum hepatitis B surface antigen levels on predicting the clinical outcomes of chronic hepatitis B infection: A meta-analysis Li-Shuai Qu, Jin-Xia Liu, Hai-Feng Zhang, Jing Zhu and Cui-Hua Lu Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China Aim: The impact of serum hepatitis B surface antigen (HBsAg) levels on the prognosis of chronic hepatitis B virus (HBV) infection remains unclear. This meta-analysis aimed to determine whether serum HBsAg levels influenced the risk of cirrhosis and hepatocellular carcinoma (HCC) development. Furthermore, we explored the role played by serum HBsAg levels in prediction of spontaneous HBsAg seroclearance. Methods: We performed this meta-analysis including 11 studies to assess the effect of HBsAg levels on predicting clinical outcomes in chronic HBV carriers. The pooled odds ratios (OR) were calculated using a random or fixed effects model. PUBMED, EMBASE, MEDLINE and the Cochrane Database were searched for articles published from 1990 to May 2014. Results: Our results showed that high HBsAg levels significantly increased the risk of developing cirrhosis (OR, 2.51; 95%

INTRODUCTION

A

LTHOUGH AN EFFECTIVE vaccine has been used for more than two decades, hepatitis B virus (HBV) infection is still a global health problem.1 It is particularly prevalent in the Asia–Pacific region, where patients usually acquire the infection at the time of birth or in early childhood.2 Worldwide, more than 350 million subjects with chronic HBV infection have a 15–25% risk of dying from HBV-related advanced liver diseases, which includes hepatic decompensation, cirrhosis and hepatocellular carcinoma (HCC).3,4 The clinical manifestations of HBV infection range from acute or fulmi-

Correspondence: Professor Cui-Hua Lu, Department of Gastroenterology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong 226001, China. Email: [email protected] Conflict of interest: None. Received 21 July 2014; revision 13 October 2014; accepted 20 October 2014.

© 2014 The Japan Society of Hepatology

confidence interval [CI], 2.00–3.14; P < 0.01). Pooled data from two studies revealed that high HBsAg levels increased the risk of HCC occurrence (OR, 2.21; 95% CI, 1.52–3.22; P < 0.01). High HBsAg levels were associated with a significant increased risk of late HCC recurrence after curative resection (OR, 2.02; 95% CI, 1.48–2.77; P < 0.01), but not early recurrence (OR, 1.06; 95% CI, 0.89–1.27; P = 0.53). The pooled data indicated that low HBsAg levels were significantly in favor of spontaneous HBsAg seroclearance (OR, 7.89; 95% CI, 4.74–13.13; P < 0.01).

Conclusion: High HBsAg levels were associated with development of cirrhosis and HCC comparatively. Therefore, lower serum HBsAg levels were associated with a higher rate of spontaneous HBsAg seroclearance. Key words: cirrhosis, hepatitis B surface antigen, hepatitis B virus, hepatocellular carcinoma, recurrence, seroclearance

nant hepatitis to various forms of chronic infection, including an inactive carrier state, chronic hepatitis, cirrhosis and HCC.5 The prognosis of patients with chronic HBV infection has been studied extensively, and several important viral risk factors have been identified, such as seropositivity of hepatitis B e-antigen (HBeAg), high viral load, genotype and specific viral sequence mutations.6–9 Hepatitis B surface antigen (HBsAg) is the hallmark of HBV infection and was first reported by Blumberg and colleagues in 1968.10 The examination of HBsAg was usually used to identify HBV infection. The level of serum HBsAg reflects the transcriptional activity of cccDNA. The association between serum HBsAg and intrahepatic markers of HBV infection (integrated HBV DNA and cccDNA) has been demonstrated previously.11 HBsAg is a major biomarker that indicates active HBV infection as well as helping predict the prognosis of chronic HBV infected subjects. Recently, sensitive and reliable assays have been developed to quantify serum

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Hepatology Research 2014

HBsAg. The quantification of HBsAg levels has attracted much attention and has become an important marker for evaluating viral activity and possible host immune control over HBV infection.12 In the natural history of HBV infection, HBsAg levels vary markedly throughout different phases of chronic HBV infection and across different HBV genotypes.11,13,14 The recent introduction of HBsAg quantification has attracted much attention for its value in being able to stratify the risk of disease progression and predict the prognosis of patients with chronic HBV infection. A Taiwanese cohort study demonstrated that high HBsAg levels predicted the risk of HCC in HBeAg negative patients with low HBV DNA levels.15 Tseng et al. also demonstrated that high HBsAg levels can also predict disease progression in HBeAg negative patients.16 The latest study demonstrated that high HBsAg levels were a significant risk factor for recurrence of HCC after curative resection.17 Additionally, several other studies have also validated the relationship between HBsAg levels and spontaneous HBsAg seroclearance; all these studies pointed to the main finding that lower HBsAg levels were closely associated with a higher likelihood of HBsAg loss during long-term follow up.18–20 Considering the clinical utility and limited data of quantitative HBsAg in the management of patients with chronic HBV infection, we conducted this meta-analysis with the first objective to evaluate whether serum HBsAg levels influenced the risk of developing cirrhosis and HCC, and second, to evaluate the impact of HBsAg levels on spontaneous HBsAg seroclearance, separately.

METHODS Study objective and search strategy

T

HE SEARCH STRATEGY was based on combinations of the following terms: “hepatitis B”, “cirrhosis”, “hepatocellular carcinoma”, “HCC”, “recurrence”, “HBsAg loss” and “HBsAg seroclearance”. We searched PUBMED, MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials for all publications (from 1990 to May 2014). The search was supplemented by reviews of reference lists for all relevant studies. All relevant studies identified were included with English-language restriction. Of the 32 relevant studies, 11 were included in this meta-analysis (study flow chart is shown in Fig. 1).

Criteria for study selection and data extraction We performed searches for studies that met the following criteria: (i) patients with chronic HBV infection; (ii) separate data according to the presence of HBsAg levels were given; (iii) studies reported only as abstract were not included; and (iv) if two studies were from the same research group, only one was included. All studies that met the above criteria were included in the analysis because there was a limited number of relevant studies on the risk of developing cirrhosis and HCC. In order to evaluate the effect of serum HBsAg levels on spontaneous HBsAg seroclearance, only patients without antiviral therapy were included in this subgroup analysis.

32 relevant studies identified 17 studies excluded: 1) Meta-analysis 2) Reviews or abstracts 3) Assessing other risk factors of HCC 15 potential relevant articles for further review 18 studies excluded: 1) Duplicate studies 2) No relevant data 3) Anti-viral therapy↑

Added 4 studies from the reference list

11 studies included in this meta-analysis

© 2014 The Japan Society of Hepatology

Figure 1 Flow chart of study identification and extraction of the metaanalysis. †In order to evaluate the effect of serum hepatitis B surface antigen (HBsAg) levels on spontaneous HBsAg seroclearance, only patients without antiviral therapy were included in this subgroup analysis. HCC, hepatocellular carcinoma.

Hepatology Research 2014

Five included studies used a cut-off HBsAg value (100 IU/mL) to differentiate between patients with high and low levels. Five studies have previously defined a border between high and low viremia as 1000 IU/mL on this issue. In Sohn et al.’s study, it was shown that 4000 IU/mL was the cut-off value.17 Among all included studies, data on risk of cirrhosis and HCC according to HBsAg levels were derived from three studies. Two studies reported the risk of HBsAg levels on HCC recurrence after curative resection. Six studies assessed the impact of HBsAg levels on spontaneous HBsAg seroclearance. The following information was collected: (i) first author’s name; (ii) year of publication or presentation; (iii) total sample size and subgroup sample size for different HBsAg level groups; (iv) demographic information (mean age, sex, country, type of study, HBV genotype and the mean/median period of follow up); and (v) the rate of study end-points and separate data on different HBsAg levels. Data were extracted independently from each study using a predefined review form and disagreement was resolved by consensus. We did not weight each study by a quality score because no score has received general agreement for meta-analysis of such studies.

Statistical analysis Meta-analysis was performed according to the recommendations from the Cochrane Collaboration with Review Manager version 5.0. Two independent reviewers extracted and interpreted the related data. Mantel– Haenszel (M-H) and inverse variance (IV) methods were chosen to pool the individual studies. The effect of HBsAg levels was presented as odds ratios (OR) with 95% confidence intervals (CI) using a fixed effects model. Alternatively, random effects meta-analyses were performed when between-study heterogeneity existed. The OR for each study was calculated from the number of the derived observed patients and the number of events at the chosen end-point during follow up in both subgroups. Heterogeneity was quantified using the I2 statistic. We regarded I2 of less than 25%, 25–50% and greater than 50% as low, moderate and high amounts of heterogeneity, respectively. To evaluate the potential risk bias in the overall results of pooled analysis of the included studies, sensitivity analysis and publication bias estimate were also performed. The potential publication bias was tested using Egger’s regression test asymmetry and Begg’s test for funnel plot. Results were considered statistically significant at P < 0.05.

HBsAg levels and clinical outcome 3

RESULTS Eligible studies and baseline characteristics

A

FTER INITIAL SCREENING, 11 relevant studies were selected pertaining to the effect of serum HBsAg levels on prognosis of chronic HBV infection (flow chart of the study is shown in Fig. 1).15–25 A careful search methodology was used to avoid duplicate data and overlapping of cases. Table 1 demonstrates the feature description of the 11 included studies: sample size, type of study, country, percentage of males, mean age, HBV genotype, HBsAg cut-off value, mean/median follow up and the rate of study end-points. Among all 11 included studies, 10 studies were published from East Asian countries (six in Taiwan, two in Hong Kong, one in Korea and one in mainland China), and only one was performed in France. Among the selected studies, two studies assessed the impact of serum HBsAg levels on HCC recurrence after curative resection, three studies evaluated the risk of cirrhosis and HCC according to different HBsAg levels, and six studies assessed the impact of serum HBsAg levels on spontaneous HBsAg seroclearance. These 11 included studies enrolled a total of 12 279 patients. Sample size ranged 91–3342, with mean age ranging 34–53 years. The characteristics of the studies are summarized in Table 1.

Association between HBsAg levels and the risk of cirrhosis development during follow up Two studies reported data on the effect of HBsAg levels on risk of cirrhosis development in patients with chronic HBV infection during long-term follow up.16,22 Cirrhosis development was detected in 367 patients (8.32%), with 240 (12.1%) in patients with high HBsAg levels and 127 (5.24%) in patients with low HBsAg levels. The effect of HBsAg levels on risk of cirrhosis development is shown in Figure 2. The presence of high HBsAg levels increased the rate of cirrhosis development. High HBsAg level patients had a significantly higher cumulative risk of developing cirrhosis during long-term follow up when compared with low HBsAg level patients (OR, 2.51; 95% CI, 2.00–3.14; P < 0.01) with low heterogeneity (χ2 = 0.06, P = 0.80, I2 = 0%) (Fig. 2).

Association between HBsAg levels and the risk of HCC occurrence during follow up Two included studies reported the risk of HCC occurrence related to serum HBsAg levels among 6028 patients.15,22 A total of 355 HCC cases were diagnosed

© 2014 The Japan Society of Hepatology

Hong Kong

Taiwan

Hong Kong

Taiwan

Taiwan

Taiwan

Taiwan

France

Taiwan

China

Korea

Chan, 201119

Chen, 201220

Seto, 201218

Tseng, 201221

Tseng, 201215

© 2014 The Japan Society of Hepatology

Lee, 201322

Liu, 201323

MartinotPeignoux, 201324

Tseng, 201316

Huang, 201425

Sohn, 201417 Cohort

Cohort

Cohort

Cohort

Cohort

Cohort

Cohort

Cohort

Case–control

Case–control

Cohort

Type of study

248

1062

1068

91

2491

3342

2688

688

406

92

103

No. of patients (n)

53

52

NA

37 vs 34‡

46

NA

NA

NA

52

48

46

Age (years)

196/52

931/131

600/468

58/33

1592/899

2032/1310

1634/1054

375/313

286/120

77/15

70/33

Sex M/F (n)

NA

B: 1043 B + C: 60 C: 415 A: 29 B: 8 C: 4 D: 25 E: 7 B: 517 C: 103 NA

B: 1308 C: 312 B or B + C: 1480 C: 718

A: 1 B: 47 C: 53 B + C: 1 B: 71 C: 21 B:127§ C: 68 NA

HBV genotype (n)

4000

1000

30/218

440/622

483/585

64/27

1000

1000

1732/759

1503/1839

1588/1100

521/167

213/193

63/17

86/17

High/low HBsAg level (n)

100

1000

1000

100

100

100

100

HBsAg cut-off value (IU/mL)

33.3 months

60.0 months

13.3 years

9.0 years

8.0 years

NA

14.7 years

11.6 years

NA

14.2 years

88.0 months

Median/ mean follow up

LC: H 26/483, L 14/585 Early HCC recurrence: 457/1062 Late HCC recurrence: 148/552 Early HCC recurrence: 61/248 Late HCC recurrence: 25/176

HBsAg loss: H 5/64, L 8/27

HBsAg loss: H 24/63, L 14/17† HBsAg loss: H 51/213, L 152/193 HBsAg loss: H 70/521, L 60/167 HCC: H 137/1588, L 54/1100 HCC: H 111/1503, L 53/1837 LC: H 214/1503, L 113/1839 HBsAg loss: H 160/ 1732, L 363/759

HBsAg loss: H 3/86, L 9/17

Rate of study end-points (n/n)

L-S. Qu et al.

†Data available in 80 patients of 5 years before HBsAg seroclearance or last visit. ‡Patients underwent HBsAg seroclearance vs persistence of HBsAg. §Tested in 100 patients achieving HBsAg seroclearance (95 had amplificable polymerase chain reaction products) and 100 age- and sex-matched controls. H, high HBsAg level; HCC, hepatocellular carcinoma; L, low HBsAg level; LC, liver cirrhosis; NA, not available.

Country or area

First author, year

Table 1 Characteristics of 11 included studies

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Study or subgroup Lee 213 Tseng 2013

High HBsAg level Events Total 214 1503 26 483

HBsAg levels and clinical outcome 5

Low HBsAg level Events Total Weight 113 1839 87.9% 14 585 12.1%

1986 Total (95% Cl) 240 Total events 127 Heterogeneity: Chi2 = 0.06, df = 1 (P = 0.80); I2 = 0% Test for overall effect: Z = 8.02 (P < 0.00001)

2424 100.0%

Odds ratio M-H, fixed, 95% Cl 2.54 [2.00, 3.22] 2.32 [1.20, 4.50]

Odds ratio M-H, fixed, 95% Cl

2.51 [2.00, 3.14] 0.1 0.2

0.5

1

2

5

10

Figure 2 Forest plot for occurrence of cirrhosis: comparison of high and low hepatitis B surface antigen (HBsAg) level patients. The blocks and lines in figures indicate the estimate of odds ratio and 95% confidence interval (CI), and the sizes of blocks relate to the size of the individual study. The diamond indicates the overall estimate from the meta-analysis.

during follow up, with 248 HCC cases (8.02%) occurring in patients with high HBsAg levels and 107 events (3.64%) occurring in patients with low HBsAg levels. Pooled data from two studies on the risk of HCC occurrence among patients with high HBsAg levels compared with low HBsAg levels showed a significant risk in occurrence of HCC (OR, 2.21; 95% CI, 1.52–3.22; P < 0.01), but with high heterogeneity in the data (χ2 = 2.60, P = 0.11, I2 = 62%) (Fig. 3).

HBsAg levels and the risk of early and late HCC recurrence after curative resection Among 11 included studies, two studies reported data on the effect of serum HBsAg levels on HCC recurrence risk after curative resection in patients with HBV-related HCC.17,25 These studies included 470 patients in the high HBsAg level group and 840 patients in the low HBsAg level group. In a total of 1310 HCC patients who received curative resection, HCC recurrence was detected in 691 patients (52.7%). It has been hypothesized that early and late intrahepatic recurrence of HCC was

Study or subgroup Lee 213 Tseng 2012

High HBsAg level Events Total 111 1503 137 1588

attributable to two different mechanisms: intrahepatic metastasis and de novo multicentric carcinogenicity. We also analyzed the effect of serum HBsAg levels on early and late recurrence separately. Postoperative recurrence within 2 years was generally regarded as early recurrence. In this meta-analysis, early recurrence was observed in 518 patients (39.5%). There was no significant difference in early HCC recurrence after curative resection between high HBsAg level and low HBsAg level patients during follow up (OR, 1.06; 95% CI, 0.89–1.27; P = 0.53), with low heterogeneity in the data (χ2 = 0.90, P = 0.34, I2 = 0%) (Fig. 4). With regard to the impact of HBsAg levels on the time to recurrence, there were 173 late recurrence cases among 728 patients. During at least 2 years of follow up, the late recurrence rate of HCC was 23.8%. Pooled data from two studies on the risk of recurrence among high HBsAg level patients receiving curative resection compared with low HBsAg level showed an increased risk of late recurrence (OR, 2.02; 95% CI, 1.48–2.77; P < 0.01), with low heterogeneity in the data (χ2 = 0.58, P = 0.45, I2 = 0%) (Fig. 5).

Low HBsAg level Events Total Weight 53 1837 49.4% 54 1100 50.6%

3091 2937 100.0% Total (95% Cl) 248 Total events 107 Heterogeneity: Tau2 = 0.05, Chi2 = 2.60, df = 1 (P = 0.11); I2 = 62% Test for overall effect: Z = 4.14 (P < 0.0001)

Odds ratio M-H, random, 95% Cl 2.68 [1.92, 3.75] 1.83 [1.32, 2.53]

Odds ratio M-H, random, 95% Cl

2.21 [1.52, 3.22] 0.2

0.5

1

2

5

Figure 3 Forest plot for occurrence of hepatocellular carcinoma (HCC): comparison of high and low hepatitis B surface antigen (HBsAg) level patients. The blocks and lines in figures indicate the estimate of odds ratio and 95% confidence interval (CI), and the sizes of blocks relate to the size of the individual study. The diamond indicates the overall estimate from the meta-analysis.

© 2014 The Japan Society of Hepatology

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Study or subgroup

log[Odds Ratio]

Huang 2014 Sohn 2014

Odds ratio IV, fixed, 95% Cl

SE

Weight

0.077 0.094 –0.342 0.431

95.5% 4.5%

1.08 [0.90, 1.30] 0.71 [0.31, 1.65]

100.0%

1.06 [0.89, 1.27]

Total (95% Cl) 2

Odds ratio IV, fixed, 95% Cl

2

Heterogeneity: Chi = 0.90, df = 1 (P = 0.34); I = 0%

0.2

Test for overall effect: Z = 0.63 (P = 0.53)

0.5

1

2

5

Figure 4 Forest plot for early recurrence of hepatocellular carcinoma (HCC) after curative resection: comparison of high and low hepatitis B surface antigen (HBsAg) level patients. The blocks and lines in figures indicate the estimate of odds ratio and 95% confidence interval (CI), and the sizes of blocks relate to the size of the individual study. The diamond indicates the overall estimate from the meta-analysis.

Association between HBsAg levels and spontaneous HBsAg seroclearance during follow up Six included studies reported data on the effect of different HBsAg levels on spontaneous HBsAg seroclearance during long-term follow up in patients with HBV infection.18–21,23,24 In a total of 3859 untreated patients with chronic HBV infection, spontaneous HBsAg seroclearance was detected in 919 patients (23.8%), with 606 (51.4%) in patients with low HBsAg level and 313 (11.7%) in patients with high HBsAg level. Low HBsAg level seemingly increased the rate of HBsAg loss in all valuable studies. The pooled data assessing the impact of lower HBsAg level was significantly in favor of a preventive effectiveness of spontaneous HBsAg seroclearance (OR, 7.89; 95% CI, 4.74–13.13; P < 0.01), but with high heterogeneity (χ2 = 22.40, P < 0.01, I2 = 78%) (Fig. 6).

Sensitivity analysis We conducted sensitivity analysis on meta-analysis results regarding the effect of HBsAg levels on the prog-

Study or subgroup Huang 2014 Sohn 2014

nosis of chronic HBV infection during long-term follow up. First, the meta-analysis estimates were computed by deleting the data of studies with limited sample size; after which we reanalyzed the data of remaining reports, and the OR of overall recurrence risk were similar to the previous results (data not shown). Second, we also performed sensitivity analysis by applying different effect models. On result of the impact of HBsAg levels on the prognosis of chronic HBV infection, combined OR were calculated with a fixed effect model and a random effect model and the results were compared; the OR with a fixed effect model were similar to those with a random effect model (data not shown). Thus, sensitivity analysis performed by using different methods all indicated that the results of the current meta-analysis were comparatively reliable.

Publication bias Funnel plots were performed for the incidence of HCC, and these parameters were symmetrically displayed. Due to the small number of included relevant subgroups, the potential small-study bias was also tested

SE

Weight

Odds ratio IV, fixed, 95% Cl

0.658 0.171 1.022 0.448

87.3% 12.7%

1.93 [1.38, 2.70] 2.78 [1.15, 6.69]

100.0%

2.02 [1.48, 2.77]

log[Odds Ratio]

Total (95% Cl) Heterogeneity: Chi2 = 0.58, df = 1 (P = 0.45); I2 = 0% Test for overall effect: Z = 4.41 (P < 0.0001)

Odds ratio IV, fixed, 95% Cl

0.1

0.2

0.5

1

2

5

10

Figure 5 Forest plot for late recurrence of hepatocellular carcinoma (HCC) after curative resection: comparison of high and low hepatitis B surface antigen (HBsAg) level patients. The blocks and lines in figures indicate the estimate of odds ratio and 95% confidence interval (CI), and the sizes of blocks relate to the size of the individual study. The diamond indicates the overall estimate from the meta-analysis.

© 2014 The Japan Society of Hepatology

Hepatology Research 2014

Study or subgroup Chan 2011 Chen 2012 Liu 2013 Martinot-Peignoux 2013 Seto 2012 Tseng 2012

Low HBsAg level Events Total 9 17 14 17 363 759 8 27 152 193 60 167

HBsAg levels and clinical outcome 7

High HBsAg level Events Total 3 86 24 63 160 1732 5 64 51 213 70 521

Weight 8.2% 9.4% 26.2% 10.5% 22.3% 23.4%

Total (95% Cl) 1180 2679 100.0% 313 Total events 606 Heterogeneity: Tau2 = 0.25, Chi2 = 22.40, df = 5 (P = 0.0004); I2 = 78% Test for overall effect: Z = 7.95 (P < 0.00001)

Odds ratio M-H, random, 95% Cl 31.13 [6.98, 138.74] 7.58 [1.97, 29.15] 9.01 [7.26, 11.18] 4.97 [1.45, 17.02] 11.78 [7.38, 18.78] 3.61 [2.41, 5.41]

Odds ratio M-H, random, 95% Cl

7.89 [4.74, 13.13] 0.01

0.1

1

10

100

Figure 6 Forest plot for occurrence of spontaneous hepatitis B surface antigen (HBsAg) seroclearance: comparison of high and low HBsAg level patients. The blocks and lines in figures indicate the estimate of odds ratio and 95% confidence interval (CI), and the sizes of blocks relate to the size of the individual study. The diamond indicates the overall estimate from the meta-analysis.

using Egger’s regression test asymmetry and Begg’s test for funnel plot. The result indicated that the conclusions of this meta-analysis were relatively stable and that publication bias was unlikely to affect the results of this meta-analysis.

DISCUSSION

H

EPATITIS B SURFACE antigen was identified more than 40 years ago. It has been used by most practicing physicians as one of the serological tests to determine the etiology of hepatitis but not to monitor disease progression in patients with chronic HBV infection. Over the years, HBsAg has proven to be a steady marker that can be used to predict clinical outcomes. There is growing interest in the use of quantitative HBsAg as a prognostic marker in chronic hepatitis B patients. However, current knowledge concerning the role of HBsAg levels in the prognosis of chronic HBV infection has been limited and inconclusive. This meta-analysis of 11 included studies, which assessed the risk of developing cirrhosis and HCC between different HBsAg level groups, indicated a significantly higher risk of advanced liver disease in patients with high HBsAg levels at baseline. Using the pooled crude odds ratios from the included studies, we found that high HBsAg levels were associated with a 2.51-fold increased risk of cirrhosis, and a 2.21-fold increased risk of HCC occurrence compared with low HBsAg levels, respectively. Prior to this meta-analysis, several studies had specifically evaluated the prognostic significance of HBsAg levels in patients with chronic HBV infection. As to the prediction of disease progression, most longitudinal cohort studies have already

agreed that chronic hepatitis, cirrhosis and HCC are sequential complications of chronic hepatitis B infection. The association between HBsAg level and HCC was first revealed by the ERADICATE-B cohort, in which Tseng et al. reported that in patients with HBV DNA of less than 2000 IU/mL, a HBsAg level below 1000 IU/mL was associated with a 2% incidence of HCC at 20 years which increased to 8% with a HBsAg level above 1000 IU/mL. They suggested that a HBsAg level of less than 1000 IU/mL could be considered to define low-risk patients who are infected with HBV genotype B or C.15 Similarly, the REVEAL study from Taiwan indicated that like HBV DNA, the cumulative risk for cirrhosis and HCC is also highly correlated with HBsAg levels. The cumulative risk for cirrhosis was 4.8%, 8.8% and 16.2% for participants with serum HBsAg levels of less than 100, 100–999 and 1000 IU/mL or more, respectively. On the other hand, the cumulative risk for HCC was 1.4%, 4.5% and 9.2% for those with serum HBsAg levels of less than 100, 100–999 and 1000 IU/mL or more, respectively.22 In this analysis, our data supported that high HBsAg levels were associated with a significantly higher risk of the occurrence of advanced liver disease. Furthermore, as a marker of HBV infection, there has been a paucity concerning studies of HBsAg levels of patients undergoing HCC resection, probably in part due to the lack of interest in hepatitis virology among liver surgeons who manage these patients. In this study, we also examined this association between HBsAg levels at recruitment and the risk of HCC recurrence after curative resection. Based on the hypothesis that early and late intrahepatic recurrence of HCC was attributable to two different mechanisms – intrahepatic metastasis and de novo multicentric carcinogenicity – we also

© 2014 The Japan Society of Hepatology

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investigated the impact of HBsAg levels on early and late intrahepatic recurrence, separately.26 Our results supported that high HBsAg levels were associated with a high risk of late recurrence after curative resection of HCC, although the rate of early recurrence was not higher in high HBsAg level patients compared with the patients with low HBsAg levels. In Sohn et al.’s article, 46 (19%) patients received antiviral therapy before HCC resection.17 Even considering the effect of HBsAg decline and preventive HCC recurrence by antiviral therapy, this tends to underestimate rather than overestimate the risk of high HBsAg levels. The precise mechanism for occurrence of advanced liver disease and recurrent carcinogenesis associated with high HBsAg level in patients with chronic HBV infection was still unclear. As is known, the occurrence of cirrhosis usually results from an accumulation of extracellular matrix arising from liver cell injury, and HCC may subsequently emerge in the setting of cirrhosis.27–29 High viral load has been widely used as an indicator for active viral replication, which is considered to be the driving force of liver disease progression.7,30 It is generally believed that there was a positive correlation between HBsAg and HBV DNA levels.31 HBsAg is translated from mRNA with the transcriptional template-active cccDNA, which is the reflection of the number of infected hepatocytes. The clinical relevance of HBsAg levels is inferred from the relationship of this marker to the intrahepatic amount of cccDNA.32 There is a positive correlation between serum HBsAg concentrations and the intrahepatic amounts of total HBV DNA and cccDNA, which is responsible for viral persistence. Taking these lines of evidence, high HBsAg levels in patients may indicate even higher cccDNA levels and confer further increased viral replication and even higher HCC risk.13,32,33 It is widely accepted that spontaneous clearance of HBsAg correlates with favorable clinical outcomes because it usually indicates disease remission.34,35 Spontaneous HBsAg seroclearance occurs at an annual incidence of 1–2% among chronic hepatitis B patients.36,37 Previous studies have shown that lower HBsAg levels were associated with a higher chance of HBsAg loss in patients with chronic HBV infection who received nucleoside/nucleotide analog or pegylated interferon treatment.38,39 However, there are still limited data regarding the role played by HBsAg levels in prediction of spontaneous HBsAg seroclearance in the natural history of untreated chronic hepatitis B patients. In a longitudinal study of untreated chronic hepatitis B patients with negative HBeAg from Hong Kong, all patients who underwent HBsAg seroclearance had base-

© 2014 The Japan Society of Hepatology

Hepatology Research 2014

line HBsAg of less than 1000 IU/mL, which has 100% sensitivity and 100% negative predictive value to predict HBsAg seroclearance.19 Tseng et al. suggested that lower serum HBsAg levels in the early HBeAg-negative phase are associated with a higher rate of HBsAg loss, and a HBsAg level of less than 100 IU/mL is an appropriate cut-off value for predicting HBsAg loss over time.31 In Japan, Kobayashi et al. also indicated that HBsAg levels of 2000 IU/mL or less could increase the rate of HBsAg seroclearance significantly.40 In this meta-analysis, similar to previous studies, despite recommended cutoffs varying among the different study populations, our results pointed to the main finding that lower HBsAg levels were closely associated with a higher likelihood of HBsAg loss over time. Determination of serum HBsAg level may represent a new angle for risk stratification in chronic HBV carriers. To the best of our knowledge, this is the first metaanalysis that evaluated the effect of serum HBsAg levels on the prognosis of chronic HBV infection. However, some limitations of this meta-analysis should be discussed. First of all, the HBsAg levels vary during the different phases of chronic HBV infection. HBsAg levels are higher in HBeAg positive than in HBeAg negative patients. However, the HBeAg positive and HBeAg negative patients were all included in the analysis. We could not evaluate the risk of HBsAg level in HBsAg positive and negative patients separately for lack of relevant data. Second, compared with positive studies, negative studies may be less likely to be published and more likely to take longer to be published, which can affect the validity of meta-analysis. Third, there was significant heterogeneity among studies, such as the origin of the study (Western vs Asian), HBV genotype, cut-off value of HBsAg levels and follow-up period. Because there were several limitations existing in the current meta-analysis, our results should be interpreted with caution and likewise the conclusions of this meta-analysis should also be drawn cautiously. Therefore, future studies or analyses assessing the role of serum HBsAg levels on predicting clinical outcomes in chronic HBV carriers should be performed on the basis of overcoming such limitations. In summary, despite the limitations reported above, we still conclude that in patients with chronic hepatitis B, a higher serum HBsAg level is associated with development of cirrhosis and HCC comparatively. High HBsAg level patients had a significantly higher risk of late recurrence after primary curative resection of HCC. Therefore, a lower serum HBsAg level is associated with a higher rate of spontaneous HBsAg seroclearance. In clinical practice, the monitoring of serum HBsAg levels

Hepatology Research 2014

HBsAg levels and clinical outcome 9

may serve as useful biomarkers for predicting the clinical outcomes of subjects with chronic hepatitis B. 13

ACKNOWLEDGMENTS

T

HE AUTHORS THANK all the patients and clinical investigators who were involved in the studies included in this meta-analysis. The study was financially supported by the China Ministry of Health (no. W201202), Natural Science Foundation of Jiangsu Province (BK2012225), Foundation of Jiangsu Province (WS056) and National Nature Science Foundation of China (81302056).

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Effect of serum hepatitis B surface antigen levels on predicting the clinical outcomes of chronic hepatitis B infection: A meta-analysis.

The impact of serum hepatitis B surface antigen (HBsAg) levels on the prognosis of chronic hepatitis B virus (HBV) infection remains unclear. This met...
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