Research Article
A predictive scoring system for the seroclearance of HBsAg in HBeAg-seronegative chronic hepatitis B patients with genotype B or C infection

https://doi.org/10.1016/j.jhep.2012.12.006Get rights and content

Background & Aims

Seroclearance of hepatitis B surface antigen (HBsAg) is the most ideal end point in the treatment of chronic hepatitis B. This study develops a predictive scoring system to assess whether the addition of serum levels HBsAg may improve the predictability of HBsAg loss.

Methods

This study included 2491 untreated participants with genotype B or C HBV infection, who were HBsAg-seropositive, HBeAg-seronegative, anti-HCV-seronegative, and cirrhosis free at study entry. Regression coefficients of predictors in Cox Regression models were converted into integer scores for predicting HBsAg seroclearance. Predictive accuracy was assessed with area under the receiver operating characteristic curves (AUROC), and predictive accuracies of models with and without serum HBsAg levels were compared.

Results

Low serum levels of both HBsAg and HBV DNA were the strongest predictors of spontaneous HBsAg seroclearance. Compared to baseline serum HBsAg levels ⩾1000 IU/ml, the multivariate adjusted rate ratio of spontaneous HBsAg seroclearance was 10.96 (7.92–15.16) for those with baseline serum HBsAg levels <100 IU/ml. The predictive ability of HBsAg levels was modified by HBV viral load, showing a weaker effect in those with higher viral loads, and the strongest effect among those with undetectable viral loads. The inclusion of serum HBsAg levels greatly improved the AUROC for predicting HBsAg seroclearance at the fifth (from 0.79 [0.787–0.792] to 0.89 [0.889–0.891]) and tenth year (from 0.73 [0.728–0.732] to 0.84 [0.839–0.841]) after study entry.

Conclusions

Incorporated into an easy-to-use scoring system, HBV viral load and quantitative serum HBsAg levels can accurately predict HBsAg seroclearance.

Introduction

Chronic hepatitis B is a global public health threat due to its widespread distribution and potential to cause adverse clinical outcomes such as cirrhosis, hepatocellular carcinoma (HCC) and even death [1], [2]. The natural history of chronic hepatitis B is typically defined by several phases, which are characterized by changes and interactions among several key seromarkers including alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), anti-HBe, and hepatitis B virus (HBV) DNA [3], [4].

Previous studies have shown that HBeAg-seropositive patients are at increased risk for hepatocellular carcinoma, and HBeAg seroconversion is an important milestone for clinical management of these patients [5]. For HBeAg-seronegative patients, HBsAg seroclearance has been well-documented as the most important clinical and treatment end point, as it signals immunity to HBV, leads to an improved prognosis, and confers lower rates of HCC [6], [7]. Our previous study from the R.E.V.E.A.L.-HBV cohort found that lowering HBV DNA levels was the most significant predictor of spontaneous HBsAg seroclearance, with 95.8% of individuals reaching undetectable HBV DNA levels prior to spontaneous HBsAg seroclearance [8].

Recent technological advances enabled the rapid and inexpensive quantification of HBsAg levels in serum, stimulating interest in the role of quantitative HBsAg in the natural history of chronic hepatitis B [9]. Quantitative HBsAg has been suggested as a promising new seromarker for the immunological response to therapy for chronic hepatitis B as well as a potential predictor of liver disease progression [9], [10], [11], [12], [13]. Recently, the rapid on-treatment decline in serum HBsAg levels, as well as combination of HBsAg and HBV DNA decline, has been found to predict sustained virological response to interferon therapy, as well as HBsAg loss after treatment [14], [15], [16]. Quantitative serum HBsAg levels have also been shown to successfully distinguish inactive from active carriers in genotype C and D patients [17], [18].

A few recent studies examined the predictability of quantitative HBsAg levels for HBsAg seroclearance, and showed a reverse association between serum HBsAg levels and HBsAg seroclearance in clinical patients [19], [20], [21], [22]. However, these studies emphasized HBsAg levels as the most important predictor of seroclearance without placing enough emphasis on the role of HBV DNA levels, which has been established as an important long-term predictor of HBsAg seroclearance [19], [20], [21], [22]. These studies were limited by small sample sizes, clinic-based enrollment of treated patients, and no direct comparison between models with and without the inclusion of serum HBsAg levels. Furthermore, they did not develop a prediction scoring system for HBsAg seroclearance.

Therefore, this study aims at developing a predictive scoring system for spontaneous HBsAg seroclearance in a natural history cohort of treatment naïve HBeAg-seronegative patients affected with genotype B or C chronic hepatitis B, to assess whether the addition of serum HBsAg levels into currently available models may improve the predictability of spontaneous HBsAg seroclearance.

Section snippets

Study cohort

From 1991 to 1992, 23,820 individuals aged 30–65 years were enrolled from seven townships in Taiwan in the R.E.V.E.A.L.-HBV Study. Participants consented to a questionnaire interview, physical examination, and blood collection for testing at study entry and follow-up examinations. Consent included follow-up through physical exams, medical record review, and computerized data linkage with national health insurance, cancer registry, and death certification databases until June 30, 2004. A total of

Baseline characteristics

Among 2491 individuals and 19,997 person-years of follow-up, 523 cases of HBsAg seroclearance occurred, giving an incidence rate of 26.15 per 1000 person-years. The average age of study participants was 46.4 years, and most were male (63.9%). Most had serum ALT levels less than the ULN (86%), body mass index (BMI) less than 30 kg/m2 (95.7%), were genotype B (58.9%), had serum HBV DNA <2000 IU/ml (66.4%), and serum HBsAg levels less than 1000 IU/ml (62.5%) (Table 1).

Cumulative lifetime incidence of HBsAg seroclearance

The cumulative lifetime incidence

Discussion

Fully elucidating the determinants of HBsAg seroclearance and predicting its occurrence is important for the prevention of liver disease progression [7], [29], [30]. Our previous study found that decreasing serum HBV DNA level was the most important predictor of HBsAg seroclearance [8]. However, recent studies have shown an association between serum HBsAg levels and HBsAg seroclearance [17], [19]. This study is the first to examine whether the addition of quantitative serum HBsAg levels into

Conclusions

The addition of serum HBsAg levels to current HBV DNA-based models significantly improves the predictability of HBsAg seroclearance among genotype B and C HBeAg-seronegative individuals. Both serum HBsAg and HBV DNA levels should be considered in the future monitoring of chronic hepatitis B, as they provide complementary information. Additional studies exploring HBsAg kinetics among different populations are still needed.

Financial support

The Department of Health, Taiwan; Bristol-Myers Squibb Co., USA; Academia Sinica, Taiwan; and the National Health Research Institutes (NHRI-EX98-9806PI), Taiwan.

The sponsors of this study had no role in study design, data collection, data analysis, data interpretation, or writing of this report. Moreover, the corresponding author of this manuscript had full access to all data in the study and had final responsibility for the decision to submit the results of this study for publication.

Conflict of interest

Dr. Batrla-Utermann is an employee of Roche Diagnostics, and Dr. Iloeje is an employee of Bristol-Myers Squibb. The other authors report no potential conflict of interest.

Authors’ contributions

Dr. Chien-Jen Chen had full access to all of the data in the study and takes responsibility for the integrity of the data as well as the accuracy of the data analysis.

Study concept and design: C.-J.C., J.L., M.-H.L., H.-I.Y.

Acquisition of data: J.L., M.-H.L., C.-L.J., S.-N.L., L.-Y.W., S.-L.Y., H.-I.Y., C.-J.C.

Analysis and interpretation of data: J.L., M.-H.L., H.-I.Y., C.-J.C.

Drafting of the manuscript: J.L.

Critical revision of the manuscript for important intellectual content: J.L., M.-H.L.,

Acknowledgements

Other members of R.E.V.E.A.L.-HBV Study Group are as follows: National Taiwan University Hospital: C.Y. Hsieh, H.S. Lee, P.M. Yang, C.H. Chen, J.D. Chen, S.P. Huang, C.F. Jan. National Taiwan University: T.H.H. Chen. National Defense Medical Center: C.A. Sun. Taipei City Psychiatric Center: M.H. Wu. Tzu Chi University: S.Y. Chen. Shin Kong Wu Ho-Su Memorial Hospital: K.E. Chu. Huhsi Health Center, Penghu County: S.C. Ho, T.G. Lu. Provincial Penghu Hospital: W.P. Wu, T.Y. Ou. Sanchi Health

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