Journal of the Formosan Medical Association (2021) 120, 847e853

Available online at www.sciencedirect.com

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journal homepage: www.jfma-online.com

Original Article

Usefulness of quantitative hepatitis B

surface antigen testing in hepatitis B
community-based screening
Kao-Chi Chang a, Chih-Yi Lee c, Te-Sheng Chang a,d,e,
Chao-Hung Hung b, Wei-Ming Chen a, Mei-Yen Chen f,
Tung-Jung Huang g, Wen-Nan Chiu d, Jing-Hong Hu d,
Yu-Chih Lin h, Wei-Cheng Huang i, Nien-Tzu Hsu j,
Sheng-Nan Lu b,j,*

a
Division of Hepatology and Gastroenterology, Department of Internal Medicine, Chang Gung
Memorial Hospital, Chiayi, Taiwan
b
Department of Internal Medicine, Division of Hepato-Gastroenterology, Kaohsiung Chang Gung
Memorial Hospital, Taiwan
c
Department of Laboratory Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
d
Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Yunlin, Taiwan
e
School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
f
College of Nursing, Chang Gung University of Science and Technology, Chiayi, Taiwan
g
Division of Thoracic Medicine, Chang Gung Memorial Hospital, Yunlin, Taiwan
h
Division of Family Medicine, Chang Gung Memorial Hospital, Yunlin, Taiwan
i
Department of Geriatric, Chang Gung Memorial Hospital, Chiayi, Taiwan
j
Biostatistics and Bioinformatics Center of Kaohsiung Chang Gung Memorial Hospital, Kaohsiung,
Taiwan

Received 3 June 2020; received in revised form 15 August 2020; accepted 21 August 2020

KEYWORDS Background/Purpose: Low viral load (LVL) of hepatitis B virus (HBV) is a predictor of chronic
Hepatitis B virus; HBV infection. However, the usefulness of quantitative hepatitis B surface antigen (qHBsAg)
Quantitative hepatitis in predicting LVL in community-based screening has not been well studied. We aimed to mea-
B surface antigen; sure the prevalence of LVL in HBV carriers and validate the efficacy of qHBsAg in predicting
HBV DNA; LVL.
Community-based Methods: This community-based screening study was conducted in Taiwan. HBV DNA was as-
screening tool sayed in HBsAg carriers. Participants were randomized to training and validation sets to deter-
mine the ability of qHBsAg to predict LVL. Receiver operating characteristic curves were used
to identify the best cutoff values in the training set.

* Corresponding author. Department of Internal Medicine, Division of Hepato-Gastroenterology, Kaohsiung Chang Gung Memorial Hospital,
123, Ta Pei Road, Niao Sung, Kaohsiung County 833, Taiwan.
E-mail address: juten@ms17.hinet.net (S.-N. Lu).

https://doi.org/10.1016/j.jfma.2020.08.031
0929-6646/Copyright ª 2020, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
848 K.-C. Chang et al.

Results: Among the 2919 participants, 359 (12.2%) were HBsAg carriers. There were 132 and
137 carriers in the training and validation sets, respectively. Significant correlations were
found between qHBsAg and HBV DNA in both training and validation sets. Thirty and 29 partic-
ipants with qHBsAg <8 IU/mL in the training and validation sets, respectively, had LVL. Using
8 IU/mL as the cutoff, negative predictive value (NPV) of qHBsAg for HBV DNA levels >2000 IU/
mL was 100%. The best cutoff level of qHBsAg to predict HBV LVL was 200 IU/mL, with a sensi-
tivity, specificity, and accuracy of 75.0%, 76.1%, and 75.8%, respectively, in the training set.
The positive predictive value and NPV were 70.0% and 77.9%, respectively, in the validation
set.
Conclusion: Approximately 60% of HBsAg carriers had HBV LVL, and qHBsAg <8 IU/mL accu-
rately predicts LVL. This quantitative test provides additional information for community-
based screening.
Copyright ª 2020, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).

Introduction Patients and methods

Chronic hepatitis B virus (HBV) infection is a global health
problem and an important endemic disease in Taiwan. The
estimated global prevalence of chronic HBV infection was
3.5% (257 million people) in 2016.1,2 Approximately 11%e
20% of the general Taiwanese population lived with
chronic HBV infection before the universal hepatitis B
vaccination program was launched in 1984. This was the
highest prevalence in the world. The hepatitis B surface
antigen (HBsAg) seropositive rate in the generation born
since the vaccination program has declined dramatically
from 11% to 0.9% in 2012.3 Nevertheless, cohorts born
before 1984 in Taiwan still have a high prevalence of
HBsAg. Persistent HBV infection reflects a dynamic inter-
action between host immune responses. The virus has a
wide disease spectrum, including an inactive carrier
without any complications throughout life, chronic hepa-
titis, liver fibrosis, liver cirrhosis, and hepatocellular car-
cinoma (HCC).4 Previous studies defined inactive carriers
as those who typically have qHBsAg <1000 IU/mL, HBV
DNA level <2000 IU/mL, and normal alanine aminotrans-
ferase (ALT) levels.5 Approximately 60%e85% of patients
have an inactive form of the disease that does not require
lifelong antiviral therapy, whereas others develop liver
fibrosis, liver cirrhosis, cirrhosis, or HCC.6 Among unvac-
cinated Taiwanese patients, a substantial portion with
chronic HBV infection are at a high risk of developing liver
cirrhosis and HCC. For this reason, community-based
screenings to detect individuals who are positive for
HBsAg are frequently conducted; the screening tool that is
most often used is qualitative HBsAg. In the past 10 years,
researchers have focused on the use of HBsAg quantifica-
tion to predict disease activity and monitor the response
to treatment in chronic HBV infection. Nevertheless, there
are few studies on the use of HBsAg quantification in
community-based screening. Therefore, we aimed to
evaluate the usefulness of quantitative HBsAg in
community-based screening to measure the prevalence of
HBV LVL in HBV carriers and to validate qHBsAg as a pre-
dictor of HBV LVL.
A community-based HBsAg screening study was conducted
in the central coastal areas of western Taiwan from January
to December in 2018. We set up screening stations in
coastal villages and towns of Yunlin and Changhua counties
in order to screen for HBV for local residents over 18 years
old. All participants were tested for qHBsAg, and the
aspartate aminotransferase (AST) and ALT levels were
evaluated. Residual sera were stored for checking HBV DNA
if the participant’s qHBsAg was >0.05 IU/mL. To avoid the
influence of anti-viral treatments on the correlation of HBV
DNA and qHBsAg,7,8 we excluded patients who were being
treated with nucleos(t)ide analogs.
The screening tool used was Abbott Architect HBsAg, a
widely used assay introduced by Abbott Ireland Diagnostic
Division (Finisklin Business Park, Sligo, Ireland) with a lower
limit of detection of 0.05 IU/mL and an upper limit of
detection of 250 IU/mL. When the value of HBsAg exceeded
250 IU/mL, dilution was performed with Abbott Architect
HBsAg analysis automatically with a dilution factor of
1:500. HBV DNA was also assessed in the screened patients
who were seropositive for qHBsAg and had available stored
sera. The levels of HBV DNA were quantified using COBAS
AmpliPrep/COBAS TaqMan HBV test version 2.0, with a
lower limit of detection of 20 IU/mL. The correlations be-
tween qHBsAg and HBV DNA were analyzed using linear
correlation and regression after loge-log transformation.
We determined whether qHBsAg could be used to predict
HBV DNA in a community-based setting.
All the finally included participants were randomly
divided into the training set and validation set with a ratio
of 1:1 by using the SURVEYSELECT procedure in SAS soft-
ware (Version 9.4, SAS Institute Inc., Cary, NC, USA). The
receiver operating characteristic (ROC) curves were used to
identify the best cutoff values for sensitivity, specificity,
and accuracy in the training set first, and then the cutoff
value was validated using the validation set. The positive
predictive value (PPV) and negative predictive value (NPV)
were also calculated in both the training and validation
sets. The prevalence was expressed as percentage.
Hepatitis B community-based screening with qHBsAg 849

All patients gave written informed consent to partici- HBV DNA tests in community-based screening is very
pate in the research testing. This study was approved by limited, because it is expensive and requires suitable lab-
the institutional review board of Chang Gung Memorial oratory equipment and technicians. The HBsAg cutoff
Hospital, Taiwan. values of 8, 20, or 200 IU/mL, which are all used to predict
HBV DNA, are all <250 IU/mL and can be easily evaluated in
Results local clinics or hospitals without dilution. In other words,
quantitative testing with no dilution has similar costs to the
traditionally used qualitative testing and can meet the
A total of 2934 individuals participated in a community-
demand of predicting the HBV DNA level. At least three
based screening program; of these, 359 were positive for
commercialized quantitative HBsAg assays are available,
qHBsAg, resulting in a prevalence of 12.2%. After excluding
which are as follows: the Architect HBsAg (Abbott Labora-
15 participants who were treated with nucleos(t)ide ana-
tories), the DiaSorin Liaison XL, and the Elecsys HBsAg II
logs, 2919 participants were randomized into the training
Quant assay (Roche Diagnostic). All three assays are less
set (n Z 1460) and a validation set (n Z 1459). Of these,
expensive, fully automated, and have been extensively
132 and 137 patients, respectively, had available stored
evaluated.9e11 Our study used Abbott Architect HBsAg for
serum for further evaluation of HBV DNA.
HBsAg quantification and demonstrated the efficacy of the
The participants’ baseline characteristics are presented
quantitative HBsAg test as a first-line screening tool in a
in Table 1. The mean age was 64.9  14.3 years, and 1064
community-based cohort in Taiwan.
(36.5%) and 1855 (63.5%) were men and women, respec-
Similar to previous studies, we found that HBV DNA and
tively. Most (n Z 2801, 96%) of participants were born
qHBsAg levels were significantly correlated; however, our
before 1984 (non-vaccinated cohort). The HBsAg-positive
correlation coefficients of 0.693 and 0.696 in the training
participants were younger and had higher AST and ALT
and validation sets were not large enough to have predic-
levels than the HBsAg-negative participants. Among the
tive values. Prior studies also showed that this correlation
qHBsAg-positive participants with available HBV DNA data,
was especially pronounced in patients with positive hepa-
166 (61.7%) individuals had HBV DNA levels of <2000 IU/mL.
titis B e-antigen (HBeAg).12 Yang et al. demonstrated the
The baseline characteristics were comparable between
relationship of HBV DNA and qHBsAg not only in HBeAg-
HBsAg-positive participants with or without available HBV
positive patients but also in HBeAg-negative patients aged
DNA data. The training and validation sets were comparable
>40 years.13 Although we did not analyze serum HBeAg in
in terms of age, sex, transaminase levels, and HBV DNA and
our community-based screening program, according to the
qHBsAg levels (Supplemental Table 1).
natural course of HBV and the old age of our participants
The correlations between serum HBV DNA levels and
(qHBsAg-positive patients were 62.5  12.4 years old), we
serum HBsAg titers in patients with HBsAg are shown in
believe that most of our patients should be HBeAg-
Fig. 1. After log-log transformation, a significantly linear
negative.
correlation was observed between qHBsAg and HBV DNA in
The correlation of HBV DNA and qHBsAg could be influ-
both the training (n Z 132, r Z 0.693, P < 0.001) and
enced by anti-viral treatments.7,8 Excluding patients who
validation (n Z 137, r Z 0.696, P < 0.001) sets.
were undergoing treatment for HBV should have improved
Thirty (22.7%) and 29 (21.2%) patients in the training and
the correlation between qHBsAg and HBV DNA. Neverthe-
validation sets, respectively, had qHBsAg levels of <8 IU/
less, qHBsAg was still a sufficiently strong predictor of HBV
mL, and all of them had HBV DNA levels of <2000 IU/mL.
DNA levels, probably because of the complex virology of
The NPV of qHBsAg >8 IU/mL for predicting HBV DNA levels
HBsAg production. In recent years, the understanding of the
of >2000 IU/mL was 100%. Using the ROC curves for qHBsAg
molecular virology of HBsAg has improved.14 There are
to predict HBV DNA levels of >2000 IU/mL, the area under
three kinds of HBsAg proteins that form the viral envelope,
the ROC curve was 0.819 and 0.811 in the training and
which are as follows: small HBsAg, middle HBsAg, and large
validation sets, respectively (Fig. 2). In the training set, the
HBsAg. These proteins are produced and secreted by three
ROC curve was also used to calculate the best cutoff value
different pathways: the HBsAg endoplasmic reticulum (ER)-
for qHBsAg to predict HBV DNA levels of >2000 IU/mL. The
secretory pathway, the viral DNA replication pathway
best cutoff value was 200 IU/mL, with a sensitivity of
through multivesicular bodies, and the episomal integrated
75.0%, a specificity of 76.1%, and an accuracy of 75.8%. We
HBV DNA pathway. Recent studies in chronically HBV-
validated this cutoff value in the validation set and ob-
infected chimpanzees have shown that the main pathway
tained a PPV of 70.0% and an NPV of 77.9%. The other cutoff
for HBsAg production differs depending on the phase of
values of qHBsAg to predict HBV DNA levels of >2000 IU/mL
chronic hepatitis B infection.15 Nevertheless, the current
were calculated. The NPV of qHBsAg >20 IU/mL to predict
qHBsAg assays detect all three forms of circulating HBsAg
HBV DNA levels of >2000 IU/mL was 97.4% and 95% in the
that are synthesized in these different pathways. These
training and validation sets, respectively (Table 2).
data suggest the difficulty and limitation of using qHBsAg to
predict the precise serum HBV DNA levels that we sus-
Discussion pected would improve after excluding patients receiving
anti-viral treatment for HBV.
Community-based screening for chronic HBV infection is Nevertheless, the low qHBsAg level needed to predict
always conducted in Taiwan with qualitative HBsAg tests as HBV DNA when the HBV DNA level was >2000 IU/mL has
the first-line screening tool. The participants with positive excellent NPV. When the qHBsAg level is <8 IU/mL, the NPV
findings are referred to the hospital for further HBV DNA in both training and validation sets was 100%. The cutoff
quantifications to evaluate the disease activity. The use of level for predicting HBV DNA levels of >2000 IU/mL is very
 850
Table 1 Baseline participant characteristics.
Total participants qHBsAg negative qHBsAg positive p-valuea qHBsAg positive without qHBsAg positive with HBV p-valueb
(n Z 2919) (n Z 2575) (n Z 344) HBV DNA data (n Z 75) DNA data (n Z 269)
Age (y) 64.9  14.3 65.3  14.6 62.5  12.4 <0.001 64.7  11.5 61.9  12.6 0.089
Male 1064 (36.5%) 932 (36.2%) 132 (38.4%) 0.431 32 (42.7%) 100 (37.2%) 0.387
Female 1855 (63.6%) 1643 (63.8%) 212 (61.6%) 43 (57.3%) 169 (62.8%)
AST (IU/mL) 27.0  15.6 26.8  15.3 29.0  17.6 0.024 31.9  19.5 28.2  17.0 0.118
ALT (IU/mL) 25.0  19.1 24.7  19.0 27.5  20.1 0.012 28.3  22.1 27.3  19.5 0.706
qHBsAg (IU/mL) 2144.85  9685.83 1950.0  11,754.9 2199.18  9049.99 0.865
qHBsAg (IU/mL) 118.90 (9.65e999.68)c 52.58 (6.73e828.88)c 129.24 (11.24e1035.76)c 0.190d
Log qHBsAg 1.87  1.43 1.70  1.42 1.92  1.43 0.246
qHBsAg <8 (IU/mL) 79 (23.0%) 20 (26.7%) 59 (21.9%) 0.389
qHBsAg <20 (IU/mL) 108 (31.4%) 29 (38.7%) 79 (29.4%) 0.125
qHBsAg <200 (IU/mL) 202 (58.7%) 47 (62.7%) 155 (57.6%) 0.433
HBV DNA (IU/mL) 13003196.7  105967757.0
HBV DNA (IU/mL) 724.4 (49.0e7413.1)c
Log HBV DNA 2.92  1.82
HBV DNA <2000 (IU/mL) 166 (61.7%)
Data are presented as n (%), mean  standard deviation (SD).
a
Comparison for qHBsAg positive and qHBsAg negative.
b
Comparison for qHBsAg positive with HBV DNA data and qHBsAg positive without HBV DNA data.
c
Median (interquartile range (IQR)).
d
ManneWhitney U test.

K.-C. Chang et al.

Hepatitis B community-based screening with qHBsAg
Figure 1 Significant correlation of log HBV DNA and log qHBsAg, training set n Z 132, valiation set n Z 137. The data of HBV DNA
and HBsAg quantification was presented with log-log transformation. Patients with non-detected HBV DNA were labeled as 0 in the
log HBV DNA diagram. Patients with a detected HBV DNA level but one that was lower than the lowest limit (<20 IU/mL) in our
institute were labeled as 1. Patients with a HBV DNA level that one was higher than the upper limit (>170,000,000 IU/mL) were
labeled as 9.
important in clinical practice. According to the recent
guidelines of the American Association for the Study of Liver
Diseases (AASLD), chronic hepatitis B patients with negative
HBeAg should be treated when their HBV DNA levels are
2000 IU/mL and ALT levels are more than two times higher
of the upper limit of normal.16 The Asian-Pacific clinical
practice guidelines on the management of HBV also recom-
mend the same cutoff value of HBV DNA and ALT levels for
the noncirrhotic HBeAg-negative HBV patients as indications
for anti-viral therapy.17 Previous studies defined HBeAg-
negative patients as inactive carriers who typically have
qHBsAg of <1000 IU/mL, HBV DNA levels of <2000 IU/mL,
and normal ALT levels.18,19 Inactive carriers have low rates
Figure 2 Receiver operating characteristics (ROC) curve,
qHBsAg > 200 IU/mL to predict HBV > 2000 IU/mL.
851
of cirrhosis and HCC and significantly better prognosis than
active HBV patients. With limited medical resources, it is
important to distinguish inactive carriers requires less close
monitoring from active HBV patients who may benefit from
stringent follow-up and initiation of antiviral treatment. In
our study, we found that the best cutoff value of qHBsAg to
predict HBV DNA levels of >2000 IU/mL was 200 IU/mL.
Although the sensitivity, specificity, and accuracy were
75.0%, 76.1%, and 75.8%, respectively, in the training set,
and the PPV and NPV were 70.0% and 77.9% in the validation
set, we accept them reluctantly, and these data may be
adequate for clinical practice. However, the outstanding
NPV of qHBsAg to predict HBV DNA can easily and directly
identify a portion of inactive carriers. The NPV is 100%, while
using the cutoff qHBsAg value of 8 IU/mL. When we set the
cutoff value of qHBsAg at 20 IU/mL, the NPV was 97.4% and
95.0% in the training and validation sets, respectively, which
are both excellent for clinical practice. In addition, these
levels of serum qHBsAg are easily obtained using the Abbott
Architect HBsAg, which has a detection range of 0.5 IU/mL to
250 IU/mL without any further dilution. For these reasons,
when using qHBsAg in community-based cohort screenings, it
would be unnecessary to check the serum HBV DNA levels
when the qHBsAg level is <8 IU/mL or perhaps <20 IU/mL. In
this screening program, 30 (22.7%) patients in the training
set and 29 (21.2%) in the validation set had qHBsAg of <8 IU/
mL, whereas 39 (29.6%) patients in the training set and 40
(29.2%) in the validation set had qHBsAg of <20 IU/mL.
These findings suggest that we could have refrained from
doing at least one-fourth of the serum HBV DNA quantifica-
tion tests.
The AASLD guidelines suggest that HBeAg-negative and
anti-HBe-positive patients with normal ALT levels and
HBV DNA levels of <2000 IU/mL should be monitored with
ALT determination every 3 months in the first year and
every 6e12 months thereafter.16 In Taiwan, an area of
high prevalence of HCC, in addition to regularly following
ALT, physicians should also perform abdominal ultrasound
examinations and alpha-fetoprotein evaluations in the
patients every 6 months according to the tumor doubling
852 K.-C. Chang et al.

time.20 After excluding liver fibrosis or cirrhosis using

1.000)
0.999)
0.927)
1.000)
0.994)
0.866)
non-invasive serologies or elastography and HCC using
abdominal ultrasonography with alpha-fetoprotein mea-
surement, we could easily classify patients with low

(0.833,
(0.865,
(0.762,
(0.828,
(0.831,
(0.670,
qHBsAg as inactive carriers and could arrange a longer
follow-up period.

1.000
0.974
0.859
1.000
0.950
0.779
NPV This study has several limitations. In this cross-sectional
community-based screening study, we did not routinely
measure serum HBeAg. Considering the natural course of
HBV infection, we concluded that most of our patients
would be HBeAg-negative because of their advanced age.
0.533)
0.569)
0.741)
0.642)
0.687)
0.812)
Previous studies demonstrated that HBsAg production dif-
fers among HBV genotypes, and serum HBsAg levels are
higher in genotype A-infected patients than in genotype B-,
(0.334,
(0.358,
(0.469,
(0.448,
(0.483,
(0.568,
C-, and D-infected patients.21e23 Unfortunately, we were
unable to obtain information on the HBV genotypes in this
0.431
0.462
0.611
0.546
0.588
0.700

community-based study.
PPV

In conclusion, the prevalence of HBsAg (12.2%) in our

case series was equal to that of the general population in
Taiwan, and approximately 60% of HBsAg carriers had HBV
LVL in this population. Using qHBsAg of >8 IU/mL or >20 IU/
0.647)
0.697)
0.828)
0.722)
0.769)
0.815)

mL as cutoff values, HBV DNA levels of <2000 IU/mL can be

predicted accurately. Based on ROC curve, the best cutoff
values of qHBsAg to predict HBV DNA levels >2000 IU/mL
(0.472,
(0.525,
(0.675,
(0.556,
(0.609,
(0.663,

should be 200 IU/ml, with sensitivity, specificity, accuracy,

Accuracy

PPV, and NPV of approximately 75%. This quantitative

0.561
0.614
0.758
0.642
0.693
0.745

HBsAg test provides more information than the traditional

qualitative HBsAg test.

Funding
0.450)
0.542)
0.846)
0.489)
0.603)
0.857)

This work was financially supported by the Health Promo-

tion Administration, Ministry of Health and Welfare
(0.243,
(0.327,
(0.659,
(0.265,
(0.372,
(0.660,
Different cutoff values of qHBsAg to predict HBV DNA >2000 IU/mL.

(PMRPG6H0021) and the Ministry of Science and Technology

Specificity

(MOST107-2314-B182A-111). The content of this research

may not represent the opinion of the Health Promotion
0.341
0.432
0.761
0.372
0.487
0.769

Administration, Ministry of Health and Welfare.

Declaration of Competing Interest

1.000)
0.999)
0.868)
1.000)
0.996)
0.822)

All authors declare no conflicts of interest.

(0.882,
(0.880,
(0.597,
(0.911,
(0.883,
(0.579,

Acknowledgments
Sensitivity
1.000
0.977
0.750
1.000
0.966
0.712

We thank our colleagues at the Chiayi and Yunlin Chang

Gung Memorial Hospitals who supported and executed the
community-based screening, as well as the research assis-
tants who helped us in the laboratory analyses and collec-
tion of clinical information.
Cutoff

200

200

Appendix A. Supplementary data

20

20
8

Supplementary data to this article can be found online at

https://doi.org/10.1016/j.jfma.2020.08.031.
Validation set
Patients set
Training set

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