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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 current models may increase the
predictability of spontaneous HBsAg seroclearance in a large community-based natural
history study of previously untreated individuals.
In accordance with recent studies which reported serum HBsAg levels as the most important
predictor of HBsAg seroclearance among HBeAg-seronegative individuals,[19-22] our study
also found the importance of serum HBsAg levels in predicting HBsAg seroclearance.
Previous studies emphasized serum HBsAg levels alone as an independent predictor [19-22].
However, our study further emphasizes the important role of HBV viral loads in predicting
HBsAg seroclearance in addition to serum HBsAg levels.
We found a significant biological gradient between decreasing serum HBsAg levels and
increasing rates of HBsAg seroclearance, even after adjustment for serum HBV DNA level.
The cumulative lifetime incidence of HBsAg seroclearance was significantly higher among
individuals with undetectable HBV DNA levels. Although the effect of serum HBsAg levels
was extremely high for those with undetectable serum HBV DNA levels, its effect decreased
strikingly, among those with baseline serum HBV DNA levels ≥2,000 IU/mL.
The predictive ability of serum HBsAg levels varies according to different phases of disease
and is, most importantly, HBV DNA dependent. Thus, serum HBV DNA levels continue to
play a crucial role in spontaneous HBsAg seroclearance. It is also important to lower serum
levels of HBsAg in order to maximize the probability of HBsAg seroclearance, especially in
those with undetectable HBV DNA levels.
Based on results from the R.E.V.E.A.L.-HBV study, in Asian chronic hepatitis B patients
with genotypes B or C infection who were HBeAg- seropositive, serum HBV DNA levels
were the most significant predictor of HBsAg seroclearance, while serum HBsAg levels did
not play a significant role [31]. In this study, among HBeAg-seronegative Asian patients
infected with genotypes B or C with predominantly normal ALT levels and viral loads
≥2,000 IU/mL, serum HBV DNA and HBsAg levels were equivalently important for the
prediction of HBsAg seroclearance. Among those who were HBeAg-seronegative with viral
loads <2,000 IU/mL, serum HBsAg levels became the most important predictor, while HBV
DNA levels were less important (Table 2). Thus, the study by Tseng et al. may not have
found HBV DNA levels to predict HBsAg seroclearance because the study was limited to
individuals with low viral loads [19]. We did not find ALT levels to be significant, perhaps
due to the low frequency of ALT elevation in this cohort. However, this finding is in
agreement with previous studies in genotype B and C patients [8, 19-21].
Current treatment guidelines use HBV DNA levels as the main tool for monitoring chronic
hepatitis B, but have begun to incorporate serum HBsAg levels,[7] and suggest that the use of serum HBsAg levels in addition to serum HBV DNA levels may further refine clinical
management of patients with chronic hepatitis B. Studies have shown a positive correlation
between serum HBsAg and liver cccDNA levels, although this positive correlation was not
always found in HBeAg-seronegative patients [6, 11, 12, 32]. Serum HBsAg levels may
reflect the translation of mRNA’s produced from cccDNA, although the association between
HBsAg and HBV replication seems to break down in HBeAg-negative disease [9, 12, 32].
Serum HBsAg may reflect the balance between the virus and host immune response rather
than viral replication alone, although its exact role is still unclear.
Previous studies have proposed cutoff points of serum HBsAg levels for the prediction of
HBsAg seroclearance. However, it is important to note that probability of HBsAg
seroclearance is a continuum, which varies with the unique clinical profile of each patient
instead of being defined by HBsAg levels alone. In this cohort study, two separate scorebased
prediction models were developed that were able to accurately estimate the probability
of HBsAg seroclearance for different clinical profiles. While the first model containing only
serum HBV DNA levels provided moderate predictive accuracy of the 5-year and 10-year
probability of HBsAg seroclearance, the addition of serum HBsAg levels provided a
significant improvement in both 5-year and 10-year predictive accuracy. The model
containing both HBV DNA and serum HBsAg levels showed excellent calibration correlation
coefficients greater than 0.95.
The score-based prediction model has been widely used by the Framingham Heart Study to
estimate the risk of coronary heart disease [25]. In the case of chronic hepatitis B, this
methodology has been successfully applied in predicting the long-term risk of HCC [26, 27].
The predictive score system in this study not only incorporates other well-known predictors
of HBsAg seroclearance, but captures a profile-based probability distribution for spontaneous HBsAg seroclearance that can be used to further stratify risk groups and refine clinical
management of patients with chronic hepatitis B. A simple score-based prediction model can
potentially eliminate the need for complicated calculations in clinical settings, allowing
clinicians to easily make clinical decisions in patient treatment while helping clinicians to
provide a personalized consultation to each patient.
There are some limitations to be noted. This study only included baseline serum HBsAg
levels, thus the long-term change in serum HBsAg levels must be further elucidated. An
ongoing study from the R.E.V.E.A.L. group will perform long-term repeated measurements
of HBsAg levels to examine HBsAg kinetics and its association with seroclearance and
clinical outcomes. In addition, participants in this study were treatment naïve chronic HBV
carriers. Therefore, the applicability of these results to patients undergoing treatment needs to be explored. Lastly, this study was limited to participants between 30 and 65 years old mostly infected at birth through perinatal infection with HBV genotype B and/or C. Therefore, rates of seroclearance in this study may differ from other genotypes. In addition, the predictive score needs to be clarified in younger carriers, those infected in adulthood, or in individuals infected with other HBV genotypes.
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