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Editorial: HBsAg serum levels in HBeAg-negative chronic HBV
infection—is it a matter of genotype? Authors’ reply
In their Editorial Alexopoulou and Karayiannis comment on our find-
ings of the impact of the HBV genotype and frequent mutations on
HBV DNA and qHBsAg levels in HBeAg-negative chronic HBV-
The authors of the Editorial point out that our
data about qHBsAg levels
might be of clinical relevance, as the
qHBsAg seems not to be accurate enough in identifying inactive car-
riers, irrespective of their HBV genotype. Indeed, in our study
qHBsAg levels vary significantly up to 1.4 log among the HBV geno-
types A-E. When applying the qHBsAg cut-off < 1000 IU/mL, which
has been implemented in the recent EASL guideline,
differences were observed between the genotypes, although rou-
tinely used test systems for HBsAg detection offer a high sensitivity
irrespective of the genotype.
While only the minority of HBV geno-
type E- and A-infected patients (13% and 18%, respectively) had
qHBsAg levels < 1000 IU/mL, significantly more genotype B- and D-
infected patients (68% and 49%, respectively) had levels below this
cut-off. Our findings are in line with the mentioned Spanish study in
which also significant genotype-dependent differences in qHBsAg
levels were observed in HBeAg-negative patients.
The authors of
this study suggested that genotype-specific cut-offs might increase
the diagnostic accuracy of qHBsAg for inactive carrier discrimination.
This appears as a reasonable approach, however, one limitation
might be that (expensive) genotype testing has to be performed for
accurate interpretation in this large patient population. But geno-
type-dependent differences have to be considered also in other clini-
cal situations, as qHBsAg cut-offs were validated as prognostic
factors for the risk of HCC development
and for predicting treat-
ment response to therapy with pegylated interferon and with
However, another important task must be to evaluate and
understand the molecular virology leading to the genotype-depen-
dent differences in qHBsAg levels as this might also affect new
treatment concepts for HBV and possibly also for HBV/Hepatitis
delta (HDV) coinfection as HDV uses HBsAg for its envelope.
More than 10 years ago Sugiyama et al reported in vitro data about
genotype-dependent differences in HBsAg secretion in different
HBeAg-positive HBV genomes,
which is in line with more recent
in vitro studies.
We observed in another in vivo study that also
the composition of secreted HBsAg regarding the relative amounts
of the different surface proteins (small, middle and large HBsAg) is
strongly HBV genotype-dependent in HBeAg-negative chronic HBV
This is reflected by genotype-dependent differ-
ences in the morphology and the particle-type of the secreted sub-
viral particles (SVPs), which harbour most of the secreted HBsAg.
Because the two forms of SVPs (filaments and spheres) are
secreted via different cellular pathways, these observations reflect
most probably also genotype-dependent differences in the cellular
assembly and secretion process of SVPs.
However, HBsAg loss as
a functional cure is the main treatment goal and several novel anti-
viral strategies for HBV and HBV/HDV coinfection target HBsAg.
Therefore, it might be useful for the development of future anti-
viral strategies to further explore genotype-specific differences in
The authors’ declarations of personal and financial interests are
unchanged from those in the original article.
© 2018 John Wiley & Sons Ltd