A great deal of progress on defining the use of qHBsAg clinically has been made over the last

two decades. A number of questions about the use of qHBsAg have been answered or partially
answered with emerging questions under active investigation in almost all new trials of evolving
medications (30 new drugs, 15+ pharma companies). Precise control mechanisms for HBsAg
production in HBV are being defined with both cytoplasmic mRNA, cccDNA templates and
integrated DNA as sources of HBsAg that are being defined and refined. A small discrepancy
between qHBsAg and serum HBV DNA exists with HBeAg (+) patients with a poorer
correlation with HBeAg(-) patients probably due to changes in the core and precore regions as
well as viral integrants. A historical correlation between cccDNA levels and HBsAg is being
discussed in the literature and relationships are being further defined. qHBsAg is commonly used
to help stage patients HBV status especially for indeterminate stages where ALT and HBV DNA
may be in the gray zone. qHBsAg status also helps with the prognosis of patients from two
perspectives: 1) levels often relate to risk for liver cancer and 2) risk for developing cirrhosis
when used in combination with other serological and viral factors. There are two well validated
assays available globally from Abbott-Architect and Roche-Elecsys that have test sensitivities as
low as 0.05 IU/ml. A greater research investment from industry and governments on the virology
and immunology of HBV and the control of HBV replication could help answer outstanding
questions. In addition, the role of qHBsAg in the clinical treatment field is been actively
investigated, and also used by many clinicians world-wide especially as a predictor to virologic
response to natural immune control and also for approved HBV therapies. Of particular interest
is the role of qHBsAg for predict non response to HBV therapies, especially interferon that is
ready now to be used in clinical practice with negative predictive values that exceed 90%.
Defining the end point of oral antiviral therapy is still being defined besides a binary +/measurable response is not sufficient to decide on who should stay on oral nucleos(t) therapy
long term and who should be stopped. Current American Association for the Study of Liver
Diseases and European Association for the Study of the Liver guidelines with respect to an end
point for therapy are clearly defining HBsAg clearance as the current best goal of therapy,
because reversion to HBeAg positivity does occur after terminating therapy, and the because loss
of HBsAg is infrequently encountered new therapies are needed. Importantly, qHBsAg might be
particularly helpful in patients with undetectable HBV DNA, even with a highly sensitive
polymerase chain reaction assay. In contrast to undetectable HBV DNA, which provides no
further information for the virologic responders and who should continue on monotherapy or be
considered for add-on treatment or in whom treatment discontinuation is advised. With HBsAg
continuously being shed and detected and, based on the observations of previous studies,
qHBsAg with serial monitoring in patients with undetectable HBV DNA may be utilized to
determine the end points of therapy and validate the durability of current and new antiviral
agents. Nevertheless, quantification of serum HBsAg is currently available commercially in
many countries and there is an opportunity to make maximal use of qHBsAg in clinical practice
today in combination with our laboratory, clinical and commercial factors. It is also important to
be familiar with HBsAg variants and their clinical consequences in terms of immune escape
mutants, and how these variant influence the qHBsAg assay. The time is ripe for full clearance
by all regulatory agency who oversee diagnostic testing for HBV to approve qHBsAg in the US
and globally.