Despite the availability of effective
vaccines and
antiviral therapy over the past two to three decades,
chronic hepatitis B virus (HBV)
infection remains a major global health threat as a leading cause of
cirrhosis and
liver cancer. Functional HBV cure defined as
hepatitis B surface antigen (
HBsAg) loss and undetectable serum HBV
DNA is associated with improved clinical outcomes in patients with chronic HBV
infection. However, spontaneous loss of
HBsAg is rare and occurs in only 1% of all
HBsAg-positive individuals annually. Furthermore, the rate of functional cure with currently available
antiviral therapy is even lower, <1% patients on treatment per year. Nonetheless,
HBsAg loss has become the new target or therapeutic endpoint for
antiviral treatment. Recently, there has been much excitement surrounding the development of novel
antiviral agents such as
small interfering RNA (
siRNA), core assembly modulators (CAMs),
nucleic acid polymers (
NAPs) among others, which may be used in combination with nucleos(t)ide analogs and possibly
immunomodulatory therapies to achieve functional cure in a significant proportion of patients with
chronic hepatitis B. Novel assays with improved sensitivity for detection of very low levels of
HBsAg and to determine the source of
HBsAg production will also be required to measure efficacy of newer
antiviral treatments for HBV cure. In this narrative review, we will define HBV cure, discuss various sources of
HBsAg production, evaluate rates of
HBsAg loss with current and future
antiviral agents, review clinical factors associated with spontaneous
HBsAg loss, and explore clinical implications of functional cure.