Unrevealing the natural course of the so-called "inactive HBsAg or HBV carrier state".

When hepatitis B surface antigen (HBsAg), originallynamed ‘‘Australia antigen,’’ was discovered in the 1960s[1, 2], its link with viral hepatitis could not be recognizedfor some time, since most individuals carrying this antigenhad little if any evidence of underlying hepatitis. Then,following the identiﬁcation of its association with viralhepatitis in 1967 and 1968 [3, 4], the glossary was modiﬁedfrom Australia antigen to Hepatitis Associated, SerumHepatitis, Hepatitis B antigen, and ﬁnally to HBsAg.However, regardless of the terms used, all evidence gath-ered over the years has clearly supported the view thatmany HBsAg-positive individuals harbor normal or nearlynormal liver enzymes (alanine/aspartate aminotrasferase,ALT/AST) and have little if any liver damage [5–8].Therefore the terms ‘‘healthy,’’ ‘‘asymptomatic,’’ and‘‘inactive’’ carriers of HBsAg, or of hepatitis B virus(HBV) have been introduced, to distinguish such individ-uals from patients with chronic viral hepatitis B. In supportof this concept were also the ﬁndings of serological testingfor hepatitis B e antigen (HBeAg) and its correspondingantibody (anti-HBe) by sensitive radioimmunossay (RIA)methods [9] and the immunohistochemical observations onthe expression of HBV proteins in the liver. Thus, serumHBeAg and liver hepatitis B core antigen (HBcAg), twomarkers of HBV replication, were reported to be negativein these carriers [10] while liver histology was essentiallynormal but with numerous ‘‘ground-glass’’ hepatocytesexpressing abundant hepatitis B surface proteins [11–13]from viral sequences integrated into their genome [12];however, HBcAg expression was clearly negative [14, 15].The wide acceptance of the view that HBsAg-positivepersons who are HBeAg-negative and anti-HBe positivehave inactive HBV infection without associated liver dis-ease dominated worldwide for many years and subse-quently led to doubts on whether HBeAg-negative chronichepatitis B (CHB) described from the early 1980s [16] wasreally existent or not and if it could actually be attributed toHBV replication. Moreover, in clinical practice HBsAg-positive individuals, labeled as healthy or inactive ‘‘carri-ers,’’ attracted little interest and only few investigatorsworldwide took their time to follow-up such carriers pro-spectively. However, with the introduction in clinical re-search of molecular hybridization and polymerase chainreaction (PCR) techniques, HBV cloning and sequencing,and the discovery of replication-competent HBeAg-nega-tive HBV mutants [17], it was soon realized that HBeAg-negativity/anti-HBe-positivity with normal ALT levels isneither synonymous with absence of HBV replication andof HBV-induced liver damage nor it represents a perma-nent, life-lasting condition. Thus the term ‘‘inactiveHBsAg carrier state’’ rather than ‘‘inactive HBV carrier’’has been widely applied and is still recommended in recenthepatitis B guidelines [18–20].Currently, it is generally perceived that the inactiveHBsAg carrier state represents the third phase in the naturalcourse of chronic HBV infection. It follows a previous,immunologically active, phase of HBeAg-positivity withreplicating HBV and increased ALT activity, during whichHBeAg clears and anti-HBe develops [21, 22]. This phasemay remain stably inactive and even ﬁnish in resolution ofHBV infection with clearance of HBsAg and development