Accordingly, a decline of HBV-DNA means reduction of HBV replication. In contrast, HBsAg can be derived from both mature virions and defective particles. Thus serum HBsAg level not only reflects the cccDNA transcription

or mRNA translation, but also host immune control over HBV infection.[54, 55] The relationships between qHBsAg, intrahepatic HBV-DNA, and serum HBV-DNA concentration have been analyzed recently. In HBeAg-positive CHB, qHBsAg positively correlated with intrahepatic HBV-DNA and serum HBV-DNA concentration.[56, 57] On the contrary, qHBsAg correlated poorly with serum HBV-DNA and did not correlate with intrahepatic screening assay HBV-DNA in HBeAg-negative CHB.[57] With regard to clinical phenotypes, qHBsAg was much higher in HBeAg-positive patients with immune tolerance and immune clearance phases than HBeAg-negative patients.[58, 59] An Italian study showed that the combination of qHBsAg < 1000 IU/mL and serum HBV-DNA level < 2000 IU/mL can predict inactive HBV carrier state with a positive predictive value of 88% and negative predictive value of 97% in HBV genotype D patients.[60] Our recent study also showed that low serum levels of HBsAg (< 100 IU/mL), alone or in combination with HBV-DNA levels, at 1 year after HBeAg seroconversion could

predict HBsAg loss in patients with HBV genotype B or C infection.[61] In addition, qHBsAg was better than serum HBV-DNA level for the prediction of spontaneous HBsAg loss in HBeAg-negative carriers with a low viral load (< 2000 IU/mL). HBsAg level < 10 IU/mL was the strongest predictor of HBsAg loss in patients with a low viral C1GALT1 load.[62] The earlier Trichostatin A manufacturer lines of evidence indicate that there exists a correlation between qHBsAg and liver disease progression. In the recent update of REVEAL-HBV study, qHBsAg was analyzed in 3411 HBV carriers. The results showed that both HBsAg and HBV-DNA levels are independent predictors of HCC development. The multivariate-adjusted HR of developing HCC increased significantly from 1.0 (reference) for serum levels of HBV-DNA (IU/mL)/HBsAg (IU/mL) of < 2000/< 100

to 9.22 (95% CI: 4.34–19.58) for serum levels of HBV-DNA (IU/mL)/HBsAg (IU/mL) of ≥ 2000/≥ 100.[63] Our hospital-based Elucidation of Risk Factors for Disease Control or Advancement in Taiwanese Hepatitis B Carriers (ERADICATE-B) study (Fig. 1) also showed similar findings. A total of 2688 non-cirrhotic Taiwanese CHB patients were followed for a mean of 14.7 years. HCC risk increased when patients had increased HBV-DNA level (HR: 4.7; 95% CI: 2.2–10.0), increased qHBsAg (HR: 7.2; 95% CI: 1.8–28.6), and elevated ALT level (HR: 6.6; 95% CI: 2.2–19.8).[64] Although the incidence of HCC is significantly associated with baseline serum HBV-DNA levels in a dose–response relationship,[6, 49, 64] inactive or low-risk HBV carriers (serum HBV-DNA levels < 2000 IU/mL) still have significantly higher HR for HCC compared with individuals without HBV infection (HR: 4.6; 95% CI: 2.5–8.3).