Elimination of Hepatitis B: Is It a Mission Possible?
© The Author(s). 2017
Received: 9 December 2016
Accepted: 16 February 2017
Published: 15 March 2017
Chronic hepatitis B virus (HBV) infection is a global public health issue. Although the disease cannot be cured effectively, disease management has been improved over the past decade. The introduction of potent nucleos(t)ide analogues (NAs) to suppress viral replication represented a giant leap in the control of this disease. It has been shown that tenofovir treatment, a potent NA, complements current immunoprophylaxis to diminish mother-to-infant transmission in pregnant women with a high viral load. For patients with chronic HBV infection, quantitative hepatitis B surface antigen is a useful tool to define inactive carriers and to guide antiviral therapy. Quantification of HBV mutants is also useful in predicting long-term outcomes more precisely than ever. The next challenge is how to achieve an HBV cure; although immunotherapy is a promising strategy, the current results from two clinical trials using therapeutic vaccines to induce HBV-specific immune response in patients with chronic HBV infection are disappointing. In the coming years, we are expecting to see a combination of therapeutic agents with various modes of action to complete the mission of HBV elimination.
KeywordsHBV Chronic hepatitis B HBsAg Immunotherapy
Chronic hepatitis B virus (HBV) infection continues to be a major global public health issue despite the availability of effective HBV vaccines for over three decades. Recent data estimated that more than 240 million individuals worldwide are positive for hepatitis B surface antigen (HBsAg) . Several viral, host, and environmental factors have been identified in subjects who are at increased risk of developing liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC) .
Although HBV has been discovered for more than half a century, a cure for chronic hepatitis B (CHB) remains a challenging task . Currently approved antiviral treatments for CHB include nucleos(t)ide analogues (NAs) and interferon. NAs effectively suppress HBV replication to undetectable levels through inhibition of viral reverse transcriptase. However, rebound of viremia frequently occurs after discontinuation of NA, primarily because of the persistence of the active transcriptional template of HBV covalently closed circular DNA (cccDNA). In contrast, interferon is known to have a dual effect – direct suppression of viral replication and indirect enhancement of host immunity against the virus. Nevertheless, the overall viral response rate of 30% to interferon is far from satisfactory. In this minireview, recent advances of HBV management and strategies to eliminate HBV will be summarized and discussed.
Management of patients with CHB
Role of quantitative HBsAg in predicting HCC development and treatment response
The application of qualitative HBsAg in the clinical management of CHB patients has been increasingly adopted . It is generally believed that serum HBV DNA level is a major driver of disease progression in CHB patients . In particular, patients with serum HBV DNA levels ≥ 2000 IU/mL at study entry have an increased risk of developing HCC over time. In contrast, those with HBV DNA levels < 2000 IU/mL are usually designated as low viral load patients. Data from two independent cohorts from Taiwan consistently showed that serum HBsAg levels of 1000 IU/mL could stratify different HCC risks in patients with low viral loads [6, 7]. In addition to HCC risks, a lower serum HBsAg level (<1000 vs. > 1000 IU/mL) has also been shown as an indicator of lower risk of viral relapse, hepatitis B e antigen (HBeAg)-negative hepatitis, and cirrhosis development in CHB patients [8–11]. These emerging data infer that we may define minimal-risk HBV carriers by combining low viral load (<2000 IU/mL) and low HBsAg level (<1000 IU/mL) . Another clinical usefulness of quantitative HBsAg is to guide physicians regarding cessation of antiviral therapy. Serum HBsAg levels > 20,000 IU/mL at week 24 of treatment are used to predict non-responders in HBeAg-positive patients receiving 12-month pegylated interferon therapy . In addition, quantitative HBsAg may predict who can maintain a sustained viral response after stopping NA treatment [13–15]. Although the reported HBsAg cutoff levels ranged from 10 to 150 IU/mL, the data consistently showed that the lower the HBsAg level, the lower the risk of viral and clinical relapse. Further large-scale prospective studies are needed to define a reliable HBsAg cutoff level for identification of CHB patients who can cease NA treatment safely.
Role of quantitative viral mutants in predicting different clinical outcomes
Quantification of HBV variants and its clinical application
Nie et al. 
Yang et al. 
Tseng et al. 
Bayliss et al. 
Selective inhibitory polymerase chain reaction
Next generation sequencing
PC (G1896A) & BCP (A1762T/G1764A) mutants
PC (G1896A) & BCP (A1762T/G1764A) mutants
BCP mutants (A1762T/G1764A)
HBV whole genome
Sensitivity to detect minor strains
18 HBeAg-positive patients
203 HBeAg-positive patients receiving interferon-based treatment
151 HBeAg-negative patients with a median follow-up period of 9 years.
157 HBeAg-positive patients receiving 4-year tenofovir treatment
Levels of PC and BCP mutants may predict the time of HBeAg seroconversion
Quantitative analysis of PC and BCP mutants can predict interferon-induced
A higher percentage of BCP mutant is associated with higher risks of cirrhosis development
Detectable BCP or PC mutants are associated with a lower probability of HBsAg loss during tenofovir therapy.
Strategies to eliminate HBV
Combination of TDF and immunoprophylaxis to minimize mother-to-child transmission (MTCT) of HBV
Summary of 2 clinical trials using tenofovir to reduce mother-to-infant transmission on top of standard immunoprophylaxis
Chen et al. 
Pan et al. 
Prospective non-randomized control trial
Prospective randomized control trial
No. of mother
TDF (N = 92), Control (N = 56)
TDF (N = 97), Control (N = 100)
TDF vs. Control
TDF vs. Control
Time of intervention
30–32 weeks of gestation
30-32 weeks of gestation
Maternal viral load
Maternal HBeAg-positive rate
Mother-to-infant transmission rate
TDF (1.54%) vs. Control (10.71%), P = 0.0481*
Intention-to-treat analysis: TDF (5%) vs. Control (18%), P = 0.007**
Per-protocol analysis: TDF (0%) vs. Control (7%), P = 0.01
The possible mission of functional cure for HBV
Potent NA treatment has improved the management of CHB infection over the past decade . Prolonged NA treatment has halted disease progression and halved the HCC incidence in CHB patients who have already developed liver cirrhosis [33–35]. The next challenge is to achieve functional HBV cure and the development of new agents with various modes of action is urgently awaited. In the clinical practice, additional unmet needs should also be addressed. The first is to identify patients who require HCC surveillance. Previous studies have indicated that approximately 25–40% of patients with CHB infection will develop HCC in their lifetime, and therefore HCC surveillance is indicated . Although prediction of HCC is difficult, it is possible to identify true inactive HBV carriers who are at the lowest risk of HCC development by combining multiple host, viral, and liver fibrosis markers. The current criteria to define inactive carriers include normal ALT level, negative HBeAg, HBV DNA < 2000 IU/mL, and HBsAg < 1000 IU/mL; their HCC risk is comparable to that of the normal population . The possibility of further reduction of HCC risks by including biomarkers, such as a liver biomarker indicating early liver fibrosis stage, along with the current criteria should be explored.
The second issue to be addressed is whether HCC development could be prevented by earlier initiation of NA treatment in CHB patients. Most of the evidence of HCC risk reduction comes from prolonged NA treatment in patients with HBV-related liver cirrhosis [33–35]. However, all studies show that HCC still develops during long-term NA therapy. This fact may suggest HCC development is inevitable once advanced liver fibrosis has occurred. Further evidence has been provided by the recent finding that the integration of the HBV genome into the host chromosome, which is considered as an oncogenic event, could be detected at the early stage of chronic infection . Collectively, it is conceivable to achieve an HCC-free era through early initiation of NA therapy before emergence of significant fibrosis or massive viral genome integration. This may be implemented into practice by widening the therapeutic target of HBV carriers and earlier identification using more comprehensive screening. This strategy may provide an alternative method to eliminate HCC risk before curing HBV. However, this concept needs to be proved by clinical studies.
Various measures, including universal hepatitis B vaccination and interruption of transmission routes, are required to reach the ultimate goal of global HBV eradication. Potent NA treatment has remarkably improved the prevention of MTCT and management of CHB. We are expecting to see less disease progression and less HCC development in CHB patients following initiation of prolonged NA therapy. However, the current armamentarium does not completely clear HBsAg, and new combination treatment modalities are needed to achieve a functional HBV cure in the near future, hopefully by the year 2030 .
Covalently closed circular DNA
Chronic hepatitis B
Cytotoxic T cell
Hepatitis B e antigen
Hepatitis B surface antigen
We thank Miss Shin-Hwa Yu for drafting the figure and grant support from Liver Disease Prevention & Treatment Research Foundation, Taiwan.
This work was supported by the grants from the Ministry of Science and Technology, Executive Yuan, Taiwan (MOST 105-2314-B-303-008).
T-CT drafted the manuscript. J-HK provided important intellectual content. Both authors read and approved the final manuscript.
J-HK is consultant for Abbvie, Bristol-Myers Squibb, and Gilead Sciences; on speaker’s bureau for Abbvie, Roche, Bristol-Myers Squibb, Gilead Sciences, and Novartis. T-CT declares no competing interests.
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