• Discontinuation of NUC before HBsAG loss is feasible in patients with HBeAg- Negative Chronic Hepatitis B (CHB). Around 20% of patients achieve HBsAg loss after 2-3 years of follow up.  Sustained virologic response ± HBsAg loss was noted in 20-30% of patients,and ~40% CHB patients required re-treatment. (Lampertico P and Berg T, 2018)
• There are prospective Randomised Controlled Trials (RCT) looking at stopping long-term NA therapy,examples include the DARING-B and FINITE Study.The RCTs noticed undetectable HBcrAg and/low qHBsAg at the time of stopping,indicating lower relapse risk and increased chance of HBsAg loss.(Papatheodoridis) (Van Bommel) (Hsu) (Seto)
• HBV RNA and HBcrAg may be useful biomarkers . A study looked at using Pre-genomic HBV RNA (pgRNA) and HBcrAg to predict outcomes in HBeAg negative patients who discontinue NUC before HBsAg loss,observing severe ALT flares after NA cessation exclusively in patients with a detectable HBcrAg in the serum at the time of NUC discontinuation. (100% specificity 100% positive predictive value (PPV)). 

• pgRNA was detected in 3 out of 4 patients who subsequently developed a severe ALT flare. (100% specificity, 100% PPV, 75% sensitivity) (Carey, 2020)
• Low HBsAg levels at EOT consistently show to predict favourable outcomes. When NUC is stopped at HBsAg < 103 IU/mL, subsequent off-treatment HBsAg loss is 20-30%, comparing to off­ treatment HBsAg loss at <10% when HBsAg levels were 103 – 104 IU/mL. (Berg T and Lampertico P,2021)
• New Anti-HBV strategies are needed to foster HBsAg decline in untreated and NUC treated patients.

• HBsAG loss is the new treatment end point for CHB. A study with 5409 CHB patients on entecavir (ETV) observed that HBsAg seroclearance group had higher transplant-free survival (Hazard Ratio (HR)=0 .10) and lower incidence of HCC. (Kim GA.1 2014) Another meta–analysis of 190,000 CHB patients also observed HBsAg loss is associated  with improved patient outcomes, with relative risk (RR) of transplant/death being 0.22, and RR of HCC being 0.30. (Anderson, 2020)
• In recent years, there has been a focus of combining novel therapies (antigen reduction, replication inhibition immune stimulation) to combat HBV infection. Capsid Assembly Modulators (CAMS) are a new class of direct antivirals in research now, and a 2-3 log reduction in HBV DNA with no change in HBsAg levels was observed in 28 days dosing. However, CAMS + ETV resulted in a further 1 . 5 log reduction in HBV DNA, concluding that CAM + NUC intensifies viral suppression.(SHCJune 2021)
• There are studies focusing on the use of siRNAs and Antisense Oligonucleotides (ASOs) to reduce HBV antigen burden. A study by Gane in 2019 noted that by 12 weeks of treatment, there was a 1.5  log reduction in HBsAg. 

• But will HBsAg reduction restore HBV-specific immunity? An animal study of siRNA in transgenic mice with high HBsAg titers concluded that 3 log drop in HBsAg was not associated with immune restoration. (Michler T, 2020)
• This then lead to a study with mouse models with high HBsAg titers receiving siRNA and an immunotherapeutic vaccine. Overall, there was an increase in HBsAg reduction, with all animal models achieving HBsAg loss and restoration of CD4+, CD8+ and humoral immune responses. (Michler T, 2020) This suggests that HBV antigen suppression is needed for immune induction by therapeutic vaccine.

Low Dose Steroids

• HBV reaction is observed in CHB patients receiving corticosteroid,with 91.7% experiencing at least 1 log increase in serum HBV DNA at 12 months. (Wong G, 2018) The 1-year cumulative incidence of hepatitis flares after receiving corticosteroid is 7.8% at 12 months.
• A study analyzed the risk of infectious complications in patients taking corticosteroids. Data pooled from 71 controlled trials concluded that there is no increased risk of infection in patients taking <10mg/day or a cumulative dose <700mg of prednisolone.(Audreas E, 1989) Another study looking at long-term low-dose steroid (<10mg/day) for over 4 weeks in 145 Rheumatoid Arthritis (RA) patients concluded that there was no effect of low dose steroids on HBV Reactivation. (Jeong WS, ACR/ARHP Meeting)

New Biologics

• There is a low risk of HBV reactivation in patients with resolved Hepatitis B receiving Ritiuximab for RA. 21% patients had >50% increase in anti-HBs levels,0% seroreverted to HBsAg,and 3% patients became HBV DNA positive (Varisco V.J Rheutology)

• A study looked at HBV reactivation in patients treated with Tumour Necrosis Factor (TNF) antagonists. 39% of patients who were HBsAg positive experienced HBV reactivation, and 5% patients who had experienced resolved HBV infection had HBV reactivation.
• Risk stratification for HBV reactivation in RA patients receiving biological therapy is required. Screening and prevention for HBV reactivations are in place for patients planned for Biological therapy.

Prof. Henry Chan

• Commercial assays (Architect platform and Elecsys) for qHBsAg are now available for routine practice, and highly corelate (r=0.96) (Sonneveld MJ, 2011).
• HBV DNA quantification alone is not always able to identify inactive carriers. The combination of HBsAg and HBV DNA levels can identify inactive carriers. (HBsAg level < 1000 IU/mL + HBV DNA level <2000 IU/mL) This has been confirmed with PPV>87% in studies by Brunetto (2010), Manesis (2010), Martinot-Peignoux (2011).
• The combination of HBsAg and HBV DNA can also predict HBsAq clearance. In patient group where HBV DNA was ≤ 2000 IU/mL and HBsAg was ≤1000 IU/mL, HBsAg seroclearance after 5 years was 9%. Using a lower HBsAg quantity of <100IU/mL, seroclearance rate was 18.2% at 5 years. (Chan HL, 2011
• A Systematic Review on 11studies (1716 patients), concluded that end of treatment HBsAg cut off at 100 IU/mL best predicts HBsAg loss of 21.1-58.8% vs 3.3%-7.4% when HBsAg >100 IU/mL (Liu J, 2019).

Prof. Robert Gish

• HBsAg loss is associated with better outcomes: less cirrhosis, HCC and mortality. Low HBsAg (<1000 IU/mL) is able to distinguish between true
  inactive and active HBeAg-negative CHB in natural history. Moreover, low HBsAg is the best predictor for relapse after NA discontinuation.
• Cost of qHBsAg test averages at 37 USD across 24 responders, from 1-150 USD. Standardizing and normalizing the cost to the GDP of a country, makes it more affordable and accessible.
• A Provider Survey on the Global Use of qHBsAg found that in 43 responders from 24 countries, it is available to 29 responders, and 24 responders use it routinely. The main highlight was 41/43 responders would use it if recommended by guidelines. Therefore, the lack of inclusion by guidelines supports the argument that qHBsAg is not ready for routine practice.
• Recommendations about qHBsAg are still not in AASLD, EASL & APASL guidelines.