Hepatitis B virus reactivation during immunosuppressive therapy: Appropriate risk stratification

Our understanding of hepatitis B virus (HBV) reactivation during immunosuppresive therapy has increased remarkably during recent years. HBV reactivation in hepatitis B surface antigen (HBsAg)-positive individuals has been well-described in certain immunosuppressive regimens, including therapies containing corticosteroids, anthracyclines, rituximab, antibody to tumor necrosis factor (anti-TNF) and hematopoietic stem cell transplantation (HSCT). HBV reactivation could also occur in HBsAg-negative, antibody to hepatitis B core antigen (anti-HBc) positive individuals during therapies containing rituximab, anti-TNF or HSCT.For HBsAg-positive patients, prophylactic antiviral therapy is proven to the effective in preventing HBV reactivation. Recent evidence also demonstrated entecavir to be more effective than lamivudine in this aspect. For HBsAg-negative, anti-HBc positive individuals, the risk of reactivations differs with the type of immunosuppression. For rituximab, a prospective study demonstrated the 2-year cumulative risk of reactivation to be 41.5%, but prospective data is still lacking for other immunosupressive regimes. The optimal management in preventing HBV reactivation would involve appropriate risk stratification for different immunosuppressive regimes in both HBsAg-positive and HBsAg-negative, anti-HBc positive individuals.     

Stability of hepatitis B surface antigen over time: implications for studies using stored sera

In chronic hepatitis B, quantitative measurements of hepatitis B surface antigen (HBsAg) have been studied increasingly using stored sera to determine its usefulness in disease management. However, the stability of stored HBsAg levels has not been established. The current study determines prospectively the stability of HBsAg levels in sera stored for 1 year. Fresh sera from 105 samples were divided into 5 aliquots. The first aliquot was used to determine HBsAg at the time of blood sampling. The remaining four aliquots were stored at -20°C and thawed at 3, 6, 9, and 12 months to determine the HBsAg levels. HBsAg was measured by adopting the research protocol using the Elecsys HBsAg II assay. At baseline, age and HBV DNA showed a significant correlation with HBsAg levels (r = -0.291, P = 0.003 and r = 0.256, P = 0.003, respectively). There was no overall significant difference observed between the HBsAg levels measured at the different time points. There was high correlation between each consecutive time points from baseline to 3 months, 3-6 months, 6-9 months, and 9-12 months (r = 0.991, 0.987, 0.989, 0.993, respectively, all P < 0.001). The overall log difference in HBsAg levels between baseline and at 12 months was 0.03 (range, -0.29 to 0.85), with over 99% of samples showing no significant change (defined as >1 log) after 12 months. In conclusion, HBsAg levels remained stable in stored frozen sera for 12 months without significant changes, and could be used to quantify HBsAg accurately.     

Future prevention and treatment of chronic hepatitis B infection

Vaccination for hepatitis B virus (HBV) infection and treatment for chronic hepatitis B, while effective for primary prevention and control of the disease, still have their limitations. Global coverage of HBV immunization needs improvement. Several patient populations are noted to have suboptimal seroprotective rates after HBV vaccination. There are currently several potential new vaccines undergoing animal and human studies, most notably vaccines containing immunostimulatory DNA sequences. Long-term nucleoside analogue therapy is necessary in achieving permanent virologic suppression. Potential new treatments explore new mechanisms of action, including the inhibition of hepatitis B surface antigen release, targeting antifibrotic mechanism, and immunomodulation through novel interferons and therapeutic vaccines. The clinical application of potential new vaccines and therapies would enhance the prevention of HBV infection and treatment of chronic hepatitis B.     

Evidence of serologic activity in chronic hepatitis B after surface antigen (HBsAg) seroclearance documented by conventional HBsAg assay

Background

Possible serologic activity after hepatitis B surface antigen (HBsAg) seroclearance documented by conventional assays in chronic hepatitis B (CHB) has not been thoroughly investigated.

Methods

We determined the levels of serum hepatitis B virus (HBV) DNA, hepatitis B core-related antigen (HBcrAg), and linearized HBsAg (CLEIA prototype) in 329 CHB patients (72.0% male) after HBsAg seroclearance was documented by a conventional HBsAg assay.

Results

The median interval between presentation and HBsAg seroclearance was 69.4 months. The median age at HBsAg seroclearance was 50 years. Assays for serum HBV DNA, HBcrAg, and linearized HBsAg were performed at a median time interval of 11.2 months after HBsAg loss. Linearized HBsAg and HBcrAg were detectable in 85 (25.8%) and 69 (21%) patients, respectively, and one or both serologic markers were detectable in 133 patients (40.4%). Serum HBV DNA was detectable in only 7 patients (2.1%). There was no correlation between linearized HBsAg and HBcrAg levels (r = 0.095, p = 0.924). The incidences of detectable linearized HBsAg and HBcrAg did not differ between patient samples taken at 6–12 and >12 months after HBsAg seroclearance (p = 0.146 and 0.079, respectively). Among patients with detectable serologic markers, median levels of linearized HBsAg (p = 0.581) and HBcrAg (p = 0.951) did not significantly change with time after HBsAg seroclearance.

Conclusion

Using novel HBcrAg and linearized HBsAg assays, viral serologic activity after HBsAg seroclearance was demonstrated in more than 40% of CHB patients. These tests have potential applications in diagnosing and prognosticating CHB patients with HBsAg seroclearance.     

Novel developments of hepatitis B: treatment goals,agents and monitoring tools

Introduction: Chronic hepatitis B (CHB) infection causes considerable morbidity and mortality and hence should be a target for global elimination. In recent years, advances have been made in understanding the disease pathophysiology and the relationship to clinical outcome. Novel treatment targets are actively being sought in the hope of improving the treatment outlook.

Areas covered: We discussed the cascade of cure of CHB with respect to the degree of persistence of viral genome and proteins. Several novel antiviral agents either targeting the virus or the host are in different clinical phases of development. Serum hepatitis B core-related antigen and HBV RNA are novel markers, which might have a role in the prediction of specific clinical outcomes such as development of hepatocellular carcinoma or virological relapse after cessation of antiviral therapy. These markers may also be used to monitor treatment response in the drug trials.

Expert commentary: Global elimination of CHB is challenged by extremely low awareness of illness and poor access to care. CHB and its related complications can be reduced by birth dose vaccine, antiviral therapy, and alleviated by complication screening. Treatment options for CHB will expand in the next decade and early functional cure is not an impractical goal.     

Prevention of hepatocellular carcinoma in chronic viral hepatitis B and C infection

Hepatocellular carcinoma(HCC)is a leading cause of cancer-related mortality worldwide,with the majority of cases associated with persistent infection from hepatitis B virus(HBV)or hepatitis C virus(HCV).Natural history studies have identified risk factors associated with HCC development among chronic HBV and HCV infection.High-risk infected individuals can now be identified by the usage of risk predictive scores.Vaccination plays a central role in the prevention of HBV-related HCC.Treatment of chronic HBV infection,especially by nucleoside analogue therapy,could also reduce the risk of HBV-related HCC.Concerning HCV infection,besides the advocation of universal precautions to reduce the rate of infection,pegylated interferon and ribavirin could also reduce the risk of HCV-related HCC among those achieving a sustained virologic response.Recently there has been mounting evidence on the role of chemopreventive agents in reducing HBV-and HCV-related HCC.The continued advances in the understanding of the molecular pathogenesis of HCC would hold promise in preventing this highly lethal cancer.     

Reduction of liver stiffness following resolution of acute flares of chronic hepatitis B

Background  

Measuring liver stiffness is becoming more popular as a non-invasive tool for assessing liver fibrosis.