Case of hepatitis B virus reactivation after ibrutinib therapy in which the patient remained negative for hepatitis B surface antigens throughout the clinical course

A 71-year-old man was diagnosed with B-cell chronic lymphocytic leukemia. He was negative for hepatitis B surface antigen (HBsAg), positive for antibodies against the hepatitis B surface and core, and negative for hepatitis B virus (HBV)-DNA before starting chemotherapy. A total of 13 months after the initiation of ibrutinib (a Bruton's tyrosine kinase inhibitor), the patient's alanine aminotransferase levels suddenly increased to 427 U/L. As the level of serum HBV-DNA increased to 5.2 logIU/mL, a diagnosis of HBV reactivation was made, whereas the patient remained negative for HBsAg. The patient's serum alanine aminotransferase levels normalized after the initiation of entecavir at a dose of 1 mg/day. However, it took >1 year to achieve an undetectable level of HBV-DNA, even with an add-on therapy of tenofovir disoproxil fumarate. Interestingly, the patient remained negative for HBsAg throughout the clinical course owing to triple HBsAg escape mutations: Q101K, M133L, and G145A.     

Novel strategies for the early diagnosis of hepatitis B virus reactivation

Hepatitis B virus (HBV) reactivation under systemic chemotherapy or immunosuppressive therapy is a serious complication among HBV-resolved patients. Some medications, such as more than 2 weeks of corticosteroid therapy, can influence HBV reactivation; therefore, screening tests that measure hepatitis B surface antigen (HBsAg), hepatitis B core antibody, and hepatitis B surface antibody before therapy are required. Additionally, because HBV reactivation has been reported in patients positive for HBsAg treated with immune checkpoint inhibitors (ICIs), the prophylactic administration of nucleos(t)ide analogues prior to administering ICIs is recommended for HBsAg-positive patients. Under these circumstances, highly sensitive novel biomarkers are expected to be used for the early diagnosis of HBV reactivation. A fully automated high-sensitivity HBsAg assay (detection limit: 5 mIU/ml) by Lumipulse HBsAg-HQ, with 10-fold higher sensitivity than that of conventional assays, is currently used. Furthermore, ultra-sensitive HBsAg assays using a semi-automated immune complex transfer chemiluminescence enzyme immunoassay (ICT-CLEIA; detection limit: 0.5 mIU/ml) have been developed. Recently, a fully automated, novel high-sensitivity hepatitis B core-related antigen assay (iTACT-HBcrAg; cut-off value: 2.1 Log U/mL) has been developed and reported. The utility of ICT-CLEIA and iTACT-HBcrAg for the diagnosis of HBV reactivation appears comparable to the use of HBV DNA. In this review, we provide the latest information related to medications that influence HBV reactivation and recently developed novel biomarkers that predict and monitor HBV reactivation.     

Unexpected hepatitis B virus transmission after liver transplant from nucleic acid testing- and serology-negative liver donors who are hepatitis C viremic

The opioid epidemic has led to increased availability of organs for liver transplantation. The success of direct-acting antiviral therapy for hepatitis C (HCV) has led to the acceptance of HCV viremic donor organs. Nucleic acid testing (NAT) has led to increased detection of HCV and hepatitis B (HBV) in potential donors. A total of 36 patients underwent liver transplantation from donation after brain death donors who were HCV NAT-positive, and three of them were diagnosed with HBV several months after. All three recipients received livers from HCV viremic donors who were negative for HBV by serology and NAT. Soon after liver transplantation, HCV was treated, and all achieved sustained virologic response. They became HBV DNA-positive shortly thereafter. To date, there have been no reported cases of unexpected HBV transmission since universal donor NAT was implemented in 2013. We postulate that the inhibitory effect of HCV viremia on HBV may have prolonged the “NAT window period” in these donors beyond the 20–22 days quoted for solitary HBV infection. These cases highlight the need for more intensive and prolonged screening for HBV in recipients of livers from HCV viremic donors.     

Discordance of hepatitis B vaccination policies for healthcare workers between the USA,the UK,and Germany

The hepatitis B (HB) vaccine is effective for the prevention of HB virus infection. It has been widely accepted that an anti‐HB surface antibody (HBs) level ≥10 mIU/mL is protective against HB virus infection. Although transient infection can occur in individuals who attain a peak level of anti‐HBs ≥10 mIU/mL after primary vaccination, long‐term follow‐up studies show that successful primary vaccination can prevent individuals from acute clinical hepatitis and chronic infection. Healthcare workers (HCWs) are at‐risk individuals. Based on the accumulated data, the USA considers an anti‐HBs level ≥10 mIU/mL to constitute successful vaccination for HCWs. In contrast, because some anti‐HBs assays cannot accurately measure in the low anti‐HBs range, including 10 mIU/mL, the UK and Germany consider an anti‐HBs level ≥100 mIU/mL to constitute successful vaccination for HCWs. In the USA and UK, a booster dose is unnecessary for HCWs after successful vaccination. In Germany, anti‐HBs testing is recommended for HCWs who are at particularly high individual exposure risk 10 years after successful primary immunization, and a booster dose is offered if the anti‐HBs level has declined to ?100 mIU/mL. The differences in the goal of HB vaccination, reliability of anti‐HBs assays, and use of booster vaccination cause discordance in HB vaccination policies for HCWs.     

Comparison between quantitative hepatitis B surface antigen,hepatitis B e‐antigen and hepatitis B virus DNA levels for predicting virological response to pegylated interferon‐α‐2b therapy in hepatitis B e‐antigen‐positive chronic hepatitis B

Aim: The aim of this study was to compare the clinical applicability of quantitative serum hepatitis B surface antigen (HBsAg), hepatitis B e‐antigen (HBeAg) and hepatitis B virus (HBV) DNA for predicting virological response (VR) to pegylated interferon (PEG‐IFN) therapy. Methods: Thirty HBeAg‐positive chronic hepatitis B patients who received PEG‐IFN‐α‐2b for 48 weeks were enrolled. Quantitative HBsAg, HBeAg and HBV DNA were measured before, during and after the therapy. Paired liver biopsies were performed before and after treatment for covalently closed circular (ccc)DNA and intrahepatic HBV DNA analysis. Results: VR at 48 weeks post‐treatment, defined as HBeAg seroconversion and HBV DNA less than 10 000 copies/mL was achieved in 10 (33.3%) patients. Responders had significantly lower baseline HBsAg, HBeAg, cccDNA and intrahepatic HBV DNA levels than non‐responders. Baseline and reduced levels of log₁₀ HBsAg and log₁₀ HBeAg correlated well with those of log₁₀ cccDNA and log₁₀ total intrahepatic HBV DNA. Responders showed consistent decrease in serum HBsAg, HBeAg and HBV DNA levels during therapy. HBeAg level of 2.0 log₁₀ sample to cut‐off ratio at week 24 on therapy provided the best prediction of sustained virological response, with sensitivity and negative predictive values of 85% and 92%, respectively. One patient (3.3%) who cleared HBsAg at follow up exhibited a more rapid decline in serum HBsAg during therapy than those who developed VR without HBsAg clearance. Conclusion: Quantitative measurement of serum HBeAg during therapy may be superior to serum HBsAg and HBV DNA as a prediction of HBeAg seroconversion. Kinetics of HBsAg levels on therapy may help predict HBsAg clearance after treatment.     

Predictors of sustained functional cure in hepatitis B envelope antigen‐negative patients achieving hepatitis B surface antigen seroclearance with interferon‐alpha–based therapy

Hepatitis B surface antigen (HBsAg) loss is considered a functional cure in chronic hepatitis B (CHB). However, the durability of HBsAg loss after stopping treatment remains unknown. This study aimed to assess the sustained functional cure achieved by interferon therapy in hepatitis B envelope antigen (HBeAg)‐negative CHB patients. In this prospective study, 176 HBeAg‐negative CHB patients with functional cure were enrolled for 12 weeks of cessation treatment, and treatment information and baseline data were collected. Hepatitis B virus (HBV) biomarkers and clinical biochemical indicators were evaluated every 3 months; liver imaging examinations were performed every 3‐6 months during the 48‐week follow‐up. The sustained functional cure was evaluated. After the 48‐week follow‐up, the sustained functional cure rate was 86.63%. The cumulative rates of HBsAg reversion and HBV DNA reversion were 12.79% and 2.33%, respectively. Consolidation treatment ≥ 12 weeks after HBsAg loss achieved a significantly higher rate of sustained functional cure and significantly lower rate of HBsAg reversion than consolidation treatment < 12 weeks (76.19% vs 90.00%, P = 0.022 and 23.81% vs 9.23%, P = 0.014, respectively). Patients with hepatitis B surface antibody (HBsAb) had higher rate of sustained functional cure than patients achieving HBsAg loss but without HBsAb (89.86% vs 73.53%, P = 0.012). Consolidation treatment ≥ 12 weeks (odds ratio [OR] 16.478; 95% confidence interval [CI], 2.135‐127.151; P = 0.007) and high HBsAb levels (OR 8.312; 95% CI, 1.824‐37.881; P = 0.006) were independent predictors of sustained functional cure. Results suggested that 12 weeks of consolidation therapy after HBsAg clearance and elevated HBsAb levels help to improve functional cure.