Research ArticleRisk of hepatitis B surface antigen seroreversion after corticosteroid treatment in patients with previous hepatitis B virus exposure
Graphical abstract
Introduction
Chronic HBV infection remains a considerable global health problem despite vaccination.1 Approximately 2 billion people of the world population have been infected; an estimated 257 million people are living with HBV infection (defined as HBsAg positive).2 HBsAg seroclearance, which may occur either spontaneously or after antiviral treatment,[3], [4], [5] is currently regarded as the functional cure of chronic hepatitis B (CHB).[6], [7], [8] Neither disappearance of HBsAg in patients with CHB nor recovery from a self-limiting acute hepatitis B guarantees lifelong protection. Some patients may suffer from occult hepatitis B infection (OBI), a status of undetectable serum HBsAg yet detectable serum and/or intrahepatic HBV DNA.9 Past or resolved HBV infection may still lead to HCC, cirrhotic complications and liver-related death.[3], [4], [5]
HBV reactivation during chemotherapy or immunosuppressive therapy is a well-known phenomenon and a major concern as it may be complicated by fulminant hepatic failure and death.10 OBI reactivation may take place with increasing HBV DNA replication in patients during immunosuppression therapy.11 Among all immunosuppressive agents, corticosteroids are the most widely used in a spectrum of acute and chronic immune-mediated diseases.12 The degree of immunosuppression increases with dose and duration of treatment. A daily dose of prednisolone, or equivalent, above 20 mg for longer than 2 weeks is generally considered to induce clinically significant immunosuppression.13 The latest American Gastroenterological Association Institute (AGA) guideline on the prevention and treatment of HBV reactivation during immunosuppressive drug therapy defined HBsAg-positive patients treated with moderate-dose (10–20 mg prednisolone daily, or equivalent) or high-dose (>20 mg prednisolone daily, or equivalent) corticosteroids for ≥4 weeks as being at high risk of HBV reactivation.14 Nonetheless, our recent real-world cohort study showed that even a short course (less than 7 days) of high-dose corticosteroids might increase the risk of hepatitis flares.15
On the other hand, the risk of HBV reactivation in patients with OBI or previous HBV exposure is not as well established. A recent AGA technical review stated that prolonged courses (longer than 4 weeks) of moderate- to high-dose corticosteroids for >4 weeks may lead to HBV reactivation in 1%–10% of patients; whereas either short courses (short than 1 week) of high-dose corticosteroids or prolonged courses of low-dose corticosteroids only lead to reactivation in less than 1%.16 In this real-world territory-wide cohort study, we aimed to evaluate the impact of the duration and dosage of corticosteroids on the risk of hepatitis flare in patients with previous HBV exposure.
Section snippets
Study design and data source
We performed a retrospective territory-wide cohort study using data from the Clinical Data Analysis and Reporting System (CDARS) of the Hospital Authority (HA), Hong Kong. CDARS facilitates the retrieval of clinical data captured from different operational systems for analysis and reporting and provides good quality information to support retrospective clinical and management decisions by integrating the clinical data residing in the Data Warehouse.17 It covers all public hospitals and clinics
Demographic characteristics
We first identified 472,138 individuals who were prescribed with any corticosteroid from January 1, 2001 to December 31, 2010. We excluded patients who did not have both anti-HBc and anti-HBs checked or for whom the results were indeterminate. Among the 12,997 individuals who fulfilled the inclusion and exclusion criteria, 10,561 patients were anti-HBs positive only; 970 anti-HBc positive only; 830 anti-HBs & anti-HBc both positive; and 636 anti-HBs & anti-HBc both negative (i.e. HBV unexposed)
Discussion
This large-scale cohort study aimed to establish the importance of anti-HBs and anti-HBc status in HBsAg seroreversion, as well as the effect of peak dose and duration of corticosteroids on the risk of hepatitis flare in a real-life setting where HBV is highly prevalent. In the Asia Pacific region, many people have been exposed to HBV and some of them have cleared HBsAg spontaneously. We found that patients with serological evidence of previous HBV exposure without immunity, i.e. anti-HBc
Financial support
This work was partly supported by the Direct Grant of The Chinese University of Hong Kong (Reference no: 4054405).
Conflict of interest
Grace Wong has served as an advisory committee member for Gilead Sciences and Janssen, and as a speaker for Abbott, Abbvie, Bristol-Myers Squibb, Echosens, Furui, Gilead Sciences, Janssen and Roche. Vincent Wong has served as an advisory committee member for AbbVie, Allergan, Echosens, Gilead Sciences, Janssen, Perspectum Diagnostics, Pfizer and Terns; and a speaker for Bristol-Myers Squibb, Echosens, Gilead Sciences and Merck. Grace Lui has served as an advisory committee member for Gilead,
Authors’ contributions
Grace Wong, Becky Yuen, Yee-Kit Tse, and Terry Yip had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors were responsible for the study concept and design. Grace Wong, Becky Yuen, Yee-Kit Tse, Terry Yip and Hester Luk were responsible for the acquisition and analysis of data. All authors were responsible for the interpretation of data, the drafting, and critical revision of the manuscript for
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