Elsevier

Journal of Hepatology

Volume 72, Issue 1, January 2020, Pages 57-66
Journal of Hepatology

Research Article
Risk of hepatitis B surface antigen seroreversion after corticosteroid treatment in patients with previous hepatitis B virus exposure

https://doi.org/10.1016/j.jhep.2019.08.023Get rights and content

Highlights

  • HBsAg patients (anti-HBc+ but anti-HBs) are at increased risk of HBsAg seroreversion after corticosteroid therapy.

  • The peak daily dose of corticosteroid is a more important risk factor for hepatitis flares than treatment duration.

  • In contrast, dose and duration of corticosteroid use are not associated with the risk of HBsAg reversion.

Background & Aims

Systemic corticosteroids may cause HBV reactivation, but the impact on patients with previous HBV exposure is poorly defined. We aimed to study the risk of HBsAg seroreversion and hepatitis flare in patients with previous HBV exposure.

Methods

Patients who were negative for HBsAg and received corticosteroids between 2001–2010 were included. Patients who were positive for antibody to HBsAg (anti-HBs) and/or to HBcAg (anti-HBc) were defined as having previous HBV exposure. The primary endpoint was HBsAg seroreversion; the secondary endpoint was hepatitis flare (alanine aminotransferase >80 U/L) at 1 year.

Results

A total of 12,997 patients fulfilled the inclusion criteria: anti-HBs positive only (n = 10,561); anti-HBc positive only (n = 970); anti-HBs & anti-HBc positive (n = 830) and anti-HBs & anti-HBc negative (n = 636). HBsAg seroreversion occurred in 165 patients. Patients who were anti-HBc positive only had a higher risk of HBsAg seroreversion (1-year incidence 1.8%) than those negative for both anti-HBs & anti-HBc (0%; p = 0.014). Patients with previous HBV exposure had a similarly low risk of liver failure as unexposed individuals (1.1% vs. 0.9%). The risk of a hepatitis flare started to increase in those receiving corticosteroids at peak daily doses of 20–40 mg (adjusted hazard ratio [HR] 2.19, p = 0.048) or >40 mg (aHR 2.11, p = 0.015) prednisolone equivalents for <7 days, and was increased at treatment durations of 7–28 days and >28 days (aHR 2.02–3.85; p <0.001–0.012).

Conclusions

In HBsAg-negative patients who were only anti-HBc positive, high peak daily doses of corticosteroids increased the risk of hepatitis flare, but not seroreversion. The rate of liver failure was low and similar in HBV exposed and unexposed individuals; there were no deaths, nor any requirement for liver transplantation.

Lay summary

It is important to know the hepatitis B virus (HBV) status before starting corticosteroid therapy. Patients with resolved HBV infection without detectable immunity are at an increased risk of HBV surface antigen seroreversion after corticosteroid therapy. High peak daily doses of corticosteroids (>40 mg prednisolone equivalents) increase the risk of hepatitis flare, but not seroreversion, in patients with previous exposure to HBV, irrespective of the duration of treatment. Interval monitoring of liver biochemistries is essential for the early detection of hepatitis flares in these patients.

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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