Published: 2 March 2017

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Medicines and Hepatitis B Reactivation

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Prescriber Update 38(1): 2-3
March 2017

The natural course of hepatitis B virus (HBV) infection depends on the interaction between viral replication and the host’s immune response. HBV persists in the body even when there is evidence of serological recovery¹. Therefore, HBV reactivation can occur in patients with a history of HBV infection. Reactivation can occur spontaneously but is more common in the setting of immune suppression or cancer chemotherapy². It can also occur in patients undergoing solid organ or haematopoietic stem cell transplantation¹.

HBV reactivation is a rare but distinctive syndrome defined by a sudden and marked increase in HBV replication. It is usually accompanied by elevations in serum aminotransferase levels and sometimes by jaundice. Reactivation can be severe causing acute liver failure and death².

The prevalence of HBV reactivation reported in the literature ranges widely. This is due to most studies being case reports or small case series that use different definitions of HBV reactivation³.

The exact mechanism of HBV reactivation is unclear but the initiating factor is thought to be loss of immune control over viral replication².

Medicines Implicated in HBV Reactivation

A range of immunosuppressive agents have been implicated in HBV reactivation. Many novel and targeted agents for the treatment of malignant, inflammatory and autoimmune conditions have been associated with clinical evidence of HBV reactivation³.

The risk of HBV reactivation to specific medicine classes has been estimated by the American Gastroenterological Association based on a comprehensive review of the literature (Table 1)^3,4,5.

Table 1: Risk estimates of HBV reactivation according to medicine class^3,4,5

Risk estimate of hepatitis B reactivation	Medicine class	Medicine examples	Additional information
High (>10%)	B-cell depleting agents	Rituximab	Associated with highest risk due to their potent and durable immunosuppressive effect.
	Corticosteroids	High dose (eg, prednisone ≥20 mg for ≥4 weeks)	Directly affect T-cell function and promote HBV DNA replication. Risk varies according to dose, duration and route of administration.
Moderate (1–10%)	TNFα inhibitors	Infliximab Etanercept Adalimumab	TNFα is a first line of defence in viral infections. Inhibition of TNFα increases the risk of HBV reactivation.
	Cytokine inhibitors and integrin inhibitors	Ustekinumab Natalizumab	Evidence largely based on case reports. The risk may be due to their known relative potency of immunosuppression.
	Tyrosine kinase inhibitors	Imatinib Nilotinib	Moderately immunosuppressive. Risk has been associated with the treatment of conditions including chronic myeloid leukaemia and gastrointestinal stromal tumours.
	Corticosteroids	Moderate dose (eg, prednisone <20 mg for ≥4 weeks)
Low (<1%)	Traditional immunosuppression	Azathioprine Mercaptopurine Methotrexate	Most cases involve co-administration with corticosteroids or other immunomodulators, thereby increasing the risk.
	Corticosteroids	Low dose (eg, prednisone for <1 week) Intra-articular corticosteroids

The Medicines Adverse Reactions Committee recently reviewed information on the risk of HBV reactivation with the use of direct-acting antivirals (eg, Viekira Pak, Viekira Pak-RBV, Harvoni) for the treatment of hepatitis C⁶. These data sheets are in the process of being updated to include information on the risk of HBV reactivation.

Prophylaxis of HBV Reactivation

Generally, the outcome is poor when antiviral treatment is started after HBV reactivation is already established³. Therefore, patients at risk of HBV reactivation should be screened for HBV and appropriate antiviral prophylaxis should be considered³.

Cases Reported in New Zealand

The Centre for Adverse Reactions Monitoring (CARM) has received three reports of suspected hepatitis B reactivation. The suspect medicines reported in these cases were normal immunoglobulin in the first case; rituximab, tacrolimus and prednisone in the second case; and abiraterone in the third case.

Please continue to report any suspected adverse reactions and interactions to CARM. Reports can be submitted on paper or electronically (https://nzphvc.otago.ac.nz/).

References

1. Lok AS, Bonis PA. 2016. Hepatitis B virus reactivation associated with immunosuppressive therapy. UpToDate. URL: www.uptodate.com/contents/hepatitis-b-virus-reactivation-associated-with-immunosuppressive-therapy (accessed 15 December 2016).
2. Di Bisceglie AM, Lok AS, Martin P, et al. 2015. Recent US Food and Drug Administration warnings on hepatitis B reactivation with immune-suppressing and anticancer drugs: just the tip of the iceberg? Hepatology 61(2): 703-11.
3. Pattullo V. 2016. Prevention of Hepatitis B reactivation in the setting of immunosuppression. Clinical and Molecular Hepatology 22(2): 219-37.
4. Perrillo R, Gish R, Falck-Ytter Y. 2015. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 148(1): 221-44.
5. Reddy KR, Beavers KL, Hammond SP, et al. 2015. American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 148(1): 215-19.
6. Medsafe. 2016. Safe Prescribing of Direct-Acting Antivirals for Treatment of Hepatitis C - It's Complicated. Prescriber Update 37(4): 50-51.