Reactivation of Hepatitis B Virus and Its Prevention in Patients with Rheumatic Diseases Receiving Immunosuppressive Therapy

Eun-Jung Park; Kyu-sik Choi; Byung-Cheol Song

doi:10.4078/jrd.2017.24.5.261

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Park, Choi, and Song: Reactivation of Hepatitis B Virus and Its Prevention in Patients with Rheumatic Diseases Receiving Immunosuppressive Therapy

Review Article

J Rheum Dis 2017;24(5):261-270.

Published online: 31 October 2017

DOI: https://doi.org/10.4078/jrd.2017.24.5.261

Reactivation of Hepatitis B Virus and Its Prevention in Patients with Rheumatic Diseases Receiving Immunosuppressive Therapy

Eun-Jung Park¹, Kyu-sik Choi², Byung-Cheol Song¹

¹Department of Internal Medicine, Jeju, Korea

²Jeju National University School of Medicine, Jeju, Korea

Corresponding to: Byung-Cheol Song, Department of Internal Medicine, Jeju National University School of Medicine, 15 Aran 13-gil, Jeju 63241, Korea. E-mail: drsong8177@naver.com

Received 30 June 201711 September 2017 Accepted 11 September 2017

This is a Open Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Introduction of biologic agents to treat patients with rheumatic diseases and cancer has improved clinical outcomes. However, this advance increases the risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen carrier and even in resolved HBV infection, which can lead to liver failure and even death. In particular, the risk of HBV reactivation is heightened by the use of B-cell depleting agents such as rituximab, high dose corticosteroid, and anti-tumor necrosis factor-α. Therefore, identification of individuals at risk, and understanding the mechanism of HBV reactivation are essential to preventing HBV reactivation before initiating immunosuppressive therapy. Here, we review the mechanism, incidence, and prevention of HBV reactivation in the setting of immunosuppression.

Keywords: Hepatitis B reactivation, Immunosuppressive agents, Rheumatic diseases

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Table 1.

Incidence of HBV reactivation without antiviral prophylaxis in various diseases

Diseases	HBV reactivation without antiviral prophylaxis (%)		References
Diseases	HBsAg-positive	Resolved HBV infection	References
Bone marrow/hematopoietic stem cell transplantation	66∼81	6∼10	40∼42
Solid organ transplantation	50∼90	0.9∼5	15
Lymphoma	18∼72	9∼41.5	5, 7, 10, 24∼32
Leukemia	61	2.8∼12.5	39, 43
Breast cancer	21∼68	NA	7, 13, 33∼38
Head and neck cancer	19.3∼29.4	NA	7, 13
Hepatocellular carcinoma (systemic chemotherapy)	36	11	44
Hepatocellular carcinoma (transarterial chemoembolization)	20.5∼29.7	9.3∼11	45∼47
Gastrointestinal cancer	6.9∼18.1	NA	7, 13
Lung cancer	14.2∼23	NA	7
Rheumatic diseases receiving anti-TNF therapy	6.9∼39	0∼5	49∼52, 59, 61, 62
Inflammatory bowel diseases receiving anti-TNF^*	36	0.7	60, 63

HBV: hepatitis B virus, HBsAg: hepatitis B surface antigen, TNF: tumor necrosis factor, NA: not applicable.

^* Case reports or small case series reporting HBV reactivation.

Table 2.

Prospective, randomized trials of antiviral therapy to prevent HBV reactivation

Studies	Patients (number)	HBV status	Diseases	Treatment	Antiviral agents	HBV reactivation (%)		p-value
Studies	Patients (number)	HBV status	Diseases	Treatment	Antiviral agents	Prophylaxis	Control^*	p-value
Lau et al. [75]	30	HBsAg (+)	Lymphoma	Chemotherapy	Lamivudine	0.0	53.0	0.002
Hsu et al. [25]	52	HBsAg (+)	Lymphoma	Chemotherapy	Lamivudine	11.5	56.0	0.001
Long et al. [76]	42	HBsAg (+)	Breast cancer	Chemotherapy	Lamivudine	0	28.6	0.021
Huang et al. [77]	80	HBsAg (−)/anti-HBc (+)	Lymphoma	Rituximab-containing chemotherapy	Entecavir	2.4	17.9	0.027
Huang et al. [78]	121	HBsAg (+)	Lymphoma	Rituximab-containing chemotherapy	Entecavir vs. Lamivudine	6.6/30.0	NA	0.001

HBV: hepatitis B virus, HBsAg: hepatitis B surface antigen, HBc: hepatitis B core, NA: not applicable.

^* Control patients either remained untreated or had delayed treatment only after HBV reactivation.

Table 3.

The risk of HBV reactivation and policy for antiviral prophylaxis in HBsAg-positive or anti-HBc-positive patients who received immunosuppressive therapy

Risk group (>10%)	HBV reactivation estimates	Antiviral prophylaxis [85]
High-risk	1. B cell– depleting agents such as rituximab and ofatumumab	≥ 12 months
	– HBsAg positive: (A)
	– HBsAg negative/anti-HBc positive: (A)
	2. Anthracycline derivatives such as doxorubicin and epirubicin	≥ 6 months
	– HBsAg positive: (A)
	3. Corticosteroid therapy (moderate/high dose) for ≥4 weeks	≥ 6 months
	– HBsAg positive: (B)	(strong recommendation)
Moderate-risk (1%∼10%)	1. TNF-alpha inhibitors: infliximab, etanercept, adalimumab, certolizumab	6 months
		– The American gastroenterological association (AGA) suggests antiviral prophylaxis over monitoring for patients at moderate risk undergoing immunosuppressive drug therapy.
	– HBsAg positive: (B)
	– HBsAg negative/anti-HBc positive: (C)
	2. Other cytokine inhibitors and integrin inhibitors: abatacept, ustekinumab, natalizumab, vedolizumab
	– HBsAg positive: (C)	– Patients who place a higher value on avoiding long-term use of antiviral therapy and the cost associated with its use and a lower value on avoiding the small risk of reactivation (particularly in those who are HBsAg negative) may reasonably select no prophylaxis over antiviral prophylaxis.
	– HBsAg negative/anti-HBc positive: (C)
	3. Tyrosine kinase inhibitors: imatinib, nilotinib
	– HBsAg positive: (B)
	– HBsAg negative/anti-HBc positive: (C)
	4. Corticosteroid therapy for ≥4 weeks
	– HBsAg positive (low dose): (C)
	– HBsAg negative/anti-HBc positive: (C) (moderate/high dose)
	5. Anthracycline derivatives: doxorubicin and epirubicin
	– HBsAg negative/anti-HBc positive: (C)
Low-risk (<1%)	1. Traditional immunosuppressive agents: azathioprine,	The AGA suggests against routinely
	6-mercaptopurine, methotrexate	using antiviral prophylaxis in patients
	– HBsAg positive/anti-HBc positive: (A)	undergoing immunosuppressive drug
	– HBsAg negative/anti-HBc positive: (A)	therapy who are at low risk for HBV
	2. Intraarticular corticosteroids	reactivation
	– HBsAg positive/anti-HBc positive: (A)
	– HBsAg negative/anti-HBc positive: (A)
	3. Corticosteroid therapy for ≤1 week
	– HBsAg positive/anti-HBc positive: (B)
	– HBsAg negative/anti-HBc positive: (A)
	4. Corticosteroid (low dose) therapy for ≥4 weeks
	– HBsAg negative/anti-HBc positive: (B)

Confidence in evidence was graded as follows: (A) high confidence that the estimate lies within group risk boundaries, (B) moderate confidence that the estimate lies within group risk boundaries, (C) little or no confidence that the estimate lies within group risk boundaries. Glucocorticoids: prednisone (or equivalent): low dose, <10 mg; moderate dose, 10∼20 mg; high dose, >20 mg. HBV: hepatitis B virus, HBsAg: hepatitis B surface antigen, HBc: hepatitis B core. Adopted from the article Perrillo et al. (Gastroenterology 2015;148:221-244.e3) [10] with original copyright holder's permission.

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