Hepatitis B reactivation in the setting of chemotherapy and immunosuppression - prevention is better than cure

Table 1 Populations at high risk for hepatitis B virus infection that should be screened[4]

Individuals born in areas of high (≥ 8%) or intermediate prevalence (2%-7%) for HBV (HBsAg positive) including immigrants and adopted children

Asia, Africa, South Pacific Islands: All countries

Middle East (except Cyprus and Israel)

Eastern Europe: All countries except Hungary

European Mediterranean: Malta and Spain

The Arctic (indigenous populations of Alaska, Canada, and Greenland)

South America: Ecuador, Guyana, Suriname, Venezuela, and Amazon regions of Bolivia, Brazil, Colombia, and Peru

Caribbean: Antigua and Barbuda, Dominica, Granada, Haiti, Jamaica, St. Kitts and Nevis, St. Lucia, and Turks and Caicos

Central America: Guatemala and Honduras

Other groups recommended for screening

United States born persons not vaccinated as infants whose parents were born in regions with high HBV endemicity (8%)

Household and sexual contacts of HBsAg-positive persons

Persons who have ever injected drugs

Persons with multiple sexual partners or history of sexually transmitted disease

Men who have sex with men

Inmates of correctional facilities

Individuals with chronically elevated ALT or AST

Individuals infected with HCV or HIV

Patients undergoing renal dialysis

All pregnant women

Persons needing immunosuppressive therapy

HBV: Hepatitis B virus; HBsAg: Hepatitis B surface antigen; HCV: Hepatitis C virus; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; HIV: Human immunodeficiency virus.

Table 2 Immunosuppressive drug classes and corresponding risk estimates of hepatitis B virus reactivation[63,80]

Drug class	Drug	Risk estimate of HBVrfor HBsAg positive	Risk estimate of HBVr forHBsAg negative/anti-HBc positive
B-cell depleting agents	Rituximab (anti-CD20)	High (30%-60%)	High (> 10%)
	Ofatumumab (anti-CD20)
Anthracycline derivatives	Doxorubicin	High (15%-30%)	High (> 10%)
	Epirubicin
TNF-α inhibitors	Infliximab	Moderate (1%-10%)	Moderate (1%)
	Etanercept
	Adalimumab
Cytokine inhibitors	Abatacept (anti-CD80, -86)	Moderate (1%-10%)	Moderate (1%)
and integrin inhibitors	Ustekinumab (anti-IL-12, -23)
	Natalizumab (binds α4-integrin)
	Vedolizumab [binds integrin α4β7 (LPAM-1)]
Tyrosine kinase inhibitors	Imantinib	Moderate (1%-10%)	Moderate (1%)
	Nilotinib
Corticosteroids	High dose, e.g., prednisone ≥ 20 mg for ≥ 4 wk	High (> 10%)	NA
	Moderate dose, e.g., prednisone < 20 mg for ≥ 4 wk	Moderate (1%-10%)	Moderate (1%-10%)
	Low dose, e.g., prednisone for < 1 wk	Low (< 1%)	Low (<< 1%)
	Intra-articular corticosteroids	Low (< 1%)	Low (<< 1%)
Traditional immunosuppression	Azathioprine	Low (< 1%)	Low (<< 1%)
	6-mercaptopurine
	Methotrexate

TNF: Tumour necrosis factor; IL: Interleukin; LPAM: Lymphocyte Peyer’s patch adhesion molecule; NA: Not available; HBVr: Hepatitis B reactivation; HBsAg: Hepatitis B surface antigen.

Table 3 Comparison of International Associations’ guidelines on the management of hepatitis B virus in the setting of chemotherapy and immunosuppression

Association guidelines	HBV screening population	Screening test	Antiviral prophylaxis		Antiviral drug recommended	Monitoring in untreated
			HBsAg + ve, anti-HBc + ve	HBsAg - ve, Anti-HBc + ve	for prophylaxis	anti-HBc + ve patients
American Gastroenterological Association 2014[63,80]	High risk of HBVr (> 10%)	HBsAg and anti-HBc; HBV DNA if serology + ve	Yes (B1)	Yes (B1) if taking:	Drug with high barrier to resistance is favoured over lamivudine (B2)	No recommendation (knowledge gap)
	B-cell depleting agents		Continue until at least 6 mo after completion of chemotherapy	B-cell depleting agents
	Anthracycline derivatives			Anthracycline derivatives
	High dose corticosteroids (≥ 20 mg prednisone for ≥ 4 wk)			Continue until at least 12 mo after completion of chemotherapy for B-cell depleting agents
	Moderate risk of HBVr (1%-10%)	HBsAg and anti-HBc; HBV DNA if serology + ve	Yes (B2)	Yes (B2) if taking	Drug with high barrier to resistance is favoured over lamivudine (B2)	No recommendation (knowledge gap)
	TNF-α inhibitors		Continue until at least 6 mo after completion of chemotherapy	TNF-α inhibitors
	Cytokine or integrin inhibitors			Cytokine or Integrin inhibitors
	Tyrosine kinase inhibitors			Tyrosine kinase inhibitors
	High dose corticosteroids (≥ 20 mg prednisone for ≥ 4 wk)			Continue until at least 6 mo after completion of chemotherapy
	Low risk of HBVr (< 1%)	Routine screening not recommended	Not recommended (B2)	Not recommended (B2)	Not applicable	No recommendation (knowledge gap)
	Traditional immunosuppression	Screen for HBV as per CDC guidelines[4]; manage accordingly
	Intra-articular corticosteroids
	Systemic corticosteroids for < 1 wk
American Association for the Study of Liver Disease 2009[110]	Anyone at high risk of HBV infection; Table 1 (II-3)	HBsAg and anti-HBc	Yes (regardless of HBV DNA level)	No recommendation (knowledge gap)	Lamivudine (I) or telbivudine (III) if the anticipated treatment duration is short (< 12 mo) and baseline HBV DNA is not detectable	Monitoring recommended; no specific test/frequency provided
			Maintain for 6 mo completion of chemotherapy (III)		Tenofovir or entecavir if anticipated treatment duration > 12 mo (III)
			If baseline HBV DNA > 2000 IU/mL, continue antiviral until endpoints as per immunocompetent patients (III)
European Association for the Study of Liver Disease 2012[103]	All candidates for chemo- and immunosuppressive therapy (A1)	HBsAg and anti-HBc; HBV DNA if serology + ve	Yes (A1)	Yes if:	Lamivudine if HBV DNA < 2000 IU/mL and the treatment duration is short/finite (B1)	ALT and HBV DNA every 1-3 mo
			Regardless of HBV DNA level	HBV DNA detectable	Entecavir or tenofovir if HBV DNA is high, lengthy or repeated cycles of immunosuppression (C1)	Treat upon evidence of HBVr (C1)
			Continue until 12 mo after cessation of chemotherapy	Taking rituximab (C2)
				Bone marrow or stem cell transplantation (C2)
				Treat as per HBsAg + ve
				No if:
				HBV DNA undetectable; monitor
Asian-Pacific Association for the Study of Liver Disease 2012[109]	All patients prior to receiving immunosuppression or chemotherapy	HBsAg (IVA)	Yes	No; monitor		HBV DNA should be closely monitored and treated with nucleos(t)ide analogue when needed (IVA)
		Test anti-HBc if patient due to receive biological agent	HBVr prophylaxis with lamivudine; Continue until 6 mo after end of chemotherapy (IA)
			Alternatively use entecavir or tenofovir (IIIA)
			Continue HBV treatment if clinically indicated (IA)
American Society of Clinical Oncology Provisional Clinical Opinion 2010[111]	Advise against routine serological screening. Screen those with	HBsAg; anti-HBc if receiving rituximab	Consider role of antiviral therapy	No specific recommendation provided	No specific recommendation provided	No specific recommendation provided
	High risk of HBV exposure; evidence of liver disease		Do not delay chemotherapy
	Therapeutic regimen with high risk of HBVr including all patients undergoing rituximab therapy
	Haematopoetic stem cell transplant

The grade of recommendation and/or level of evidence have been noted where available. AGA and EASL guidelines: evidence grade A: High quality; B: Moderate quality; C: Low quality. Recommendation grade 1: Strong; 2: Weak. I: Randomised controlled trials; AASLD guidelines: II-1: Non-randomised controlled trials; II-2: Cohort or case-control studies; II-3: Case series; III: Expert opinion. APASL guidelines: Quality of evidence ranked from I (highest) to V (lowest); strength of recommendations ranked A (strongest) to D (weakest). HBV: Hepatitis B virus; HBVr: Hepatitis B virus reactivation; CDC: The Centre for Disease Control; + ve: Positive; - ve: Negative; ALT: Alanine aminotransferase.