Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies treated with anticancer therapy

Table 1 Drug classes and corresponding risks of HBV reactivation[49,67]

Drug class	Drug	Risk of HBV reactivation for HBsAg-positive patients	Risk of HBV reactivation for HBsAg-negative/anti-HBc-positive patients
Monoclonal antibody	Rituximab	High (30%-60%)	High (> 10%)
	Ofatumumab
	Obinutuzumab
Anthracycline chemotherapy	Doxorubicin	High (15%-30%)	High (> 10%)
	Epirubicin
	Daunorubicin
Corticosteroids	High dose, e.g., Prednisolone ≥ 20 mg for ≥ 4 wk	High (> 10%)	Not available
	Moderate dose, e.g., Prednisolone < 20 mg for ≥ 4 wk	Moderate (1%-10%)	Moderate (1%-10%)
	Low dose, e.g., Prednisolone < 1 wk	Low (< 1%)	Low (< 1%)
Tyrosine kinase inhibitors	Imatinib, nilotinib	Moderate (1%-10%)	Moderate (1%-10%)
Traditional immunosuppressive agents	Methotrexate, azathioprine, 6-mercaptopurine	Low (< 1%)	Low (< 1%)

HBV: Hepatitis B virus.

Table 2 Prospective studies on HBV reactivation in haematology patients with resolved hepatitis B virus infection (HBsAg negative anti-HBc positive patients)

Author/year	Disease	Study design	Sample size	Definition of HBV reactivation	Rate of HBV reactivation	Risk factor(s) identified for HBV reactivation	Death from HBV reactivation
Yeo et al[99] 2009	Diffuse large B-cell lymphoma	All patients were observed every 2-3 wk during anticancer therapy and every 6-8 wk for 9 mo after anticancer therapy	46	HBsAg seroconversion (the reappearance of HBsAg) with an increase in HBV DNA levels when compared with baseline HBV DNA levels, in the absence of acute infection with HAV, HCV, or other systemic infections	25% in patients receiving R-CHOP	Absence of anti-HBs, use of rituximab and male sex	20% died of HBV reactivation
		Start lamivudine upon HBV reactivation
Huang et al[107] 2013	B-cell lymphoma	Entecavir prophylaxis (continued until 3 mo after completing chemotherapy) vs preemptive treatment	80	Elevation of HBV viral load to 2000 IU/mL with two consecutive determinations (2 wk apart)	Incidence was 4.3% in entecavir group and 25.9% in the control group at 1.5 yr	Lack of entecavir prophylaxis	Nil
Seto et al[45] 2014	CD20 positive B-cell lymphoma	HBV DNA monitoring every 4 wk	63	HBV DNA ≥ 10 IU/mL	2-yr cumulative rate 41.5%	Anti-HBs < 10 mIU/mL	Nil
		Start entecavir upon detection of HBV reactivation
Hsu et al[16] 2014	CD20 positive B-cell lymphoma	HBV DNA monitoring every 4 wk	150	> 10-fold increase in HBV DNA, compared with previous nadir levels	Incidence was 10.4%	Absence of anti-HBs	Nil
		Start entecavir upon detection of HBV reactivation
Kusumoto et al[46] 2015	CD20 positive B-cell lymphoma	HBV DNA monitoring every 4 wk	269	HBV DNA ≥ 11 IU/mL	Incidence was 8.3% at 1.5 yr	Anti-HBs < 10 mIU/mL and baseline HBV DNA below level of quantification	Nil
		Start entecavir upon detection of HBV reactivation

HBV: Hepatitis B virus; HBsAg: Hepatitis B surface antigen; HBc: Hepatitis B core antigen.

Table 3 Comparison of international guidelines on the management of patients with hepatitis B virus infection receiving chemotherapy

Association guidelines	HBV screening	Screening tests	HBsAg positive patients	HBsAg negative, anti-HBc positive patients	Antiviral drug recommended	Duration of antiviral therapy
EASL 2012[91]	All candidates for chemo- and immunosuppressive therapy	HBsAg, anti-HBc, HBV DNA if serology positive	Prophylactic antiviral therapy, test for HBV-DNA level	Test for HBV DNA; provide prophylactic antiviral therapy if detectable HBV DNA; monitor ALT and HBV DNA levels closely if no detectable HBV DNA	Lamivudine if HBV DNA < 2000 IU/mL and the treatment duration is finite and short, Entecavir or tenofovir if HBV DNA is high, and/or lengthy and repeated cycles of immunosuppression	12 mo after cessation of therapy
APASLD 2012[92]	All patients prior to receiving immunosuppression or chemotherapy	HBsAg, anti-HBc	Prophylactic antiviral therapy	Monitor HBV-DNA	Lamivudine or entecavir or tenofovir	Continue until 6 mo after end of chemotherapy
AGA 2015[49]	High risk of HBV reactivation (> 10%) and moderate risk of HBV reactivation (1%-10%)	HBsAg, anti-HBc , HBV DNA if serology positive	Prophylactic antiviral therapy	Antiviral prophylaxis over monitoring for patients if the chemotherapy is associated with high or moderate risk of HBV reactivation	Drug with high barrier to resistance is favored over lamivudine	6 mo after discontinuation of therapy and at least 12 mo for B-cell depleting agents
	Routine screening not recommended for low risk of HBV reactivation (< 1%)
AASLD 2009[93], no update in the version in 2016[126]	Anyone at high risk of HBV infection	HBsAg and anti-HBc	Prophylactic antiviral therapy	No recommendation	Lamivudine or telbivudine if the anticipated treatment duration is < 12 mo and baseline HBV DNA is not detectable	Maintain for 6 mo after completion of chemotherapy
					Tenofovir or entecavir if anticipated treatment duration > 12 mo
ASCO 2015[94]	Risk-adapted HBV screening strategy	HBsAg, anti-HBc , HBV DNA if serology positive	Prophylactic antiviral therapy	Consider	Entecavir, tenofovir	Minimum of 6 mo after stopping therapy, longer than 12 mo for patients receiving anti-CD20 monoclonal antibodies
				Antiviral prophylaxis if the systemic cancer therapy is associated with high risk of HBV reactivation

HBV: Hepatitis B virus; EASL: European Association for the Study of the Liver; APASLD: Asian Pacific Association for the Study of the Liver; AGA: American Gastroenterology Association; AASLD: American Association for the Study of Liver Diseases; ASCO: American Society of Clinical Oncology.