Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies in the targeted therapy era

Table 1 Studies of hepatitis B virus reactivation in patients receiving chimeric antigen receptor-T cell therapy

Ref.	Indication for CAR-T	N	CHB, n	Past resolved HBV infection, n	Antiviral prophylaxis, % patients	Definition of HBV reactivation	Rate of HBV reactivation	HBV-related death
Prospective studies
Liu et al[87], 2020	B-cell lymphoma	17	6	11	100% for CHB, and 45.5% for past infection (entecavir)	Elevation of HBV DNA levels to > 1000 IU/mL and/or HBsAg reverse seroconversion in HBsAg-negative patients	0	0
Yang et al[89], 2020	DLBCL	15	15	0	100% (lamivudine, entecavir, tenofovir, or adefovir dipivoxil)	Positive follow-up HBV-DNA test if the baseline HBV-DNA is undetectable/negative or > 10-fold increase from baseline	20%	0
Li et al[86], 2021	ALL, B-cell lymphoma	30	0	30	No prophylaxis	Elevation of HBV DNA ≥ 100 IU/mL for two consecutive measurements	6.6%	0
Wang et al[88], 2020	ALL, B-cell lymphoma, PCM	70	12	29	100% for CHB (entecavir, tenofovir disoproxil, or lamivudine). Nil for patients with past HBV infection	> 1 log increase in HBV DNA, HBV DNA-positive when previously negative, HBV DNA > 2000 IU/mL if no baseline level was available, or reverse sero-conversion from HBsAg-negative to positive	16.7% with chronic infection and 34.4 % with past infection	0
Retrospective studies
Cao et al[83], 2020	ALL, NHL	89	19	37	100% for chronic infection, and 5.4% for past infection	100-fold increase in HBV DNA when compared with baseline or HBV DNA ≥ 103 IU/mL in a patient with a previously undetectable level or reverse seroconversion from HBsAg negative to HBsAg positive	5.3% for CHB	0
Han et al[85], 2020	Multiple myeloma	9	1	8	100% for CHB, 25% for past infection (lamivudine/entecavir)	HBsAg seroconversion or increase in HBV DNA levels by at least 10-fold or 1 × 109 copies/mL	12.5% for past infection	0
Cui et al[84], 2021	DLBCL, B-ALL	20	5	15	100% for CHB (entecavir or tenofovir), 13.3% for past HBV infection (entecavir)	For CHB: (1) ≥ 2 log increase in HBV DNA compared to the baseline level; (2) HBV DNA ≥ 3 log IU/mL in a patient with previously undetectable level; and (3) HBV DNA ≥ 4 log IU/mL if the baseline level is not available. For resolved HBV infection: HBV DNA is detectable; reverse HBsAg seroconversion	6.2% for past infection	0

AASLD: American Association for the Study of Liver Diseases; ALL: Acute lymphoblastic leukemia; CAR: Chimeric antigen receptor; CHB: Chronic hepatitis B; CLL: Chronic lymphocytic leukemia; DLBCL: Diffuse large B-cell lymphoma; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; NHL: Non-Hodgkin lymphoma; PCM: Plasma cell myeloma.

Table 2 Studies of hepatitis B virus reactivation in patients receiving Bruton’s tyrosine kinase inhibitors (all studies are retrospective)

Ref.	Disease type		Therapy	N			CHB, n		Past resolved HBV infection, n	Antiviral prophyl-axis, % patients		Definition of HBV reactivation		Rate of HBV reactivation, % patients	HBV-related death
Hammond et al[108], 2018	CLL, MCL, LPL		Ibrutinib	21			0		21	4.8%		HBV DNA > 100 IU/mL on 2 consecutive measurements ± reappearance of HBsAg		9.5%	0
Innocenti et al[109], 2019	CLL		Ibrutinib	34			0		12	42% for past infection (lamivudine)		Increase in serum ALT and HBV DNA in HBsAg-positive patients or elevation of HBV DNA ± HBsAg recurrence in anti-HBc-positive patients		8.3%	0
Innocenti et al[110], 2022	CLL		Ibrutinib	108			0		108	67.6% (lamivudine)		HBsAg seroconversion and/or an increase of serum HBV DNA by ≥ 1 log above the LLD of the assay		1.9%	0
Ni et al[111], 2022	DLBCL		Ibrutinib or zanu-brutinib	55			4		26	100% for CHB and 34.6% for past infection (entecavir)		> 1 log increase in HBV DNA, HBV DNA-positive when previously negative, HBV DNA > 2000 IU/mL if no baseline level was available, or reverse seroconversion from HBsAg-negative to -positive		7.69% for past infection	0

CHB: Chronic hepatitis B; CLL: Chronic lymphocytic leukaemia; DLBCL: Diffuse large B-cell lymphoma; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; LLD: Lower limit of detection; LPL: Lymphoplasmacytic lymphoma; MCL: Mantle cell lymphoma; ALT: Alanine aminotransferase; anti-HBc: Antibody to hepatitis B core.

Table 3 Studies of hepatitis B virus reactivation in patients receiving immune checkpoint inhibitors (all studies were retrospective)

Ref.	Disease type	Therapy	N	CHB, n	Past resolved HBV infection, n	Antiviral prophylaxis, % patients	Definition of HBV reactivation	Rate of HBV reactivation	HBV-related death
Zhang et al[129], 2019	Solid tumors, lymphoma (7%)	PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab, toripalimab, camrelizumab, sintilimab, atezolizumab)	114	114	0	74.6% received prophylaxis (entecavir, tenofovir, lamivudine, telbivudine, adefovir)	AASLD 2018 guidelines	6 (5.3%)	0
Wong et al[127], 2021	Solid tumors	PD-1 inhibitors (nivolumab, pembrolizumab, spartalizumab), PD-L1 inhibitors (atezolizumab, avelumab, durvalumab), CTLA-4 inhibitors (ipilimumab, tremelimumab)	990	397	225	100% for CHB, and 11.3% for past HBV infection (entecavir, TAF, TDF, lamivudine, telbivudine, ADV)	AASLD 2018 guidelines	2/397 (0.5%); none in the resolved HBV group	0
Yoo et al[128], 2022	Solid tumors, lymphoma (1.8%)	PD-1 inhibitors (nivolumab, pembrolizumab), PD-L1 inhibitors (atezolizumab, avelumab), CTLA-4 inhibitors (ipilimumab, tremelimumab)	3465	511	564	90.8% for CHB, 1.1% for HBsAg negative patients (entecavir, tenofovir, lamivudine, telbivudine, adefovir, clevudine)	AASLD 2018 guidelines	1% for chronic HBV infection, 0% for past HBV infection	0
Lasagna et al[126], 2023	Solid tumors	Pembrolizumab, nivolumab, atezolizumab	150	0	150	Nil	AASLD 2018 guidelines	0%	0

AASLD: American Association for the Study of Liver Diseases; ADV: Adefovir dipivoxil; CHB: Chronic hepatitis B; CTLA4: Cytotoxic T-lymphocyte-associated protein 4; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; PD-1: Programmed cell death protein 1; PD-L1: Programmed cell death ligand 1; TAF: Tenofovir alafenamide; TDF: Tenofovir disoproxil fumarate.

Table 4 Drug classes and corresponding risk of hepatitis B virus reactivation[6]

Drug class	Drug or dose	Risk of HBV reactivation
		For HBsAg-positive patients	For HBsAg-negative/anti-HBc-positive patients
Anti-CD20 monoclonal antibodies	Rituximab, obinutuzumab, ofatumumab	High (30%-60%)	High (> 10%)
Anthracycline chemotherapy	Doxorubicin, daunorubicin, epirubicin	High (15%-30%)	High (> 10%)
Steroids	Moderate/high dose ≥ 4 wk	High (> 10%)	Moderate (1%-10%)
	Low dose ≥ 4 wk	Moderate (1%-10%)	Low (< 1%)
	Low dose ≤ 1 wk	Low (< 1%)	Low (< 1%)
Tyrosine kinase inhibitors	Imatinib, nilotinib, dasatinib	High to moderate	Low (< 1%)
Immune checkpoint inhibitors	Nivolumab, pembrolizumab	High (> 10%)	Uncertain
Proteasome inhibitor	Bortezomib	Moderate (1%-10%)	Moderate (1%-10%)

HBV: Hepatitis B virus; HBsAg: Hepatitis B surface antigen; anti-HBc: Antibody to hepatitis B core.

Table 5 International guidelines on prevention of hepatitis B in patients with a history of hepatitis B virus infection who are candidates for chemotherapy

Guideline	HBV screening	Screening tests	HBsAg-positive patients	HBsAg-negative, anti-HBc-positive patients	Choice of antiviral agent	Duration of antiviral therapy	Monitoring after prophylaxis	Ref.
American Gastroenterological Association 2015 guideline	High risk of HBV reactivation (> 10%) and moderate risk of HBV reactivation (1%-10%). Routine screening not recommended for low risk of HBV reactivation (< 1%)	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 LMV	6 mo after discontinuation of therapy and at least 12 mo for B-cell depleting agents	Not defined	[6]
European Association for the Study of the Liver 2017	All candidates for CT or IST	HBsAg, anti-HBc, and anti-HBs	Anti-HBV prophylaxis	Anti-HBV prophylaxis if they are at high risk of HBV reactivation. Pre-emptive therapy for moderate (10%) or low (1%) risk of HBV reactivation, and monitor HBsAg and/or HBV DNA every 1-3 mo during and after IST	ETV or TDF or TAF	At least 12 mo (18 mo for high-risk therapy) after the last course of therapy	LFT and HBV DNA every 3 to 6 mo during prophylaxis and for ≥ 12 mo after NA withdrawal	[3]
American Association for the Study of Liver Diseases 2018	All patients for CT and IST	HBsAg and anti-HBc	Anti-HBV prophylaxis	On-demand therapy except for patients receiving anti-CD20 antibody therapy or SCT (monitor ALT, HBV DNA, HBsAg every 1-3 mo)	ETV or TDF or TAF	At least 6 mo after discontinuation of IST. At least 12 mo for B cell-depleting agents	For up to 12 mo after cessation of anti-HBV therapy	[7]
American Society of Clinical Oncology 2020 update	All candidates for CT or IST	HBsAg, anti-HBc, and anti-HBs	Anti-HBV prophylaxis	High risk, e.g., anti-CD20 antibody therapy or stem cell transplantation: Prophylaxis. Others: On-demend therapy (monitor HBsAg and HBV DNA every 3 mo)	ETV, TDF, TAF	At least 12 mo after cessation of IST	High risk: Monthly for the first 3 mo after NA withdrawal and then every 3 mo (duration not specified). Resolved HBV and not high risk: Not necessary	[4]
The Asian Pacific Association for the Study of the Liver 2021	All patients planned to receive IST	HBsAg, anti-HBs and anti-HBc, quanti-tative HBV DNA for HBsAg-positive patients	Anti-HBV prophylaxis in high and moderate-risk groups, and low-risk group with advanced liver fibrosis or cirrhosis. Pre-emptive treatment in low-risk group without advanced liver fibrosis or cirrhosis	Anti-HBV prophylaxis in high-risk group and moderate-risk group with advanced liver fibrosis or cirrhosis. Pre-emptive treatment in low-risk group without advanced liver fibrosis or cirrhosis	ETV, TDF or TAF	6 mo after the completion of IST for HBsAg-positive patients, without advanced liver fibrosis or cirrhosis and with low level of HBV DNA	HBV DNA every 3 mo	[5]

High risk of hepatitis B virus reactivation (> 10%), moderate risk (1%-10%), low risk (< 1%). ALT: Alanine aminotransferase; CT: Chemotherapy; ETV: Entecavir; HBV: Hepatitis B virus; HBsAg: Hepatitis B surface antigen; IST: Immunosuppresive therapy; LFT: Liver function test; LMV: Lamivudine; NA: Nucleotide analog; SCT: Stem cell transplant; TDF: Tenofovir; TAF: Tenofovir alafenamide fumarate; anti-HBc: Antibody to hepatitis B core; TAF: Tenofovir alafenamide; TDF: Tenofovir disoproxil fumarate.

Table 6 Recommendations for management strategy of hepatitis B virus-infected cancer patients receiving novel agents for hematological malignancies

Therapy	Chronic HBV infection	Past resolved HBV infection
CAR-T (e.g., axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel)	Antiviral prophylaxis	Antiviral prophylaxis
Bispecific antibodies (e.g., glofitamab, mosunetuzumab)	Antiviral prophylaxis	Antiviral prophylaxis
BTK inhibitors (e.g., ibrutinib, acalabrutinib, zanubrutinib)	Antiviral prophylaxis	Antiviral prophylaxis or monitoring and pre-emptive therapy1
BCL-2 inhibitors (venetoclax)	Antiviral prophylaxis	Antiviral prophylaxis or monitoring and pre-emptive therapy1
Anti-CD19 monoclonal antibody (blinatumumab)	Antiviral prophylaxis	Antiviral prophylaxis
Anti-CD22 monoclonal antibody (inotuzumab)	Antiviral prophylaxis	Antiviral prophylaxis
Anti-CD79 monoclonal antibody (polatuzumab)	Antiviral prophylaxis	Antiviral prophylaxis
Anti-CD38 monoclonal antibody (daratumumab)	Antiviral prophylaxis	Antiviral prophylaxis

¹Pre-emptive therapy is monitoring of serum hepatitis B virus DNA every 1-3 mo during and after immunosuppression, and starting antiviral therapy with entecavir or tenofovir in the case of detectable hepatitis B virus DNA levels.

HBV: Hepatitis B virus; CAR: Chimeric antigen receptor; BTK: Bruton tyrosine kinase; BCL: B-cell lymphoma.