Copyright
©The Author(s) 2023.
World J Gastroenterol. Sep 7, 2023; 29(33): 4942-4961
Published online Sep 7, 2023. doi: 10.3748/wjg.v29.i33.4942
Published online Sep 7, 2023. doi: 10.3748/wjg.v29.i33.4942
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 |
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 |
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 |
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%) |
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] |
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 |
- Citation: Mak JWY, Law AWH, Law KWT, Ho R, Cheung CKM, Law MF. Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies in the targeted therapy era. World J Gastroenterol 2023; 29(33): 4942-4961
- URL: https://www.wjgnet.com/1007-9327/full/v29/i33/4942.htm
- DOI: https://dx.doi.org/10.3748/wjg.v29.i33.4942