Skip to main content
Top
Published in: Virology Journal 1/2024

Open Access 01-12-2024 | Entecavir | Research

Hepatitis B relapse after entecavir or tenofovir alafenamide cessation under anti-viral prophylaxis for cancer chemotherapy

Authors: Hsin-Wei Fang, Po-Lin Tseng, Tsung-Hui Hu, Jing-Houng Wang, Chao-Hung Hung, Sheng-Nan Lu, Chien-Hung Chen

Published in: Virology Journal | Issue 1/2024

Login to get access

Abstract

Background

No study has comparing hepatitis B virus (HBV) relapse rates among patients with both cancer and hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) who completed anti-viral prophylaxis for chemotherapy and then stopped taking entecavir or tenofovir alafenamide (TAF).

Methods

A total of 227 HBeAg-negative cancer patients without cirrhosis who previously took entecavir (n = 144) or TAF (n = 83) for antiviral prophylaxis were enrolled.

Results

The cumulative incidence of virological and clinical relapse at 2 years was 37% and 10.4%, respectively, in the entecavir group, and 46.7% and 19.5%, respectively, in the TAF group. The multivariate analysis revealed that the use of hematologic malignancy, TAF use, and high-viremia group at baseline were independent risk factors for virological relapse, and use of rituximab, TAF use, higher FIB-4 index and high-viremia group at baseline were independent risk factors for clinical relapse. After propensity score-matching, the patients who discontinued TAF therapy still exhibited higher virological (P = 0.031) and clinical relapse rates (P = 0.012) than did those who discontinued entecavir therapy. The patients were allocated to high- (> 2000 IU/mL), moderate- (between 20 and 2000 IU/mL) and low- (< 20 IU/mL) viremia groups. In the high-viremia group, those who had taken TAF for antiviral prophylaxis had higher rates of virological and clinical relapse than did those who had taken entecavir; in the moderate- and low-viremia groups, no significant difference in virological and clinical relapse rates was detected between the entecavir and TAF groups. Three patients experienced hepatic decompensation upon clinical relapse. All three patients were lymphoma and underwent rituximab therapy. One patient developed acute on chronic liver failure and died even though timely retreatment.

Conclusions

In patients with both cancer and CHB who underwent antiviral prophylaxis, TAF use was associated with a higher chance of HBV relapse than entecavir use after nucleos(t)ide analogue cessation, particularly in the high-viremia group. Patients who are hematologic malignancy and undergo a rituximab-containing cytotoxic therapy should be monitored closely after withdrawal from prophylactic NA treatment.
Literature
1.
go back to reference Protzer U, Maini MK, Knolle PA. Living in the liver: hepatic infections. Nat Rev Immunol. 2012;12:201–13.CrossRefPubMed Protzer U, Maini MK, Knolle PA. Living in the liver: hepatic infections. Nat Rev Immunol. 2012;12:201–13.CrossRefPubMed
2.
go back to reference Yeo W, Zee B, Zhong S, Chan PKS, Wong WL, Ho WM, et al. Comprehensive analysis of risk factors associating with Hepatitis B virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy. Br J Cancer. 2004;90:1306–11.CrossRefPubMedPubMedCentral Yeo W, Zee B, Zhong S, Chan PKS, Wong WL, Ho WM, et al. Comprehensive analysis of risk factors associating with Hepatitis B virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy. Br J Cancer. 2004;90:1306–11.CrossRefPubMedPubMedCentral
3.
go back to reference Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology. 2006;43:209–20.CrossRefPubMed Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology. 2006;43:209–20.CrossRefPubMed
4.
go back to reference Liu CJ, Chen PJ, Chen DS, Kao JH. Hepatitis B virus reactivation in patients receiving cancer chemotherapy: natural history, pathogenesis, and management. Hepatol Int. 2013;7:316–26.CrossRefPubMed Liu CJ, Chen PJ, Chen DS, Kao JH. Hepatitis B virus reactivation in patients receiving cancer chemotherapy: natural history, pathogenesis, and management. Hepatol Int. 2013;7:316–26.CrossRefPubMed
5.
go back to reference Terrault NA, Lok ASF, McMahon BJ, Chang K-M, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67:1560–99.CrossRefPubMed Terrault NA, Lok ASF, McMahon BJ, Chang K-M, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67:1560–99.CrossRefPubMed
6.
go back to reference Lampertico P, Agarwal K, Berg T, et al. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370–98.CrossRef Lampertico P, Agarwal K, Berg T, et al. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370–98.CrossRef
7.
go back to reference Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HLY, Chen CJ, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10:1–98.CrossRefPubMed Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HLY, Chen CJ, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10:1–98.CrossRefPubMed
8.
go back to reference Chien RN, Kao JH, Peng CY, Chen CH, Liu CJ, Huang YH, et al. Taiwan consensus statement on the management of chronic hepatitis B. J Formos Med Assoc. 2019;118:7–38.CrossRefPubMed Chien RN, Kao JH, Peng CY, Chen CH, Liu CJ, Huang YH, et al. Taiwan consensus statement on the management of chronic hepatitis B. J Formos Med Assoc. 2019;118:7–38.CrossRefPubMed
9.
go back to reference Lee IC, Chao Y, Li CP, Su CW, Lan KH, Lin HC, et al. Risk of renal events during tenofovir disoproxil fumarate and entecavir antiviral prophylaxis in HBsAg-positive cancer patients undergoing chemotherapy. J Viral Hepat. 2018;25:1599–607.CrossRefPubMed Lee IC, Chao Y, Li CP, Su CW, Lan KH, Lin HC, et al. Risk of renal events during tenofovir disoproxil fumarate and entecavir antiviral prophylaxis in HBsAg-positive cancer patients undergoing chemotherapy. J Viral Hepat. 2018;25:1599–607.CrossRefPubMed
10.
go back to reference Toka B, Koksal AS, Eminler AT, Tozlu M, Uslan MI, Parlak E. Comparison of tenofovir disoproxil fumarate and entecavir in the prophylaxis of HBV reactivation. Dig Dis Sci. 2021;66:2417–26.CrossRefPubMed Toka B, Koksal AS, Eminler AT, Tozlu M, Uslan MI, Parlak E. Comparison of tenofovir disoproxil fumarate and entecavir in the prophylaxis of HBV reactivation. Dig Dis Sci. 2021;66:2417–26.CrossRefPubMed
11.
go back to reference Murakami E, Wang T, Park Y, Hao J, Lepist EI, Babusis D, et al. Implications of efficient hepatic delivery by tenofovir alafenamide (GS-7340) for hepatitis B virus therapy. Antimicrob Agents Chemother. 2015;59:3563–9.CrossRefPubMedPubMedCentral Murakami E, Wang T, Park Y, Hao J, Lepist EI, Babusis D, et al. Implications of efficient hepatic delivery by tenofovir alafenamide (GS-7340) for hepatitis B virus therapy. Antimicrob Agents Chemother. 2015;59:3563–9.CrossRefPubMedPubMedCentral
12.
go back to reference Chan HL, Fung S, Seto WK, Chuang WL, Chen CY, Kim HJ, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1:185–95.CrossRefPubMed Chan HL, Fung S, Seto WK, Chuang WL, Chen CY, Kim HJ, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1:185–95.CrossRefPubMed
13.
go back to reference Buti M, Gane E, Seto WK, Chan HL, Chuang WL, Stepanova T, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1:196–206.CrossRefPubMed Buti M, Gane E, Seto WK, Chan HL, Chuang WL, Stepanova T, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1:196–206.CrossRefPubMed
14.
go back to reference Inada K, Kaneko S, Kurosaki M, Yamashita K, Kirino S, Osawa L, et al. Tenofovir alafenamide for prevention and treatment of hepatitis B virus reactivation and de novo hepatitis. JGH Open. 2021;5:1085–91.CrossRefPubMedPubMedCentral Inada K, Kaneko S, Kurosaki M, Yamashita K, Kirino S, Osawa L, et al. Tenofovir alafenamide for prevention and treatment of hepatitis B virus reactivation and de novo hepatitis. JGH Open. 2021;5:1085–91.CrossRefPubMedPubMedCentral
15.
go back to reference Lee IC, Lan KH, Su CW, Li CP, Chao Y, Lin HC, et al. Efficacy and renal safety of prophylactic tenofovir alafenamide for HBV-infected cancer patients undergoing chemotherapy. Int J Mol Sci. 2022;23:11335.CrossRefPubMedPubMedCentral Lee IC, Lan KH, Su CW, Li CP, Chao Y, Lin HC, et al. Efficacy and renal safety of prophylactic tenofovir alafenamide for HBV-infected cancer patients undergoing chemotherapy. Int J Mol Sci. 2022;23:11335.CrossRefPubMedPubMedCentral
16.
go back to reference Chiu SM, Kuo YH, Wang JH, Hung CH, Hu TH, Lu SN, et al. Associations of HBV genotype B vs C infection with relapse after cessation of entecavir or tenofovir therapy. Clin Gastroenterol Hepatol. 2020;18:2989–97.CrossRefPubMed Chiu SM, Kuo YH, Wang JH, Hung CH, Hu TH, Lu SN, et al. Associations of HBV genotype B vs C infection with relapse after cessation of entecavir or tenofovir therapy. Clin Gastroenterol Hepatol. 2020;18:2989–97.CrossRefPubMed
17.
go back to reference Kuo MT, Hu TH, Hung CH, Wang JH, Lu SN, Tsai KL, et al. Hepatitis B virus relapse rates in chronic hepatitis B patients who discontinue either entecavir or tenofovir. Aliment Pharmacol Ther. 2019;49:218–28.CrossRefPubMed Kuo MT, Hu TH, Hung CH, Wang JH, Lu SN, Tsai KL, et al. Hepatitis B virus relapse rates in chronic hepatitis B patients who discontinue either entecavir or tenofovir. Aliment Pharmacol Ther. 2019;49:218–28.CrossRefPubMed
18.
go back to reference Chen CH, Peng CY, Kuo YH, Hu TH, Hung CH, Wang JH, et al. Earlier and higher rate of hepatitis B virus relapse after discontinuing tenofovir versus entecavir in hepatitis B e antigen-positive patients. J Infect Dis. 2022;225:1974–81.CrossRefPubMed Chen CH, Peng CY, Kuo YH, Hu TH, Hung CH, Wang JH, et al. Earlier and higher rate of hepatitis B virus relapse after discontinuing tenofovir versus entecavir in hepatitis B e antigen-positive patients. J Infect Dis. 2022;225:1974–81.CrossRefPubMed
19.
go back to reference Liaw YF, Kao JH, Piratvisuth T, Chan HLY, Chien RN, Liu CJ, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol Int. 2012;6:531–61.CrossRefPubMed Liaw YF, Kao JH, Piratvisuth T, Chan HLY, Chien RN, Liu CJ, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol Int. 2012;6:531–61.CrossRefPubMed
20.
go back to reference Vallet-Pichard A, Mallet V, Nalpas B, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection: comparison with liver biopsy and fibrotest. Hepatology. 2007;46:32–6.CrossRefPubMed Vallet-Pichard A, Mallet V, Nalpas B, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection: comparison with liver biopsy and fibrotest. Hepatology. 2007;46:32–6.CrossRefPubMed
21.
go back to reference D’Agostino RBB. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med. 1998;17:2265–81.CrossRefPubMed D’Agostino RBB. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med. 1998;17:2265–81.CrossRefPubMed
22.
go back to reference Austin PC. Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies. Pharm Stat. 2011;10:150–61.CrossRefPubMed Austin PC. Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies. Pharm Stat. 2011;10:150–61.CrossRefPubMed
23.
go back to reference An J, Shim JH, Kim SO, Choi J, Kim SW, Lee D, et al. Comprehensive outcomes of on- and off-antiviral prophylaxis in hepatitis B patients undergoing cancer chemotherapy: a competing risks analysis. J Med Virol. 2016;88:1576–86.CrossRefPubMed An J, Shim JH, Kim SO, Choi J, Kim SW, Lee D, et al. Comprehensive outcomes of on- and off-antiviral prophylaxis in hepatitis B patients undergoing cancer chemotherapy: a competing risks analysis. J Med Virol. 2016;88:1576–86.CrossRefPubMed
24.
go back to reference Kuo MT, Tseng PL, Chou YP, Chang KC, Tsai MC, Kuo YH, et al. Role of hepatitis B surface antigen in hepatitis B virus relapse after entecavir or tenofovir prophylaxis in patients undergoing cancer chemotherapy. J Gastroenterol Hepatol. 2018;33:1766–72.CrossRefPubMed Kuo MT, Tseng PL, Chou YP, Chang KC, Tsai MC, Kuo YH, et al. Role of hepatitis B surface antigen in hepatitis B virus relapse after entecavir or tenofovir prophylaxis in patients undergoing cancer chemotherapy. J Gastroenterol Hepatol. 2018;33:1766–72.CrossRefPubMed
25.
go back to reference Kim In K, Kim Byeong G, Kim W, Kim D, Kim Yoon J, Yoon J-H, et al. Clinical prediction of failure of lamivudine prophylaxis for hepatitis B virus-infected patients undergoing cytotoxic chemotherapy for malignancy. Antimicrob Agents Chemother. 2012;56:5511–9.CrossRefPubMed Kim In K, Kim Byeong G, Kim W, Kim D, Kim Yoon J, Yoon J-H, et al. Clinical prediction of failure of lamivudine prophylaxis for hepatitis B virus-infected patients undergoing cytotoxic chemotherapy for malignancy. Antimicrob Agents Chemother. 2012;56:5511–9.CrossRefPubMed
26.
go back to reference Chen CH, Hung CH, Hu TH, Wang JH, Lu SN, Su PF, et al. Association between level of hepatitis B surface antigen and relapse after entecavir therapy for chronic HBV infection. Clin Gastroenterol Hepatol. 2015;13:1984–92.CrossRefPubMed Chen CH, Hung CH, Hu TH, Wang JH, Lu SN, Su PF, et al. Association between level of hepatitis B surface antigen and relapse after entecavir therapy for chronic HBV infection. Clin Gastroenterol Hepatol. 2015;13:1984–92.CrossRefPubMed
27.
go back to reference Jeng WJ, Chen YC, Chien RN, Sheen IS, Liaw YF. Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B. Hepatology. 2018;68:425–34.CrossRefPubMed Jeng WJ, Chen YC, Chien RN, Sheen IS, Liaw YF. Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B. Hepatology. 2018;68:425–34.CrossRefPubMed
28.
go back to reference Chen CH, Hung CH, Wang JH, Lu SN, Hu TH, Lee CM. Long-term incidence and predictors of hepatitis B surface antigen loss after discontinuing nucleoside analogues in noncirrhotic chronic hepatitis B patients. Clin Microbiol Infect. 2018;24:997–1003.CrossRefPubMed Chen CH, Hung CH, Wang JH, Lu SN, Hu TH, Lee CM. Long-term incidence and predictors of hepatitis B surface antigen loss after discontinuing nucleoside analogues in noncirrhotic chronic hepatitis B patients. Clin Microbiol Infect. 2018;24:997–1003.CrossRefPubMed
29.
go back to reference Evens AM, Jovanovic BD, Su YC, Raisch DW, Ganger D, Belknap SM, et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann Oncol. 2011;22:1170–80.CrossRefPubMed Evens AM, Jovanovic BD, Su YC, Raisch DW, Ganger D, Belknap SM, et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann Oncol. 2011;22:1170–80.CrossRefPubMed
30.
go back to reference Huang YH, Hsiao LT, Hong YC, Chiou TJ, Yu YB, Gau JP, et al. Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J Clin Oncol. 2013;31:2765–72.CrossRefPubMed Huang YH, Hsiao LT, Hong YC, Chiou TJ, Yu YB, Gau JP, et al. Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J Clin Oncol. 2013;31:2765–72.CrossRefPubMed
31.
go back to reference Hsu C, Tsou HH, Lin SJ, Wang MC, Yao M, Hwang W, et al. Chemotherapy-induced hepatitis B reactivation in lymphoma patients with resolved HBV infection: a prospective study. Hepatology. 2014;59:2092–100.CrossRefPubMed Hsu C, Tsou HH, Lin SJ, Wang MC, Yao M, Hwang W, et al. Chemotherapy-induced hepatitis B reactivation in lymphoma patients with resolved HBV infection: a prospective study. Hepatology. 2014;59:2092–100.CrossRefPubMed
32.
go back to reference Chang WY, Chiu YC, Chiu FW, Hsu YC, Tseng TC, Cheng PN, et al. High risk of clinical relapse in patients with chronic hepatitis B virus infection after cessation of prophylactic antiviral therapy for rituximab-containing chemotherapy. J Infect Dis. 2020;222:1345–52.CrossRefPubMed Chang WY, Chiu YC, Chiu FW, Hsu YC, Tseng TC, Cheng PN, et al. High risk of clinical relapse in patients with chronic hepatitis B virus infection after cessation of prophylactic antiviral therapy for rituximab-containing chemotherapy. J Infect Dis. 2020;222:1345–52.CrossRefPubMed
33.
go back to reference Perrillo RP, Gish R, Falck-Ytter YT. American gastroenterological association institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology. 2015;148:221–44.CrossRefPubMed Perrillo RP, Gish R, Falck-Ytter YT. American gastroenterological association institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology. 2015;148:221–44.CrossRefPubMed
34.
go back to reference Xiao G, Yang J, Yan L. Comparison of diagnostic accuracy of aspartate aminotransferase to platelet ratio index and fibrosis-4 index for detecting liver fibrosis in adult patients with chronic hepatitis B virus infection: a systemic review and meta-analysis. Hepatology. 2015;61:292–302.CrossRefPubMed Xiao G, Yang J, Yan L. Comparison of diagnostic accuracy of aspartate aminotransferase to platelet ratio index and fibrosis-4 index for detecting liver fibrosis in adult patients with chronic hepatitis B virus infection: a systemic review and meta-analysis. Hepatology. 2015;61:292–302.CrossRefPubMed
35.
Metadata
Title
Hepatitis B relapse after entecavir or tenofovir alafenamide cessation under anti-viral prophylaxis for cancer chemotherapy
Authors
Hsin-Wei Fang
Po-Lin Tseng
Tsung-Hui Hu
Jing-Houng Wang
Chao-Hung Hung
Sheng-Nan Lu
Chien-Hung Chen
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Virology Journal / Issue 1/2024
Electronic ISSN: 1743-422X
DOI
https://doi.org/10.1186/s12985-024-02338-6

Other articles of this Issue 1/2024

Virology Journal 1/2024 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.