0

The full content of Annals is available to subscribers

Subscribe/Learn More  >
Reviews |

Hepatitis B Virus Reactivation and Prophylaxis During Solid Tumor Chemotherapy: A Systematic Review and Meta-analysisHBV Reactivation in Solid Tumors

Sonali Paul, MD, MS; Akriti Saxena, MD; Norma Terrin, PhD; Kathleen Viveiros, MD; Ethan M. Balk, MD, MPH; and John B. Wong, MD
[+] Article, Author, and Disclosure Information

This article was published online first at www.annals.org on 24 November 2015.


Tufts Medical Center, Massachusetts General Hospital, and Boston Medical Center, Boston, Massachusetts, and Brown University School of Public Health, Providence, Rhode Island.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Grant Support: By the National Center for Advancing Translational Sciences and National Institutes of Health (grants UL1 TR001064 and UL1 TR000073). Dr. Paul received grant support through the 2013 to 2014 Bristol-Myers Squibb Virology Research Training Program.

Disclosures: Dr. Paul reports grants from National Center for Advancing Translational Sciences, National Institutes of Health, and the 2013 to 2014 Bristol-Myers Squibb Virology Research Training Program during the conduct of the study. Dr. Wong reports nonfinancial support from the American Association for the Study of Liver Diseases (as a member of systematic review writing group for an HBV practice guideline) outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-1121.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.

Reproducible Research Statement:Study protocol, statistical code, and data set: Available from Dr. Paul upon request (e-mail, sonali.paul2@gmail.com).

Requests for Single Reprints: Sonali Paul, MD, MS, Massachusetts General Hospital Gastroenterology Associates, 55 Fruit Street, Blake 4, Boston, MA 02114; e-mail, sonali.paul2@gmail.com.

Current Author Addresses: Dr. Paul: Massachusetts General Hospital Gastroenterology Associates, 55 Fruit Street, Blake 4, Boston, MA 02114.

Dr. Saxena: Boston Medical Center, Gastroenterology, Moakley Building, 2nd Floor, 830 Harrison Avenue, Boston, MA 02118.

Dr. Terrin: Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, 35 Kneeland Street, 9th Floor, Boston, MA 02111.

Dr. Viveiros: Division of Gastroenterology and Hepatology, Tufts Medical Center, 800 Washington Street, Box 233, Boston, MA 02111.

Dr. Balk: Center for Evidence-Based Medicine, Brown University School of Public Health, Box G-S121-8, Providence, RI 02912.

Dr. Wong: Division of Clinical Decision Making, Tufts Medical Center, 35 Kneeland Street, 7th Floor, Boston, MA 02111.

Author Contributions: Conception and design: S. Paul, N. Terrin, K. Viveiros, J.B. Wong.

Analysis and interpretation of the data: S. Paul, A. Saxena, N. Terrin, J.B. Wong.

Drafting of the article: S. Paul, N. Terrin, J.B. Wong.

Critical revision of the article for important intellectual content: S. Paul, N. Terrin, K. Viveiros, E.M. Balk, J.B. Wong.

Final approval of the article: S. Paul, N. Terrin, K. Viveiros, E.M. Balk, J.B. Wong.

Statistical expertise: N. Terrin, E.M. Balk, J.B. Wong.

Obtaining of funding: S. Paul.

Collection and assembly of data: S. Paul, A. Saxena.


Ann Intern Med. 2016;164(1):30-40. doi:10.7326/M15-1121
Text Size: A A A

Background: Solid tumor chemotherapy regimens pose a risk for hepatitis B virus (HBV) reactivation, but screening and antiviral prophylaxis remains controversial because of insufficient evidence.

Purpose: To determine the risk for HBV reactivation with and without antiviral prophylaxis and the effectiveness of prophylaxis in adults with solid tumors and chronic or resolved HBV infection.

Data Sources: MEDLINE through 1 July 2015 and Web of Science, Cochrane Central Register of Controlled Trials, TOXNET, and Scopus through 1 March 2015.

Study Selection: 26 English-language observational studies and randomized, controlled trials in patients with chronic or resolved HBV receiving chemotherapy for solid tumors.

Data Extraction: Study characteristics, quality, and risk of bias were assessed by 1 researcher and verified by another independent researcher.

Data Synthesis: Random-effects model meta-analyses were used to estimate the risk and odds ratio (OR) of reactivation with versus without antiviral prophylaxis. Reactivation in chronic HBV without prophylaxis ranged from 4% to 68% (median, 25%) with substantial heterogeneity. Prophylaxis reduced the risk for HBV reactivation (OR, 0.12 [95% CI, 0.06 to 0.22]), HBV-related hepatitis (OR, 0.18 [CI, 0.10 to 0.32]), and chemotherapy interruption (OR, 0.10 [CI, 0.04 to 0.27]). In 3 studies of patients with resolved HBV infection, none received HBV prophylaxis and reactivation risk ranged from 0.3% to 9.0%.

Limitations: Significant heterogeneity in underlying study populations and treatment regimens, incomplete baseline data, possibility of publication bias, and limited study quality. Most studies were observational and from Asia.

Conclusion: In patients with chronic HBV receiving solid tumor chemotherapy, the risk for HBV reactivation is similar to the risk with other types of immunosuppressive therapy. Results support HBV screening and antiviral prophylaxis before initiation of chemotherapy for solid tumors.

Primary Funding Source: National Center for Advancing Translational Sciences and National Institutes of Health.

Figures

Grahic Jump Location
Appendix Figure 1.

Summary of evidence search and selection.

HBV = hepatitis B virus.

Grahic Jump Location
Grahic Jump Location
Figure 1.

Absolute risk for HBV reactivation without antiviral prophylaxis in patients with chronic HBV infection.

HBV = hepatitis B virus.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Absolute risk for HBV reactivation without antiviral prophylaxis in patients with chronic HBV infection, by tumor subtype.

HBV = hepatitis B virus.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 2.

Absolute risk for HBV reactivation without antiviral prophylaxis in patients with chronic HBV, by chemotherapy subtype.

HBV = hepatitis B virus; FOLFIRI = folinic acid, fluorouracil, and irinotecan hydrochloride; FOLFOX = folinic acid, fluorouracil, and oxaliplatin.

* Study recorded steroid use.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 3.

Absolute risk for secondary outcomes without antiviral prophylaxis in patients with solid tumors and chronic HBV infection.

HBV = hepatitis B virus.

Grahic Jump Location
Grahic Jump Location
Figure 3.

Odds ratio for HBV reactivation with and without antiviral prophylaxis in patients with chronic HBV infection.

HBV = hepatitis B virus.

Grahic Jump Location
Grahic Jump Location
Figure 4.

Odds ratio for secondary outcomes with and without antiviral prophylaxis in patients with chronic HBV infection.

HBV = hepatitis B virus.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 4.

Absolute risk for HBV reactivation without antiviral prophylaxis in patients with resolved HBV infection.

HBV = hepatitis B virus.

Grahic Jump Location

Tables

References

Letters

CME Activities are only available to ACP members and Individual Annals subscribers. If you are a member or a subscriber please sign in. Otherwise please become a member or subscribe to Annals.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

Submit a Comment/Letter
Hepatitis B Virus Reactivation in Patients with Solid Tumors During Chemotherapy: Universal Screening and Prevention or Selective Screening and Containment
Posted on February 6, 2016
Ayokunle T. Abegunde
Section of Digestive Diseases, Oklahoma University Health Sciences Center
Conflict of Interest: None Declared
The systematic review by Paul and colleagues is very timely.1 Lack of strong evidence that Hepatitis B virus reactivation (HBVr) negatively affects oncology mortality outcomes and limited data on the cost-effectiveness of universal screening compared with selective screening for HBV in patients scheduled to receive immunosuppressive therapy(IST) has led to justifiable caution in adopting universal screening by the American Society of Clinical Oncology(ASCO), while the American Gastroenterology Association(AGA), Centers for Disease Control and Prevention (CDC), and American Association for the Study of Liver diseases (AASLD) have recommended universal screening.2-4 Against that backdrop the systematic review by Paul and colleagues extend our knowledge on HBVr in patients with solid tumors undergoing chemotherapy. This is a sub-group of patients in which robust data on HBVr are lacking. Unfortunately, the data on the effect of HBVr on mortality did not reach statistical significance and the debate on screening is likely to continue. The concept of selective screening hinges on appropriate risk stratification or physician discretion to identify patients at risk of HBV infection and reactivation prior to chemotherapy or IST. Recent studies suggest that recognition of risk factors for HBV by physicians (hematologists, rheumatologists and medical oncologists) prescribing IST is suboptimal.5 In another study, missed opportunities for HBV-screening were attributed to physicians underestimating country of origin as a risk-factor.6 Taken together, the reported low awareness of HBV risk and low screening rates suggest that physicians prescribing IST are unlikely to correctly identify and screen all high-risk patients for HBV.5,6 This is a trend that has been reported in other studies.6,7 The extent to which this trend is influenced by divergent subspecialty guidelines is unclear, however it highlights an unmet need for patient care and physician education. Nevertheless, the systematic review by Paul and colleagues strengthen the argument for universal HBV screening before initiation of chemotherapy for solid tumors and provides good enough evidence to guide clinical care.

References
1. Paul S, Saxena A, Terrin N, Viveiros K, Balk EM, Wong JB. Hepatitis B Virus Reactivation
and Prophylaxis During Solid Tumor Chemotherapy: A Systematic Review and Meta-
analysis. Ann Intern Med. 2016;164(1):30-40.
2. Reddy KR, Beavers KL, Hammond SP et al. American Gastroenterological Association
Institute Guideline on the Prevention and Treatment of Hepatitis B Virus Reactivation During
Immunosuppressive Drug Therapy. Gastroenterology 2015; 148: 215–219.
3. 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;148:221–244.e3
4. Visram A, Chan KK, McGee P, Boro J, Hicks LK, Feld JJ. Poor recognition of risk factors
for hepatitis B by physicians prescribing immunosuppressive therapy: a call for universal
rather than risk-based screening. PLoS One. 2015 Apr 15;10(4):e0120749.
5. Bottero J, Boyd A, Lemoine M et al. Current state of and needs for hepatitis B screening:
results of a large screening study in a low-prevalent, metropolitan region. PLoS One. 2014
Mar 24;9(3):e92266.
6. Lee R, Bell C, Singh J, Hicks L. Hepatitis B screening before chemotherapy: a survey of
practitioners' knowledge, beliefs, and screening practices. J Oncol Pract, 2012. 8(6): 325–8
7. Khokhar O, Farhadi A, McGrail L, Lewis J. Oncologists and hepatitis B: a survey to
determine current level of awareness and practice of antiviral prophylaxis to prevent
reactivation. Chemotherapy, 2009. 55(2): p. 69–75.


Submit a Comment/Letter

Summary for Patients

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.

Toolkit

Buy Now for $32.00

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Advertisement
Related Articles
Topic Collections
PubMed Articles
Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.
(Required)
(Required)