Rohit Loomba, MBBS, MHSc; Ayana Rowley, PharmD; Robert Wesley, PhD; T. Jake Liang, MD; Jay H. Hoofnagle, MD; Frank Pucino, PharmD; Gyorgy Csako, MD
Acknowledgment: The authors thank Jordan Feld, MD, who provided feedback on the study results.
Grant Support: By the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases and the Clinical Center, National Institutes of Health.
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Rohit Loomba, MBBS, MHSc, CRC-4-5722, MSC-1614, 10 Center Drive, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; e-mail, email@example.com.
Current Author Addresses: Dr. Loomba: Division of Gastroenterology, Department of Medicine, University of California at San Diego, UC 303, MC063, 9500 Gilman Drive, La Jolla, CA 92093.
Drs. Rowley and Pucino: Pharmacy Department, Clinical Center, Building 10, Room 1N-257, 10 Center Drive, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD 20892.
Dr. Wesley: Hospital Epidemiology, Clinical Center, Building 10, Room 2N-228B, 10 Center Drive, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD 20892.
Dr. Liang: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Building 10/9B-16, MSC-1800, 10 Center Drive, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD 20892.
Dr. Hoofnagle: Liver Diseases Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Building 31/9A-27, MSC-1800, 31 Center Drive, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD 20892.
Dr. Csako: Department of Laboratory Medicine, Clinical Center, Building 10, Room 2C-407, 10 Center Drive, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892.
Lamivudine is increasingly being used to prevent hepatitis B reactivation in patients with cancer who test positive for hepatitis B surface antigen (HBsAg) and are undergoing chemotherapy.
To determine whether preventive lamivudine reduces chemotherapy-induced hepatitis B virus (HBV)–related morbidity and mortality in patients with cancer who test positive for HBsAg.
MEDLINE, Ovid MEDLINE, TOXNET, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials were searched in all languages until June 2007.
Clinical trials and cohort studies that reported the efficacy of preventive lamivudine versus control on HBV reactivation in patients who tested positive for HBsAg and were receiving chemotherapy were included. Additional requirements included minimum sample size (>5 participants per treatment group) and reported HBV-related morbidity and mortality data.
Two investigators independently did literature searches and data extraction, and 2 other investigators independently confirmed study eligibility and data retrieval.
Fourteen studies (2 randomized, controlled trials; 8 prospective cohort studies; and 4 retrospective cohort studies) met the predefined criteria for analysis. There were 275 patients in the preventive lamivudine group and 475 control participants for the primary end point of HBV reactivation. With preventive lamivudine, the relative risk for both HBV reactivation and HBV-related hepatitis ranged from 0.00 to 0.21. None of the patients in the preventive lamivudine group developed HBV-related hepatic failure (0 of 108 patients vs. 21 of 162 patients), and only 4 deaths were attributable to HBV (4 of 208 patients vs. 27 of 394 patients) in the preventive lamivudine group. Lamivudine was well tolerated, and no adverse effects were noted.
The studies included in the meta-analysis did not consistently report all of the outcomes of interest. Sample sizes were small and only 2 studies had a randomized, controlled design.
Preventive therapy with lamivudine for patients who test positive for HBsAg and are undergoing chemotherapy may reduce the risk for HBV reactivation and HBV-associated morbidity and mortality.
Does lamivudine prevent hepatitis B virus (HBV) reactivation among patients with cancer who test positive for hepatitis B surface antigen (HBsAg) and are undergoing chemotherapy?
This systematic review of 14 studies found that, compared with no preventive lamivudine, lamivudine reduced HBV reactivation, HBV-related hepatitis, and HBV-related hepatic failure.
Studies were small and heterogeneous. Only 2 were randomized trials, and none compared lamivudine with other, newer anti-HBV agents.
Preventive lamivudine may reduce risk for HBV reactivation and associated death in HBsAg-positive patients with cancer who are undergoing chemotherapy.
Study flow diagram.
Appendix Table. Methodological Characteristics of Clinical Trials Assessing the Efficacy of Preventive Lamivudine
Table 1. Characteristics of Clinical Trials Assessing the Efficacy of Preventive Lamivudine
Forest plot of clinical trials assessing hepatitis B virus reactivation (top) and hepatitis B virus–related hepatic failure (bottom).
*Preventive versus deferred lamivudine. †Preventive versus no lamivudine.
Forest plot of clinical trials assessing hepatitis B virus–related death (top) and hepatitis (bottom).
Table 2. Treatment Characteristics and Death in Clinical Trials Assessing the Efficacy of Preventive Lamivudine
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Deapartments of Oncology and Internal Medicine, National Taiwan University Hospital
March 4, 2009
Prophylactic lamivudine for chemotherapy-induced hepatitis B reactivation
We read with great interest the systematic review done by Loomba et al for chemotherapy-induced hepatitis B (HBV) reactivation in cancer patients who tested positive for HBV surface antigen (1). However, some of the information as quoted in that paper needs clarification.
In table 1, regarding the use of corticosteroids as one of the most important risk factors of chemotherapy-induced HBV reactivation (2), our study and the study by Lau et al were mistakenly categorized as either not reported or not using corticosteroids. In fact, both studies enrolled patients with lymphoma, and corticosteroid was an integral component of most standard chemotherapy for lymphoma. Therefore, both studies used corticosteroids for the treatment of their subjects.
In table 1, our study was in the category of prospective cohort study with historical control. In fact, our study was a randomized controlled clinical trial (ClinicalTrials.gov Identifier: NCT00201318)(3). Our study enrolled patients with newly diagnosed non-Hodgkin's lymphoma and randomized the patients to either prophylactic lamivudine during chemotherapy or therapeutic lamivudine upon hepatitis flare. The incidence of both HBV reactivation and HBV-related hepatitis flare were significantly reduced by prophylactic lamivudine. Our paper also indicated that therapeutic lamivudine neither reduced the severity of HBV-related hepatitis nor changed the patterns of HBV reactivation.
In the discussion section the authors mentioned that we proposed a duration of prophylactic lamivudine for at least 8 months after completion of chemotherapy. Although our study indicated that HBV reactivation may occur more than 6 months after completion of chemotherapy, we did not recommend a specific duration of prophylactic lamivudine. The optimal duration of prophylactic lamivudine is still unknown. Most previous studies continued lamivudine prophylaxis for 1 to 3 months after completion of chemotherapy, and the current guidelines by the American Association for the Study of Liver Diseases (AASLD) recommended prophylactic lamivudine for at least 6 months after completion of chemotherapy, based on expert consensus (4). The potential benefit of longer-term anti-viral therapy must be judged against the risk of inducing viral mutants and drug resistance. Further clinical trials to determine the optimal duration and agents of anti-viral therapy are definitely warranted.
1. Loomba R, Rowley A, Wesley R, Liang J, Hoofnagle JH, Pucino F, et al: Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann Int Med 2008; 148: 519-528
2. Cheng AL, Hsiung CA, Su IJ, Chen PJ, Chang MC, Tsao CJ, et al. Steroid-free chemotherapy decreases risk of hepatitis B virus (HBV) reactivation in HBV-carriers with lymphoma. Hepatology 2003; 37: 1320-1328
3. Hsu C, Hsiung CA, Su IJ, Hwang WS, Wang MC, Lin SF, et al: A revisit for prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-Hodgkin's lymphoma: a randomized trial. Hepatology 2008; 47: 844-853
4. Lok ASF, McMahon BJ: Chronic hepatitis B. Hepatology 2007; 507-39
University of California at San Diego
March 12, 2009
Hepatitis B reactivation due to cancer chemotherapy
We would like to thank Dr. Hsu and colleagues for their comments on our meta-analysis dealing with the beneficial role of preventive lamivudine in reducing hepatitis B reactivation during cancer chemotherapy (1). We agree that corticosteroids play an important role in chemotherapy-induced HBV reactivation and this was the reason to list the use of corticosteroids in a dedicated column in Table 1. Unfortunately, as apparent from the adjacent chemotherapy column showing administration of CHOP (where P stands for prednisone), patients from the study of Lau et al. (2) and Hsu et al. (3) were both erroneously labeled as respectively "not receiving" and "not reported" receiving corticosteroids. We also acknowledge that, instead of randomized clinical trial with therapeutic (deferred) lamivudine controls, the study by Hsu et al. (3) was inadvertently classified as prospective with historical controls in the tables 1 and figures. It should be noted, however, that we quoted the meeting abstract of the study published by the authors (3) and not the paper they reference as being quoted (4). Their full manuscript with the cited clinical trial identifier was not yet published until after the acceptance of our meta-analysis. Additionally, the corresponding authors of all the published studies and abstracts included in our meta-analysis were contacted via email for further clarifications but we were unsuccessful in getting a response. Authors may also recall that their meeting abstract title did not mention that their study was a randomized-controlled study (3) and the title was reworded only later when published in its entirety (4). Because our research synthesis did not pool data from various studies, the apparent misclassification of this study has no effect on the conclusions.
On the other hand, the statement in our Discussion section about the duration of prophylactic lamivudine was based upon a direct quote from the Conclusion section of the abstract by Hsu et al. (3): "The duration of lamivudine prophylaxis, which can reduce the incidence and severity of HBV reactivation and hepatitis during chemotherapy, may have to be no less than 8 months after completion of chemotherapy." That is, the authors indeed did recommend a specific duration (at least 8 months) of prophylactic lamivudine after discontinuation of chemotherapy (3).
2. Lau GK, Yiu HH, Fong DY, et al. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology 2003; 125(6):1742-9.
3. Hsu C HC, Su IJ, Hwang WS, Wang MC, Lin SF, Lin TH, et al. A prospective comparative study of prophylactic or therapeutic use of lamivudine for chemotherapy-associated hepatitis B (HBV) reactivation in non-Hodgkin's lymphoma patients. Gastroenterology 2006; 131:S 297; 788 A (American Gastroenterology Association Meeting Abstracts 2006).
4. Hsu C, Hsiung CA, Su IJ, Hwang WS, Wang MC, Lin SF, et al: A revisit for prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-Hodgkin's lymphoma: a randomized trial. Hepatology 2008; 47: 844-853
Loomba R, Rowley A, Wesley R, Liang TJ, Hoofnagle JH, Pucino F, et al. Systematic Review: The Effect of Preventive Lamivudine on Hepatitis B Reactivation during Chemotherapy. Ann Intern Med. 2008;148:519–528. doi: 10.7326/0003-4819-148-7-200804010-00008
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Published: Ann Intern Med. 2008;148(7):519-528.
Gastroenterology/Hepatology, Infectious Disease, Viral Hepatitis.
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