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. 2019 Sep 12;2019(9):CD005264. doi: 10.1002/14651858.CD005264.pub3

Lamivudine for preventing reactivation of hepatitis B infection in patients planned to undergo immunosuppressive therapy

Lior H Katz 1,✉, Abigail Fraser 2, Leonard Leibovici 3, Ran Tur‐Kaspa 4, Hadar Goldvaser 5
PMCID: PMC6741844

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To evaluate the beneficial and harmful effects of lamivudine in preventing reactivation of HBV during or following immunosuppressive therapy in HBsAg‐positive patients.

To estimate the optimal time of initiating lamivudine prophylactic therapy in HBsAg‐positive patients receiving immunosuppressive therapy.

Background

Chronic hepatitis B virus (HBV) infection is one of the most common infectious diseases in the world, affecting about 360 million people (The EASL Jury 2003). HBV infection causes a wide spectrum of clinical manifestations ranging from inactive carrier state, acute self‐limited or fulminant hepatitis, to chronic liver disease. Chronic hepatitis B is frequently associated with the development of liver cirrhosis and eventually hepatocellular carcinoma.

Until the last decade, the only approved treatment for chronic hepatitis B was interferon alpha. Interferon alpha is an immunomodulator agent with frequent and severe adverse events. The intervention has also been proven to be ineffective and even contraindicated in some immunosuppressed patients (Rostaing 1996). Nowadays, antiviral agents, especially lamivudine, have become another option for treating patients with chronic hepatitis B. Lamivudine, a nucleoside analogue, inhibits HBV replication and reduces viral load, leading to clinical, biochemical, serological, and histological improvement in patients with chronic hepatitis B (Lai 1998; Jarvis 1999; Dienstag 2003).

Immunosuppression caused by chronic steroid treatment, cancer chemotherapy, or immunosuppressive agents used in connection with bone marrow or organ transplantation can cause life‐threatening reactivation of HBV replication in patients with chronic hepatitis B infection (HBsAg‐positive patients) (Galbraith 1975; Hoofnagle 1982; Hanson 1985; Pariente 1988; Flowers 1990). HBV reactivation causes liver damage in two stages (Lau 2002). The first stage occurs during the immunosuppressive or cytotoxic therapy and is characterised by enhanced viral replication reflected by increased serum levels of hepatitis B envelope antigen (HBeAg) (seen only in patients without precore mutants), HBV DNA, and HBV DNA polymerase. This stage results in extensive infection of hepatocytes. In the second stage, withdrawal of the immunosuppressive or cytotoxic therapy causes restoration of immune function, leading to rapid immune‐mediated destruction of infected hepatocytes, clinically expressed as hepatitis and hepatic failure that may result in death (Hoofnagle 1982; McMilan 1995; Perrillo 2001). Patients with precore mutants (ie, who lack the HBeAg but still show continued replication even in the presence of anti‐HBe) have a great risk for reactivation (Dai 2001).

The incidence of HBV reactivation in HBsAg‐positive cancer patients undergoing cytotoxic chemotherapy is between 10% to 50% (Lok 1991; Nakamura 1996; Yeo 2000; Idliman 2003; Yeo 2003; Yeo 2004; Zhong 2004). The clinical spectrum ranges from asymptomatic reversible elevated liver enzymes to fatal hepatic failure (Galbraith 1975; Hoofnagle 1982; Lok 1991; Kumagai 1997; Yeo 2000). Mortality rates from such HBV reactivation range between 4% and 60% (Scullard 1981; Hoofnagle 1982; Steinberg 2000). Known risk factors for immunosuppression‐induced HBV reactivation include male gender, young age at infection, glucocorticoid‐based treatment, and a greater degree of immunosuppression (Vento 2002). Early reports of HBV reactivation mainly included patients with haematological malignancies (Galbraith 1975; Lok 1991; Nakamura 1996; Kumagai 1997) while more recent reports describe this phenomenon in patients with solid tumours as well (Alexopoulos 1999; Yeo 2000; Yeo 2003). Within the chemotherapeutic regimens, glucocorticoids are an important predisposing factor for reactivation of the latent HBV (Tur‐Kaspa 1986), and steroid‐free chemotherapy may decrease the risk of reactivation (Cheng 1996; Cheng 2003). HBV reactivation has also been described in transplanted patients. More than 80% of HBsAg‐positive renal transplant recipients develop progressive liver disease, which accounts for 37% to 57% mortality in this population (Fornairon 1996; Han 2001; Chan 2002). HBV reactivation is also a serious cause of morbidity and mortality in HBsAg‐positive patients who undergo haematopoietic stem cell transplantation (Pariente 1988). Furthermore, patients after allogeneic bone marrow transplantation have 21% actuarial risk of reactivation of hepatitis B, even if they are HBsAg negative, but have serum antibodies to hepatitis B antigens (Dhedin 1998). Reactivation of hepatitis B in kidney and heart transplanted patients only having antibodies to hepatitis B antigens has also been reported.

The management of HBV reactivation in immunocompromised states begins with routine screening for markers of chronic or past HBV infection prior to receiving chemotherapy or transplantation in order to identify patients at risk (Liao 2002). Exclusion of glucocorticoids from chemotherapy regimens may decrease the risk of HBV reactivation, but it carries the risk of sub‐optimal treatment of the malignancy (Liao 2002).

Lamivudine and other nucleoside analogues are used to treat HBV reactivation in immunocompromised patients, allowing completion of immunosuppressive courses (Clark 1988; Jung 1998; Al‐Taie 1999; Yeo 1999; Silvestri 2000; Liao 2002). Lamivudine is also effective in renal transplant patient in suppressing HBV replication and reducing liver damage (Tsang 2003). However, despite the use of antiviral drugs at the time of clinical hepatitis, HBsAg‐positive patients may still develop fatal hepatic failure (Yeo 1999; Steinberg 2000; Liao 2002). The reason probably being too late institution of therapy when immune‐mediated liver damage has already occurred.

Prevention may, therefore, be the key to effective management of HBV reactivation. Prophylactic or pre‐emptive lamivudine before the institution of immunosuppression seems to be a reasonable approach for preventing reactivation of HBV in the early immunosuppressive phase (Lim 2002).

We have been unable to identify any meta‐analyses or systematic reviews on the beneficial or harmful effects of lamivudine for patients in the inactive HBV carrier state who will undergo immunosuppressive therapy regardless of the cause.

Objectives

To evaluate the beneficial and harmful effects of lamivudine in preventing reactivation of HBV during or following immunosuppressive therapy in HBsAg‐positive patients.

To estimate the optimal time of initiating lamivudine prophylactic therapy in HBsAg‐positive patients receiving immunosuppressive therapy.

Methods

Criteria for considering studies for this review

Types of studies

Randomised clinical trials addressing the beneficial and harmful effects of lamivudine for prevention of clinical HBV‐related hepatitis or virological HBV‐reactivation (without clinical hepatitis) in HBsAg‐positive patients who are about to receive immunosuppressive therapy. Studies will be included irrespective of publication status, language, or blinding.

Types of participants

Inclusion criteria

Patients regardless of their sex, ethnicity, age or age of infection with the diagnosis of chronic hepatitis B, as defined by positive HBsAg without an acute infection, or by positive anti‐HBc and/or anti‐HBs antibodies with negative HBsAg ('anti‐HB core alone') without an acute infection, who are about to be treated with:

  • Anti‐cancer chemotherapy (including glucocorticoids).

  • Immunosuppressive drugs after non‐liver related transplantation (solid organ or bone‐marrow).

  • Immunosuppressive drugs after liver transplantation.

  • Immunosuppressive drugs due to other reasons (including glucocorticoids).

Exclusion criteria

  • Patients intended to undergo liver transplantation. These patients differ substantially from included patients as the infected liver is removed during transplantation.

  • Decompensated liver disease as indicated by prolonged prothrombin time (equals or more than 4 sec), decreased albumin level (less than 20 g/L), and increased total bilirubin level (more than 50 micromol/L).

  • Alanine aminotransferase (ALT) more than 10 times the upper limit of normal.

  • Treatment with antiviral therapy known to have activity against HBV within the six months before the trial.

Types of interventions

  • Any dosage of lamivudine versus no treatment or placebo.

  • Lamivudine versus alpha interferon or other anti‐viral agents with any dosage or route of administration.

  • Lamivudine, beginning before immunosuppressive therapy versus lamivudine after virological HBV reactivation.

Collateral interventions will be allowed if offered equally to both groups of the trial.

Types of outcome measures

Primary outcomes At least six weeks after the end of treatment: 1. Occurrence of viral reactivation of hepatitis B infection as defined by an increase in HBV DNA level of ten‐fold or more when compared with baseline level or an absolute increase of HBV DNA that exceeds 105 copies/ml in the absence of other systemic infection (The EASL Jury 2003). 2. Occurrence of clinical reactivation of hepatitis B (as defined in primary outcome #1) as measured by: (a) at least a three‐fold increase in ALT resulting in a value that exceeds the upper limit of the normal range or (b) an absolute increase of alanine transaminase (ALT) level to over 100 U/L compared with baseline (Yeo 2004). 3. Overall mortality.

Secondary outcomes At least six weeks after the end of treatment: 4. HBV‐related mortality. 5. Liver histology: post‐treatment liver biopsy hepatic inflammatory injury, fibrosis, and overall appearance (cirrhosis or HCC). 6. Discontinuation of immunosuppressive therapy. 7. Occurrence of lamivudine‐resistant HBV strains subsequent to treatment. 8. Occurrence of adverse events: adverse events as well as serious adverse events defined as any untoward medical occurrence in a patient in either of the two described regimens, which did not necessarily have a causal relationship with the treatment. Serious adverse events are defined according to the ICH guidelines (ICH‐GCP 1997) as any event that led to death, was life‐threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability or congenital anomaly/birth defect, any important medical event, which might have jeopardized the patient or required intervention to prevent it.

Search methods for identification of studies

Electronic searches will be performed in The Cochrane Hepato‐Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and LILACS. In addition, we will search the references of all identified studies.

The preliminary search strategies can be found in Appendix 1.

In addition, we will inquire the principal authors of identified randomised clinical trials and pharmaceutical companies involved in the production of lamivudine about additional published or unpublished randomised clinical trials.

Data collection and analysis

We will perform the review following the recommendations of The Cochrane Collaboration (Higgins 2008) and The Cochrane Hepato‐Biliary Group Module (Gluud 2008). The analyses will be performed using Review Manager 5.0 (RevMan 2008).

Study selection Two authors (LK and AG) will independently inspect each reference identified by the search and apply the inclusion criteria. For possible relevant articles or in cases of disagreement between the two authors, the full article will be obtained and inspected independently by the two authors. Should the two authors still disagree, a third independent author (LLBH) will be consulted.

Assessment of risk of bias in included studies  

Methodological quality will be defined as the confidence that the design and the report of the randomised clinical trial would restrict bias in the comparison of the intervention (Moher 1998). According to empirical evidence (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008), the methodological quality of the trials will be assessed based on sequence generation, allocation concealment, blinding of (participants, personnel, and outcome assessors), incomplete outcome data, selective outcome reporting, and other sources of bias. Quality components will be classified as follows:

Sequence generation

  • Low risk of bias (the methods used is either adequate (eg, computer generated random numbers, table of random numbers) or unlikely to introduce confounding).

  • Uncertain risk of bias (there is insufficient information to assess whether the method used is likely to introduce confounding).

  • High risk of bias (the method used (eg, quasi‐randomised trials) is improper and likely to introduce confounding).

Allocation concealment

  • Low risk of bias (the method used (eg, central allocation) is unlikely to induce bias on the final observed effect).

  • Uncertain risk of bias (there is insufficient information to assess whether the method used is likely to induce bias on the estimate of effect).

  • High risk of bias (the method used (eg, open random allocation schedule) is likely to induce bias on the final observed effect).

Blinding of participants, personnel, and outcome assessors

  • Low risk of bias (blinding was performed adequately, or the outcome measurement is not likely to be influenced by lack of blinding).

  • Uncertain risk of bias (there is insufficient information to assess whether the type of blinding used is likely to induce bias on the estimate of effect).

  • High risk of bias (no blinding or incomplete blinding, and the outcome or the outcome measurement is likely to be influenced by lack of blinding).

Incomplete outcome data

  • Low risk of bias (the underlying reasons for missingness are unlikely to make treatment effects depart from plausible values, or proper methods have been employed to handle missing data).

  • Uncertain risk of bias (there is insufficient information to assess whether the missing data mechanism in combination with the method used to handle missing data is likely to induce bias on the estimate of effect).

  • High risk of bias (the crude estimate of effects (eg, complete case estimate) will clearly be biased due to the underlying reasons for missingness, and the methods used to handle missing data are unsatisfactory).

Selective outcome reporting

  • Low risk of bias (the trial protocol is available and all of the trial's pre‐specified outcomes that are of interest in the review have been reported or similar).

  • Uncertain risk of bias (there is insufficient information to assess whether the magnitude and direction of the observed effect is related to selective outcome reporting).

  • High risk of bias (not all of the trial's pre‐specified primary outcomes have been reported or similar).

Baseline imbalance

  • Low risk of bias (there was no baseline imbalance in important characteristics).

  • Uncertain risk of bias (the baseline characteristics were not reported).

  • High risk of bias (there was a baseline imbalance due to chance or due to imbalanced exclusion after randomisation).

Other sources of bias

  • Low risk of bias (the trial appears to be free of other sources of bias).

  • Uncertain risk of bias (there is insufficient information to assess whether other sources of bias are present).

  • High risk of bias (it is likely that potential sources of bias related to specific design used, early termination due to some data‐dependent process, lack of sample size or power calculation, or other bias risks are present).

Data collection Two authors will independently extract data (LK, MP). In case of disagreement between the two authors, a third author will extract the data (LLBH). The data extraction will be discussed, decisions documented and, where necessary, the authors will be contacted for clarification. Studies will be identified by the name of the first author and year in which the study was first published and ordered chronologically.

The following data will be extracted, checked, and recorded:

  • Characteristics of studies: date, location, and setting; publication status; sponsor (specified, known or unknown); duration of follow up, immunosuppressive regimen.

  • Characteristics of participants: number of participants in each group; age; gender; HBV DNA status.

  • Characteristics of interventions: dose, schedule, point of initiation.

  • Characteristics of outcome measures: whenever possible, the number of events previously listed under 'outcome measures' will be recorded in each arm of the studies.

Measures of treatment effect

Dichotomous data The treatment effects in this meta‐analysis is only dichotomous, and these will be expressed as risk ratio (RR) with 95% confidence intervals (CI). The number needed to treat (NNT) will be derived from the risk difference (RD).

Dealing with missing data

For trials with missing data, assessment will be made in order to decide whether the missing data are 'missing at random' or not. For 'missing at random data', analyses based on the available data will only be undertaken. For 'not missing at random data', we will try to contact the original investigators in order to request the missing data. If the information will not be available, we will assess the adequacy of the methods used to deal with missingness. In the Discussion section, we will address the potential impact of missing data on the findings of the review. When patients are lost to follow‐up and missing data methods were not applied, data will be analysed according to the intention‐to‐treat (ITT) principle and the available case analysis, using as a denominator the total number of people who had data recorded for the particular outcome in question. ITT will be performed based on consideration of 'best‐case' and 'worst‐case' scenarios (Gamble 2005).

Assessment of heterogeneity

We will assess heterogeneity using the chi‐square test of heterogeneity and quantity of heterogeneity by the I2 measure of inconsistency (Higgins 2002). In case of significant heterogeneity as measured by a chi‐square test P value less than 0.1 or an I2 measure greater than 50%, we will omit the meta‐analysis or conduct a random‐effects meta‐analysis. Sources of heterogeneity will be assessed in subgroup analyses.

Assessment of reporting biases

Reporting biases will be handled following the recommendations of The Cochrane Collaboration (Higgins 2008). Funnel plot asymmetry will be used, (Higgins 2008) even though asymmetric funnel plots are not necessarily caused by publication bias, and publication bias does not necessarily cause asymmetry in a funnel plot (Egger 1997).

Data synthesis

For all analyses, we will use fixed‐effect models (Demets 1987). In case of significant heterogeneity as described earlier, we will conduct a random‐effects meta‐analysis.

Subgroup analysis and investigation of heterogeneity The following subgroup analyses will be performed to compare:

  • Type of patients: patients with cirrhosis, patients with HBeAg, patients with 'anti‐HBc alone', and patients with precore mutants.

  • Type of interventions: according to the chemotherapy regimens.

Subgroups will be interpreted as potentially different if the 95% confidence intervals do not overlap.

Sensitivity analysis

Suitable sensitivity analyses will be identified during the review process, eg, sensitivity analysis will be used when imputing missing data with replacement values. 

Acknowledgements

Peer Reviewer of the updated protocol: Tahany Awad, Denmark.

Contact Editor: Lise Lotte GLuud, Denmark.

Appendices

Appendix 1. Search Strategies

Database Period Search strategy
The Cochrane Hepato‐Biliary Group Controlled Trials Register  The date will be given when the search is performed.  lamivudin* AND ('hepatitis B' OR HBV) AND (prevent* OR prophylaxis OR preemptive)
The Cochrane Central Register of Controlled Trials on The Cochrane Library Latest issue. 1. lamivudine 2. LAMIVUDINE (MeSH) 3. HEPATITIS B explode all trees (MeSH) 4. hbv or (hepatitis next b) 5. CHEMOPREVENTION explode all trees (MeSH) 6. prevent* or prophyl* or chemoprevent* or chemoprophyl*)) 7. (#1 or #2) and (#3 or #4) and (#5 or #6) 
MEDLINE  January 1966 to the date when the search is performed. 1. lamivudine (MeSH Terms) OR lamivudine (Text Word) 2. HBV (All Fields) OR (hepatitis b ( MeSH Terms) OR hepatitis b virus ( MeSH Terms) OR hepatitis B (Text Word)) 3. chemoprevention (MeSH Terms) OR chemoprevent* (Text Word) OR chemoprophyla* OR prophyla* (Text Word) OR preemptive (Text Word) OR prevent* (Text Word)) 4. #1 AND #2 #3 5. #4 AND filter for RCTs (as appears in Appendix 5, The Cochrane Handbook) AND (("steroids" (MeSH Terms) OR steroids (Text Word)) OR ("drug therapy" (Subheading) OR "drug therapy" (MeSH Terms) OR chemotherapy (Text Word)) OR ("glucocorticoids" (MeSH Terms) OR "glucocorticoids" (Pharmacological Action) OR glucocorticoids (Text Word)) OR ("immunosuppression" (MeSH Terms) OR "immune tolerance" (MeSH Terms) OR immunosuppression (Text Word)) OR ("transplantation" (Subheading) OR "transplantation" (MeSH Terms) OR "organ transplantation" (MeSH Terms) OR transplantation (Text Word)))
EMBASE January 1980 to the date when the search is performed. 1. Lamivudine (freetext or MeSH) 2. Hepatitis B (Freetext or MeSH) 3. HBV 4. #1 and (#2 or #3) 5. #4 and filter for RCTs (as appears in Appendix 5, The Cochrane Handbook)
LILACS  1982 to the date when the search is performed. 1. lamivudine (free text or subject descriptor) 2. HBV or hepatitis B (free text or subject descriptor) 
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What's new

Date Event Description
12 September 2019 Amended This protocol is withdrawn as of 09 September 2019 because it is outdated.
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History

Protocol first published: Issue 2, 2005

Date Event Description
28 October 2008 New citation required and minor changes The protocol is updated following the revised Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).
9 September 2008 Amended Converted to new review format.
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Contributions of authors

Lior Katz (LK) ‐ responsible for the reference searches, article retrieval, study inclusion/exclusion, data extraction, analysis, interpretation of results and writing of the review. Anat Gafter (AG) ‐ responsible for the reference searches, study inclusion/exclusion, data extraction, analysis, interpretation of results and writing of the review. Abigail Fraser (AF) ‐ responsible for study inclusion/exclusion, analysis, interpretation of results and writing of the review. Ran Tur‐Kaspa (RTK) ‐ responsible for interpretation of results and writing of the review. Leonard Leibovici (LLBH) ‐ analysis, interpretation of results and writing of the review.

Declarations of interest

None known.

Notes

This protocol is withdrawn as of 09 September 2019 because it is outdated.

Withdrawn from publication for reasons stated in the review

References

Additional references

  1. Al‐Taie OH, Mork H, Gassel AM, Wilhelm M, Weissbrich B, Scheurlen M. Prevention of hepatitis B flare‐up during chemotherapy using lamivudine: case report and review of the literature. Annals of Haematology 1999;78(5):247‐9. [DOI] [PubMed] [Google Scholar]
  2. Alexopoulos CG, Vaslamatzis M, Hatzidimitriou G. Prevalence of hepatitis B virus marker positivity and evolution of hepatitis B virus profile, during chemotherapy, in patients with solid tumours. British Journal of Cancer 1999;81:69‐74. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chan TM, Fang GX, Tang CS, Cheng IK, Lai KN, Ho SK. Preemptive lamivudine therapy based on HBV DNA level in HBsAg‐positive kidney allograft recipients. Hepatology 2002;36:1246‐52. [DOI] [PubMed] [Google Scholar]
  4. Cheng AL. Steroid free chemotherapy decreases the risk of hepatitis flare‐up in hepatitis B virus carriers with non‐Hodgkin's lymphoma. Blood 1996;87:1202. [PubMed] [Google Scholar]
  5. 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;37:1320‐8. [DOI] [PubMed] [Google Scholar]
  6. Clark FL, Drummond MW, Chambers S, Chapman BA, Patton WN. Successful treatment with lamivudine for fulminant reactivated hepatitis B infection following intensive therapy for high‐grade non‐Hodgkin's lymphoma. Annals of Oncology 1998;9:385‐7. [DOI] [PubMed] [Google Scholar]
  7. Dai MS, Lu JJ, Chen YC, Perng CL, Chao TY. Reactivation of precore mutant hepatitis B virus in chemotherapy‐treated patients. Cancer 2001;92:2927‐32. [DOI] [PubMed] [Google Scholar]
  8. Demets DL. Practical aspects in data monitoring: a brief review. Statistics in Medicine 1987;6(7):753‐60. [DOI] [PubMed] [Google Scholar]
  9. Dhedin N, Douvin C, Kuentz M, Saint Marc MF, Reman O, Rieux C, et al. Reverse seroconversion of hepatitis B after allogeneic bone marrow transplantation: a retrospective study of 37 patients with pretransplant anti‐HBs and anti‐HBc. Transplantation 1998;66:616‐9. [DOI] [PubMed] [Google Scholar]
  10. Dienstag JL, Goldin RD, Heathcote EJ, Hann HW, Woessener M, Stephenson SL, et al. Histological outcome during long term lamivudine therapy. Gastroenterology 2003;124:105‐7. [DOI] [PubMed] [Google Scholar]
  11. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta‐analysis detected by a simple, graphical test. BMJ 1997;315:629‐34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Flowers MA, Heathcote J, Wanless IR, Sherman M, Reynolds WJ, Cameron RG, et al. Fulminant hepatitis as a consequence of reactivation of hepatitis B virus infection after discontinuation of low‐dose methotrexate therapy. Annals of Internal Medicine 1990;112:381‐2. [DOI] [PubMed] [Google Scholar]
  13. Fornairon S, Pol S, Legendre C, Carnot F, Mamzer‐Bruneel MF, Brechot C, et al. The long‐term virologic and pathologic impact of renal transplantation on chronic hepatitis B virus infection. Transplantation 1996;62:297‐9. [DOI] [PubMed] [Google Scholar]
  14. Galbraith RM, Eddleston AL, Williams R, Zuckerman AJ, Bagshawe KD. Fulminating hepatic failure in leukemia and choriocarcinoma related to withdrawal of cytotoxic drug therapy. Lancet 1975;2:528‐30. [DOI] [PubMed] [Google Scholar]
  15. Gamble C, Hollis S. Uncertainty method improved on best‐worst case analysis in a binary meta‐analysis. Journal of Clinical Epidemiology 2005;58:579‐588. [DOI] [PubMed] [Google Scholar]
  16. Gluud C, Nikolova D, Klingenberg SL, Whitfield K, Alexakis N, Als‐Nielsen B, et al. Cochrane Hepato‐Biliary Group. About The Cochrane Collaboration (Cochrane Review Groups (CRGs)). 2008, Issue 4. Art. No.: LIVER.
  17. Han DJ, Kim TH, Park SK, Lee SK, Kim SB, Yang WS, et al. Results on preemptive or prophylactic treatment of lamivudine in HBsAg (+) renal allograft recipients: comparison with salvage treatment after hepatic dysfunction with HBV recurrence. Transplantation 2001;71:387‐94. [DOI] [PubMed] [Google Scholar]
  18. Hanson CA, Sutherland DE, Snover DC. Fulminant hepatic failure in an HBsAg carrier renal transplant patient following cessation of immunosuppressive therapy. Transplantation 1985;39:311‐2. [DOI] [PubMed] [Google Scholar]
  19. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta‐analysis. Statistics in medicine 2002;21(11):1539‐58. [DOI] [PubMed] [Google Scholar]
  20. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 [updated February 2008]. The Cochrane Colloboration, 2008. Available from www.cochrane‐handbook.org.
  21. Hoofnagle JH, Dusheiko GM, Schafer DF, Jones EA, Micetich KC, Young RC, et al. Reactivation of chronic hepatitis B virus infection by cancer chemotherapy. Annals of Internal Medicine 1982;96(4):447‐9. [DOI] [PubMed] [Google Scholar]
  22. International Conference on Harmonisation Expert Working Group. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Guideline for good clinical practice1997 CFR & ICH Guidelines. Vol. 1, PA 19063‐2043, USA: Barnett International/PAREXEL, 1997:1. [Google Scholar]
  23. Idliman R, Arat M, Soydan E, Toruner M, Soykan H, Akubulut H, et al. Lamivudine prophylaxis for prevention of chemotherapy‐induced hepatitis B virus reactivation in hepatitis B virus carriers with malignancies. Journal of Viral Hepatitis 2004;11:141‐7. [DOI] [PubMed] [Google Scholar]
  24. Jarvis B, Faulds D. Lamivudine. A review of its therapeutic potential in chronic hepatitis B. Drugs 1999;58:101‐41. [DOI] [PubMed] [Google Scholar]
  25. Jung YO, Lee YS, Yang WS, Han DJ, Park JS, Park SK. Treatment of chronic hepatitis B with lamivudine in renal transplant recipients. Transplantation 1998;66:733‐7. [DOI] [PubMed] [Google Scholar]
  26. Kjaergard LL, Villumsen J, Gluud C. Reported methodological quality and discrepancies between large and small randomised trials in meta‐analyses. Annals of Internal Medicine 2001;135(11):982‐9. [MEDLINE: ] [DOI] [PubMed] [Google Scholar]
  27. Kumagai K, Takagi T, Nakamura S, Sawada U, Kura Y, Kodama F, et al. Hepatitis B virus carriers in the treatment of malignant lymphoma: an epidemiological study in Japan. Annals of Oncology 1997;8:107‐9. [PubMed] [Google Scholar]
  28. Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, et al. A one‐year trial of lamivudine for chronic hepatitis B. New England Journal of Medicine 1998;339:61‐8. [DOI] [PubMed] [Google Scholar]
  29. Lau GK, He ML, Fong DY, Bartholomeusz A, Au WY, Lie AK, et al. Preemptive use of lamivudine reduces hepatitis B exacerbation after allogeneic hematopoietic cell transplantation. Hepatology 2002;36:702‐9. [DOI] [PubMed] [Google Scholar]
  30. Liao CA, Lee CM, Wu HC, Wang MC, Lu SN, Eng HL. Lamivudine for the treatment of hepatitis B virus reactivation following chemotherapy for non‐Hodgkin's lymphoma. British Journal of Haematology 2002;116:166‐9. [DOI] [PubMed] [Google Scholar]
  31. Lim LL, Wai CT, Lee YM, Kong HL, Lim R, Koay E, et al. Prophylactic lamivudine prevents hepatitis B reactivation in chemotherapy patients. Alimentary Pharmacological Therapy 2002;16:1939‐44. [DOI] [PubMed] [Google Scholar]
  32. Lok ASF, Liang RHS, Chiu EKW, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy: report of a prospective study. Gastroenterology 1991;100:182‐8. [DOI] [PubMed] [Google Scholar]
  33. McMilan JS, Shaw T, Angus PW, Locarnini SA. Effect of immunosuppressive and antiviral agents on hepatitis B virus replication in vitro. Hepatology 1995;22:36‐43. [PubMed] [Google Scholar]
  34. Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta‐analyses. Lancet 1998;352(9128):609‐13. [MEDLINE: ] [DOI] [PubMed] [Google Scholar]
  35. Nakamura Y, Motokura T, Fujita A, Yamashita T, Ogata E. Severe hepatitis related to chemotherapy in hepatitis B virus carriers with hematologic malignancies. Survey in Japan, 1987‐1991. Cancer 1996;78:2210‐5. [DOI] [PubMed] [Google Scholar]
  36. Pariente EA, Goudeau A, Dubois F, Degott C, Gluckman E, Devergie A, et al. Fulminant hepatitis due to reactivation of chronic hepatitis B virus infection after allogeneic bone marrow transplantation. Digestive Diseases Science 1988;33:1185‐91. [DOI] [PubMed] [Google Scholar]
  37. Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology 2001;120:1009‐22. [DOI] [PubMed] [Google Scholar]
  38. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008.
  39. Rostaing L, Modesto A, Baron E, Cisterne JM, Chabannier MH, Durand D. Acute renal failure in kidney transplant patients treated with interferon alpha 2b for chronic hepatitis C. Nephron 1996;74:512‐6. [DOI] [PubMed] [Google Scholar]
  40. Schulz KF, Chalmers I, Hayer R, Altman D. Empirical evidence of bias. JAMA 1995;273(5):408‐12. [MEDLINE: ] [DOI] [PubMed] [Google Scholar]
  41. Scullard GH, Smith CI, Merigan TC, Robinson WS, Gregory PB. Effects of immunosuppressive therapy on viral markers in chronic active hepatitis B. Gastroenterology 1981;81:987‐91. [PubMed] [Google Scholar]
  42. Silvestri F, Ermacora A, Sperotto A, Patriarca F, Zaja F, Damiani D, et al. Lamivudine allows completion of chemotherapy in lymphoma patients with hepatitis B reactivation. British Journal of Haematology 2000;108:394‐6. [DOI] [PubMed] [Google Scholar]
  43. Steinberg JL, Yeo W, Zhong S, Chan JY, Tam JS, Chan PK, et al. Hepatitis B virus reactivation in patients undergoing cytotoxic chemotherapy for solid tumors: precore/core mutations may play an important role. Jornal of Medical Virology 2000;60:249‐55. [PubMed] [Google Scholar]
  44. The EASL Jury. EASL international consensus conference on hepatitis B. Journal of Hepatology 2003;38:533‐40. [DOI] [PubMed] [Google Scholar]
  45. Tsang WK, Tong KL, Chan HW, Tsang WK, Tong KL, Chan HW. Lamivudine therapy in renal allograft recipients with hepatitis B virus infection. Transplantation Proceeding 2003;35:278‐9. [DOI] [PubMed] [Google Scholar]
  46. Tur‐Kaspa R, Burk RD, Shaul Y, Shafrits DA. Hepatitis B virus DNA contains a glucocorticoid responsive element. Proceedings of the National Academy of Sciences of the United States of America 1986;83:1627‐31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Vento S, Cainelli F, Longhi MS. Reactivation of replication of hepatitis B and C virus after immunosuppressive therapy: an unresolved issue. Lancet Oncology 2002;3:333‐40. [DOI] [PubMed] [Google Scholar]
  48. Wood L, Egger M, Gluud LL, Schulz KF, J?ni P, Altman DG, Gluud C, Martin RM, Wood AJ, Sterne JA. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta‐epidemiological study. BMJ (Clinical Research Ed.) 2008;336(7644):601‐5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Yeo W, Steinberg JL, Tam JS, Chan PK, Leung NW, Lam KC, et al. Lamivudine in the treatment of hepatitis B virus reactivation during cytotoxic chemotherapy. Journal of Medical Virology 1999;59:263‐9. [DOI] [PubMed] [Google Scholar]
  50. Yeo W, Chan PK, Zhong S, Ho WM, Steinberg JL, Tam JS, et al. Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors. Journal of Medical Virology 2000;62:299‐307. [DOI] [PubMed] [Google Scholar]
  51. Yeo W, Chan PK, Hui P, Ho WM, Lam KC, Kwan WH, et al. Hepatitis B virus reactivation in breast cancer patients receiving cytotoxic chemotherapy: a prospective study. Journal of Medical Virology 2003;70:553‐61. [DOI] [PubMed] [Google Scholar]
  52. Yeo W, Chan PK, Ho WM, Zee B, Lam KC, Lei KI, et al. Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis B s‐antigen seropositive cancer patients undergoing cytotoxic chemotherapy. Journal of Clinical Oncology 2004;22:927‐34. [DOI] [PubMed] [Google Scholar]
  53. Zhong S, Yeo W, Schroder C, Chan PKS, Wong WL, Ho WM, et al. High hepatitis B virus DNA viral load is an important risk factor for HBV reactivation in breast cancer patients undergoing cytotoxic chemotherapy. Journal of Viral Hepatitis 2004;11:55‐9. [DOI] [PubMed] [Google Scholar]

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