CD010174

Hepatitis B immune globulin for preventing hepatitis B recurrence after liver transplantation (Protocol) Berdichevski T, Kumar S, Katz LH This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2012, Issue 10 http://www.thecochranelibrary.com Hepatitis B immune globulin for preventing hepatitis B recurrence after liver transplantation (Protocol) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS HEADER . . . . . . . . . . ABSTRACT . . . . . . . . . BACKGROUND . . . . . . . OBJECTIVES . . . . . . . . METHODS . . . . . . . . . ACKNOWLEDGEMENTS . . . REFERENCES . . . . . . . . APPENDICES . . . . . . . . HISTORY . . . . . . . . . . CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hepatitis B immune globulin for preventing hepatitis B recurrence after liver transplantation (Protocol) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 2 2 3 6 6 8 10 10 10 i [Intervention Protocol] Hepatitis B immune globulin for preventing hepatitis B recurrence after liver transplantation Tania Berdichevski1 , Sushil Kumar2 , Lior H Katz3 1 Gastroenterology Department, Wolfson Medical Center, Holon, Israel. 2 Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, USA. 3 Gastroenterology, Hepatology and Nutrition Department, MD Anderdson Cancer Center, Houston, Texas, USA Contact address: Tania Berdichevski, Gastroenterology Department, Wolfson Medical Center, Holon, 52621, Israel. chuk@012.net.il. Editorial group: Cochrane Hepato-Biliary Group. Publication status and date: New, published in Issue 10, 2012. Citation: Berdichevski T, Kumar S, Katz LH. Hepatitis B immune globulin for preventing hepatitis B recurrence after liver transplantation. Cochrane Database of Systematic Reviews 2012, Issue 10. Art. No.: CD010174. DOI: 10.1002/14651858.CD010174. Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. ABSTRACT This is the protocol for a review and there is no abstract. The objectives are as follows: We aim to assess the benefits and harms of HBIg after liver transplantation in HBV-infected patients. We will try to find the minimal effective dose and time of the HBIg treatment in order to reduce the adverse effects as well as cost of the treatment. Hepatitis B immune globulin for preventing hepatitis B recurrence after liver transplantation (Protocol) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1 BACKGROUND Description of the condition More than 350 million persons are carriers of hepatitis B virus in the world today (WHO Fact Sheet 2010). Hepatitis B virus infection has a wide spectrum of manifestations, ranging from an apparently healthy carrier state to acute fulminant hepatitis or chronic liver disease and its associated complications. Chronic hepatitis B might lead to liver cirrhosis and hepatocellular carcinoma. The lifetime risk of death due to these complications is 25% to 40% in patients with chronic hepatitis B (Realdi 1994). Orthotopic liver transplantation remains the only hope for many patients with endstage liver disease due to the hepatitis B virus (Massoumi 2011). In the 1980s the initial results with liver transplantation for chronic hepatitis B were disappointing with graft reinfection with hepatitis B virus (HBV) approaching 100% (Todo 1991; Lucey 1992; O’Grady 1992). In many patients, reinfection was associated with severe and rapidly progressive liver disease resulting in two-year graft and patient survival of 50% compared to 80% in those transplanted for other etiologies (Starzl 1989). With these poor results, and limited supply of donor organs, many centres abandoned liver transplantation for patients with chronic hepatitis B (Perrillo 1993). Description of the intervention Several trials have demonstrated that hepatitis B immune globulin (HBIg) prophylaxis reduces reinfection and improves patient and graft survival after liver transplantation in hepatitis B virus-infected recipients (Müller 1991; Samuel 1993; Konig 1994; McGory 1996; Sawyer 1998). As a result, in the 1990s long-term high-dose hepatitis B immune globulin (HBIg) became the standard prophylaxis for HBV reinfection after liver transplantation in most transplant centres. HBIg is a polyclonal preparation of human HB surface antibody (anti-HBs) purified from pooled donor plasma. It is usually given intravenously as a 10,000 IU bolus dose during the unhepatic phase of liver transplantation followed by daily doses during the first week. Subsequent doses are either given monthly or in accordance with anti-HBs titers (with a trough of 100 or 500 IU/L according to different trials). There is wide agreement that when given alone, HBIg must be given indefinitely to remain effective (Perrillo 2001). However, long-term use of HBIg entails several problems, particularly lack of effectiveness in all patients, parenteral administration, adverse effects, and cost. In addition, the supply of HBIg is unreliable (McGory 1996). To reduce the cost of HBIg therapy, attempts have been made to increase the interval between intravenous HBIg dosing or to substitute maintenance intravenous HBIg with intramuscular administration of reduced doses of HBIg. In a trial by Burbach and colleagues, intramuscular injections of 1000 IU HBIg given every two weeks resulted in reproducible and stable antibody titers that were above the minimum target antibody titer for the transplant recipients. The authors calculated that a switch from intravenous 1500 IU HBIg to intramuscular 1000 IU HBIg would reduce the cost of HBIg prophylaxis by more than 50% (Burbach 1997). There is also concern that long standing use of HBIg can lead to emergence of genetic HBV mutants that are resistant to neutralization by HBIg (Terrault 1998; Perrillo 2001). The possibility of stopping HBIg after a defined period of time post-transplantation and to switch to nucleoside analogue, particularly in low risk patients, is being actively investigated. How the intervention might work HBIg is thought to work by neutralizing circulating viruses by antiHBs binding, thereby preventing graft infection. Anti-HBs also undergoes endocytosis by hepatocytes, interacting with HB surface antigen (HBsAg) within the cells, decreasing HBsAg secretion ( Schilling 2003) and inter-hepatocyte transmission. Why it is important to do this review Long-term patient and graft survival after liver transplantation for HBV have been disappointing because of recurrence of HBV infection in the majority of patients, which led to liver failure. The introduction of HBIg has revolutionized treatment in HBV-infected liver transplanted patients, and the outcomes are compatible with those in patients transplanted for other chronic liver diseases, if not slightly better (Kim 2004). However, HBIg therapy has certain disadvantages, including high cost, parenteral administration, and lack of universal efficacy. In 2010 a review was published regarding HBIg with or without lamivudine prophylaxis for preventing hepatitis B recurrence after liver transplantation (Chen 2010). In this review it was found that the recurrence rate of HBV with long-term HBIg prophylaxis varied from 3.7% to 65%, as opposed to about 80% recurrence rate for patients not receiving any prophylaxis. This review was based mainly on heterogenous observational trials, in which the risk of bias is high. Moreover, the analysis was not stratified according to the dose of HBIg. We have not been able to identify any systematic review dealing only with randomised clinical trials on the topic. OBJECTIVES We aim to assess the benefits and harms of HBIg after liver transplantation in HBV-infected patients. Hepatitis B immune globulin for preventing hepatitis B recurrence after liver transplantation (Protocol) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 2 We will try to find the minimal effective dose and time of the HBIg treatment in order to reduce the adverse effects as well as cost of the treatment. METHODS Criteria for considering studies for this review Types of studies Randomised clinical trials. Trials will be included irrespective of publication status, language, or blinding. We will also attempt to include studies that are not randomised trials for assessment of harms only, if they are retrieved with the search for randomised trials. Types of participants Inclusion criteria People of both sexes, and irrespective of ethnic origin, who underwent liver transplantation due to end-stage hepatitis B virus (HBV) cirrhosis; hepatocellular carcinoma with positive HBsAg; or HBV-related acute liver failure, as manifested by decompensated liver disease and the presence of positive HBsAg. Patients will be included no matter their age, age of transplantation, or age at time of infection. If there are participants with liver disease due to a combination of HBV and another etiology, they will be analysed separately. • Occurrence of adverse events: (a) any clinical adverse event; (b) serious adverse events, defined as any untoward medical occurrence in a patient which did not necessarily have a causal relationship with the treatment but did, however, result in a dose reduction or discontinuation of treatment. Serious adverse events are defined according to the International Conference on Harmonization Guidelines (ICH-GCP 1997) as any event that led to death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or congenital anomaly or birth defect, or any important medical event which may have jeopardized the patient or required intervention to prevent it. Secondary outcomes • Number of patients with graft loss. • Number of patients with HBV-related mortality. • Number of patients in whom HBV DNA reappeared in the serum. • Number of patients with occurrence of HBV-related active liver disease. • Number of patients in whom hepatitis B core antigen (HBcAg) or HBsAg in the liver graft is detected. We plan to create summary of findings (SOF) tables for all primary and secondary outcomes using GRADEpro (http:// ims.cochrane.org/revman/other-resources/gradepro). Search methods for identification of studies Electronic searches Exclusion criteria • Patients who received antiviral drugs following liver transplantation. • Patients with chronic liver disease resulting from other aetiologies • Human immunodeficiency virus (HIV) co-infection. We will search the Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded (SCI Expanded) (Royle 2003). Preliminary search strategies with the expected time spans of the searches are given in Appendix 1. Types of interventions Searching other resources • HBIg versus placebo or no treatment. We will attempt to identify further trials by reviewing the reference lists and contacting the principal authors of the identified trials. Types of outcome measures Data collection and analysis Primary outcomes • All-cause mortality. • Number of patients with reappearance of hepatitis B surface antigen (HBsAg) in the serum after liver transplantation. We will perform the review following the recommendations of The Cochrane Collaboration (Higgins 2011) and the Cochrane Hepato-Biliary Group Module (Gluud 2012). The analyses will be performed using Review Manager 5.1 (RevMan 2011). Hepatitis B immune globulin for preventing hepatitis B recurrence after liver transplantation (Protocol) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 3 Selection of studies Two authors (TB and SK ) will independently inspect each reference that is identified by the search, applying the inclusion criteria. For possibly relevant articles, or in the case of disagreement between the two authors, the full article will be obtained and inspected independently by the two authors. If the two authors still disagree, they will try to resolve the issue by discussion with the third author (LK) . Data extraction and management patients, are inadequate and will be excluded for the assessment of benefits but not for assessment of harms. Allocation concealment • Low risk of bias: allocation was controlled by a central and independent randomisation unit, sequentially numbered, opaque and sealed envelopes, or similar, so that intervention allocations could not have been foreseen in advance of, or during, enrolment. • Uncertain risk of bias: the trial was described as randomised but the method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment. • High risk of bias: if the allocation sequence was known to the investigators who assigned participants or if the study was quasi-randomised. Quasi-randomised studies will be excluded for the assessment of benefits but not for assessment of harms. Two authors will extract data (TB and LK) independently. The authors will discuss the data extraction and document the decisions. Where necessary, they will contact authors of the studies for further information and clarification. Trials will be identified by the name of the first author and year in which the trial was published in full, and they will be ordered chronologically. We will extract, check, and record the following data. • Characteristics of trials: date, location, and setting; publication status; sponsor (specified, known, or unknown); duration of follow-up. • Characteristics of participants: number of participants in each group; age; sex; ethnicity; HBV DNA status before transplantation; immunosuppressive regimen after transplantation. • Characteristics of interventions: dose, duration, the mode of treatment administration, the timing of initiation. • Outcomes: whenever possible, the number of events previously listed under ’outcomes’ will be recorded in each arm of the trials. Outcomes not reported will be stated to be ’not reported’. • 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. Assessment of risk of bias in included studies Incomplete outcome data Methodological quality will be defined as the confidence we have that the design and the report of the randomised clinical trial would minimise possible bias in the comparison of the intervention with the control (Moher 1998). According to empirical evidence (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008), bias risk of the trials will be assessed based on the following domains. • Low risk of bias: the underlying reasons for missingness are unlikely to make treatment effects departure 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 introduce bias in the estimate of effect. • High risk of bias: the crude estimate of effects (e.g., complete case estimate) will clearly be biased due to the underlying reasons for missingness, and the methods used to handle missing data are unsatisfactory. Allocation sequence generation • Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards and throwing dice are adequate if performed by an independent adjudicator. • Uncertain risk of bias: the trial is described as randomised, but the method of sequence generation was not specified. • High risk of bias: the sequence generation method is not, or may not be, random. Quasi-randomised studies, those using dates, names, or admittance numbers in order to allocate Blinding of participants, personnel, and outcome assessors Selective outcome reporting • Low risk of bias: pre-defined or clinically relevant and reasonably expected outcomes are reported on. • Uncertain risk of bias: not all pre-defined or clinically relevant and reasonably expected outcomes are reported on or are Hepatitis B immune globulin for preventing hepatitis B recurrence after liver transplantation (Protocol) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 4 not reported fully, or it is unclear whether data on these outcomes were recorded or not. • High risk of bias: reappearance of HBsAg in the serum after liver transplantation was not reported on; and data on this outcome were likely to have been recorded. Other bias • Low risk of bias: the trial appears to be free of other components that could put it at risk of bias. • Uncertain risk of bias: the trial may or may not be free of other components that could put it at risk of bias. • High risk of bias: there are other factors in the trial that could put it at risk of bias, e.g., for-profit involvement, authors have conducted trials on the same topic which were funded by commercial source etc. If the risk of bias in a trial is judged as ’low’ in all the domains listed above, the trial will be considered ’low risk of bias’. If the risk of bias in the assessed trials is judged as ’uncertain’ or ’high’ in one or more of the above specified domains, then the trial will be considered ’high risk of bias’. Measures of treatment effect Assessment of heterogeneity We plan to assess heterogeneity using the Chi2 test of heterogeneity and the quantity of heterogeneity by the I2 statistic as a measure of inconsistency (Higgins 2002). In the case of significant heterogeneity as measured by a Chi2 test with P value less than 0.1, or an I2 statistic greater than 50%, we will try to explore the sources by performing subgroup analysis. If we fail to explain heterogeneity, we will omit the meta-analysis and present the results in a narrative way. Assessment of reporting biases Reporting biases will be handled following the recommendations of The Cochrane Collaboration (Higgins 2011). Funnel plot asymmetry will be used (Higgins 2011) 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). In order to be able to perform this, we will need to have at least 10 included trials. Data synthesis Fixed-effect model meta-analysis (DeMets 1987) as well as random-effects model meta-analysis (DerSimonian 1986) will be performed, and both of them will be presented in the case of significant differences in the results. In the case of similar results, we will present only the fixed-effect model meta-analysis. Dichotomous data Trial sequential analysis All treatment effects in this systematic review are dichotomous, and these will be expressed as risk ratio (RR) with 95% confidence interval (CI). Trial sequential analysis will be applied because cumulative metaanalyses are at risk of producing random errors due to sparse data and repetitive testing of the accumulating data (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010). To minimise random errors, we will calculate the required information size (that is, the number of participants needed in a meta-analysis to detect or reject a certain intervention effect) (Brok 2008; Wetterslev 2008; Thorlund 2010). The required information size calculation should also account for the heterogeneity or diversity present in the meta-analysis (Wetterslev 2008; Wetterslev 2009). In our meta-analysis, the required information size will be based on the event proportion in the control group; assumption of a plausible RR reduction of 20%, or on the RR reduction observed in the included trials with low risk of bias a risk of type I error of 5%; a risk of type II error of 20%; and the assumed heterogeneity or diversity of the meta-analysis (Wetterslev 2008; Wetterslev 2009). The underlying assumption of trial sequential analysis is that testing for significance may be performed each time a new trial is added to the meta-analysis. We will add the trials according to the year of publication, and if more than one trial has been published in a year, trials will be added alphabetically according to the last name of the first author. On the basis of the required information size, trial sequential alpha-spending and beta- 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, we will undertake only analyses based on the available data. For not missing at random data, we will try to contact the original investigators in order to request the missing data. If the information is not available, we will assess the adequacy of the methods used to deal with missingness. In the discussion section of the review, 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 intentionto-treat (ITT) principle and the available case analysis, using as the 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-worst’ case and ’worst-best’ case scenarios (Gamble 2005). Hepatitis B immune globulin for preventing hepatitis B recurrence after liver transplantation (Protocol) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 5 spending monitoring boundaries will be constructed (Wetterslev 2008; Thorlund 2009). These boundaries will determine the statistical inference one may draw regarding the cumulative metaanalysis that has not reached the required information size; if the trial sequential alpha spending monitoring boundary is crossed before the required information size is reached, firm evidence may perhaps be established and further trials may turn out to be superfluous. On the other hand, if the boundary is not surpassed, it is most probably necessary to continue doing trials in order to detect or reject a certain intervention effect if the trial sequential beta-spending monitoring boundary is not broken. If this is the case, futility may be declared. One can access the trial sequential analysis software application at www.ctu.dk/tsa (Thorlund 2011; CTU 2012). IU/L. If these data are not available, we will consider high dose as 10,000 international units (IU) of HBIg in the unhepatic phase, at least 5000 IU/day in the first week after transplantation, and at least 2000 IU/week (or 10,000 IU/month) thereafter. All the other regimens will be considered as low dose. However, we will try to compare all available regimens according to the route of administration (intravenous or intramuscular) and according to the duration of treatment (more than or less than one year). Sensitivity analysis Sensitivity analysis will be used when imputing missing data with replacement values, for example, we will exclude very large trials as well as trials with very few participants. We plan to undertake a separate meta-analysis for the trials with low risk of bias. Subgroup analysis and investigation of heterogeneity We plan the following subgroup analyses. • Comparison of trials with low risk of bias to trials with high risk of bias. • Type of patients: according to the HBV DNA status before transplantation (positive compared to negative). • Intervention: (a) according to the dose of HBIg. A high dose will be defined as a dose that maintains serum HBIg titer > 500 IU/L, intermediate dose > 200 IU/L, and low dose > 100 ACKNOWLEDGEMENTS Protocol Peer Reviewers: Jen Jung Pan, USA; Chigoziem Eke Ahizechukwu, USA; John Holden, UK. Contact Editor: Bodil Als-Nielsen, Denmark. REFERENCES Additional references Brok 2008 Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. Journal of Clinical Epidemiology 2008;61:763–9. Brok 2009 Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta-analyses may be inconclusive - Trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses. International Journal of Epidemiology 2009;38(1):287–98. Burbach 1997 Burbach GJ, Bienzle U, Neuhaus R, Hopf U, Metzger WG, Pratschke J, et al.Intravenous or intramuscular antiHBs immunoglobulin for the prevention of hepatitis B reinfection after orthotopic liver transplantation. Transplantation 1997;63(3):478–80. Chen 2010 Chen J, Yi L, Jia JD, Ma H, You H. Hepatitis B immunoglobulins and/or lamivudine for preventing hepatitis B recurrence after liver transplantation: a systematic review. Journal of Gastroenterology and Hepatology 2010;25(5):872–9. CTU 2012 Copenhagen Trial Unit. TSA - Trial Sequential Analysis. http://ctu.dk/tsa/ (accessed 15 August 2012). DeMets 1987 DeMets DL. Methods for combining randomized clinical trials: strengths and limitations. Statistics in Medicine 1987; 6(3):341–50. DerSimonian 1986 DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986;7:177–88. Egger 1997 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ (Clinical Research Ed.) 1997;315(7109):629–34. Gamble 2005 Gamble C, Hollis S. Uncertainty method improved on best-worst case analysis in a binary meta-analysis. Journal of Clinical Epidemiology 2005;58:579–88. Gluud 2012 Gluud C, Nikolova D, Klingenberg SL, Alexakis N, AlsNielsen B, Colli A, et al.Cochrane Hepato-Biliary Group. About The Cochrane Collaboration (Cochrane Review Groups (CRGs)). 2012, Issue 8. Art. No.: LIVER. Hepatitis B immune globulin for preventing hepatitis B recurrence after liver transplantation (Protocol) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 6 Higgins 2002 Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine 2002;21(11):1539–58. Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. ICH-GCP 1997 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 practice 1997 CFR & ICH Guidelines. Vol. 1, PA 19063-2043, USA: Barnett International/PAREXEL, 1997. Kim 2004 Kim WR, Poterucha JJ, Kremers WK, Ishitani MB, Dickson ER. Outcome of liver transplantation for hepatitis B in the United States. Liver Transplantation 2004;10:968–74. Kjaergard 2001 Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Annals of Internal Medicine 2001;135(11):982–9. Konig 1994 Konig V, Hopf U, Neuhaus P, Bauditz J, Schmidt CA, Blumhardt G, et al.Long-term follow-up of hepatitis B virusinfected recipients after orthotopic liver transplantation. Transplantation 1994;58(5):553–9. Lucey 1992 Lucey MR, Graham DM, Martin P, Di Bisceglie A, Rosenthal S, Waggoner JG, et al.Recurrence of hepatitis B and delta hepatitis after orthotopic liver transplantation. Gut 1992;33(10):1390–6. recurrence by passive immunization. Journal of Hepatology 1991;13(1):90–6. O’Grady 1992 O’Grady JG, Smith HM, Davies SE, Danials HM, Donaldson PT, Tan KC, et al.Hepatitis B virus reinfection after orthotopic liver transplantation. Serological and clinical implications. Journal of Hepatology 1992;14(1): 104–11. Perrillo 1993 Perrillo RP, Mason AL. Hepatitis B and liver transplantation. Problems and promises. New England Journal of Medicine 1993;329(25):1885–7. Perrillo 2001 Perrillo RP, Wright T, Rakela J, Levy G, Schiff E, Gish R, et al.A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology 2001;33 (2):424–32. Realdi 1994 Realdi G, Fattovich G, Hadziyannis S, Schalm SW, Almasio P, Sanchez-Tapias J, et al.Survival and prognostic factors in 366 patients with compensated cirrhosis type B: a multicenter study. The Investigators of the European Concerted Action on Viral Hepatitis (EUROHEP). Journal of Hepatology 1994;21(4):656–66. RevMan 2011 The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011. Royle 2003 Royle P, Milne R. Literature searching for randomized controlled trials used in Cochrane reviews: rapid versus exhaustive searches. International Journal of Technology Assessment in Health Care 2003;19(4):591–603. Massoumi 2011 Massoumi H, Martin P, Tan HH. Management of chronic hepatitis B. European Journal of Gastroenterology and Hepatology 2011;23(8):642–50. Samuel 1993 Samuel D, Muller R, Alexander G, Fassati L, Ducot B, Benhamou JP, et al.Liver transplantation in European patients with the hepatitis B surface antigen. New England Journal of Medicine 1993;329(25):1842–7. McGory 1996 McGory RW, Ishitani MB, Oliveira WM, Stevenson WC, McCullough CS, Dickson RC. Improved outcome of orthotopic liver transplantation for chronic hepatitis B cirrhosis with aggressive passive immunization. Transplantation 1996;61(9):1358–64. Sawyer 1998 Sawyer RG, McGory RW, Gaffey MJ, McCullough CC, Shephard BL, Houlgrave CW, et al.Improved clinical outcomes with liver transplantation for hepatitis B-induced chronic liver failure using passive immunization. Annals of Surgery 1998;227(6):841–50. Moher 1998 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. Schilling 2003 Schilling R, Ijaz S, Davidoff M, Lee JY, Locarnini S, Williams R, et al.Endocytosis of hepatitis B immune globulin into hepatocytes inhibits the secretion of hepatitis B virus surface antigen and virions. Journal of Virology 2003;77(16):8882–92. Müller 1991 Müller R, Gubernatis G, Farle M, Niehoff G, Klein H, Wittekind C, et al.Liver transplantation in HBs antigen (HBsAg) carriers. Prevention of hepatitis B virus (HBV) Schulz 1995 Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality Hepatitis B immune globulin for preventing hepatitis B recurrence after liver transplantation (Protocol) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 7 associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408–12. Starzl 1989 Starzl TE, Demetris AJ, Van Thiel D. Liver transplantation (2). New England Journal of Medicine 1989;321(16): 1092–9. Terrault 1998 Terrault NA, Zhou S, McCory RW, Pruett TL, Lake JR, Roberts JP, et al.Incidence and clinical consequences of surface and polymerase gene mutations in liver transplant recipients on hepatitis B immunoglobulin. Hepatology 1998;28(2):555–61. Thorlund 2009 Thorlund K, Devereaux PJ, Wetterslev J, Guyatt G, Ioannidis JP, Thabane L, et al.Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses. International Journal of Epidemiology 2009; 38(1):276–86. Thorlund 2010 Thorlund K, Anema A, Mills E. Interpreting meta-analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV-infected individuals. Clinical Epidemiology 2010;2:57–66. Thorlund 2011 Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G, Gluud C. User manual forTrial Sequential Analysis (TSA). http://ctu.dk/tsa/files/tsa_manual.pdf 2011 (accessed 15 August 2012). Todo 1991 Todo S, Demetris AJ, Van Thiel D, Teperman L, Fung JJ, Starzl TE. Orthotopic liver transplantation for patients with hepatitis B virus-related liver disease. Hepatology 1991;13 (4):619–26. Wetterslev 2008 Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. Journal of Clinical Epidemiology 2008;61:64–75. Wetterslev 2009 Wetterslev J, Thorlund K, Brok J, Gluud C. Estimating required information size by quantifying diversity in random-effects model meta-analyses. BMC Medical Research Methodology 2009;9:86. WHO Fact Sheet 2010 WHO. Hepatitis B. Fact Sheet No 204. http:// www.who.int/mediacentre/factsheets/fs204/en/ (accessed 15 August 2012). Wood 2008 Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman DG, et al.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. ∗ Indicates the major publication for the study APPENDICES Appendix 1. Search strategy for identification of studies Database Time Span Search strategy The Cochrane Hepato-Biliary Group Con- Date will be given at review stage. trolled Trials Register (’immune globulin’ OR immunoglobulin OR HBIg) AND (’hepatitis b’ OR HBV) AND ( (liver OR hepat*) AND (transplant* OR graft*) ) Cochrane Central Register of Controlled Latest issue. Trials (CENTRAL) in The Cochrane Library #1 MeSH descriptor Hepatitis B Antibodies explode all trees #2 (immune globulin OR immunoglobulin OR HBIg) #3 (#1 OR #2) Hepatitis B immune globulin for preventing hepatitis B recurrence after liver transplantation (Protocol) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 8 (Continued) #4 MeSH descriptor Hepatitis B explode all trees #5 hepatitis b OR HBV #6 (#3 OR #4) #7 MeSH descriptor Liver Transplantation explode all trees #8 (liver OR hepat*) AND (transplant* OR graft*) #9 (#7 OR #8) #10 (#3 AND #6 AND #9) MEDLINE (Ovid SP) 1948 to the date search is performed. 1. exp Hepatitis B Antibodies/ 2. (immune globulin or immunoglobulin or HBIg).mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier] 3. 1 or 2 4. exp Hepatitis B/ 5. (hepatitis b or HBV).mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier] 6. 4 or 5 7. exp Liver Transplantation/ 8. ((liver or hepat*) and (transplant* or graft*)). mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier] 9. 7 or 8 10. 3 and 6 and 9 11. (random* or blind* or placebo* or meta-analysis).mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier] 12. 10 and 11 EMBASE (Ovid SP) 1980 to the date search is performed. 1. exp hepatitis B antibody/ 2. (immune globulin or immunoglobulin or HBIg).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer] 3. 1 or 2 4. exp hepatitis B/ 5. (hepatitis b or HBV).mp. [mp=title, ab- Hepatitis B immune globulin for preventing hepatitis B recurrence after liver transplantation (Protocol) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 9 (Continued) stract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer] 6. 4 or 5 7. exp liver transplantation/ 8. ((liver or hepat*) and (transplant* or graft*)). mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer] 9. 7 or 8 10. 3 and 6 and 9 11. (random* or blind* or placebo* or metaanalysis).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer] 12. 10 and 11 Science Citation Index Expanded (SCI ex- 1900 to the date search is performed. panded) (http://apps.isiknowledge.com.ep. fjernadgang.kb.dk) # 6 #5 AND #4 # 5 TS=(random* or blind* or placebo* or metaanalysis) # 4 #3 AND #2 AND #1 # 3 TS=((liver or hepat*) and (transplant* or graft*)) # 2 TS=(hepatitis b or HBV) # 1 TS=(immune globulin or immunoglobulin or HBIg) HISTORY Protocol first published: Issue 10, 2012 CONTRIBUTIONS OF AUTHORS Tania Berdichevski (TB) - was responsible for writing up the background section, described the aims of the review, and defined the criteria for considering studies for this review including definition of primary and secondary outcomes. Lior Katz (LK) - was responsible for the definition of the search methods for identification of studies as well as for writing up the data collection and analysis in the methods section. Sushil Kumar (SK) - commented on the protocol. All authors approved the final protocol. Hepatitis B immune globulin for preventing hepatitis B recurrence after liver transplantation (Protocol) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 10 DECLARATIONS OF INTEREST None known. Hepatitis B immune globulin for preventing hepatitis B recurrence after liver transplantation (Protocol) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 11