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Hepatitis B immune globulin to prevent hepatitis B virus graft reinfection following liver transplantation: A concise review
Concise Review
A CRITICAL ASSESSMENT OF TREATMENT STRATEGIES USING HBIG FOR PREVENTION OF GRAFT HBV REINFECTION
Hepatitis B Immune Globulin to Prevent Hepatitis B Virus Graft Reinfection Following Liver Transplantation: A Concise Review
Risk Factors for Recurrence of HBV Post-OLT
DANIEL SHOUVAL* AND DIDIER SAMUEL Hepatitis B virus (HBV) infection remains a huge clinical burden worldwide, with annual death rates of 1 million.1 In the United States, approximately 300,000 new cases of acute HBV infection occur annually, 10% of whom will become HBV carriers, and 6,000 of whom will die.2 In the United States and Europe, 5% to 10% of patients undergoing orthotopic liver transplantation (OLT) have HBV-associated chronic or fulminant liver disease.3,4 Until recently, there was increasing reluctance, particularly in the United States, to refer such patients for OLT based on a high HBV reinfection rate of the graft associated with increased cost and a dismal prognosis as a result of cirrhosis, fulminant hepatitis, or fibrosing cholestatic hepatitis.5-7 Consequently, the U.S. Medicare program excluded HBV-associated liver transplantation from its reimbursement scheme.8 The growing clinical success with hepatitis B immune globulin (HBIG), however, has allowed OLT to re-emerge as a treatment option for HBV liver disease by significantly reducing rates of reinfection and prolonging survival.9-11 In fact, survival today of patients treated indefinitely with HBIG is similar and even better, as compared with patients undergoing transplantation for hepatitis C virus (HCV) cirrhosis.9,11 Given the recent success with HBIG, and pending the introduction of new antiviral agents against HBV infection, a review of this important topic is timely. In this article, we assess the current state of HBIG, including protocols for its administration, pharmacokinetics, adverse effects, treatment failures, its combined use with antiviral agents, and prospects for further progress. These advances establish a far more optimistic outlook for those with HBV infection and severe liver disease.
Abbreviations: HBV, hepatitis B virus; OLT, orthotopic liver transplantation; HBIG, hepatitis B immune globulin; HCV, hepatitis C virus; HBsAg, hepatitis B surface antigen; IC, immune complex; anti-HBs, antibody to HBsAg; anti-HBc, antibody to hepatitis B core antigen; PCR, polymerase chain reaction. From the Hoˆpital Paul Brousse, Centre Hepato Biliaire, Universite´ Paris Sud, Villejuif Cedex, France. Received June 30, 2000; accepted August 29, 2000. *Dr. Shouval was on sabbatical leave from the Liver Unit, Hadassah Hospital, Jerusalem, Israel. Address reprint requests to: Daniel Shouval, M.D., Liver Unit, Hadassah University Hospital, P.O. Box 12000, Jerusalem, 91120, Israel. E-mail: [email protected]; fax: 972-2-6420338. Copyright © 2000 by the American Association for the Study of Liver Diseases. 0270-9139/00/3206-0002$3.00/0 doi:10.1053/jhep.2000.19789
Rates of HBV reinfection and risk factors following OLT have been well characterized. Two key determinants of reinfection are the pretransplantation status of viral replication and the type of liver disease (i.e., acute vs. chronic). Patients with pretransplantation replicating virus as assessed by conventional HBV-DNA hybridization, and those with cirrhosis, are the highest at risk for graft HBV reinfection. In a large European study, HBV graft recurrence in patients with cirrhosis given no immunoprophylaxis was 67% ⫾ 4%, irrespective of HBV replicative status pre-OLT.9 In patients with evidence of viral replication before OLT (HBV-DNA⫹ or hepatitis B e antigen [HBeAg]⫹), HBV reinfection occurred in 83% ⫾ 6%. Patients with delta virus superinfection or with fulminant hepatitis B harbor a lower risk of recurrent infection (32% and 17%, respectively).9,12 The Evolution of Protocols and Proposed Mechanisms of HBIG
HBIG was first administered to an HBsAg⫹ patient in 1978,13 followed by exploratory trials of intravenous immunoprophylaxis in Germany and France between 1987 and 1991. In these patients, HBIG delayed graft reinfection if given for 2 to 6 months’ post-OLT and protected the majority of OLT recipients at risk when given for an indefinite period.9-11,14-16 These early studies were initially viewed with caution by American transplantation hepatologists, which was eventually overcome by reports of a European retrospective multicenter study9 and of 2 pivotal clinical trials in the U.S.17-20 (Table 1). Since then, the role of HBIG in preventing graft HBV reinfection has been confirmed repeatedly.21-34 The initial reluctance to administer HBIG in the U.S. was based in part on the lack of a licensed U.S. HBIG preparation for intravenous use, while in Europe, 2 such agents had been available for more than a decade. Instead, all clinical trials in the U.S. employed HBIG preparations manufactured for intramuscular use that were given intravenously. The mechanism(s) by which HBIG protects the transplanted liver against HBV reinfection are not understood. Antibodies to the common “a” determinant of the hepatitis B surface antigen (HBsAg) protect against HBV infection irrespective of subtype,35 as shown for HBIG given as pre- or immediately postexposure prophylaxis. However, its effect in OLT patients with persistent HBV infection is not clear.36 One hypothesis suggests that HBIG protects naı¨ve hepatocytes against HBV released from extrahepatic sites through the blocking of a putative HBV receptor. Antibody-dependent cell-mediated cytotoxicity may also contribute to infected target cell lysis. Regardless of the mechanism involved, there is evidence for a dose-dependent response to HBIG treatment that will protect the majority of OLT patients against HBV reinfection of the graft.9,10,24,27 Based on current understanding of the immunopathogenesis of HBV, it is unlikely that passive immunization alone will lead to eradication of infection, especially in the immunosuppressed OLT patient. However, it may neutralize circulating virions, possibly through immune precipitation and formation of immune complexes (IC).37 Resolution of HBV infec-
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TABLE 1. Efficacy of HBIG for Prevention of HBV Reinfection of the Graft-Selected Reports % Patients Reinfected With HBV Post-OLT Patients (no.)
23 110 44 53 27 209 39 24 25 13 17 15
Pre-OLT Status of Patients Nonreplicating
29 11 31 10 33 20 — NE NE NE 33 6
Replicating*
89 68 (33-81) 73 — 84 70 35 NE NE 33 38 —
Total
Reference
52 23 46 10 41 33 21 19 16 23 35 6
14 27 28 29 23 9 19 20 24 30 26 31
NOTE. Information was retrieved from the literature only for patients receiving HBIG therapy. Abbreviation: NE, not evaluable; insufficient data or small number of patients followed. (Note that there may be some overlap as to the number of patients treated in the various centers, because many of the patients treated in Europe until 1990 participated in a European multicenter survey.11) * Data on presence of HBV-DNA⫹ and/or hepatitis Be antigen–positive subjects were pooled.
tients initially treated with intravenous HBIG, provided that they are HBV-DNA⫺ preoperatively.23,42-45 However, this route of administration may be painful and affect patients’ quality of life, because life-long treatment seems necessary. Efforts to use intramuscular HBIG have been motivated by the substantial cost and unavailability of intravenous HBIG. At present, experience with the intramuscular route for HBIG is limited to a small number of patients and a short follow-up. Such protocols usually use a combination of HBIG with lamivudine and achieve similar, short-term success rates for preventing graft reinfection compared with conventional protocols. However, data obtained during a 1- to 2-year follow-up are not sufficient to allow definitive conclusions justifying the replacement of intravenous HBIG with an intramuscular protocol.44,45 Viral Load, Dosing of HBIG and Pharmacokinetics. Doses required to neutralize HBV post-OLT are greatly influenced by pretransplantation viral status. In European patients with no preoperative evidence for overt viral replication, a regimen consisting of immediate postoperative loading with daily high-dose intravenous HBIG injection is recommended.9 Postoperative maintainance of serum anti-HBs levels between 100 to 150 mIU/mL (Fig. 1) successfully prevented HBV graft reinfection in such patients. However, it did not adequately
tion has been associated with formation of IC of the IgG1 and IgG3 subclasses.38 Celis et al. suggested that immune-complexed polyclonal or monoclonal antibodies to HBsAg (antiHBs) may induce an immune-potentiating effect against HBsAg.37 Such ICs may augment the amount of HBsAg internalized by antigen-presenting cells and enhance a proliferative response of HBsAg-specific T-cell clones. However, circulating ICs of the envelope protein have been documented in patients with occult hepatitis B core antibody (anti-HBc)-positive HBV infection,39 and in patients receiving HBIG after OLT who were unable to resolve the chronic HBV infection. HBIG may also influence immune regulatory functions, as suggested for normal IgG in autoimmune disorders.40 Patients receiving long-term HBIG have a lower incidence of rejection as compared with all other indications for OLT, except for alcoholic liver disease.41 Furthermore, in some OLT patients treated with HBIG, HBV DNA is present in hepatocytes without evidence of hepatocellular injury, a host inflammatory response, or of circulating virus,20 suggesting some form of HBIG-associated immune suppression or tolerance. Protocols for Administration of Hepatitis B Immune Globulin The Conventional Protocol. Cumulative experience supports the use of HBIG to protect the majority of OLT recipients at risk against HBV graft reinfection (Table 1). There is now a consensus about the protocol for administration, as shown in Fig. 1, although new routes of administration and combination with other antiviral agents are now undergoing clinical evaluation, as discussed in the following sections. Attempts to withdraw HBIG protection 2 to 6 months following OLT have resulted in a delayed, but similar, rate of graft HBV reinfection as in nontreated historical controls.9,14,15 Variations in Protocol and Route of Injection. Most data support long-term intravenous administration of HBIG. However, by using intramuscular injections of HBIG, it may be possible to maintain adequate postoperative anti-HBs levels in stable pa-
FIG. 1. Flow-chart guidelines for administration of HBIG for prevention of HBV graft reinfection following liver transplantation.
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protect patients who were HBV-DNA⫹ preoperatively. In this latter group, the rate of HBV reinfection could be significantly reduced by using higher HBIG doses and maintaining serum anti-HBs levels ⬎500 mIU/mL, especially during the first postoperative 6 months.17 Successful neutralization of circulating HBV may depend on proper assessment of individual viral load. In persistently infected HBV carriers, virus release into the circulation is estimated at 1012 particles/24 hr, with a virion half-life of about 24 hours.46 The viral load may also be influenced by corticosteroid treatment and HBV release from extrahepatic sites.47,48 A large margin of safety is necessary to guarantee neutralization and precipitation of circulating virions, taking into account this variable viral load and the wide range in affinity and avidity to HBV envelope antigens in various HBIG preparations. This rationale underlies the need to give large antiHBs doses peri- and post-OLT, ranging between 190,000 and 120,000 units in the first and second year postsurgery, respectively. The dose may be reduced to 120,000 to 80,000 U/year in patients who are HBV-DNA⫺ (by conventional hybridization) pre-OLT. There is evidence that clearance of HBIG in the first 3 months’ post-OLT changes continuously.17 Preoperative viral load affects HBIG consumption mainly in the first postoperative week, when its half-life varies between 0.7 to 14 days. Taking into consideration the inter- and intrapatient variations in pharmacokinetics of HBIG, individual “tailoring” of HBIG administration may be indicated.17 Alternatively, one may aim for reaching trough anti-HBs levels of at least 500 mIU/mL within the first 6 months’ post-OLT, ⬎250 mIU/mL until month 12, and ⬎100-150 mIU/mL indefinitely. This strategy requires injection of high-dose HBIG and continuous monitoring of serum anti-HBs levels at an increased expense (Fig. 1), but may eliminate HBV reinfection entirely, with a 3-year graft survival of up to 81% and a 3-year patient survival of up to 96%.30 An alternative approach has been proposed in which (following anti-HBs titer stabilization post-OLT), a fixed monthly 10,000-U dose of HBIG is delivered intravenously, irrespective of preoperative viral replicative status20 (Fig. 1). This protocol accounts for inter- and intrapatient variations in antibody elimination by providing a safety margin through frequent and high universal dosing of HBIG, but requires monthly clinic visits with a corresponding increase in cost. It is important to recognize that the same HBIG may have a variable half-life in different patients, and more importantly, that there are significant differences in the pharmacokinetics and half-lives of various HBIG preparations. Such knowledge may lead to significant savings of ⬃30% in cost and an improved quality of life, enabling an extended interval of 6 to 12 weeks between intravenous injections.31 Improved standards are needed for production of HBIG preparations with respect to their binding activity to HBsAg, their half-life, and their shelf stability, especially in view of an antibody decay that occurs over time in immune globulin preparations.31,49,50 A number of HBIG preparations are used worldwide (Table 2), but information on their pharmacokinetics is limited.17,31,51-54 Differences between preparations has an effect on volume of injection and indirectly on frequency of adverse events. HBIG preparations for intravenous administration are manufactured in several European countries, although not all are licensed for intravenous use (Table 2). The European Agency
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TABLE 2. Selected HBIG Preparations
Name
IG anti-HBs IV Hepatect* Hepatitis B IG Hepatitis B IG
CAF IG-anti-HBs Hepuman† Uman-BIG H-BIG‡ HyperHep BayHep Hep-B-Gammagee
Manufacturer
LFB Biotest BioProduct Lab. Scottish Blood Products Laboratory Red Cross Berna Farma Biagini NABI Cutter/Miles Bayer Merck Sharp & Dohme
Country
Formulation
France Germany U.K. U.K., Scotland
IV IV IV IV
Belgium Switzerland Italy U.S.A. U.S.A./ Canada U.S.A.
IV IM IM/IV IM IM IM
AntiHBs (U/mL)
50 50 50 50
50 200 200/50 222 217-250 ⬎100
NOTE. All HBIG preparations formulated for intravenous (IV) use are also manufactured for intramuscular (IM) injection with higher anti-HBs concentration. * Also Ireland, Austria, Italy. † Also Italy, Spain. ‡ Originally manufactured by Abbott, U.S.A.
for Evaluation of Medicinal Products has set guidelines for the manufacturing of immune globulins for intravenous use in humans (http://www.eudra.org/emea). Comparative pharmacokinetic analysis of HBIG preparations in use worldwide is confounded by a number of factors, including lack of worldwide standardization, the variations in plasma donor pools, and the mixed use of immune globulins intended for intramuscular and intravenous application. Furthermore, viral inactivation techniques vary between HBIG preparations that undergo solvent-detergent, nano filtration, acidification, pepsin, or propionolactone treatment.51-54 The propionolactoneinduced modification of the IgG molecule used to manufacture one HBIG preparation may alter the immunogenicity of HBIG and consequently reduce its half-life.31,52 The plasma source for preparation of HBIG also varies between manufacturers. Until recently, high-titer anti-HBs/antiHBc⫹ pools obtained from healthy blood donors who had recovered from hepatitis B were used for manufacturing. Now that more immunogenic HBV vaccines containing Pre-S antigen(s) are available, plasmapharesis of such immunized donors for the generation of high anti-HBs titer pools may become more cost-effective and possibly a safer substitution for the previous donors.55 ADVERSE EVENTS FOLLOWING HBIG ADMINISTRATION
HBIG administration has a very satisfactory record of safety and tolerability, but mild to moderate adverse events have been observed. Hypersensitivity reaction or even anaphylaxis may rarely occur following HBIG administration as with other immune globulins, especially in patients with IgA deficiency. One would expect to observe the clinical signs of IC disease in OLT patients during the peri- and early postoperative period when large amounts of HBsAg are immunoprecipitated by HBIG. Surprisingly, tolerability and safety of HBIG preparations are excellent, although data on prospective monitoring of symptoms and of ICs and complement are lacking. Indirect support for the presence of ICs may be inferred from common complaints such as arthralgia, myalgia, a skin rash, and even
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central nervous system symptoms, which are occasionally accompanied by nausea and can be easily controlled with antihistamines, steroids, and analgesic agents.18 Some of these symptoms may be attributable to aggregates of antibody fragments present in the intramuscular HBIG (anti-HBs titer of 200 to 250 U/mL in an 18% protein solution), but not in the intravenous reagent, because they are rarely reported when using the HBIG manufactured for intravenous use (anti-HBs concentration approximately 50 mIU/mL in a 5% protein solution). Thus, in the U.S., 10,000 U is often injected intravenous in a volume of only 45 to 50 mL, as compared with the European HBIG injected in a volume of at least 200 mL. Diluting the intramuscular HBIG preparations to a volume of 200 to 300 mL of normal saline 0.9% and intravenous injection over a period of 2 to 4 hours may reduce adverse events, especially the back pain reported by American centers.20 The physical properties of putative ICs may depend on the quantitative ratio between HBsAg and anti-HBs. Several factors may affect these ratios, including concurrent antiviral therapy with reduction of viral load.56 In contrast, corticosteroids may augment concentration of HBsAg, leading to a paradoxical resolution of ICs through induction of HBsAg excess.57 Some of the American HBIG preparations intended for intramuscular injection and given intravenously contain thimerosal, which potentially can induce mercury poisoning; however, only one such case has been reported.58 The potential risk of transmitting blood-borne agents through administration of HBIG is extremely small.59 Paradoxically, in France, the use of HBIG prepared until 1990 before blood products were screened for HCV, was associated with a lower rate of post-OLT HCV infection as compared with HBIG manufactured from HCV-screened blood products.60 BREAKTHROUGH INFECTION AND HBV ENVELOPE PROTEIN MUTATIONS DURING HBIG THERAPY
Mutations in the envelope proteins following continuous exposure to HBIG are relatively common.61,62 The clinical significance of such mutations should be evaluated individually for each patient, because not all mutations are associated with symptomatic HBV reinfection. Nevertheless, based on limited experience, it seems that combination therapy using 2 antiviral agents simultaneously may be more effective then using the same agents sequentially. Emergence of HBV breakthrough-escape mutations often occurs as a result of a selective pressure induced by antiviral or immunomodulatory agents, or by the immune system itself.63-69 Surface gene mutants have been described in association with passive and/or active vaccination,67 in “missed” diagnosis of acute HBV infection,68 in HBV patients treated with a monoclonal anti-HBs antibody after OLT,70 and in association with failure of polyclonal HBIG post-OLT.60-69 One study reports an alarming increase in envelope protein mutations from 9% before 1992 to 54% afterward, a phenomenon that may be the result of using anti-HBs⫹ plasma donors immunized against HBV instead of anti-HBc⫹/anti-HBs⫹ for preparation of HBIG.69 Mutations often occur in the HBV neutralizing “a” determinant of the surface protein, between amino acids 121-149, which are the major target for HBIG and contain the dominant AA 142-145 with a glycine-to-arginine substitution at AA 145. Emergence of such mutations correlates with duration of treatment and with increased rate of graft failure. These mutations often remain undetected as a
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result of the limitations of the available detection assays. The clinical significance of HBsAg mutations is uncertain, because not all patients develop clinical signs of liver injury during reinfection with the escape or even with the wild-type virus, possibly partly as a result of immune suppression. Cessation of HBIG therapy may often lead to reversal from escape to wild-type viremia.64 Finally, there is no consensus yet whether HBIG therapy should be discontinued at diagnosis of a breakthrough. Most clinicians will discontinue HBIG, at least temporarily, and try one of the new antiviral agents such as lamivudine. HBIG IN COMBINATION WITH NEW ANTIVIRAL AGENTS
Recurrence of HBV infection despite HBIG monotherapy may occur, depending on pre-OLT viral replication and load. Because of limited success with interferon alfa in the peri-OLT setting,71 recent attention has focused on newer antiviral agents, including lamivudine, famciclovir, ganciclovir, and adefovir.72-79 At present, supplemental antiviral therapy to HBIG may be considered in a number of clinical situations including: 1) pre-OLT treatment in patients with overt HBV replication; 2) post-OLT treatment in patients treated with HBIG who had pretransplantation evidence of viral replication; 3) patients who developed breakthrough-escape infection while receiving HBIG therapy; 4) HBV patients after OLT who do not receive HBIG; and 5) de novo post-OLT HBV infection. Lamivudine, a nucleoside analogue and the (⫺) entantiomer of 2⬘-deoxy-3⬘-thiacytidine suppresses the synthesis of proviral DNA from viral RNA, and as a result, inhibits the viral reverse transcriptase of HBV. Thus, viral replication can initially be suppressed in almost 100% of patients, but rebound viremia will occur in ⬎80% following cessation of therapy. Lamivudine also has an immunomodulatory effect through restoration of T-cell hyporesponsiveness to nucleocapsid antigens.80 If confirmed, this exciting property may in part explain the anecdotal reports of post-OLT anti-HBs seroconversion.72 A number of studies have established lamivudine’s efficacy in the peri-OLT setting, alone or in combination with HBIG.72-77,81-83 Recurrence rates post-OLT vary from 17.5% to 50%, with higher rates observed in those with evidence of pre-OLT replication. In a trial of 13 patients, pre-OLT lamivudine with post-OLT combination of lamivudine and HBIG cleared replicating HBV from all patients within 28 days, with no evidence of circulating HBV by polymerase chain reaction (PCR) for up to 346 days.72 Two additional antiviral agents, famciclovir, a prodrug for penciclovir and ganciclovir, have been evaluated in early studies for the prevention of graft HBV reinfection with mixed success to date, and larger trials are required to establish a role for these agents.78,79 CURRENT RECOMMENDATIONS AND FUTURE PROSPECTS
To date, stable patients at risk after liver transplantation must receive between 80,000 to 120,000 units of HBIG annually and indefinitely to prevent HBV graft reinfection. The cost of HBIG is still prohibitive and, excluding France, is much higher in Europe than in the U.S., ranging between 28 to 47 cents per anti-HBs unit for the intramuscular agents, to $1 for the intravenous agents. These figures translate into an annual expense of between $22,400 and $120,000, and as a result, a significant number of eligible patients are not referred for transplantation. In the U.S. and in some European countries,
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the same HBIG preparations are available at a cost that may differ up to 50% between centers, indicating that better market research is essential before purchasing an HBIG preparation. Cost may also be reduced by adjusting the dose following anti-HBs monitoring, as well as by using HBIG preparations with longer half-lives. New developments in antiviral therapy will lower the cost and improve efficacy of treatment protocols. Lamivudine should be started at least 4 weeks before transplantation, but it is difficult to choose the ideal time, because the date of transplantation is often unpredictable. Although its use as monotherapy peri-OLT must be clarified through controlled clinical trials, we believe that the current 40% rate of breakthrough YMDD mutants (selected through antiviral therapy and associated with drug resistance) argues strongly against maintenance lamivudine monotherapy for the majority of patients.81-83 Patients who have developed resistance to lamivudine after OLT may respond to the experimental antiviral agent, adefovir dipivoxil, as has recently been observed in 4 patients who developed the YMDD mutant post OLT.84 However, we must await data from properly controlled clinical trials before selecting a new experimental agent for patients with pre-OLT HBV replication. Therefore, despite the above reservations, treatment with lamivudine before transplantation and HBIG afterward seems currently the best available strategy for such patients. Lowering the dose of HBIG and using the intramuscular route may further reduce the cost of HBV prevention after liver transplantation. In the interim, HBIG therapy should not be withdrawn unless compelling evidence is provided that either viral infection has resolved or anti-HBs seroconversion has been sustained. Such candidate patients include those with either fulminant hepatitis B or delta virus infection, whose recurrence of HBV is much lower after OLT than in patients who have had chronic hepatitis B. An attempt to induce anti-HBs seroconversion in HBIG recipients 1 year post-OLT through immunization with recombinant HBsAg has led to anti-HBs seroconversion in 14 of 17 Spanish patients during a median follow-up of 14 months, with no HBV recurrence. However, anti-HBs titers remained low, and longer follow-up is required.85 Therefore, before committing to discontinue HBIG therapy, a method must be available to definitively confirm resolution of HBV infection, and to verify occult seroconversion while receiving HBIG. Thus, improved technology for documenting viral clearance is needed to define the optimal duration of therapy. In the absence of documented viral clearance, HBIG should not be discontinued or should be replaced by antiviral therapy only under strict surveillance, preferably in clinical trials. In summary, each year, thousands of patients die worldwide from complications of HBV infection, and for many, liver transplantation is the only life-saving option. Treatment with HBIG prevents graft reinfection in the majority of patients. The introduction of new antiviral agents such as lamivudine, used in combination with HBIG, is expected to improve outcome. Controlled clinical trials are required to test whether combination therapy with 2 or more antiviral agents may have a therapeutic, pharmacokinetic, and/or cost advantage over HBIG monotherapy. Future research should test new protocols using lower HBIG doses given intravenously or intramuscularly alone or in combination with additional antiviral agents, which may
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reduce the emergence of breakthrough mutants. A mixture of new human monoclonal antibodies directed against several epitopes to the envelope proteins is now undergoing clinical evaluation.86 Because nucleoside analogues may restore some HBV-specific immunological functions, posttreatment immunization with HBV vaccines such as the pre-S/S recombinant or DNA vaccines should be evaluated in lamivudine-treated patients. Some American centers already use donor anti-HBc⫹ livers for liver transplantation in HBV recipients. Transplanting organs from anti-HBc⫹/anti-HBs⫹/HBV-DNA PCR-negative donors should be considered for recipients of livers from live donors when elective PCR testing for HBV DNA is available. Such a strategy may increase the donor pool, and used livers may also protect against recurrent HBV through adoptive transfer of immunity. As noted previously, in patients transplanted for HBV who are treated with high-dose HBIG indefinitely, the survival and quality of life are excellent and may exceed those of patients transplanted for hepatitis C.87 As a result of this impressive progress, the American Liver Foundation has recently recommended to the U.S. Health Care Financing Administration to revise its policy of not providing coverage for liver transplantation in fulminant and chronic hepatitis B.88 Indeed, the U.S. Medicare program has now approved the reimbursement for liver transplantation of patients with HBV liver disease. This welcome change in policy will provide American patients the same chance of survival as patients in several western European countries. Acknowledgment: The authors are indebted to the Universite´ Paris Sud, the Associaton Claude Bernard, and INSERM (CRI 9804), France; and the L. Naftali Research Foundation, Israel, for supporting the research required for writing this review. They thank Dr. R. Adler for her critical comments and Dr. Scott Friedman for enlightening editorial assistance. They are also grateful to the 20 colleagues who responded to their survey on the utilization of HBIG. Because of space constraints, they were unable to cite many key references. REFERENCES 1. Kane MA. Global status of hepatitis B immunization. Lancet 1996;348: 696. 2. Shapiro CN. Epidemiology of hepatitis B. Pediatr Infect Dis J 1993;12: 433-437. 3. United Network of Organ Sharing—UNOS scientific registry data, Transplant Recipients Characteristics—1988-1997, Table 22, September 1998. 4. European Liver Transplant Registry—ELTR. Registry for the European Liver Transplant Association, data analysis, 05/1968-12/1997, http:// www-eltr.vjf.inserm.fr. 5. Todo S, Demetris A, Van Thiel D, Teperman L, Fung JJ, Starzl TE. Orthotopic liver transplantation for patients with hepatitis B virus related liver disease. HEPATOLOGY 1991;13:619-626. 6. O’Grady JG, Smith HM, Davies SE, Daniels HM, Donaldson PT, Tan KC, Portmann B, et al. Hepatitis B virus re-infection after orthotopic liver transplantation. Serological and clinical implications. J Hepatol 1992;14: 104-111. 7. Davies SE, Portman BC, O’Grady JG, Aldis PM, Chaggar K, Alexander GJ, Williams R. Hepatic histologic findings after transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing cholestatic hepatitis. HEPATOLOGY 1991;13:150-157. 8. Medicare program: criteria for Medicare coverage of adult liver transplants—HCFA. Final notice. Fed Regist 1991;56:15006-15018. 9. Samuel D, Mu¨ller R, Alexander G, Fassati L, Ducot B, Benhamou JP, Bismuth H. Liver transplantation in European patients with the hepatitis B surfaces antigen. N Engl J Med 1993;329:1842-1847. 10. Samuel D, Bismuth H. Liver transplantation for hepatitis B. Gastroenterol Clin North Am 1993;22:271-283. 11. Terrault N, Wright TL. Hepatitis B virus infection and liver transplantation. Gut 1997;40:568-571.
1194 SHOUVAL AND SAMUEL 12. Lucey MR, Graham DM, Martin P, Di-Bisceglie A, Rosenthal S, Waggoner JG, Merion RM, et al. Recurrence of hepatitis B and delta hepatitis after orthotopic liver transplantation. Gut 1992;33:1390-1396. 13. Johnson PJ, Wansbrough-Jones MH, Portmann B. Familial HBsAg positive hepatoma: treatment with orthotopic liver transplantation and specific immune globulin. BMJ 1978;1:278. 14. Lauchart W, Mu¨ller R, Pichlmayr R. Long-term immunoprophylaxis of hepatitis B virus re-infection in recipients of human liver grafts. Transplant Proc 1987;XIX:4051-4053. 15. Mu¨ller R, Samuel D, Fassati LR, Benhamou JP, Bismuth H, Alexander GJM. Eurohep consensus report on the management of liver transplantation for hepatitis B virus infection. J Hepatol 1994;21:1140-1143. 16. Blumhardt G, Neuhaus WD, Bechstein L, Steffen R, Hopf U, Moller B, Raakow R, et al. Liver transplantation in HBsAg positive patients. Transplant Proc 1990;22:1577-1578. 17. McGory RW, Ishitani MB, Oliveira WM, Stevenson WC, McCullough CS, Dickson RC, Caldwell SH, et al. Improved outcome of orthotopic liver transplantation for chronic hepatitis B cirrhosis with aggressive passive immunization. Transplantation 1996;61:1358-1364. 18. al-Hemsi B, McGory RW, Shepard B, Ishitani MB, Stevenson WC, McCullough C, Pruett TL. Liver transplantation for hepatitis B cirrhosis: clinical sequela of passive immunization. Clin Transplant 1996;10:668675. 19. Sawyer RG, McGory RW, Gaffey MJ, McCullough CC, Shephard BL, Houlgrave CW, Ryan TS, et al. Improved clinical outcome with liver transplantation for hepatitis B related cirrhosis. Ann Surg 1998;227:841850. 20. Terrault NA, Zhou S, Combs C, Hahn JA, Lake JR, Roberts JP, Ascher NL, et al. Prophylaxis in liver transplant recipients using a fixed dosing schedule of hepatitis B immune globulin. HEPATOLOGY 1996;24:13271333. 21. Ko¨nig V, Hopf U, Neuhaus P, Bauditz J, Schmidt CA, Blumhardt G, Bechstein WO, et al. Long-term follow up of hepatitis B virus infected recipients after orthotopic liver transplantation. Transplantation 1994; 58:553-559. 22. Langrehr JM, Lemmens HP, Lohmann R, Neumann U, Muller AR, Platz KP, Kling N, et al. Liver transplantation in hepatitis B surface antigen positive patients with postoperative long-term immunoprophylaxis. Transplant Proc 1995;26:1215-1216. 23. Devlin J, Smith HM, O’Grady JG, Portmann B, Tan KC, Williams R. Impact of immunoprophylaxis and patient selection on outcome of transplantation for HBsAg-positive liver recipients. J Hepatol 1994;21:204210. 24. Grazi GL, Mazziotti A, Sama C, Jovine E, Stefanini F, Paladini R, Rossi R, et al. Liver transplantation in HBsAg-positive HBV-DNA–negative cirrhotics: immunoprophylaxis and long-term outcome. Liver Transpl Surg 1996;2:418-425. 25. Gugenheim J, Baldini E, Ouzan D, Mouiel J. Absence of initial viral replication and long-term high dose immune globulin administration improve results of hepatitis B virus recurrence prophylaxis after liver transplantation. Transplant Proc 1997;29:517-518. 26. Lerut JP, Donataccio M, Ciccarelli O, Roggen F, Jamart J, Laterre PF, Cornu C, et al. Liver transplantation and HBsAg-positive postnecrotic cirrhosis: adequate immunoprophylaxis and delta virus co-infection as the significant determinants of long-term prognosis. J Hepatol 1999;30: 706-714. 27. Samuel D, Bismuth A, Mathieu D, Arulnaden JL, Reynes M, Benhamou JP, Brechot C, et al. Passive immunoprophylaxis after liver transplantation in HBsAg⫹ patients. Lancet 1991;337:813-815. 28. Lemmens HP, Langrehr JM, Blumhardt G, Lohmann R, Knoop M, Verschl J, Schattenfroh N, et al. Outcome following orthotopic liver transplantation in HBsAg positive patients using short or long term immunoprophylaxis. Transplant Proc 1994;26:3622-3623. 29. Gugenheim J, Crafa F, Fabiani P, Militerno G, Goubaux B, Saint-Paul MC, Uzan D, et al. Recurrence of virus B hepatitis after liver transplantation. Gastroenterol Clin Biol 1992;16:430-433. 30. Nymann T, Shokouh-Amiri MH, Vera SR, Riely CA, Alloway RR, Gaber AO. Prevention of hepatitis B recurrence with indefinite hepatitis B immune globulin (HBIG) prophylaxis after liver transplantation. Clin Transplant 1996;10:663-667. 31. Adler R, Safadi R, Caraco Y, Rowe M, Etzioni A, Ashur Y, Shouval D. Comparison of immune reactivity and pharmacokinetics of two hepatitis B immune globulins in-patients after liver transplantation. HEPATOLOGY 1999;29:1299-1305.
HEPATOLOGY December 2000 32. Lee WC, Jerry LB, Wang CC, Chen MF, Chien RN, Chiu CT, Ling DY, et al. Long-term immunoprophylaxis for hepatitis B virus re-infection after liver transplantation. Transplant Proc 1996;28:1699-1700. 33. Angus PW. Review: hepatitis B and liver transplantation. J Gastroenterol Hepatol 1997;12:217-223. 34. Grellier L, Dusheiko GM. Hepatitis B virus and liver transplantation: concepts in antiviral prophylaxis. J Viral Hepat 1997;4:111S-116S. 35. Waters JA, Brown SE, Steward WN. Analysis of the antigenic epitopes of hepatitis B surface antigen involved in the induction of a protective antibody response. Virus Res 1992;33:1-12. 36. Wahl M, Iwarson S, Snoy P, Gerety RJ. Failure of hepatitis B immuneglobuline to protect against experimental infection in chimpanzees. J Hepatol 1989;9:198-203 37. Celis E, Abraham KG, Miller RW. Modulation of the immunological response to hepatitis B virus by antibodies. HEPATOLOGY 1987;7:763-769. 38. Rath S, Devey ME. IgG subclass composition of antibodies to HBsAg in circulating immune complexes from patients with hepatitis B virus infection. Clin Exp Immunol 1988;72:164-167. 39. Ackerman Z, Wands JR, Gazitt Y, Brechot C, Kew M, Shouval D. Enhancement of HBsAg detection in serum of anti-HBc positive patients following removal of circulating immune complexes. J Hepatol 1994;20: 398-404. 40. Yu Z, Lennon VA. Mechanism of intravenous immune globuline in antibody mediated autoimmune disease. N Engl J Med 1999;340:227-228. 41. Farges O, Saliba F, Fahramant H, Samuel D, Bismuth A, Bismuth H. Incidence of acute and chronic rejection after liver transplantation as a function of the primary disease: possible influence of alcohol and polyclonal immunoglobulins. HEPATOLOGY 1996;23:240-248. 42. Burbach GJ, Bienzle U, Neuhaus R, Hopf U, Metzger WG, Pratschke J, Neuhaus P. Intravenous or intramuscular anti-HBs immune globulin for the prevention of hepatitis B re-infection after orthotopic liver transplantation. Transplantation 1997;63:478-480. 43. Tchervenkov JI, Tector AJ, Barkun JS, Sherker A, Forbers CD, Elias N, Cantarovich M, et al. Recurrence-free long-term survival after liver transplantation for hepatitis B using interferon-alpha pretransplant and hepatitis B immune globulin posttransplant. Ann Surg 1997;226:356-368. 44. Yao FY, Osorio RW, Roberts JP, Poordad FF, Briceno MN, GarciaKennedy R, Gish RR. Intramuscular hepatitis B immune globulin combined with lamivudine for prophylaxis against hepatitis B recurrence after liver transplantation. Liver Transpl Surg 5;1999:491-496. 45. Yoshida EM, Erb SR, Partovi N, Scudamore CH, Chung SW, Frighetto L, Eggen HJ, et al. Liver transplantation for chronic hepatitis B infection with the use of combination lamivudine and low-dose hepatitis B immune globulin. Liver Transpl Surg 1999;5:520-525. 46. Nowak MA, Bonhoeffer S, Hill AM, Boehme R, Thomas HC, McDade H. Viral dynamics in hepatitis B virus infection. Proc Natl Acad Sci U S A 1996;93:4398-4402. 47. Tur-Kaspa R, Burk RD, Shaul Y, Shafritz D. Hepatitis B virus DNA contains a glucocorticoid responsive element. Proc Natl Acad Sci U S A 1986;83:1627-1631. 48. Feray C, Zignego AL, Samuel D, Bismuth A, Reynes M, Tiollais P, Bismuth H, et al. Persistent hepatitis B virus infection of mononuclear blood cells without concomitant liver infection. Transplantation 1990;49: 1155-1158. 49. Barker LF, Lorenz D, Rastogi SC, Gerety RJ, Finlayson JS, Seligmann EB. Study of proposed international reference preparation hepatitis B immune globulin. WHO expert committee on biological standardization. WHO/BS 1977;77.1164:1-17. 50. Stamm B, Gerlich W, Thomssen R. Quantitative determination of antibodies against hepatitis B surface antigen: measurements of its binding capacity. J Biol Standard 1980;8:59-68. 51. Scheiermann N. Kuwert EK. Uptake and elimination of hepatitis B immune globulins after intramuscular application in man. Dev Biol Standard 1983;54:347-355. 52. Stephan W, Fasold H. Intraveno¨ses human immunoglobulin durch chemische modifizierung mit beta propiolacton. Radiochemische Unterschungen [in German]. Arzneim Forschung 1980;12:2090-2093. 53. Wahl M, Hermodsson S, Kjellman H, Iwarson S. Recovery and turnover of hepatitis B immuneglobulin in volunteers. Dev Biol Standard 1983;54: 341-345. 54. Glo¨ckner WM. Kinetik von immunglobulin G nach intraveno¨ser oder intramuskula¨rer applikation. In: Kornhuber B, Castro LA, eds. PatientInfektion-Immunglobulin Munchen. Berlin-Heidelberg: Springer-Verlag, 1984:33-38.
HEPATOLOGY Vol. 32, No. 6, 2000 55. Branger M, Elias A, Vitrano L, Jaulin P. Collection of anti-HBs hyperimmune plasma: stimulation by Genhevac B in weakly immunized donors. Rev Fr Transfus Hemobiol 1992;35:325-334. 56. Nityanand S, Holm G, Lefvert AK. Immune complex mediated vasculitis in hepatitis B and C infections and the effects of anti-viral therapy. Clin Immunol Immuno Pathol 1997;82:250-257. 57. Raz E, Michaeli J, Brezis M, Popovtzer MM, Gazitt Y, Shouval D. Improvement of immune-complex nephritis associated with hepatitis B surface antigen excess. Am J Nephrol 1989;9:162-166. 58. Lowell JA, Burgess S, Shenoy S, Curci JA, Peters M, Howard TK. Mercury poisoning associated with high dose hepatitis B–immune globulin administration after liver transplantation for chronic hepatitis B. Liver Transpl Surg 1996;2:475-478. 59. Dodd RY. Infectious risk of plasma donations: relationship to safety of intravenous immune globulins. Clin Exp Immunol 1996;104:31S-34S. 60. Feray C, Gigou M, Samuel D, Ducot B, Maisonneuve P, Reynes M. Incidence of hepatitis C in patients receiving different preparations of hepatitis B immune globulins after liver transplantation. Ann Intern Med 1998;128:810-816. 61. Hunt CM, McGill JM, Allen MI, Condreay LD. Clinical relevance of hepatitis B viral mutations. Concise Review. HEPATOLOGY 2000;31:10371044. 62. Locarnini S, Birch C. Antiviral chemotherapy for chronic hepatitis B infection: lessons learned from treating HIV-infected patients. J Hepatol 1999;30:536-550. 63. Oon CJ, Lim GK, Ye Z, Goh KT, Tan KL, Yo SL, Hopes E, et al. Molecular epidemiology of hepatitis B virus vaccine variants in Singapore. Vaccine 1995;13:699-702. 64. Trautwein C, Schrem H, Tillmann HL, Kubicka S, Walker D, Boker KH, Maschek HJ, et al. Hepatitis B virus mutations in the Pre-S genome before and after liver transplantation. HEPATOLOGY 1996;24:482-488. 65. Carman WF, Trautwein C, van-Deursen FJ, Coleman K, Dornan E, McIntyre G, Waters J, et al. Hepatitis B virus envelope variations after transplantation with and without hepatitis B immune globulin prophylaxis. HEPATOLOGY 1996;24:489-493. 66. Sterneck M, Gunther S, Gerlach J, Naoumov NV, Santatonio T, Fischer L, Rogiers X, et al. Hepatitis B virus sequence changes evolving in liver transplant recipients with fulminant hepatitis. J Hepatol 1997;26:754764. 67. Ghany GM, Ayola B, Villamil F, Gish RG, Rojter S, Vierling JM, Lok A. Hepatitis B virus mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis. HEPATOLOGY 1998;27:213-222. 68. Terrault NA, Zhou S, McCory RW, Pruett TL, Lake JR, Roberts JP, Ascher NL, et al. Incidence and clinical significance of surface and polymerase gene mutations in liver transplant recipients on hepatitis B immunoglobulin. HEPATOLOGY 1998;28:555-561. 69. Protzer-Knolle U, Naumann U, Bartenschlager R, Berg T, Hopf U, Meyerzum-Buschenfelde KH, Neuhaus P, et al. Hepatitis B virus with antigenically altered hepatitis B surface antigen is selected by high dose hepatitis B immune globulin after liver transplantation HEPATOLOGY 1998;27:254263. 70. McMahon G, Ehrlich PH, Moustafa ZA, McCarthy LA, Dottavio D, Tolpin MD, Nadler PL, et al. Genetic alterations in the gene encoding the major HBsAg: DNA and immunological assay of recurrent HBsAg derived from monoclonal antibody–treated liver transplant recipients. HEPATOLOGY 1992;15:757-766. 71. Marcellin P, Samuel D, Areias J, Loriot MA, Arulnaden JL, Gigou M, David MF, et al. Pretransplantation interferon treatment and recurrence of hepatitis B virus infection after liver transplantation for hepatitis B–related end-stage liver disease. HEPATOLOGY 1994;19:6-12.
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72. Grellier L, Mutimer D, Ahmed M, Brown D, Burroughs AK, Rolles K, McMaster P, et al. Lamivudine prophylaxis against reinfection in liver transplantation for hepatitis B cirrhosis. Lancet 1996;348:1212-1215. 73. Bain GV, Kneteman NM, Ma MM, Gutfreund K, Shapiro JA, Fischer K, Tipples G, et al. Efficacy of lamivudine in chronic hepatitis B patients with active viral replication and decompensated cirrhosis undergoing liver transplantation. Transplantation 1996;62:1456-1462. 74. Bartholomew MM, Jansen RW, Jeffers LJ, Reddy KR, Johnson LC, Bunzendahl H, Condreay LD, et al. Hepatitis B virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation. Lancet 1997;349:20-22. 75. Markowitz JS, Martin P, Conrad AJ, Markmann JF, Seu P, Yersiz H, Goss JA, et al. Prophylaxis against hepatitis B recurrence following liver transplantation using combination of lamivudine and hepatitis B immune globulin. HEPATOLOGY 1998;28:585-589. 76. Nery JR, Weppler D, Rodriguez M, Ruiz P, Schiff ER, Tzakis AG. Efficacy of lamivudine in controlling hepatitis B virus recurrence after liver transplantation. Transplantation 1998;65:1615-1621. 77. Mutimer D, Pillay D, Dragon E, Tang H, Ahmed M, O’Donnell K, Shaw J, et al. High pre-treatment serum hepatitis B virus titer predicts failure of lamivudine prophylaxis and graft re-infection after liver transplantation. J Hepatol 1999;30:715-721. 78. Kruger M, Tillman HL, Trautwein C, Bode U, Oldhafer K, Maschek H, Boker et al. Famciclovir treatment of hepatitis B virus recurrence after liver transplantation: a pilot study. Liver Transplant Surg 1996;2:253262. 79. Roche B, Samuel D, Gigou M, Feray C, Virot V, Majno P, Majno P, et al. Long-term ganciclovir therapy for hepatitis B virus infection after liver transplantation. J Hepatol 1999;31:584-592 80. Boni C, Bertoletti A, Penna A, Cavalli A, Pilli M, Urbani S, Scognamiglio P, et al. Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B. J Clin Invest 1998;102:968-975. 81. Perrillo R, Rakela J, Dienstag J, Levy G, Martin P, Wright T, Caldwell S, et al. Multicenter study of lamivudine therapy for hepatitis B after liver transplantation. HEPATOLOGY 1999;29:1581-1586. 82. Mutimer D, Pillay D, Shields P, Cane P, Ratcliffe D, Martin B, Buchaus, et al. Outcome of lamivudine resistant hepatitis B virus infection in liver transplant recipients. Gut 2000;46:10-113. 83. McCaughan GW, Spencer J, Koorey D, Bowden S, Bartholomeusz A, Littlejohn M, Verran D, et al. Lamivudine therapy in patients undergoing liver transplantation for hepatitis B virus precore mutant-associated infection: high resistance rates in treatment of recurrence but universal prevention if used as prophylaxis with very low dose hepatitis B immune globulin. Liver Transpl Surg 1999;5:512-519. 84. Perrilo R, Schiff E, Yoshida E, Statler A, Hirsch K, Wright T, et al. Adefovir Dipivoxil for the treatment of lamivudine resistant hepatitis B mutants. HEPATOLOGY 2000;32:129-134 85. Sanchez-Fueyo A, Rimola A, Grande L, Costa J, Mas A, Navasa M, Cirera I, et al. Hepatitis B immunoglobulin discontinuation followed by hepatitis B virus vaccination: a new strategy in the prophylaxis of hepatitis B virus recurrence after liver transplantation. HEPATOLOGY 2000;31:496501. 86. Eren R, Lubin I, Terkieltaub D, Ben-Moshe O, Zauberman A, Uhlmann R, Tzahor T, et al. Human monoclonal antibodies specific to hepatitis B virus generated in a human/mouse radiation chimera: the Trimera system. Immunology 1998;93:154-161. 87. Dickson RC, Wright RM, Bacchetta MD, Bodily SE, Caldwell SH, Driscoll CJ, Pruett TL, et al. Quality of life of hepatitis B and C patients after liver transplantation. Clin Transplant 1997;11:282-285. 88. Vierling JM, Teperman LW, Brownstein AP (eds). Hepatitis B and liver transplantation. Semin Liver Dis 2000;20:1S-35S.
A CRITICAL ASSESSMENT OF TREATMENT STRATEGIES USING HBIG FOR PREVENTION OF GRAFT HBV REINFECTION
Hepatitis B Immune Globulin to Prevent Hepatitis B Virus Graft Reinfection Following Liver Transplantation: A Concise Review
Risk Factors for Recurrence of HBV Post-OLT
DANIEL SHOUVAL* AND DIDIER SAMUEL Hepatitis B virus (HBV) infection remains a huge clinical burden worldwide, with annual death rates of 1 million.1 In the United States, approximately 300,000 new cases of acute HBV infection occur annually, 10% of whom will become HBV carriers, and 6,000 of whom will die.2 In the United States and Europe, 5% to 10% of patients undergoing orthotopic liver transplantation (OLT) have HBV-associated chronic or fulminant liver disease.3,4 Until recently, there was increasing reluctance, particularly in the United States, to refer such patients for OLT based on a high HBV reinfection rate of the graft associated with increased cost and a dismal prognosis as a result of cirrhosis, fulminant hepatitis, or fibrosing cholestatic hepatitis.5-7 Consequently, the U.S. Medicare program excluded HBV-associated liver transplantation from its reimbursement scheme.8 The growing clinical success with hepatitis B immune globulin (HBIG), however, has allowed OLT to re-emerge as a treatment option for HBV liver disease by significantly reducing rates of reinfection and prolonging survival.9-11 In fact, survival today of patients treated indefinitely with HBIG is similar and even better, as compared with patients undergoing transplantation for hepatitis C virus (HCV) cirrhosis.9,11 Given the recent success with HBIG, and pending the introduction of new antiviral agents against HBV infection, a review of this important topic is timely. In this article, we assess the current state of HBIG, including protocols for its administration, pharmacokinetics, adverse effects, treatment failures, its combined use with antiviral agents, and prospects for further progress. These advances establish a far more optimistic outlook for those with HBV infection and severe liver disease.
Abbreviations: HBV, hepatitis B virus; OLT, orthotopic liver transplantation; HBIG, hepatitis B immune globulin; HCV, hepatitis C virus; HBsAg, hepatitis B surface antigen; IC, immune complex; anti-HBs, antibody to HBsAg; anti-HBc, antibody to hepatitis B core antigen; PCR, polymerase chain reaction. From the Hoˆpital Paul Brousse, Centre Hepato Biliaire, Universite´ Paris Sud, Villejuif Cedex, France. Received June 30, 2000; accepted August 29, 2000. *Dr. Shouval was on sabbatical leave from the Liver Unit, Hadassah Hospital, Jerusalem, Israel. Address reprint requests to: Daniel Shouval, M.D., Liver Unit, Hadassah University Hospital, P.O. Box 12000, Jerusalem, 91120, Israel. E-mail: [email protected]; fax: 972-2-6420338. Copyright © 2000 by the American Association for the Study of Liver Diseases. 0270-9139/00/3206-0002$3.00/0 doi:10.1053/jhep.2000.19789
Rates of HBV reinfection and risk factors following OLT have been well characterized. Two key determinants of reinfection are the pretransplantation status of viral replication and the type of liver disease (i.e., acute vs. chronic). Patients with pretransplantation replicating virus as assessed by conventional HBV-DNA hybridization, and those with cirrhosis, are the highest at risk for graft HBV reinfection. In a large European study, HBV graft recurrence in patients with cirrhosis given no immunoprophylaxis was 67% ⫾ 4%, irrespective of HBV replicative status pre-OLT.9 In patients with evidence of viral replication before OLT (HBV-DNA⫹ or hepatitis B e antigen [HBeAg]⫹), HBV reinfection occurred in 83% ⫾ 6%. Patients with delta virus superinfection or with fulminant hepatitis B harbor a lower risk of recurrent infection (32% and 17%, respectively).9,12 The Evolution of Protocols and Proposed Mechanisms of HBIG
HBIG was first administered to an HBsAg⫹ patient in 1978,13 followed by exploratory trials of intravenous immunoprophylaxis in Germany and France between 1987 and 1991. In these patients, HBIG delayed graft reinfection if given for 2 to 6 months’ post-OLT and protected the majority of OLT recipients at risk when given for an indefinite period.9-11,14-16 These early studies were initially viewed with caution by American transplantation hepatologists, which was eventually overcome by reports of a European retrospective multicenter study9 and of 2 pivotal clinical trials in the U.S.17-20 (Table 1). Since then, the role of HBIG in preventing graft HBV reinfection has been confirmed repeatedly.21-34 The initial reluctance to administer HBIG in the U.S. was based in part on the lack of a licensed U.S. HBIG preparation for intravenous use, while in Europe, 2 such agents had been available for more than a decade. Instead, all clinical trials in the U.S. employed HBIG preparations manufactured for intramuscular use that were given intravenously. The mechanism(s) by which HBIG protects the transplanted liver against HBV reinfection are not understood. Antibodies to the common “a” determinant of the hepatitis B surface antigen (HBsAg) protect against HBV infection irrespective of subtype,35 as shown for HBIG given as pre- or immediately postexposure prophylaxis. However, its effect in OLT patients with persistent HBV infection is not clear.36 One hypothesis suggests that HBIG protects naı¨ve hepatocytes against HBV released from extrahepatic sites through the blocking of a putative HBV receptor. Antibody-dependent cell-mediated cytotoxicity may also contribute to infected target cell lysis. Regardless of the mechanism involved, there is evidence for a dose-dependent response to HBIG treatment that will protect the majority of OLT patients against HBV reinfection of the graft.9,10,24,27 Based on current understanding of the immunopathogenesis of HBV, it is unlikely that passive immunization alone will lead to eradication of infection, especially in the immunosuppressed OLT patient. However, it may neutralize circulating virions, possibly through immune precipitation and formation of immune complexes (IC).37 Resolution of HBV infec-
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TABLE 1. Efficacy of HBIG for Prevention of HBV Reinfection of the Graft-Selected Reports % Patients Reinfected With HBV Post-OLT Patients (no.)
23 110 44 53 27 209 39 24 25 13 17 15
Pre-OLT Status of Patients Nonreplicating
29 11 31 10 33 20 — NE NE NE 33 6
Replicating*
89 68 (33-81) 73 — 84 70 35 NE NE 33 38 —
Total
Reference
52 23 46 10 41 33 21 19 16 23 35 6
14 27 28 29 23 9 19 20 24 30 26 31
NOTE. Information was retrieved from the literature only for patients receiving HBIG therapy. Abbreviation: NE, not evaluable; insufficient data or small number of patients followed. (Note that there may be some overlap as to the number of patients treated in the various centers, because many of the patients treated in Europe until 1990 participated in a European multicenter survey.11) * Data on presence of HBV-DNA⫹ and/or hepatitis Be antigen–positive subjects were pooled.
tients initially treated with intravenous HBIG, provided that they are HBV-DNA⫺ preoperatively.23,42-45 However, this route of administration may be painful and affect patients’ quality of life, because life-long treatment seems necessary. Efforts to use intramuscular HBIG have been motivated by the substantial cost and unavailability of intravenous HBIG. At present, experience with the intramuscular route for HBIG is limited to a small number of patients and a short follow-up. Such protocols usually use a combination of HBIG with lamivudine and achieve similar, short-term success rates for preventing graft reinfection compared with conventional protocols. However, data obtained during a 1- to 2-year follow-up are not sufficient to allow definitive conclusions justifying the replacement of intravenous HBIG with an intramuscular protocol.44,45 Viral Load, Dosing of HBIG and Pharmacokinetics. Doses required to neutralize HBV post-OLT are greatly influenced by pretransplantation viral status. In European patients with no preoperative evidence for overt viral replication, a regimen consisting of immediate postoperative loading with daily high-dose intravenous HBIG injection is recommended.9 Postoperative maintainance of serum anti-HBs levels between 100 to 150 mIU/mL (Fig. 1) successfully prevented HBV graft reinfection in such patients. However, it did not adequately
tion has been associated with formation of IC of the IgG1 and IgG3 subclasses.38 Celis et al. suggested that immune-complexed polyclonal or monoclonal antibodies to HBsAg (antiHBs) may induce an immune-potentiating effect against HBsAg.37 Such ICs may augment the amount of HBsAg internalized by antigen-presenting cells and enhance a proliferative response of HBsAg-specific T-cell clones. However, circulating ICs of the envelope protein have been documented in patients with occult hepatitis B core antibody (anti-HBc)-positive HBV infection,39 and in patients receiving HBIG after OLT who were unable to resolve the chronic HBV infection. HBIG may also influence immune regulatory functions, as suggested for normal IgG in autoimmune disorders.40 Patients receiving long-term HBIG have a lower incidence of rejection as compared with all other indications for OLT, except for alcoholic liver disease.41 Furthermore, in some OLT patients treated with HBIG, HBV DNA is present in hepatocytes without evidence of hepatocellular injury, a host inflammatory response, or of circulating virus,20 suggesting some form of HBIG-associated immune suppression or tolerance. Protocols for Administration of Hepatitis B Immune Globulin The Conventional Protocol. Cumulative experience supports the use of HBIG to protect the majority of OLT recipients at risk against HBV graft reinfection (Table 1). There is now a consensus about the protocol for administration, as shown in Fig. 1, although new routes of administration and combination with other antiviral agents are now undergoing clinical evaluation, as discussed in the following sections. Attempts to withdraw HBIG protection 2 to 6 months following OLT have resulted in a delayed, but similar, rate of graft HBV reinfection as in nontreated historical controls.9,14,15 Variations in Protocol and Route of Injection. Most data support long-term intravenous administration of HBIG. However, by using intramuscular injections of HBIG, it may be possible to maintain adequate postoperative anti-HBs levels in stable pa-
FIG. 1. Flow-chart guidelines for administration of HBIG for prevention of HBV graft reinfection following liver transplantation.
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protect patients who were HBV-DNA⫹ preoperatively. In this latter group, the rate of HBV reinfection could be significantly reduced by using higher HBIG doses and maintaining serum anti-HBs levels ⬎500 mIU/mL, especially during the first postoperative 6 months.17 Successful neutralization of circulating HBV may depend on proper assessment of individual viral load. In persistently infected HBV carriers, virus release into the circulation is estimated at 1012 particles/24 hr, with a virion half-life of about 24 hours.46 The viral load may also be influenced by corticosteroid treatment and HBV release from extrahepatic sites.47,48 A large margin of safety is necessary to guarantee neutralization and precipitation of circulating virions, taking into account this variable viral load and the wide range in affinity and avidity to HBV envelope antigens in various HBIG preparations. This rationale underlies the need to give large antiHBs doses peri- and post-OLT, ranging between 190,000 and 120,000 units in the first and second year postsurgery, respectively. The dose may be reduced to 120,000 to 80,000 U/year in patients who are HBV-DNA⫺ (by conventional hybridization) pre-OLT. There is evidence that clearance of HBIG in the first 3 months’ post-OLT changes continuously.17 Preoperative viral load affects HBIG consumption mainly in the first postoperative week, when its half-life varies between 0.7 to 14 days. Taking into consideration the inter- and intrapatient variations in pharmacokinetics of HBIG, individual “tailoring” of HBIG administration may be indicated.17 Alternatively, one may aim for reaching trough anti-HBs levels of at least 500 mIU/mL within the first 6 months’ post-OLT, ⬎250 mIU/mL until month 12, and ⬎100-150 mIU/mL indefinitely. This strategy requires injection of high-dose HBIG and continuous monitoring of serum anti-HBs levels at an increased expense (Fig. 1), but may eliminate HBV reinfection entirely, with a 3-year graft survival of up to 81% and a 3-year patient survival of up to 96%.30 An alternative approach has been proposed in which (following anti-HBs titer stabilization post-OLT), a fixed monthly 10,000-U dose of HBIG is delivered intravenously, irrespective of preoperative viral replicative status20 (Fig. 1). This protocol accounts for inter- and intrapatient variations in antibody elimination by providing a safety margin through frequent and high universal dosing of HBIG, but requires monthly clinic visits with a corresponding increase in cost. It is important to recognize that the same HBIG may have a variable half-life in different patients, and more importantly, that there are significant differences in the pharmacokinetics and half-lives of various HBIG preparations. Such knowledge may lead to significant savings of ⬃30% in cost and an improved quality of life, enabling an extended interval of 6 to 12 weeks between intravenous injections.31 Improved standards are needed for production of HBIG preparations with respect to their binding activity to HBsAg, their half-life, and their shelf stability, especially in view of an antibody decay that occurs over time in immune globulin preparations.31,49,50 A number of HBIG preparations are used worldwide (Table 2), but information on their pharmacokinetics is limited.17,31,51-54 Differences between preparations has an effect on volume of injection and indirectly on frequency of adverse events. HBIG preparations for intravenous administration are manufactured in several European countries, although not all are licensed for intravenous use (Table 2). The European Agency
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TABLE 2. Selected HBIG Preparations
Name
IG anti-HBs IV Hepatect* Hepatitis B IG Hepatitis B IG
CAF IG-anti-HBs Hepuman† Uman-BIG H-BIG‡ HyperHep BayHep Hep-B-Gammagee
Manufacturer
LFB Biotest BioProduct Lab. Scottish Blood Products Laboratory Red Cross Berna Farma Biagini NABI Cutter/Miles Bayer Merck Sharp & Dohme
Country
Formulation
France Germany U.K. U.K., Scotland
IV IV IV IV
Belgium Switzerland Italy U.S.A. U.S.A./ Canada U.S.A.
IV IM IM/IV IM IM IM
AntiHBs (U/mL)
50 50 50 50
50 200 200/50 222 217-250 ⬎100
NOTE. All HBIG preparations formulated for intravenous (IV) use are also manufactured for intramuscular (IM) injection with higher anti-HBs concentration. * Also Ireland, Austria, Italy. † Also Italy, Spain. ‡ Originally manufactured by Abbott, U.S.A.
for Evaluation of Medicinal Products has set guidelines for the manufacturing of immune globulins for intravenous use in humans (http://www.eudra.org/emea). Comparative pharmacokinetic analysis of HBIG preparations in use worldwide is confounded by a number of factors, including lack of worldwide standardization, the variations in plasma donor pools, and the mixed use of immune globulins intended for intramuscular and intravenous application. Furthermore, viral inactivation techniques vary between HBIG preparations that undergo solvent-detergent, nano filtration, acidification, pepsin, or propionolactone treatment.51-54 The propionolactoneinduced modification of the IgG molecule used to manufacture one HBIG preparation may alter the immunogenicity of HBIG and consequently reduce its half-life.31,52 The plasma source for preparation of HBIG also varies between manufacturers. Until recently, high-titer anti-HBs/antiHBc⫹ pools obtained from healthy blood donors who had recovered from hepatitis B were used for manufacturing. Now that more immunogenic HBV vaccines containing Pre-S antigen(s) are available, plasmapharesis of such immunized donors for the generation of high anti-HBs titer pools may become more cost-effective and possibly a safer substitution for the previous donors.55 ADVERSE EVENTS FOLLOWING HBIG ADMINISTRATION
HBIG administration has a very satisfactory record of safety and tolerability, but mild to moderate adverse events have been observed. Hypersensitivity reaction or even anaphylaxis may rarely occur following HBIG administration as with other immune globulins, especially in patients with IgA deficiency. One would expect to observe the clinical signs of IC disease in OLT patients during the peri- and early postoperative period when large amounts of HBsAg are immunoprecipitated by HBIG. Surprisingly, tolerability and safety of HBIG preparations are excellent, although data on prospective monitoring of symptoms and of ICs and complement are lacking. Indirect support for the presence of ICs may be inferred from common complaints such as arthralgia, myalgia, a skin rash, and even
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central nervous system symptoms, which are occasionally accompanied by nausea and can be easily controlled with antihistamines, steroids, and analgesic agents.18 Some of these symptoms may be attributable to aggregates of antibody fragments present in the intramuscular HBIG (anti-HBs titer of 200 to 250 U/mL in an 18% protein solution), but not in the intravenous reagent, because they are rarely reported when using the HBIG manufactured for intravenous use (anti-HBs concentration approximately 50 mIU/mL in a 5% protein solution). Thus, in the U.S., 10,000 U is often injected intravenous in a volume of only 45 to 50 mL, as compared with the European HBIG injected in a volume of at least 200 mL. Diluting the intramuscular HBIG preparations to a volume of 200 to 300 mL of normal saline 0.9% and intravenous injection over a period of 2 to 4 hours may reduce adverse events, especially the back pain reported by American centers.20 The physical properties of putative ICs may depend on the quantitative ratio between HBsAg and anti-HBs. Several factors may affect these ratios, including concurrent antiviral therapy with reduction of viral load.56 In contrast, corticosteroids may augment concentration of HBsAg, leading to a paradoxical resolution of ICs through induction of HBsAg excess.57 Some of the American HBIG preparations intended for intramuscular injection and given intravenously contain thimerosal, which potentially can induce mercury poisoning; however, only one such case has been reported.58 The potential risk of transmitting blood-borne agents through administration of HBIG is extremely small.59 Paradoxically, in France, the use of HBIG prepared until 1990 before blood products were screened for HCV, was associated with a lower rate of post-OLT HCV infection as compared with HBIG manufactured from HCV-screened blood products.60 BREAKTHROUGH INFECTION AND HBV ENVELOPE PROTEIN MUTATIONS DURING HBIG THERAPY
Mutations in the envelope proteins following continuous exposure to HBIG are relatively common.61,62 The clinical significance of such mutations should be evaluated individually for each patient, because not all mutations are associated with symptomatic HBV reinfection. Nevertheless, based on limited experience, it seems that combination therapy using 2 antiviral agents simultaneously may be more effective then using the same agents sequentially. Emergence of HBV breakthrough-escape mutations often occurs as a result of a selective pressure induced by antiviral or immunomodulatory agents, or by the immune system itself.63-69 Surface gene mutants have been described in association with passive and/or active vaccination,67 in “missed” diagnosis of acute HBV infection,68 in HBV patients treated with a monoclonal anti-HBs antibody after OLT,70 and in association with failure of polyclonal HBIG post-OLT.60-69 One study reports an alarming increase in envelope protein mutations from 9% before 1992 to 54% afterward, a phenomenon that may be the result of using anti-HBs⫹ plasma donors immunized against HBV instead of anti-HBc⫹/anti-HBs⫹ for preparation of HBIG.69 Mutations often occur in the HBV neutralizing “a” determinant of the surface protein, between amino acids 121-149, which are the major target for HBIG and contain the dominant AA 142-145 with a glycine-to-arginine substitution at AA 145. Emergence of such mutations correlates with duration of treatment and with increased rate of graft failure. These mutations often remain undetected as a
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result of the limitations of the available detection assays. The clinical significance of HBsAg mutations is uncertain, because not all patients develop clinical signs of liver injury during reinfection with the escape or even with the wild-type virus, possibly partly as a result of immune suppression. Cessation of HBIG therapy may often lead to reversal from escape to wild-type viremia.64 Finally, there is no consensus yet whether HBIG therapy should be discontinued at diagnosis of a breakthrough. Most clinicians will discontinue HBIG, at least temporarily, and try one of the new antiviral agents such as lamivudine. HBIG IN COMBINATION WITH NEW ANTIVIRAL AGENTS
Recurrence of HBV infection despite HBIG monotherapy may occur, depending on pre-OLT viral replication and load. Because of limited success with interferon alfa in the peri-OLT setting,71 recent attention has focused on newer antiviral agents, including lamivudine, famciclovir, ganciclovir, and adefovir.72-79 At present, supplemental antiviral therapy to HBIG may be considered in a number of clinical situations including: 1) pre-OLT treatment in patients with overt HBV replication; 2) post-OLT treatment in patients treated with HBIG who had pretransplantation evidence of viral replication; 3) patients who developed breakthrough-escape infection while receiving HBIG therapy; 4) HBV patients after OLT who do not receive HBIG; and 5) de novo post-OLT HBV infection. Lamivudine, a nucleoside analogue and the (⫺) entantiomer of 2⬘-deoxy-3⬘-thiacytidine suppresses the synthesis of proviral DNA from viral RNA, and as a result, inhibits the viral reverse transcriptase of HBV. Thus, viral replication can initially be suppressed in almost 100% of patients, but rebound viremia will occur in ⬎80% following cessation of therapy. Lamivudine also has an immunomodulatory effect through restoration of T-cell hyporesponsiveness to nucleocapsid antigens.80 If confirmed, this exciting property may in part explain the anecdotal reports of post-OLT anti-HBs seroconversion.72 A number of studies have established lamivudine’s efficacy in the peri-OLT setting, alone or in combination with HBIG.72-77,81-83 Recurrence rates post-OLT vary from 17.5% to 50%, with higher rates observed in those with evidence of pre-OLT replication. In a trial of 13 patients, pre-OLT lamivudine with post-OLT combination of lamivudine and HBIG cleared replicating HBV from all patients within 28 days, with no evidence of circulating HBV by polymerase chain reaction (PCR) for up to 346 days.72 Two additional antiviral agents, famciclovir, a prodrug for penciclovir and ganciclovir, have been evaluated in early studies for the prevention of graft HBV reinfection with mixed success to date, and larger trials are required to establish a role for these agents.78,79 CURRENT RECOMMENDATIONS AND FUTURE PROSPECTS
To date, stable patients at risk after liver transplantation must receive between 80,000 to 120,000 units of HBIG annually and indefinitely to prevent HBV graft reinfection. The cost of HBIG is still prohibitive and, excluding France, is much higher in Europe than in the U.S., ranging between 28 to 47 cents per anti-HBs unit for the intramuscular agents, to $1 for the intravenous agents. These figures translate into an annual expense of between $22,400 and $120,000, and as a result, a significant number of eligible patients are not referred for transplantation. In the U.S. and in some European countries,
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the same HBIG preparations are available at a cost that may differ up to 50% between centers, indicating that better market research is essential before purchasing an HBIG preparation. Cost may also be reduced by adjusting the dose following anti-HBs monitoring, as well as by using HBIG preparations with longer half-lives. New developments in antiviral therapy will lower the cost and improve efficacy of treatment protocols. Lamivudine should be started at least 4 weeks before transplantation, but it is difficult to choose the ideal time, because the date of transplantation is often unpredictable. Although its use as monotherapy peri-OLT must be clarified through controlled clinical trials, we believe that the current 40% rate of breakthrough YMDD mutants (selected through antiviral therapy and associated with drug resistance) argues strongly against maintenance lamivudine monotherapy for the majority of patients.81-83 Patients who have developed resistance to lamivudine after OLT may respond to the experimental antiviral agent, adefovir dipivoxil, as has recently been observed in 4 patients who developed the YMDD mutant post OLT.84 However, we must await data from properly controlled clinical trials before selecting a new experimental agent for patients with pre-OLT HBV replication. Therefore, despite the above reservations, treatment with lamivudine before transplantation and HBIG afterward seems currently the best available strategy for such patients. Lowering the dose of HBIG and using the intramuscular route may further reduce the cost of HBV prevention after liver transplantation. In the interim, HBIG therapy should not be withdrawn unless compelling evidence is provided that either viral infection has resolved or anti-HBs seroconversion has been sustained. Such candidate patients include those with either fulminant hepatitis B or delta virus infection, whose recurrence of HBV is much lower after OLT than in patients who have had chronic hepatitis B. An attempt to induce anti-HBs seroconversion in HBIG recipients 1 year post-OLT through immunization with recombinant HBsAg has led to anti-HBs seroconversion in 14 of 17 Spanish patients during a median follow-up of 14 months, with no HBV recurrence. However, anti-HBs titers remained low, and longer follow-up is required.85 Therefore, before committing to discontinue HBIG therapy, a method must be available to definitively confirm resolution of HBV infection, and to verify occult seroconversion while receiving HBIG. Thus, improved technology for documenting viral clearance is needed to define the optimal duration of therapy. In the absence of documented viral clearance, HBIG should not be discontinued or should be replaced by antiviral therapy only under strict surveillance, preferably in clinical trials. In summary, each year, thousands of patients die worldwide from complications of HBV infection, and for many, liver transplantation is the only life-saving option. Treatment with HBIG prevents graft reinfection in the majority of patients. The introduction of new antiviral agents such as lamivudine, used in combination with HBIG, is expected to improve outcome. Controlled clinical trials are required to test whether combination therapy with 2 or more antiviral agents may have a therapeutic, pharmacokinetic, and/or cost advantage over HBIG monotherapy. Future research should test new protocols using lower HBIG doses given intravenously or intramuscularly alone or in combination with additional antiviral agents, which may
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reduce the emergence of breakthrough mutants. A mixture of new human monoclonal antibodies directed against several epitopes to the envelope proteins is now undergoing clinical evaluation.86 Because nucleoside analogues may restore some HBV-specific immunological functions, posttreatment immunization with HBV vaccines such as the pre-S/S recombinant or DNA vaccines should be evaluated in lamivudine-treated patients. Some American centers already use donor anti-HBc⫹ livers for liver transplantation in HBV recipients. Transplanting organs from anti-HBc⫹/anti-HBs⫹/HBV-DNA PCR-negative donors should be considered for recipients of livers from live donors when elective PCR testing for HBV DNA is available. Such a strategy may increase the donor pool, and used livers may also protect against recurrent HBV through adoptive transfer of immunity. As noted previously, in patients transplanted for HBV who are treated with high-dose HBIG indefinitely, the survival and quality of life are excellent and may exceed those of patients transplanted for hepatitis C.87 As a result of this impressive progress, the American Liver Foundation has recently recommended to the U.S. Health Care Financing Administration to revise its policy of not providing coverage for liver transplantation in fulminant and chronic hepatitis B.88 Indeed, the U.S. Medicare program has now approved the reimbursement for liver transplantation of patients with HBV liver disease. This welcome change in policy will provide American patients the same chance of survival as patients in several western European countries. Acknowledgment: The authors are indebted to the Universite´ Paris Sud, the Associaton Claude Bernard, and INSERM (CRI 9804), France; and the L. Naftali Research Foundation, Israel, for supporting the research required for writing this review. They thank Dr. R. Adler for her critical comments and Dr. Scott Friedman for enlightening editorial assistance. They are also grateful to the 20 colleagues who responded to their survey on the utilization of HBIG. Because of space constraints, they were unable to cite many key references. REFERENCES 1. Kane MA. Global status of hepatitis B immunization. Lancet 1996;348: 696. 2. Shapiro CN. Epidemiology of hepatitis B. Pediatr Infect Dis J 1993;12: 433-437. 3. United Network of Organ Sharing—UNOS scientific registry data, Transplant Recipients Characteristics—1988-1997, Table 22, September 1998. 4. European Liver Transplant Registry—ELTR. Registry for the European Liver Transplant Association, data analysis, 05/1968-12/1997, http:// www-eltr.vjf.inserm.fr. 5. Todo S, Demetris A, Van Thiel D, Teperman L, Fung JJ, Starzl TE. Orthotopic liver transplantation for patients with hepatitis B virus related liver disease. HEPATOLOGY 1991;13:619-626. 6. O’Grady JG, Smith HM, Davies SE, Daniels HM, Donaldson PT, Tan KC, Portmann B, et al. Hepatitis B virus re-infection after orthotopic liver transplantation. Serological and clinical implications. J Hepatol 1992;14: 104-111. 7. Davies SE, Portman BC, O’Grady JG, Aldis PM, Chaggar K, Alexander GJ, Williams R. Hepatic histologic findings after transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing cholestatic hepatitis. HEPATOLOGY 1991;13:150-157. 8. Medicare program: criteria for Medicare coverage of adult liver transplants—HCFA. Final notice. Fed Regist 1991;56:15006-15018. 9. Samuel D, Mu¨ller R, Alexander G, Fassati L, Ducot B, Benhamou JP, Bismuth H. Liver transplantation in European patients with the hepatitis B surfaces antigen. N Engl J Med 1993;329:1842-1847. 10. Samuel D, Bismuth H. Liver transplantation for hepatitis B. Gastroenterol Clin North Am 1993;22:271-283. 11. Terrault N, Wright TL. Hepatitis B virus infection and liver transplantation. Gut 1997;40:568-571.
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