ORIGINAL ARTICLE. Robert Perrillo Hepatology Division, Baylor University Medical Center, Dallas, TX

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1 LIVER TRANSPLANTATION 15: , 2009 ORIGINAL ARTICLE Hepatitis B Virus Prevention Strategies for Antibody to Hepatitis B Core Antigen Positive Liver Donation: A Survey of North American, European, and Asian-Pacific Transplant Programs Robert Perrillo Hepatology Division, Baylor University Medical Center, Dallas, TX Prophylactic therapy is generally used to prevent reactivated hepatitis B after transplantation of an antibody to hepatitis B core antigen (anti-hbc) positive liver. To gain insight into current practice, a questionnaire was ed to 89 liver transplant physicians in the United States, Europe, and Asia/Australia and 4 hepatitis B experts. Addressees were asked if they prefer lamivudine or other nucleoside analogs and whether these drugs are used indefinitely. They were also questioned about the use of hepatitis B immune globulin (HBIg), the preferred duration of its administration, and whether treatment strategies differ according to the knowledge of the serologic status of the recipient. Responses were obtained from 78 physicians. All transplant physicians reported the use of nucleoside analog therapy, and 5% prefer lamivudine (58% versus 81% for US and non-us physicians, P 0.05). Sixty-one percent use HBIg (38% always, 23% sometimes). HBIg was used more frequently in the United States than other parts of the world (9% versus 4%, P 0.03). Eighty-one percent of transplant physicians use nucleoside analog therapy for an indefinite period, but the duration of HBIg treatment varies widely. Although some centers omit nucleoside analog or HBIg therapy in antibody to hepatitis B surface antigen positive recipients, 90% will not omit these agents if the recipient is positive for anti-hbc alone. In conclusion, nucleoside analog therapy is nearly always used for anti-hbc positive livers, and most transplant physicians treat for an indefinite period. Lamivudine continues to be preferred as first-line therapy. Many programs also use HBIg, but there is wide variation in the way this is administered. Further study is needed to determine the most cost-beneficial regimen. Liver Transpl 15: , AASLD. Received May 27, 2008; accepted September 22, It has been known for more than a decade that antibody to hepatitis B core antigen (anti-hbc) positive liver donation is associated with a risk of hepatitis B reactivation in the allograft. 1,2 Prior to the development of antiviral therapy, the risk was observed to be highest (50%-75%) for recipients without past hepatitis B virus (HBV) infection, lowest (0%-5%) for individuals with anti-hbc and antibody to hepatitis B surface antigen (anti-hbs), and intermediate (0%-18%) for individuals positive for anti-hbs or anti-hbc 1-5 As a result of these data, the standard of care at many centers has become providing antiviral and/or hepatitis B immune globulin (HBIg) prophylaxis to the recipient when a donor is anti-hbc positive. This meant the use of HBIg before lamivudine became available in By 2001, 90% of United States liver transplant programs reported that they used lamivudine, either alone or with HBIg. In chronic hepatitis B, prolonged treatment of hepatitis B with lamivudine results in a much higher rate of drug resistance in comparison with other nucleoside analogs. 7 It is unknown, however, if a lower rate of resistance is clinically important when an anti-hbc Abbreviations: Ab, antibody; ADV, adefovir; anti-hbc, antibody to hepatitis B core antigen; anti-hbs, antibody to hepatitis B surface antigen; ECV, entecavir; EMT, emtricitabine; HBIg, hepatitis B immune globulin; HBV, hepatitis B virus; IM, intramuscular; IV, intravenous; LAM, lamivudine; PCR, polymerase chain reaction; TDF, tenofovir. Address reprint requests to Robert P. Perrillo, M.D., Hepatology Division, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX Telephone: ; FAX: ; roberper@baylorhealth.edu DOI /lt.2175 Published online in Wiley InterScience ( American Association for the Study of Liver Diseases.

2 224 PERRILLO positive liver is used, and it is also not known if nucleoside analogs other than lamivudine are currently preferred by transplant physicians. Furthermore, it is uncertain if the greater antiviral potency of entecavir, tenofovir, or telbivudine has resulted not only in diminished use of lamivudine but also in less enthusiasm for the use of HBIg. To gain a current perspective on these issues, an international group of physicians with experience in liver transplantation and a panel of experts in the area of hepatitis B therapy were questioned about the prophylactic drug regimens that they use or would recommend, respectively. PATIENTS AND METHODS In January, 2007, a -item survey was electronically submitted to 89 transplant physicians, including 82 transplant hepatologists and 7 surgical directors of liver transplantation. The survey was also submitted to a panel of 4 experts in the area of hepatitis B therapy. The major objective was to analyze what transplant centers are currently using to prevent reactivated hepatitis B in the allograft or, in the case of the expert panel, what is considered to be the most suitable prophylactic regimen in this clinical situation. The transplant physicians were located in the United States (n 5), South America (n 1), Europe (n 22), Canada (n ), and Asia/Australia (n 4). Three of the 4 hepatitis B experts were located in the United States, and the fourth was located in Australia. The survey was intentionally brief to increase the response rate to the following questions: 1. Do you prefer the use of lamivudine to prevent HBV infection when a liver from an anti-hbc donor is transplanted? Possible responses were always, sometimes, and never. 2. If not, what oral nucleoside analog is used? Options given were adefovir, tenofovir, entecavir, telbivudine, or other with a request to define. 3. How long do you use nucleoside analog therapy? Possible responses were months, months, indefinitely, or other with a request to define. 4. Do you use HBIg? Possible responses were always, sometimes, and never. 5. If so, how long do you use it? Options given were months, months, or other with a request to define.. How is HBIg given at your institution? Responses included: Anhepatic only, intramuscular (IM). Anhepatic only, intravenous (IV). Monthly IV or IM for months. Monthly IV or IM for months. Other with a request to define. Interim disclosure of results was not given to any of the participants before submission of their responses. If an electronic response was not obtained, a second request was sent within a week. In 5 instances, a third notice was sent to physicians who had initially expressed an interest in responding. When clarifications were deemed necessary, the respondents were electronically asked to supply further information. As policies may differ according to the serologic status of the recipient, a second brief survey was sent out to all who initially responded. The following questions were asked: 1. All respondents were asked if their centers use these organs in HBV-naïve recipients. 2. For those centers reporting the use of HBIg, the following questions were asked: a. Do you omit HBIg if the recipient is anti-hbs positive but anti-hbc negative? b. Do you omit HBIg if the recipient is anti-hbc positive but anti-hbs negative? c. Do you omit HBIg if the recipient is both anti-hbs positive and anti-hbc positive? 3. For those centers which do not use HBIg, the following questions were asked: a. Do you omit nucleoside analog therapy if the recipient is anti-hbs positive but anti-hbc negative? b. Do you omit nucleoside analog therapy if the recipient is anti-hbc positive but anti-hbs negative? c. Do you omit nucleoside analog therapy if the recipient is both anti-hbs positive and anti- HBc positive? RESULTS Eighty-two (88%) of those queried completed the initial survey. This included 78 transplant physicians (71 transplant hepatologists and 7 surgical directors) and 4 hepatitis B experts. The 78 transplant physicians represented 52 liver transplant programs in the United States, 19 in Europe, 4 in Canada, and 3 in Asia/ Australia. All but 2 respondents answered the questions in their entirety, and clarification of responses was obtained from 10. Two transplant hepatologists indicated that anti-hbc donors were used only in HBsAg carriers at their institution. One of these hepatologists indicated what would be preferred therapy in HBV-naïve or seroconvalescent recipients, and the responses were used in the final data analysis. The other did not. Table 1 describes the findings of the initial survey according to physician involvement in liver transplantation and geographic location. All respondents indicated that nucleoside analog therapy is always used for an anti-hbc positive liver. Fifty-one transplant physicians (5%) and 2 of the 4 experts (50%) said that they always use lamivudine (Fig. 1). This group included 30 of 52 American transplant physicians (58%) and 21 of 2 from other countries (81%; P 0.05 by 2-tailed Fisher s exact test). Eleven transplant physicians (14%) indicated that lamivudine is never used as first-line therapy (Fig. 1). Within this subgroup, 7 indicated that they always use entecavir, and 3 always use adefovir. Sixteen transplant physicians (21%) reported using

3 ANTI-HBC POSITIVE LIVER DONATION 225 TABLE 1. Survey Responses from 78 Transplant Hepatologists and 4 Hepatitis B Experts Group Identity Always Sometimes Never Lamivudine Alternative Duration of Nucleoside Use HBIg Use HBIg Administration Nucleos(t)ide Analogs Indefinite Other Always Sometimes Never Other/Comments US Hepatologists 1 Yes x x 2 Yes x x High-dose HBIg for 1 month IV if the patient is HBV-naïve 3 Yes x x 4 Yes x x x 5 Yes x x Yes x x 7 Yes x months on the basis of the months surgeon s decision 8 Yes x x 9 Yes x x 10 Yes x x x 11 Yes x x If no response to HBV vaccine Yes x x 13 Yes x x Anhepatic only 14 Yes x x IM for 3 months if the patient is anti- HBs( ) 15 Yes x x x 7 days IV followed by IM if the patient is anti-hbs( ) 1 Yes x x 2 months IM 17 Yes x x 2 years IM 18 Yes x x 19 Yes x x High dose IV for 1 week 20 Yes x x 21 Yes x x Anhepatic only 22 Yes x x x 23 Yes x x x 24 Yes x x Considering ECV months 25 Yes x x High dose IV for 3 days 1 Yes* ECV preferred x x x 2 Yes ECV preferred x x 3 Yes ADV x x Anhepatic only 4 Yes ADV x x 5 Yes ADV x x x Yes ADV x x Anhepatic and then IM indefinitely 7 Yes ADV x x x Anhepatic and IM for months 8 Yes ADV, TDF, or ECV 9 Yes ADV, TDF x x x x x x High dose for 1 week and then months

4 22 PERRILLO TABLE 1. (Continued) LAM Alternative Nucleos(t)ide Group Identity Always Some Never Analogs Duration of Nucleoside Use HBIg Use HBIg Administration Indefinite Other Always Some Never Other/Comments 10 Yes ADV x x x 11 Yes ADV x x Anhepatic only 1 Yes ADV preferred x x x 2 Yes ECV preferred x x 3 Yes ECV preferred 1 year/ x x Duration determined by donor serum indefinitely HBV DNA 4 Yes ADV, TDF 2-3 years x x 5 Yes ADV preferred x x Yes ECV preferred x x x 7 Yes ECV preferred x x 8 Yes ECV or EMT x x Anhepatic only TDF preferred 9 Yes ADV preferred x x Liver only used in Ab( ) recipient 10 Yes ECV preferred x x Low dose IM for 1 week US surgical directors 1 Yes x x x HBIg use is based on donor serum HBV DNA 2 Yes x x High dose IV for 1 week, IV monthly for months, and then IM to 18 months 3 Yes x x Anhepatic only 4 Yes x x Anhepatic only 5 Yes x x High dose IV for 1 week Yes ECV preferred x x High dose IV for 1week EUR hepatologists 1 Yes x x Only used if the patient is Ab( ) 2 Yes x x Anhepatic only if the patient is Ab( ); variable duration based on surgeon s preference 3 Yes x x 4 Yes x x High dose daily for 1 week and then weekly for 3 weeks 5 Yes x x Yes x x

5 ANTI-HBC POSITIVE LIVER DONATION 227 TABLE 1. (Continued) LAM Alternative Nucleos(t)ide Group Identity Always Some Never Analogs Duration of Nucleoside Use HBIg Use HBIg Administration Indefinite Other Always Some Never Other/Comments 7 Yes x x 8 Yes x x Anhepatic IM; repeat for 4-7 days 9 Yes x x 10 Yes x x x 11 Yes x x Yes x x 13 Yes x x x If the patient is Ab( ), no HBIg is used; otherwise, monthly IV 14 Yes x x Indefinite 15 Yes ECV x x 1 Yes* x x Indefinite HBIg use if donor serum HBV DNA 10 5 ; otherwise, none 17 Yes LAM ADV or TDF mos x 1 year 18 Yes x x LAM is used only if the recipient is Ab( ) EUR surgical director Yes x x x Canadian hepatologists 1 Yes x x Livers rarely used in HBsAg( ) patients 2 Yes x x x 3 Yes x x 4 Yes x x Asian hepatologists 1 Yes x x 2 Yes x x 3 Yes x x Either LAM or HBIg is used indefinitely if the patient is Ab( ) Expert panel 1 Yes x x 2 Yes x x 3 Yes ADV x x x 4 Yes ECT TDF or TDF emtricitabine (ECV) x x Reduce HBIg over 2-3 months on the basis of donor serum HBV DNA by PCR Abbreviations: Ab, antibody; ADV, adefovir; anti-hbs, antibody to hepatitis B surface antigen; ECV, entecavir; EMT, emtricitabine; HBIg, hepatitis B immune globulin; HBV, hepatitis B virus; IM, intramuscular; IV, intravenous; LAM, lamivudine; PCR, polymerase chain reaction; TDF, tenofovir. * If cost is an issue. All anhepatic usage is IV unless otherwise stated

6 228 PERRILLO Figure 1. Preferred use of lamivudine and other nucleoside analogs as well as duration of use reported by 78 transplant physicians. Abbreviations: ADV, adefovir; ECV, entecavir; Figure 2. Use of hepatitis B immune globulin in the United States and other geographic regions as reported by 78 transplant physicians. The difference in hepatitis B immune globulin use in the United States versus other parts of the world is statistically significant at P lamivudine sometimes, including 3 who had recently decided to switch to entecavir, 7 who occasionally use adefovir, and 3 who admitted to not having a preference for a particular nucleoside analog. Sixty-three transplant physicians (81%) reported a preference for indefinite use of nucleoside analog therapy, whereas 10 (13%) preferred to use nucleoside analog therapy for to months only (Fig. 1). The 5 remaining transplant physicians expressed a preference for either finite treatment in excess of 1 year or a treatment duration that was determined by the serum HBV DNA status of the donor or physician preference (Table 1). Two experts recommended other nucleoside analogs over lamivudine as first-line therapy. Three of the 4 experts reported a preference for indefinite use of nucleoside analog therapy, whereas the remaining individual recommended treatment for to months only (Table 1). The initial survey also demonstrated that HBIg is frequently used in conjunction with nucleoside analog therapy (Fig. 2). Thirty of the 78 transplant physicians (38%) reported always using HBIg, and an additional 18 (23%) use it sometimes. There is greater usage of HBIg in the United States (3 of 52 or 9%) in comparison with other countries ( of 2 or 4%, P 0.03 by Fisher s exact test; Fig. 2). There is little uniformity, however, with respect to how HBIg is used (Fig. 3). Seven transplant physicians (including 2 surgical directors) use HBIg only during the anhepatic phase, prefer to use it for months, and 9 prefer using it for months only. The remaining transplant physicians use HBIg over a broad range of intervals varying from 3 doses postoperatively to indefinite usage (Table 1 and Fig. 3). Only 3 respondents, 1 each in the United States, Europe, and Asia, use HBIg indefinitely. As respondents were not asked to differentiate whether IV or IM administration was preferred beyond the immediate operative period, the specific route of administration for Figure 3. Duration of hepatitis B immune globulin use. Percentages are based on a total of 48 transplant physicians who reported using hepatitis B immune globulin. prolonged periods of administration could not be accurately calculated. However, 15 respondents reported the route of administration for defined interval use (ie, defined as neither anhepatic only nor indefinite): 7 by the IM route (mean duration of use, 29 weeks; range, weeks) and 8 by the IV route (mean duration of administration, 14 weeks; range, 5-24 weeks). Two of the hepatitis B experts recommended short-term use of HBIg. Sixty-four (78%) of the initial respondents answered the second survey. This included 57 transplant hepatologists, 5 surgical directors, and 2 experts. Forty-four were from the United States, 14 were from Europe, 3 were from Canada, and 3 were from the Asia-Pacific region. Table 2 describes the results of the second survey. Eleven of 35 (31%) respondents who indicated that they use HBIg do not use these organs in HBV-naïve

7 ANTI-HBC POSITIVE LIVER DONATION 229 TABLE 2. Results of the Second Survey Depicting How the HBV Serologic Status of the Recipient Affects the Treatment Decision After the Transplantation of an Anti-HBc Positive Allograft Recipient Antibody Status Treatment Group Use of Graft in HBV-Naïve Anti-HBs( ), Anti-HBc( ) Anti-HBc( ), Anti-HBs( ) Anti-HBs( ), Anti-HBc( ) HBIG used with nucleoside analog (n 35)* Yes, 24 (9%) No, 11 (31%) Omit HBIg 19 (54%) 4 (11%) 21 (0%) Use HBIg 1 (4%) 31 (89% 14 (40%) Nucleoside analog used without HBIG (n 29)* Yes, 25 (8%) No, 4 (14%) Omit nucleoside analog 10 (34%) 2 (7%) 8 (28%) Use nucleoside analog 19 (%) 27 (93%) 21 (72%) P value Abbreviations: anti-hbc, antibody to hepatitis B core antigen; anti-hbs, antibody to hepatitis B surface antigen; HBIg, hepatitis B immune globulin; HBV, hepatitis B virus. *The figure includes 1 academic expert in each group. Two-sided Fisher s exact test. patients. Nineteen (54%) responded that they omit HBIg if the recipient is anti-hbs positive alone, with only 1 indicating that the titer of the antibody is important to this decision. By contrast, only 4 (11%) of respondents indicated that they omit HBIg if the recipient is anti- HBc positive and anti-hbs negative. Twenty-one (0%) answered that they routinely omit HBIg in recipients who are positive for both anti-hbs and anti-hbc. In general, centers that are comfortable withholding HBIg for anti-hbs/anti-hbc positive recipients also omit HBIg for recipients positive for anti-hbs alone. Twelve respondents (34%) indicated that they use HBIg in all recipients independently of antibody status. Only 4 of the 29 centers (14%) that use nucleoside analog therapy alone do not use these anti-hbc positive livers in HBV-naïve patients (Table 2). Ten of 29 (34%) omit nucleoside analog therapy if the recipient is anti-hbs positive alone. Only 2 of 29 (7%) omit therapy if the recipient is anti-hbc positive alone. Eight (28%) indicated that they omit nucleoside analogs if the recipient is both anti-hbs positive and anti-hbc positive. In general, centers that are comfortable withholding nucleoside analog therapy for anti-hbs/anti-hbc positive recipients also omit therapy for recipients positive for anti-hbs alone. Eighteen respondents (2%) indicated that they use nucleoside analog therapy in all recipients independently of antibody status. DISCUSSION Livers obtained from anti-hbc positive donors are increasingly being used in many transplant centers because of the ever-widening disparity between the number of organs needed and the number available. According to the United Network of Organ Sharing, 2.2% of deceased liver donors were anti-hbc positive in 1995; this increased to 4.9% in 2000 and to 5.5% in The population prevalence for anti-hbc alone in the United States is 1% to 4%, but this has been estimated to vary from 10% in certain parts of Europe and the Middle East to 30% or more in Asia. 9 Thus, the availability and utilization of these donors can be assumed to be even more common in countries with a high prevalence of hepatitis B. Antiviral therapy has become the standard of care in many centers to prevent hepatitis B reactivation after anti-hbc positive liver donation because this can result in chronic hepatitis and be severe. 2,10 However, preventive treatment regimens remain largely empirical, and there is no standardized or generally accepted approach. As a result, many questions remain unanswered. For example, it is not clear if antiviral therapy needs to be given to all recipients of anti-hbc positive organs. It is also not known how long nucleoside analog therapy needs to be given, if there is any therapeutic advantage for drugs with better resistance profiles than lamivudine, or whether additional benefit results from the use of HBIg. Previous studies have largely described the experience of individual transplant centers, and many have reported using lamivudine, alone or with HBIg, because this was all that was available when prophylactic regimens were devised. 3-5,11-15 The present study not only provides a current perspective on antiviral therapy after anti-hbc liver donation but also is the first to compare the treatment preferences of liver transplant physicians in the United States to those of physicians elsewhere in the world. The survey demonstrated that approximately twothirds of transplant physicians consider lamivudine to be the drug of choice after anti-hbc liver donation. Lamivudine was found to be statistically more likely to be used outside the United States (P 0.05). The increased cost of alternative nucleoside analogs may be a factor, particularly in Europe and Canada, where national health insurance largely subsidizes drug cost.

8 230 PERRILLO Another reason for the high frequency of lamivudine usage in the global transplant community, however, may be the belief that the low intrahepatic content of HBV associated with anti-hbc positive livers is unlikely to lead to the selection of a drug-resistant virus. Although this is a reasonable assumption, it should be noted that several studies have reported lamivudine resistance in the setting of anti-hbc liver donation.,15,1 In 1 report, YMDD-mutant HBV and clinical breakthrough occurred 3 years after transplantation despite successful vaccination and short-term HBIg in addition to lamivudine maintenance. 1 Although most of the cases of lamivudine resistance have thus far occurred in HBV-naïve recipients, the incidence in nonnaïve recipients remains unknown. It is possible that drugs with better resistance profiles than lamivudine will be used more commonly in the future if resistance is recognized as an increasing clinical problem. The survey also demonstrated that the majority of centers continue to use HBIg, with nearly 40% of programs indicating that they always use it and more than 20% indicating that they sometimes use it. However, the mode of delivery and, in particular, the duration of treatment vary considerably (Table 1 and Fig. 3). HBIg use was found to be significantly more common in the United States than elsewhere in the world (P 0.03). The results of the study reaffirm the findings of a survey of US transplant centers that was completed 3 years after lamivudine became available; the authors presented a hypothetical case of an anti-hbc donor for an HBV-naïve recipient. It should be noted, however, that in that study, 78% of centers reported using HBIg and 11% used it as monotherapy; this is considerably higher than the usage rate in the current survey. Thus, the current study suggests that there may be a real decline in the use of HBIg. The rationale for the use of HBIg for anti-hbc positive liver donation is unclear, but several considerations are worth discussing. The protective benefit of HBIg is generally thought to be due to its ability to neutralize HBsAg-coated virions in the circulation or HBsAg-containing leukocytes in the allograft. In geographic areas with intermediate or high HBV prevalence, the majority (0%-70%) of anti-hbc positive blood donors have been found to be HBV DNA negative with a variety of highly sensitive polymerase chain methods 17,18 The frequency of undetectable HBV DNA in anti-hbc positive blood donors is even higher (80%- 100%) in countries with low HBV prevalence such as the United States. 9,19,20 Thus, it seems very unlikely that subdetectable amounts of circulating HBsAg would occur in the circulation or hepatic leukocytes of these donors. Another rationale for the use of HBIg extends from in vitro experiments suggesting that this biological material could have antiviral activity. In 1 study, both monoclonal and polyclonal HBsAg-specific immunoglobulins, once internalized into human hepatocytes, were shown to inhibit the secretion of HBsAg and HBV virions. 21 The in vivo relevance of this observation is not known, however, and further confirmation of these findings is needed. In summary, there does not seem to be a well-established scientific rationale for the use of HBIg after anti-hbc liver donation. Even though its mechanism of action remains undefined, the results of a recent French study suggest that HBIg does reduce the rate of HBV infection after the receipt of an anti- HBc positive liver graft in both HBV-naïve and HBV experienced patients. 22 Rates of HBV infection were 33% for naïve patients receiving HBIg versus 7% for a historical cohort that had not received this material. Also, none of the anti-hbs positive and/or anti-hbc positive recipients receiving HBIg developed an infection versus 37% of those who did not receive this material. The results of the current study indicated that many centers adapt different policies based on the serologic status of the recipient. Most respondents who admitted to using HBIg in the first set of survey questions are comfortable not using it in patients who are anti-hbs positive alone or when anti-hbs is detected in conjunction with anti-hbc. With few exceptions, those physicians who admitted to not using HBIg for anti-hbs/ anti-hbc positive recipients also do not use HBIg for recipients who are anti-hbs positive alone. In the opinion of the author, the decision to reduce the level of protection for patients positive for anti-hbs alone is a relative cause for some concern unless there is a high titer of antibody because low-titer anti-hbs has been found to be a poor reflection of past exposure and immunity in low-risk patient populations. 23 Moreover, the presence of anti-hbs alone has been shown to provide incomplete protection in untreated recipients of anti- HBc positive grafts. 2,22 In contrast, the current survey showed that the vast majority of centers do not modify their approach to HBIg or nucleoside analog use if the recipient is anti-hbc positive alone. This may be explainable by a greater concern that these patients frequently have occult HBV DNA in their liver tissue This study has several limitations. First, the dose of HBIg used was not specifically addressed. This is important for cost-utility considerations and has added significance when you consider that its mechanism of action remains unclear and there is no proof that it provides additional protection in this clinical situation. Also, the study can be criticized for not having addressed the issue of antibody response to HBV vaccinations and how this specifically relates to treatment strategy, particularly with respect to HBIg. This seems less important an issue, however, because it is well recognized that the vaccine-induced neutralizing antibody has often been found to be weak and poorly sustained after transplantation. 1,27 In summary, the use of nucleoside analog therapy is nearly universal after transplantation of an anti-hbc positive liver, and most centers continue to use lamivudine indefinitely. However, since a study done in 2001, several centers in the United States have begun to use alternatives to lamivudine such as entecavir and adefovir, possibly because of lower rates of drug resistance or enhanced antiviral potency. On the basis of the high frequency of lamivudine use, it appears that concern over the potential for drug resistance is minimal, even

9 ANTI-HBC POSITIVE LIVER DONATION 231 though a number of lamivudine-resistant cases have been reported in the literature, particularly in HBVnaïve patients. Many transplant centers continue to use HBIg, but there is broad variation in the way this is administered. It is surprising that despite a growing trend to use less of this very costly material in HBsAgpositive transplant recipients, a substantial number of transplant physicians either use it for relatively long periods or choose the more costly high-dose IV route of administration in this lower risk setting. 28,29 Many centers modify the prophylactic regimen on the basis of the HBV antibody status of the recipient. However, this seems to be less of a concern in centers that use nucleoside analog therapy alone. In the author s opinion, the significant economic cost associated with these prophylactic regimens, particularly when therapy is administered indefinitely, justifies a multinational study of nucleoside analog therapy, with and without HBIg. Such a study might do well to incorporate a discrete interval of nucleoside analog therapy. Because of the large number of patient observations needed, such a study would be most feasibly conducted and have the greatest impact on cost utility in regions of intermediate-to-high HBV prevalence. If such a study were not to be conducted, an alternative measure that could provide useful information would be the establishment of an international registry of outcomes using these varied prophylactic strategies. REFERENCES 1. Wachs ME, Amend WJ, Ascher NL, Bretan PN, Emond J, Lake JR, et al. The risk of transmission of hepatitis B from HBsAg ( ), HBcAb ( ), HBIgM ( ) organ donors. 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