Survival After Orthotopic Liver Transplantation: The Impact of Antibody Against Hepatitis B Core Antigen in the Donor

Transcription

1 LIVER TRANSPLANTATION 15: , 2009 ORIGINAL ARTICLE Survival After Orthotopic Liver Transplantation: The Impact of Antibody Against Hepatitis B Core Antigen in the Donor Lei Yu, 1-3 Thomas Koepsell, 3 Lisa Manhart, 3 and George Ioannou 1,2 1 Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA; 2 Research Enhancement Award Program, Veterans Affairs Puget Sound Health Care System, Seattle, WA; and 3 Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA Liver transplantation using grafts from donors with antibody against hepatitis B core antigen (anti-hbc) increases the recipients risk of developing hepatitis B virus (HBV) infection post-transplantation. Our aim was to assess whether using such grafts was associated with reduced posttransplantation survival and whether this association depended on recipients prior exposure to HBV on the basis of their pretransplantation serological patterns. Data were derived from the United Network for Organ Sharing on adult, cadaveric, first-time liver transplants performed between 1994 and Among recipients who did not have HBV infection before transplantation, those with anti-hbc positive donors had significantly worse unadjusted posttransplantation patient survival than recipients with anti-hbc negative donors [hazard ratio, 1.35; 95% confidence interval (CI), ]. However, after adjustments for other predictors of posttransplantation survival, including donor age, donor race, and recipient underlying liver diseases, patient survival was not significantly different between the 2 groups (hazard ratio, 1.09; 95% CI, ). Among recipients without antibody against hepatitis B surface antigen (anti-hbs), use of anti-hbc positive donor grafts was associated with a trend toward worse survival (adjusted hazard ratio, 1.18; 95% CI, ), whereas no such trend was observed among recipients positive for anti-hbs. In conclusion, in patients without HBV infection before transplantation, using anti-hbc positive donors was not independently associated with worse posttransplantation survival. Matching these donors to recipients with anti-hbs pre-transplantation may be especially safe. Liver Transpl 15: , AASLD. Received September 23, 2008; accepted March 10, See Editorial on Page 1164 Liver transplantation using grafts from donors positive for antibody against hepatitis B core antigen (anti-hbc) increases the recipients risk of hepatitis B virus (HBV) infection post-transplantation, as defined by the detection of hepatitis B surface antigen (HBsAg). 1-6 The underlying mechanism may be related to the observation that HBV can persist in the liver for many years after initial recovery, 7 and it can be reactivated in the setting Abbreviations: anti-hbc, antibody against hepatitis B core antigen; anti-hbs, antibody against hepatitis B surface antigen; BMI, body mass index; CI, confidence interval; HBIG, hepatitis B immunoglobulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ICU, intensive care unit; INR, international normalized ratio; NASH, nonalcoholic steatohepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SD, standard deviation; UNOS, United Network for Organ Sharing. This research was based on data derived from the United Network for Organ Sharing on January 18, This research was supported by the American Liver Foundation and American Association for the Study of Liver Diseases through the Jan Albrecht Award (to G. Ioannou), by the Veterans Affairs Puget Sound Health Care System through the Research Enhancement Award Program (to L. Yu), by the National Institutes of Health through a T32 training grant (to L. Yu), and by the Health Resources and Services Administration (contract ). The content of this work is the responsibility of the authors alone and does not necessarily reflect the views or policies of the US Department of Health and Human Services. Address reprint requests to Lei Yu, M.D., Division of Gastroenterology, Department of Medicine, University of Washington School of Medicine, 1959 NE Pacific Street, Box , Seattle, WA Telephone: ; leiy@medicine.washington.edu DOI /lt Published online in Wiley InterScience ( American Association for the Study of Liver Diseases.

2 1344 YU ET AL. of immunosuppression. 8 There are, however, conflicting data with respect to overall survival among these recipients. Dickson et al. 2 reported that 78% (18/23) of recipients with anti-hbc positive donor grafts developed HBV infection post-transplantation, with significantly decreased 4-year patient survival in comparison with recipients with anti-hbc negative grafts [hazard ratio, 2.4; 95% confidence interval (CI) ]. In contrast, Prieto et al. 3 did not find a survival difference between the 2 groups despite a similarly high frequency of HBV infection (50%, 15/30) among recipients with anti-hbc positive grafts. More recent studies have shown effective prophylaxis against HBV infection in recipients with anti-hbc positive grafts using lamivudine with or without hepatitis B immunoglobulin (HBIG), but few have analyzed patient or graft survival All of these studies involved a relatively small number of patients from selected transplant centers. No studies have adjusted for other important predictors of posttransplantation survival such as donor age, donor race, 16,17 cold ischemia time, 18,19 or recipient markers of liver disease severity. 17 Despite these uncertainties, anti-hbc positive donor livers continue to be used because of the current organ shortage, especially when the recipient is severely ill or has HBV-related cirrhosis. 3,9,20,21 With the exclusion of recipients with a pretransplantation diagnosis of HBV, it has been shown that when anti-hbc positive donor grafts were used in recipients who also harbored anti- HBc with or without antibody against hepatitis B surface antigen (anti-hbs), 2,3,5,6 there was a lower incidence of HBV infection post-transplantation. The protective effect of such matching, however, was not complete, 2,6 and the number of patients involved in these studies was too small for firm conclusions to be drawn. It also remains unclear whether posttransplantation survival was affected when anti-hbc positive donor livers were matched to anti-hbc positive or anti- HBs positive recipients. To more carefully examine these questions in a large and representative population, in the current study we aimed to assess whether anti-hbc positive donor grafts were associated with worse patient and graft survival following liver transplantation after adjustments for other important predictors of posttransplantation survival using data reported to the United Network for Organ Sharing (UNOS) from 1994 to We also aimed to assess whether this association depended on recipients prior exposure to HBV or vaccination on the basis of their pretransplantation HBV serological patterns. PATIENTS AND METHODS Study Design and Data Source We performed a retrospective cohort study using data compiled by UNOS. 22 Transplant centers in the United States are required to submit to UNOS standardized data collection forms, including the Transplant Candidate Registration Form, which contains patient information at the time of listing for liver transplantation, the Deceased Donor Registration Form, which contains information on all consented recovered and nonrecovered donors, the Transplant Recipient Registration Form, which includes the patient status at discharge, pretransplant and posttransplant clinical information, and treatment data, and the Transplant Recipient Follow-Up Form, which is generated 6 months post-transplant and on each subsequent transplant anniversary. The Transplant Recipient Follow-Up Form contains information on patient survival, clinical data, and treatment. After these forms are submitted to UNOS, the data are compiled into a single Standard Transplant Analysis and Research file. A detailed description of the UNOS database has been reported elsewhere. 23 We obtained a Standard Transplant Analysis and Research file from UNOS that included all liver transplants performed in the United States through January 18, Study Population Donor anti-hbc has been recorded on the Deceased Donor Registration form since April 1, 1994; we therefore included liver transplants performed between April 1, 1994 and January 18, We excluded recipients younger than 18 years of age (n 6568) and those who had donors under 10 years of age (n 568), living donors (n 1961), split-liver donors (n 717), non heart-beating donors (n 816), simultaneous organ transplants (n 1937), or previous liver transplants (n 4065). In our main analysis, we also excluded recipients who tested positive for HBsAg pre-transplantation or carried the diagnosis of HBV (n 2947). We additionally excluded transplants with donors who tested positive for HBsAg (n 50) or antibody against hepatitis C virus (HCV; n 850). Among the remaining 37,155 transplants, 4.1% (n 1535) had missing data on donor anti-hbc, and this left 35,620 transplants in the univariate analyses, including 1270 with positive donor anti-hbc. Patients with the diagnosis of HBV were analyzed separately, and a similar exclusion was applied to them as well. Definition of Outcomes Patient survival was measured in years from transplantation until death from any cause. Patients who remained alive or were lost to follow-up as of January 18, 2007 were censored at the time of last known follow-up for the analysis of patient survival. Graft survival was measured in years from transplantation until liver failure (with or without retransplantation) or patient death from any cause, whichever came first. Patients who remained alive without liver failure or were lost to follow-up as of January 18, 2007 were censored at the time of last known follow-up for the analysis of graft survival. Predictors of Posttransplantation Survival We assessed whether any observed differences in posttransplantation survival between recipients with and

3 SURVIVAL AFTER ORTHOTOPIC LIVER TRANSPLANTATION 1345 without anti-hbc positive donors were confounded by donor and recipient characteristics known to affect posttransplantation survival. 17 These included donor age, gender, and race and recipient age, gender, race, underlying liver diseases, and body mass index (BMI). Underlying liver diseases were based on diagnoses reported to UNOS after liver transplantation. Recipients who received exception scores for hepatocellular carcinoma (HCC) based on the more recent Model for End- Stage Liver Disease allocation system were characterized as having HCC instead of their primary liver disease. We included recipients serum albumin, total bilirubin, creatinine, and international normalized ratio (INR) at the time of transplantation as markers for liver disease severity. We also adjusted for the cold ischemia time, year of transplantation, and urgency of transplantation. We used recipient location prior to transplantation (intensive care unit, hospital ward, or home) as a surrogate marker for urgency. 24 Among recipients of anti-hbc positive donor grafts for whom data on lamivudine or HBIG use were available (n 374 in ), we also assessed the potential effect of these treatments on patient survival. Effect Modification Among recipients without a pretransplantation diagnosis of HBV, we tested whether any survival difference between recipients with and without anti-hbc positive donors depended on recipient HBV serological patterns. Routinely tested recipient HBV serological markers include anti-hbc and anti-hbs with 4 potential patterns: (1) anti-hbs negative and anti-hbc negative, indicating a lack of evidence of prior HBV exposure; (2) anti- HBs negative and anti-hbc positive, indicating possible prior exposure; (3) anti-hbs positive and anti-hbc negative, indicating HBV vaccination; and (4) anti-hbs positive and anti-hbc positive, indicating recovered HBV infection. We also tested whether any survival difference between recipients with and without anti- HBc positive donors depended on recipients diagnosis of hepatitis C infection pre-transplantation. Statistical Analysis Cox proportional hazards regression was used to compare patient and graft survival in recipients with and without anti-hbc positive donors before and after adjustments for other predictors of posttransplantation survival. 25 The assumption of proportional hazards was tested by graphical and weighted residual methods. In the multivariate analysis, we decided a priori to include all predictors of posttransplantation survival except INR, which was not recorded in close to 50% of recipients during the study period. Given that the mean INR was not significantly different between the 2 exposure groups, its inclusion would have resulted in a loss of sample size and precision. All predictors were modeled continuously except for gender, race, underlying liver diseases, pretransplantation location, and transplantation year categories ( , , , and ). Trends in anti-hbc positive donor use over the 13-year study period were assessed with the chi-square test for trends. The Kaplan- Meier method was used to estimate patient survival at 1 year among recipients who received an anti-hbc positive graft between 2004 and For these recipients, the log-rank test was used to compare survival between those who were and those who were not using lamivudine or HBIG. We also performed the same univariate and multivariate analyses among recipients who carried the diagnosis of HBV pre-transplantation (excluded in the primary study population) to assess the effect of anti-hbc positive donor organs on their survival. All analyses were performed with STATA 9.0 software (Stata Corp., College Station, TX). To simultaneously adjust for multiple predictors of posttransplantation survival in multivariate analyses, we excluded transplants with missing data for the following characteristics: recipient BMI (n 1007), creatinine (n 303), total bilirubin (n 459), albumin (n 808), and cold ischemia time (n 3691). We also excluded 659 transplants with very abnormal data (because they might have been recorded erroneously) and 170 transplants with implausible data (almost certainly recorded erroneously), as defined in the next paragraph; this left 28,494 transplants in the multivariate analyses, including 997 with positive donor anti-hbc. Transplants with missing data on both recipient anti- HBc and recipient anti-hbs were further excluded (n 7465) when we examined their effect on the relationship between donor anti-hbc status and posttransplantation survival. After these exclusions, the distribution of important confounding variables based on donor anti- HBc status, such as recipient age and BMI, donor age, and recipient liver disease etiologies, remained similar to the distribution before these exclusions. Very abnormal values were defined as follows: cold ischemia time, 0.5 to 1or 24 to 48 hours; BMI, 10 to 15 or 55 to 65 kg/m 2 ; serum creatinine, 0 to 0.1 or 15 to 20 mg/dl; serum total bilirubin, 0 to 0.1 or 45 to 100 mg/dl; and serum albumin, 0to 0.5 or 6 to 10 g/dl. Implausible data were even more extreme than the very abnormal values. RESULTS Among recipients without a pretransplantation diagnosis of HBV infection, anti-hbc positive donors accounted for 3.6% (1270/35,620) of adult, cadaveric, first-time liver transplants from 1994 to This increased significantly from 1.8% in 1994 to 6.0% in 2006 (P 0.001; Fig. 1). Among 11 UNOS regions, the proportion of transplants involving anti-hbc positive donors ranged from 1.2% to 8.5% (P 0.001). Compared to recipients with anti-hbc negative donors, recipients with anti-hbc positive donors had similar pretransplantation mean BMI, albumin, creatinine, and INR. The 2 groups, however, had significantly different underlying liver diseases (P 0.001; Table 1). Most strikingly, recipients with anti-hbc positive donors had a higher proportion of HCV infection (41.2% versus

4 1346 YU ET AL. Figure 1. Proportion of liver transplant recipients who did not have hepatitis B virus infection pre-transplantation with antibody against hepatitis B core antigen positive donors (April 1994 to January 2006). 32.9%) and HCC (15.5% versus 10.2%) and a lower proportion of cholestatic liver diseases (5.3% versus 12.4%). Recipients with anti-hbc positive donor grafts were also more likely to harbor anti-hbc themselves with (25.5% versus 9.1%) or without (17.6% versus 8.5%) anti-hbs (P 0.001; Table 1). Compared to anti- HBc negative donors, anti-hbc positive donors were older (mean age, versus years; P ) and more likely to be black (26.6% versus 11.5%; P 0.001). Before adjustments for other predictors of posttransplantation survival, recipients with anti-hbc positive donors had significantly worse patient survival than those with anti-hbc negative donors (hazard ratio, 1.35; 95% CI, ; Table 2). After adjustments for other predictors of posttransplantation survival, patient survival was not significantly different between the 2 groups (hazard ratio, 1.09; 95% CI, ). Similar results were found for graft survival. Although anti-hbc positive donor organs appear to affect recipients without HCV infection (hazard ratio, 1.46; 95% CI, ) more adversely than recipients with HCV infection (hazard ratio, 1.17; 95% CI, ) in the univariate analysis, this effect was not significant after adjustments for other predictors of survival (hazard ratio, 1.10, and 95% CI, for recipients without HCV; hazard ratio, 1.06, and 95% CI, for recipients with HCV). Although using grafts from anti-hbc positive donors did not significantly influence adjusted patient (Table 3) or graft survival (data not shown) in any subgroup of recipients on the basis of their HBV serological patterns, use of such grafts appeared to affect recipients without anti-hbs more adversely than those with anti- HBs (Table 3). We did not observe a higher matching rate (anti-hbc positive donors with anti-hbc positive or anti-hbs positive recipients) in more recent years (data not shown). Since 2004, data with respect to the use of lamivudine and HBIG became available in the UNOS database. From January 1, 2004 through January 18, 2006, 374 recipients who did not have a pretransplantation diagnosis of HBV infection received anti-hbc positive donor grafts. Among them, 24.5% (92/374) received either lamivudine or HBIG. The use of these medications was not associated with recipient anti-hbc or anti-hbs status. One-year survival was not significantly different between those who were using lamivudine or HBIG and those who were not (94.1% versus 88.6% respectively, P 0.9). Among recipients with HBV infection pre-transplantation (n 2797), 387 (13.8%) received anti-hbc positive donor organs. There was no apparent adverse effect on patient survival related to anti-hbc positive donor organs before (hazard ratio, 0.90; 95% CI, ) or after (hazard ratio, 1.06; 95% CI, ) adjustments for other predictors of posttransplantation survival. DISCUSSION Using comprehensive clinical data from UNOS, we did not find a significant association between use of anti- HBc positive donors and posttransplantation patient or graft survival after adjusting for other predictors of posttransplantation survival. Among recipients without HBV infection pre-transplantation, older donor age, a higher proportion of donor black race, 16 and a higher proportion of recipient HCV and HCC, 24 which are known risk factors for decreased posttransplantation survival, likely confounded the association between anti-hbc positive donors and worse survival observed in the univariate analysis. Among recipients without HBV infection pre-transplantation, a number of small studies have suggested that the rate of posttransplantation HBV infection varies, depending on recipients HBV serological patterns as indications of prior exposure or vaccination. 2,3,5,6 The rate of infection among recipients negative for both anti-hbc and anti-hbs has ranged from 38% (3/8) 4 to 100% (3/3) 6 versus the range of 0% (0/2 2 and 0/4 3 )to 13% (2/15) 5 among recipients positive for anti-hbc. The protective effect of anti-hbs has been similarly varied, with infection rates ranging from 0% (0/7, 5 0/2, 3 and 0/13 6 ) to 33% (1/3). 2 Despite the small number of patients involved, several studies have advocated actively matching anti-hbc positive donors to recipients with serological evidence of HBV exposure or vaccination. 3,5,6 The effect of this strategy was evident in the current study, in which recipients with anti-hbc positive grafts were much more likely to harbor anti-hbc with or without anti-hbs pre-transplantation (Table 1). We wanted to test whether the potential benefit of matching in reducing posttransplantation HBV infection translates into improved patient and graft survival among recipients without HBV infection pre-transplantation. Using a much larger sample than prior studies, we found no significant association between use of anti- HBc positive donors and posttransplantation survival, regardless of recipients HBV serological patterns (Table 3). One possibility is that despite the large sample size,

5 SURVIVAL AFTER ORTHOTOPIC LIVER TRANSPLANTATION 1347 TABLE 1. Characteristics of Liver Transplant Recipients Without HBV Infection Pre-Transplantation by Donor Anti-HBc Status Total (n 35,620) Anti-HBc Negative Donor (n 34,350) Anti-HBc Positive Donor (n 1270) P Value Age (years, mean SD) BMI (kg/m 2, mean SD) Laboratory studies at transplant Creatinine (mg/dl, mean SD) Total bilirubin (mg/dl, mean SD) INR (mean SD) Albumin (g/dl, mean SD) Male (%) Race (%) White Black Hispanic Asian Other Underlying liver disease (%) HCV Alcohol NASH Cryptogenic PBC and PSC Autoimmune Heptocellular carcinoma Cholangiocarcinoma Fulminant Other HBV serology (%) Anti-HBs negative, anti-hbc negative Anti-HBs negative, anti-hbc positive Anti-HBs positive, anti-hbc negative Anti-HBs positive, anti-hbc positive Cold ischemia time (hours, mean SD) Causes of death 0.09 Cardiovascular Rejection Infection Malignancy Biliary Vascular Hepatitis Other Location before transplant (%) 0.06 Home Ward ICU Other Donor age (years, mean SD) Donor male (%) Donor race (%) White Black Hispanic Asian Other Transplant year (%) April 1994 to December January 98 to December January 01 to December January 04 to January Abbreviations: anti-hbc, antibody against hepatitis B core antigen; anti-hbs, antibody against hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; ICU, intensive care unit; INR, international normalized ratio; NASH, nonalcoholic steatohepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SD, standard deviation.

6 1348 YU ET AL. TABLE 2. Association Between Donor Anti-HBc Status and Posttransplant Patient and Graft Survival Among Recipients Without HBV Infection Pre-Transplantation Total (n 35,620) Anti-HBc Negative Donor (n 34,350) Anti-HBc Positive Donor (n 1270) Follow-up length (patient years) 130,428 3,962 Patient deaths 8, Mortality per 100 patient years Unadjusted hazard ratio (95% CI) for patient survival ( ) Adjusted hazard ratio (95% CI) for patient survival* ( ) Unadjusted hazard ratio (95% CI) for graft survival ( ) Adjusted hazard ratio (95% CI) for graft survival* ( ) Abbreviations: anti-hbc, antibody against hepatitis B core antigen; CI, confidence interval; HBV, hepatitis B virus. *Adjusted for donor age, gender, and race; recipient age, gender, race, underlying liver diseases, body mass index, serum albumin, creatinine, total bilirubin at the time of transplant, and location before transplant; transplant year; and cold ischemia time. TABLE 3. Association Between Donor anti-hbc Status and Posttransplant Patient Survival in 4 Groups of Recipients Without HBV Infection Pre-Transplantation on the Basis of Their HBV Serology Recipient HBV Serology Anti-HBs Negative, Anti-HBc Negative (n 15,111) Anti-HBs Negative, Anti-HBc Positive (n 1947) Anti-HBs Positive, Anti-HBc Negative (n 1880) Anti-HBs Positive, Anti-HBc Positive (n 2091) Anti-HBc negative donor (n 20,273) 14, Anti-HBc positive donor (n 756) Unadjusted hazard ratio (95% CI) 1.32 ( ) 1.43 ( ) 1.01 ( ) 0.95 ( ) Adjusted hazard ratio (95% CI)* 1.18 ( ) 1.22 ( ) 0.84 ( ) 0.86 ( ) Abbreviations: anti-hbc, antibody against hepatitis B core antigen; anti-hbs, antibody against hepatitis B surface antigen; CI, confidence interval; HBV, hepatitis B virus. *Adjusted for donor age, gender, and race; recipient age, gender, race, underlying liver diseases, body mass index, serum albumin, creatinine, total bilirubin at the time of transplant, and location before transplant; transplant year; and cold ischemia time. we did not have sufficient statistical power to detect small differences in survival, especially in the groups of recipients negative for anti-hbs with or without anti- HBc. In these 2 groups, recipients of anti-hbc positive donor grafts had approximately 20% worse patient survival after adjustments for important confounders, but this did not reach statistical significance (Table 3). An alternative explanation may be that matching does reduce the risk of posttransplantation HBV, but it does not affect overall survival because effective prophylaxis now exists even when matching is not feasible Dodson et al. 9 first reported 100% success using a combination of lamivudine and HBIG to prevent posttransplantation HBV infection (0/15) among recipients who received an anti-hbc positive graft with a mean follow-up of 15 months. Eight of these 15 patients were negative for both anti-hbc and anti-hbs. Yu et al. 10 subsequently reported similar success using lamivudine alone with a mean duration of follow-up of 17 months. A study from Taiwan, where the prevalence of anti-hbc positive donors was 63%, reported an incidence of posttransplantation HBV of 44% (7/16) without lamivudine versus 0% (0/44) with lamivudine among recipients with anti-hbc positive grafts. 26 Even though none of these studies were randomized and there are currently no published guidelines for prophylaxis against HBV infection post-transplantation when anti-hbc positive grafts are used, these overwhelmingly positive results likely increased the practice of prophylaxis. In the current study, close to 25% of recipients of an anti-hbc positive graft were using lamivudine or HBIG in recent years, but there was no significant difference in patient survival at 1 year. Although this may represent a real lack of survival benefit attributable to prophylaxis despite its efficacy in preventing posttransplantation HBV, it is also possible that a survival difference becomes apparent only with longer follow-up. Future studies should focus on longterm effects of prophylaxis on survival as well as the possibility of viral resistance, which has been reported with lamivudine. 27 Finally, anti-hbc positive donor grafts may not lead

7 SURVIVAL AFTER ORTHOTOPIC LIVER TRANSPLANTATION 1349 to worse survival because posttransplantation HBV infection has a mild clinical course and is treatable. The severity of posttransplantation HBV infection was first described by Wachs et al., 1 who reported that, of 3 recipients who developed the infection post-transplantation, 1 died of liver failure within 1 year, 1 had cirrhosis, and 1 had active chronic hepatitis; all were presumably related to HBV. 1 Subsequent studies, however, have suggested a less worrisome outcome. Manzarbeitia el al. 6 reported that of 5 recipients who developed HBV, only 2 had mild allograft dysfunction. Both were successfully treated with lamivudine alone or in conjunction with HBIG. Similarly, 12 of 15 Spanish patients with posttransplantation HBV were alive with a median follow-up of 39 months, whereas the other 3 patients died of non HBV-related causes. The study also reported good virological response to lamivudine. 3 A recent review suggested that anti-hbc positive donor grafts may be used to expand donor availability without mentioning specific criteria for matching with recipient HBV serology or clinical status. 28 This more liberal approach is evident in the current study (Fig. 1), likely reflecting the combined effect of the organ shortage 29 and the relatively benign clinical outcome associated with anti-hbc positive grafts observed more recently. 3,5,6,9,13 There are, however, significant variations in the rate of anti-hbc positive donor graft usage among US transplant regions, as we have observed. According to a survey published in 2003, only 57% of transplant centers would consider using anti-hbc positive donors in recipients without serological evidence of prior exposure to HBV. 20 Our finding substantiates the growing body of evidence that anti-hbc positive donors may be used safely with patient and graft survival comparable to those observed with anti-hbc negative donors. Such information is important for transplant physicians when communicating with potential recipients. Currently, the prevalence of anti-hbc in the general population is estimated to be between 4.3% and 5.4%, 30 which is similar to the proportion of recipients with anti-hbc positive donors in recent years. There are, however, no data on whether the prevalence of anti-hbc among organ donors in the United States is similar to that of the general population. It is also unclear how many anti-hbc positive donor livers remain unused. Our study has several limitations, the most important being the inability to assess the rate of posttransplantation HBV infection, as defined by the detection of HBsAg after transplantation in patients who were negative before transplantation. This variable, which is documented in the Transplant Recipient Follow-Up Form, unfortunately was not reported for more than 80% of recipients. Knowing accurately the rate of HBV infection would have allowed us to determine whether the lack of survival disadvantage was a result of prevention of posttransplantation HBV by matching (or prophylaxis) or a result of a mild clinical course despite the presence of posttransplantation HBV. Second, the UNOS database did not have data on serum or liver HBV DNA, which may be useful in determining recipients risk of developing HBV when anti-hbc positive grafts were used. 13 Furthermore, even though UNOS has been reporting lamivudine use since 2004, it is unclear from the database whether it is for the purpose of prophylaxis or active treatment of posttransplantation HBV. Finally, a fair number of patients had to be excluded because of missing data for 1 or more covariates for multivariate analyses, so technically the results apply only to those with complete data. Our study also has several important strengths. Even though the association between anti-hbc positive donors and posttransplantation HBV is well established, 1-6 there are conflicting data on the overall survival experience among recipients. UNOS, which contains all liver transplants performed in the United States, offered an opportunity to analyze the largest and most representative sample of patient and graft survival to date. Despite the exclusion of recipients with incomplete data, there remained more than 20,000 recipients, of which close to 1000 received anti-hbc positive organs, in the multivariate analysis (see the Patients and Methods section). UNOS collects detailed pretransplantation variables that are known predictors of posttransplantation survival; our ability to adjust for these variables provides a less confounded assessment of the true effect of donor anti-hbc positivity on recipient outcome. Finally, the effect of recipient HBV pretransplantation serological patterns was tested in an a priori fashion; the sample size again allows a firmer conclusion to be drawn in comparison with prior studies. Although the aforementioned limitations affected our ability to confirm reasons behind our findings, they do not affect the validity of our primary analysis of patient and graft survival. In conclusion, the findings of the current study are reassuring for recipients of anti-hbc positive donor grafts as they, on average, have survival times similar to those with anti-hbc negative donor grafts when other predictors of posttransplantation survival are taken into account. The use of such grafts is certainly safe among recipients with HBV infection pre-transplantation. For recipients without HBV infection pre-transplantation, matching these grafts with those who have anti-hbs prior to transplantation, as a result of either vaccination or prior exposure to HBV, may be especially safe. These data may be useful for future liver transplant recipients and their physicians in the organ allocation process. 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. Transplantation 1995;59: Dickson RC, Everhart JE, Lake JR, Wei Y, Seaberg EC, Wiesner RH, et al. Transmission of hepatitis B by transplantation of livers from donors positive for antibody to hepatitis B core antigen. The National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Gastroenterology 1997;113: Prieto M, Gomez MD, Berenguer M, Cordoba J, Rayon JM,

8 1350 YU ET AL. Pastor M, et al. De novo hepatitis B after liver transplantation from hepatitis B core antibody-positive donors in an area with high prevalence of anti-hbc positivity in the donor population. Liver Transpl 2001;7: Douglas DD, Rakela J, Wright TL, Krom RA, Wiesner RH. The clinical course of transplantation-associated de novo hepatitis B infection in the liver transplant recipient. Liver Transpl Surg 1997;3: Dodson SF, Issa S, Araya V, Gayowski T, Pinna A, Eghtesad B, et al. Infectivity of hepatic allografts with antibodies to hepatitis B virus. Transplantation 1997;64: Manzarbeitia C, Reich DJ, Ortiz JA, Rothstein KD, Araya VR, Munoz SJ. Safe use of livers from donors with positive hepatitis B core antibody. Liver Transpl 2002;8: Michalak TI, Pasquinelli C, Guilhot S, Chisari FV. Hepatitis B virus persistence after recovery from acute viral hepatitis. J Clin Invest 1994;94: Lok AS, Liang RH, Chiu EK, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study. Gastroenterology 1991;100: Dodson SF, Bonham CA, Geller DA, Cacciarelli TV, Rakela J, Fung JJ. Prevention of de novo hepatitis B infection in recipients of hepatic allografts from anti-hbc positive donors. Transplantation 1999;68: Yu AS, Vierling JM, Colquhoun SD, Arnaout WS, Chan CK, Khanafshar E, et al. Transmission of hepatitis B infection from hepatitis B core antibody positive liver allografts is prevented by lamivudine therapy. Liver Transpl 2001;7: Holt D, Thomas R, Van Thiel D, Brems JJ. Use of hepatitis B core antibody-positive donors in orthotopic liver transplantation. Arch Surg 2002;137: ; discussion Roque-Afonso AM, Feray C, Samuel D, Simoneau D, Roche B, Emile JF, et al. Antibodies to hepatitis B surface antigen prevent viral reactivation in recipients of liver grafts from anti-hbc positive donors. Gut 2002;50: Nery JR, Nery-Avila C, Reddy KR, Cirocco R, Weppler D, Levi DM, et al. Use of liver grafts from donors positive for antihepatitis B-core antibody (anti-hbc) in the era of prophylaxis with hepatitis-b immunoglobulin and lamivudine. Transplantation 2003;75: Hoofnagle JH, Lombardero M, Zetterman RK, Lake J, Porayko M, Everhart J, et al. Donor age and outcome of liver transplantation. Hepatology 1996;24: Busquets J, Xiol X, Figueras J, Jaurrieta E, Torras J, Ramos E, et al. The impact of donor age on liver transplantation: influence of donor age on early liver function and on subsequent patient and graft survival. Transplantation 2001;71: Feng S, Goodrich NP, Bragg-Gresham JL, Dykstra DM, Punch JD, DebRoy MA, et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant 2006;6: Ioannou GN. Development and validation of a model predicting graft survival after liver transplantation. Liver Transpl 2006;12: Furukawa H, Todo S, Imventarza O, Casavilla A, Wu YM, Scotti-Foglieni C, et al. Effect of cold ischemia time on the early outcome of human hepatic allografts preserved with UW solution. Transplantation 1991;51: Totsukali E, Fung JJ, Ishizawa Y, Nishimura A, Ono H, Toyoki Y, et al. Synergistic effect of cold and warm ischemia time on postoperative graft outcome in human liver transplantation. Hepatogastroenterology 2004;51: Burton JR Jr, Shaw-Stiffel TA. Use of hepatitis B core antibody-positive donors in recipients without evidence of hepatitis B infection: a survey of current practice in the United States. Liver Transpl 2003;9: Munoz SJ. Use of hepatitis B core antibody-positive donors for liver transplantation. Liver Transpl 2002;8:S82 S United Network for Organ Sharing. Available at: Accessed March Dickinson DM, Bryant PC, Williams MC, Levine GN, Li S, Welch JC, et al. Transplant data: sources, collection, and caveats. Am J Transplant 2004;4(suppl 9): Forman LM, Lewis JD, Berlin JA, Feldman HI, Lucey MR. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 2002;122: Cox D. Regression models and life tables. J R Stat Soc Ser B 1972;34: de Villa VH, Chen YS, Chen CL. Hepatitis B core antibodypositive grafts: recipient s risk. Transplantation 2003;75: S49 S Yen RD, Bonatti H, Mendez J, Aranda-Michel J, Satyanarayana R, Dickson RC. Case report of lamivudineresistant hepatitis B virus infection post liver transplantation from a hepatitis B core antibody donor. Am J Transplant 2006;6: Busuttil RW, Tanaka K. The utility of marginal donors in liver transplantation. Liver Transpl 2003;9: Annual Report of the Scientific Registry of Transplant Recipients and the Organ Procurement and Transplantation Network: Transplant Data Available at: Accessed March Coleman PJ, McQuillan GM, Moyer LA, Lambert SB, Margolis HS. Incidence of hepatitis B virus infection in the United States, : estimates from the National Health and Nutrition Examination Surveys. J Infect Dis 1998;178: