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Impact of Anti-Hepatitis B Core-Positive Donors in Liver Transplantation: A Survival Analysis
Impact of Anti-Hepatitis B Core-Positive Donors in Liver Transplantation: A Survival Analysis Q. Lai, A. Molinaro, G. Spoletini, G. Mennini, M. Grieco, M. Merli, S.G. Corradini, P.B. Berloco, and M. Rossi ABSTRACT Introduction. The current shortage of organs for liver transplantation (OLT) requires expansion of the donor pools. A possible approach to this problem may be the use of donors positive for antibody against hepatitis B core antigen (anti-HBc). However, it is not clear whether recipients who receive anti-HBc-positive livers show worse survival. The aim of this study was to retrospectively analyze the patient and graft survivals of two groups of OLT recipients according to the anti-HBc status of their respective donors. Methods. We stratified 133 patients into group 1 (n ⫽ 120; anti-core-negative donors) versus group 2 (n ⫽ 13; anti-core-positive donors). Results. Comparing the two groups by univariate analysis, there was no significant differences with regard to recipient, donor, or transplant characteristics. Group 2 showed worse 5-year patient (46.2% vs 72.0%; P ⫽ .006) and graft survivals (38.5% vs 68.4%; P ⫽ .003). After adjustment for several risk factors for post-OLT death and graft failure, there was no significant difference between patients who received anti-core-positive versus anti-core-negative donors, in terms of patient and graft survivals, particularly only after adjustment for Model for End-stage Liver Disease (MELD) degree of severity. Conclusion. The use of anti-HBc-positive donors resulted in worse post-OLT patient and graft survival rates. Unlike the results obtained in the United States, we did not find possible confounders in our results, excluding MELD ⱖ 20. However, due to the small size of our cohort, future prospective multicenter studies are required to clarify the safety of anti-core-positive grafts. HE CURRENT SHORTAGE of organs for liver transplantation (OLT) requires expansion of the donor pool. One possible approach to this problem is the use of nonstandard grafts, including organs from donors who are positive for antibody against hepatitis B core antigen (anti-HBc). They are routinely used for hepatitis B virus (HBV)-positive and for anti-core-positive recipients or in severily ill naive patients.1 However, the use of anti-HBc-positive grafts is associated with an increased risk of HBV infection after OLT,2 due to viral reactivation from posttransplant immunosuppression.3 Despite these results, it is not clear whether recipients who receive anti-HBc livers display worse survivals. Many studies have evaluated the role of prophylactic therapies against HBV reactivation after OLT, using lamivudine with or without hepatitis B immunoglobulin,4 but few reports have analyzed patient or graft survivals.5 The aim of this monocenter study was to analyze patient and graft survivals among recipients according to the anti-HBc status of their respective donors.
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0041-1345/11/$–see front matter doi:10.1016/j.transproceed.2010.09.101 274
MATERIALS AND METHODS A retrospective cohort study examined an OLT database of 180 liver transplantations performed from January 2003 to May 2009. We excluded donors and/or recipients younger than 18 years (n ⫽ 6), living donors (n ⫽ 6), combined transplantations (n ⫽ 4), acute From the Departments of General Surgery and Organ Transplantation (Q.L., G.S., G.M., M.G., P.B.B., M.R.) and Gastroenterology (A.M., M.M., S.G.C.), Sapienza University, Umberto I Hospital, Rome, Italy. Partly supported by Inter-University Consortium for Organ Transplantation. Q.L. designed the study, collected the data, wrote the first draft, and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. Q.L. is the guarantor. Address reprint requests to Q. Lai, MD, Department of General Surgery and Organ Transplantation, Sapienza University, Umberto I Hospital, Viale del Policlinico 155, Rome 00161, Italy. E-mail: [email protected] © 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 43, 274 –276 (2011)
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liver failure cases (n ⫽ 6), and retransplantations (n ⫽ 14). We also excluded patients without sufficient data (n ⫽ 11), yielding 133 transplants for the final analysis. The cohort was divided according to donor HBc status: group 1 (n ⫽ 120) was composed of anti-core-negative donors, while group 2 (n ⫽ 13) anti-corepositive donors. Results were reported as mean values ⫾ standard deviations or percentages. Categorical and continuous variables were compared using Fisher exact test or Student t test, respectively. A P value below or equal to .05 was considered significant. Cox proportional hazards regression was used to analyze predictors of patient and graft survivals. The Kaplan-Meier method was used to estimate patient and graft survivals, comparing groups 1 and 2 with the log-rank test. All analyses and plots were performed using SPSS 16.0 software.
RESULTS
Among the recipients 13/133 (9.8%) received grafts from anti-HBc-positive donors. Group 2 included a higher values of percentage of hepatitis C virus (HCV) and HBV recipients (38.5% and 23.1%, compared to 28.4% and 5.8%, respectively), mean Model for End Stage Liver Disease (MELD) (17.6 vs 15.4), donor age (mean age: 56.9 vs 49.8 years), and percentage of patients experiencing initial poor graft function post-OLT (30.8% vs 18.3%). However, there were no significant differences for recipient, donor, or transplant characteristics (Table 1). Table 1. Characteristics of Liver Transplant Recipients According to Donor Anti-Hepatitis B Core Status
Recipient Age (y) Male (%) Creatinine (mg/dL) Total bilirubin (mg/dL) INR MELD MELD ⬎ 20 (%) CTP Underlying liver disease (%) HCV HBV Alcohol Cryptogenic Biliary cirrhosis Other Hepatocellular carcinoma Donor Donor age (y) Donor male (%) DRI Transplantation IPGF (%)
(n ⫽ 120)
(n ⫽ 13)
54.3 ⫾ 9.5 95 (79.2) 0.9 ⫾ 0.3 4.5 ⫾ 6.3 1.50 ⫾ 0.46 15.4 ⫾ 5.7 24 (20.0) 8.9 ⫾ 2.1
52.4 ⫾ 10.8 9 (69.2) 1.0 ⫾ 0.3 7.3 ⫾ 1.1 1.58 ⫾ 0.31 17.6 ⫾ 6.3 3 (23.1) 9.2 ⫾ 1.8
34 (28.4) 7 (5.8) 15 (12.5) 5 (4.2) 4 (3.3) 3 (2.5)
5 (38.5) 3 (23.1) 2 (15.3) 1 (7.7) 1 (7.7) 0 (—)
52 (43.3)
1 (7.7)
49.8 ⫾ 18.9 72 (60.0) 1.45 ⫾ 0.37
56.9 ⫾ 15.1 9 (69.2) 1.54 ⫾ 0.33
0.168 0.370 0.468
22 (18.3)
4 (30.8)
0.231
0.821 0.305 0.688 0.037 0.921 0.770 0.516 0.581 0.120
Table 2. Predictive Factors for the Risk of Recipient Death and Graft Loss After Liver Transplantation Variables
Recipient death MELD Anti-core Graft lost MELD Anti-core
SE
Wald
P-value
HR (95.0% CI)
0.02 0.42
22.2 5.3
⬍.0001 .021
1.11 (1.06–1.16) 0.37 (0.16–0.86)
0.02 0.40
13.7 6.0
⬍.0001 .014
1.09 (1.04–1.13) 0.38 (0.17–0.82)
SE, standard error; HR, hazard ratio; CI, confidence intervals; MELD, Model for End-stage Liver Disease.
In the multivariate model, pre-OLT MELD value and anti-core status were unique predictors of recipient death and graft loss, after adjustment for recipient age, gender, and viral status as well as donor age and gender (Table 2). Group 2 showed worse 5-year patient (46.2% vs 72.0%; P ⫽ .006) and graft survivals (38.5% vs 68.4%; P ⫽ .003; Table 3 and Fig 1). After adjustment for several well-known risk factors for post-OLT death and graft failure, namely, donor age, hepatocellular carcinoma (HCC), HCV, donor risk index, and MELD, the worse survivals were confirmed among the anti-core-positive group. Only after stratification for MELD gravity (cutoff value: 20) was no significant difference observed between anti-core-positive and -negative patients in terms of patient and graft survivals (P ⫽ .337 and .298, respectively; data not shown). DISCUSSION
The use of anti-HBc-positive donors represents one approach to the shortage of organs; however, it is not clear whether one can safely use anti-core-positive grafts. In the United States, 4.8% of anti-core-positive donors were reported5 to show similar results compared to the general population (4.3% to 5.4%).6 In Italy, the current prevalence of anti-HBc-positive individuals is estimated to be 4.85%7; however, a dramatic decline in HBV infection has occurred in Italy only in recent years.8 The elderly population is likely to have an higher anti-HBc-positive prevalence, as reported in other European countries.9 These efforts may explain the discrepancy of values reported in our experience (9.8% of anti-core-positive donors) compared to overall Italian data. Actually, in our center, 37% of grafts are obtained from donors at least 60 years old. Our analysis revealed a significant association between the use of anti-HBc-positive donors and worse post-OLT Table 3. Patient and Graft Survivals in the Two Groups
MELD, Model for End-stage Liver Disease; CTP, Child-Turcotte-Pugh score; HCV, hepatitis C virus; HBV, hepatitis B virus; DRI, donor risk index; IPGF, initial poor graft function.
Patient survival Group 1 Group 2 Graft survival Group 1 Group 2
1y
3y
5y
P*
85.8 53.8
77.4 46.2
72.0 46.2
.006
83.3 46.2
78.3 38.5
68.4 38.5
.003
*P value calculated by log-rank test.
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Fig 1. Patient and graft survivals in the two groups (group 1: no anti-core-positive donors; group 2: anti-core-positive donors).
patient and graft survival rates. Similar results were obtained by Yu et al5 among a large cohort of OLT patients transplanted in the United States. However, after adjusting for donor age, HCV status, HCC, and donor race, there was no substantial difference in terms of patient and graft survivals. All of these parameters had proven significant upon univariate analysis, with a prevalence of HCC and HCV recipients and higher rates of black and elderly donors among the anti-HBc-positive group. Unlike these results, our experience showed homogeneous variables for anti-core-positive versus anti-core-negative groups. We speculate that the substantial differences between our results and the North American ones may be related to donor and recipient characteristics. In fact, in Italy, a higher rate of HCV and HCC patients are transplanted; at the same time, grafts from elderly donors are more frequently used, and black donors are uncommon. These data likely minimize the differences between the two groups analyzed in our report; additionally, these factor reduce the differences already minimized by the small sample. Only after adjustment for MELD ⱖ20 were no differences reported between anti-core-positive and anti-corenegative patients upon log-rank testing. However, due to the small number of patients in this subgroup, we could not evaluate the possible role of MELD as a confounder in our analysis. Our study had several limitations. First, the small sample size did not allow us to perform further statistical tests, with the intent to exclude the possible role of confounders in our analysis. Moreover, the small number of anti-core-positive donors in our cohort did not enable us to attain absolute certainty in our results. This study was retrospectively conducted on a monocenter experience: therefore, we believe that future prospective multicenter studies are
required to clarify the safety of anti-core-positive grafts for OLT. ACKNOWLEDGMENTS We thank the “Liver Transplant Group” of Sapienza University.
REFERENCES 1. Angelico M, Gridelli B, Strazzabosco M; A.I.S.F. Commission on Liver Transplantation: Practice of adult liver transplantation in Italy. Recommendations of the Italian Association for the Study of the Liver (A.I.S.F.). Dig Liver Dis 37:461, 2005 2. Manzarbeitia C, Reich DJ, Ortiz JA, et al: Safe use of livers from donors with positive hepatitis B core antibody. Liver Transpl 8:556, 2002 3. Palmore TN, Shah NL, Loomba R, et al: Reactivation of hepatitis B with reappearance of hepatitis B surface antigen after chemotherapy and immunosuppression. Clin Gastroenterol Hepatol 7:1130, 2009 4. Avelino-Silva VI, D Albuquerque LA, Bonazzi PR, et al: Liver transplant from anti-HBc-positive, HBsAg-negative donor into HBsAg-negative recipient: is it safe? A systematic review of the literature. Clin Transplant 2010 Apr 28 5. Yu L, Koepsell T, Manhart L, et al: Survival after orthotopic liver transplantation: the impact of antibody against hepatitis B core antigen in the donor. Liver Transpl 15:1343, 2009 6. Coleman PJ, McQuillan GM, Moyer LA, et al: Incidence of hepatitis B virus infection in the United States, 1976 –1994: estimates from the National Health and Nutrition Examination Surveys. J Infect Dis 178:954, 1998 7. Manzini P, Girotto M, Borsotti R, et al: Italian blood donors with anti-HBc and occult hepatitis B virus infection. Haematologica 92:1664, 2007 8. D’Amelio R, Matricardi PM, Biselli R, et al: Changing epidemiology of hepatitis B in Italy: public health implications. Am J Epidemiol 135:1012, 1992 9. Jilg W, Hottenträger B, Weinberger K, et al: Prevalence of markers of hepatitis B in the adult German population. J Med Virol 63:96, 2001
T
0041-1345/11/$–see front matter doi:10.1016/j.transproceed.2010.09.101 274
MATERIALS AND METHODS A retrospective cohort study examined an OLT database of 180 liver transplantations performed from January 2003 to May 2009. We excluded donors and/or recipients younger than 18 years (n ⫽ 6), living donors (n ⫽ 6), combined transplantations (n ⫽ 4), acute From the Departments of General Surgery and Organ Transplantation (Q.L., G.S., G.M., M.G., P.B.B., M.R.) and Gastroenterology (A.M., M.M., S.G.C.), Sapienza University, Umberto I Hospital, Rome, Italy. Partly supported by Inter-University Consortium for Organ Transplantation. Q.L. designed the study, collected the data, wrote the first draft, and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. Q.L. is the guarantor. Address reprint requests to Q. Lai, MD, Department of General Surgery and Organ Transplantation, Sapienza University, Umberto I Hospital, Viale del Policlinico 155, Rome 00161, Italy. E-mail: [email protected] © 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 43, 274 –276 (2011)
ANTI-HEPATITIS B CORE-POSITIVE DONORS
275
liver failure cases (n ⫽ 6), and retransplantations (n ⫽ 14). We also excluded patients without sufficient data (n ⫽ 11), yielding 133 transplants for the final analysis. The cohort was divided according to donor HBc status: group 1 (n ⫽ 120) was composed of anti-core-negative donors, while group 2 (n ⫽ 13) anti-corepositive donors. Results were reported as mean values ⫾ standard deviations or percentages. Categorical and continuous variables were compared using Fisher exact test or Student t test, respectively. A P value below or equal to .05 was considered significant. Cox proportional hazards regression was used to analyze predictors of patient and graft survivals. The Kaplan-Meier method was used to estimate patient and graft survivals, comparing groups 1 and 2 with the log-rank test. All analyses and plots were performed using SPSS 16.0 software.
RESULTS
Among the recipients 13/133 (9.8%) received grafts from anti-HBc-positive donors. Group 2 included a higher values of percentage of hepatitis C virus (HCV) and HBV recipients (38.5% and 23.1%, compared to 28.4% and 5.8%, respectively), mean Model for End Stage Liver Disease (MELD) (17.6 vs 15.4), donor age (mean age: 56.9 vs 49.8 years), and percentage of patients experiencing initial poor graft function post-OLT (30.8% vs 18.3%). However, there were no significant differences for recipient, donor, or transplant characteristics (Table 1). Table 1. Characteristics of Liver Transplant Recipients According to Donor Anti-Hepatitis B Core Status
Recipient Age (y) Male (%) Creatinine (mg/dL) Total bilirubin (mg/dL) INR MELD MELD ⬎ 20 (%) CTP Underlying liver disease (%) HCV HBV Alcohol Cryptogenic Biliary cirrhosis Other Hepatocellular carcinoma Donor Donor age (y) Donor male (%) DRI Transplantation IPGF (%)
(n ⫽ 120)
(n ⫽ 13)
54.3 ⫾ 9.5 95 (79.2) 0.9 ⫾ 0.3 4.5 ⫾ 6.3 1.50 ⫾ 0.46 15.4 ⫾ 5.7 24 (20.0) 8.9 ⫾ 2.1
52.4 ⫾ 10.8 9 (69.2) 1.0 ⫾ 0.3 7.3 ⫾ 1.1 1.58 ⫾ 0.31 17.6 ⫾ 6.3 3 (23.1) 9.2 ⫾ 1.8
34 (28.4) 7 (5.8) 15 (12.5) 5 (4.2) 4 (3.3) 3 (2.5)
5 (38.5) 3 (23.1) 2 (15.3) 1 (7.7) 1 (7.7) 0 (—)
52 (43.3)
1 (7.7)
49.8 ⫾ 18.9 72 (60.0) 1.45 ⫾ 0.37
56.9 ⫾ 15.1 9 (69.2) 1.54 ⫾ 0.33
0.168 0.370 0.468
22 (18.3)
4 (30.8)
0.231
0.821 0.305 0.688 0.037 0.921 0.770 0.516 0.581 0.120
Table 2. Predictive Factors for the Risk of Recipient Death and Graft Loss After Liver Transplantation Variables
Recipient death MELD Anti-core Graft lost MELD Anti-core
SE
Wald
P-value
HR (95.0% CI)
0.02 0.42
22.2 5.3
⬍.0001 .021
1.11 (1.06–1.16) 0.37 (0.16–0.86)
0.02 0.40
13.7 6.0
⬍.0001 .014
1.09 (1.04–1.13) 0.38 (0.17–0.82)
SE, standard error; HR, hazard ratio; CI, confidence intervals; MELD, Model for End-stage Liver Disease.
In the multivariate model, pre-OLT MELD value and anti-core status were unique predictors of recipient death and graft loss, after adjustment for recipient age, gender, and viral status as well as donor age and gender (Table 2). Group 2 showed worse 5-year patient (46.2% vs 72.0%; P ⫽ .006) and graft survivals (38.5% vs 68.4%; P ⫽ .003; Table 3 and Fig 1). After adjustment for several well-known risk factors for post-OLT death and graft failure, namely, donor age, hepatocellular carcinoma (HCC), HCV, donor risk index, and MELD, the worse survivals were confirmed among the anti-core-positive group. Only after stratification for MELD gravity (cutoff value: 20) was no significant difference observed between anti-core-positive and -negative patients in terms of patient and graft survivals (P ⫽ .337 and .298, respectively; data not shown). DISCUSSION
The use of anti-HBc-positive donors represents one approach to the shortage of organs; however, it is not clear whether one can safely use anti-core-positive grafts. In the United States, 4.8% of anti-core-positive donors were reported5 to show similar results compared to the general population (4.3% to 5.4%).6 In Italy, the current prevalence of anti-HBc-positive individuals is estimated to be 4.85%7; however, a dramatic decline in HBV infection has occurred in Italy only in recent years.8 The elderly population is likely to have an higher anti-HBc-positive prevalence, as reported in other European countries.9 These efforts may explain the discrepancy of values reported in our experience (9.8% of anti-core-positive donors) compared to overall Italian data. Actually, in our center, 37% of grafts are obtained from donors at least 60 years old. Our analysis revealed a significant association between the use of anti-HBc-positive donors and worse post-OLT Table 3. Patient and Graft Survivals in the Two Groups
MELD, Model for End-stage Liver Disease; CTP, Child-Turcotte-Pugh score; HCV, hepatitis C virus; HBV, hepatitis B virus; DRI, donor risk index; IPGF, initial poor graft function.
Patient survival Group 1 Group 2 Graft survival Group 1 Group 2
1y
3y
5y
P*
85.8 53.8
77.4 46.2
72.0 46.2
.006
83.3 46.2
78.3 38.5
68.4 38.5
.003
*P value calculated by log-rank test.
276
LAI, MOLINARO, SPOLETINI ET AL
Fig 1. Patient and graft survivals in the two groups (group 1: no anti-core-positive donors; group 2: anti-core-positive donors).
patient and graft survival rates. Similar results were obtained by Yu et al5 among a large cohort of OLT patients transplanted in the United States. However, after adjusting for donor age, HCV status, HCC, and donor race, there was no substantial difference in terms of patient and graft survivals. All of these parameters had proven significant upon univariate analysis, with a prevalence of HCC and HCV recipients and higher rates of black and elderly donors among the anti-HBc-positive group. Unlike these results, our experience showed homogeneous variables for anti-core-positive versus anti-core-negative groups. We speculate that the substantial differences between our results and the North American ones may be related to donor and recipient characteristics. In fact, in Italy, a higher rate of HCV and HCC patients are transplanted; at the same time, grafts from elderly donors are more frequently used, and black donors are uncommon. These data likely minimize the differences between the two groups analyzed in our report; additionally, these factor reduce the differences already minimized by the small sample. Only after adjustment for MELD ⱖ20 were no differences reported between anti-core-positive and anti-corenegative patients upon log-rank testing. However, due to the small number of patients in this subgroup, we could not evaluate the possible role of MELD as a confounder in our analysis. Our study had several limitations. First, the small sample size did not allow us to perform further statistical tests, with the intent to exclude the possible role of confounders in our analysis. Moreover, the small number of anti-core-positive donors in our cohort did not enable us to attain absolute certainty in our results. This study was retrospectively conducted on a monocenter experience: therefore, we believe that future prospective multicenter studies are
required to clarify the safety of anti-core-positive grafts for OLT. ACKNOWLEDGMENTS We thank the “Liver Transplant Group” of Sapienza University.
REFERENCES 1. Angelico M, Gridelli B, Strazzabosco M; A.I.S.F. Commission on Liver Transplantation: Practice of adult liver transplantation in Italy. Recommendations of the Italian Association for the Study of the Liver (A.I.S.F.). Dig Liver Dis 37:461, 2005 2. Manzarbeitia C, Reich DJ, Ortiz JA, et al: Safe use of livers from donors with positive hepatitis B core antibody. Liver Transpl 8:556, 2002 3. Palmore TN, Shah NL, Loomba R, et al: Reactivation of hepatitis B with reappearance of hepatitis B surface antigen after chemotherapy and immunosuppression. Clin Gastroenterol Hepatol 7:1130, 2009 4. Avelino-Silva VI, D Albuquerque LA, Bonazzi PR, et al: Liver transplant from anti-HBc-positive, HBsAg-negative donor into HBsAg-negative recipient: is it safe? A systematic review of the literature. Clin Transplant 2010 Apr 28 5. Yu L, Koepsell T, Manhart L, et al: Survival after orthotopic liver transplantation: the impact of antibody against hepatitis B core antigen in the donor. Liver Transpl 15:1343, 2009 6. Coleman PJ, McQuillan GM, Moyer LA, et al: Incidence of hepatitis B virus infection in the United States, 1976 –1994: estimates from the National Health and Nutrition Examination Surveys. J Infect Dis 178:954, 1998 7. Manzini P, Girotto M, Borsotti R, et al: Italian blood donors with anti-HBc and occult hepatitis B virus infection. Haematologica 92:1664, 2007 8. D’Amelio R, Matricardi PM, Biselli R, et al: Changing epidemiology of hepatitis B in Italy: public health implications. Am J Epidemiol 135:1012, 1992 9. Jilg W, Hottenträger B, Weinberger K, et al: Prevalence of markers of hepatitis B in the adult German population. J Med Virol 63:96, 2001