- Email: [email protected]
Prevention of de novo hepatitis B infection in liver allograft recipients with previous hepatitis B infection or hepatitis B vaccination
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2002 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 97, No. 9, 2002 ISSN 0002-9270/02/$22.00 PII S0002-9270(02)04351-4
Prevention of de novo Hepatitis B Infection in Liver Allograft Recipients With Previous Hepatitis B Infection or Hepatitis B Vaccination R. Ba´rcena Maruga´n, M.D., F. Garcı´a-Hoz, M.D., M. Va´zquez Romero, M.D., R. Nash, M.D., M. Mateos, M.D., R. Gonza´lez Alonso, M.D., M. Garcı´a Gonza´lez, M.D., and A. Garcı´a Plaza, M.D. Gastroenterology Service and Microbiology and Virology Service, Hospital Ramo´n y Cajal, Madrid, Spain
OBJECTIVES: To assess de novo hepatitis B virus (HBV) transmission from liver donors with HBV serum markers (HBM) to their recipients and the need for HBV vaccination before liver transplantation. METHODS: A total of 108 orthotopic liver transplantations for nonviral disease and the risk of developing de novo hepatitis B based on HBMs before transplantation have been studied. Of the 108 patients, 94 met the study criteria and were divided into two groups: 27 who had HBMs before transplantation (from past infection or by previous vaccination) and 67 who had no HBM. Development of de novo hepatitis B was determined by analytical, serological, and histological parameters. RESULTS: No case (0%) of de novo hepatitis B was detected in the pretransplantation HBM group, whereas there were 10 cases (14.5%) in the other group (p ⬍ 0.005). CONCLUSIONS: The presence of pretransplantation HBM in liver transplant recipients protects these patients against the development of de novo hepatitis B. This is especially important considering that there is a high prevalence of donors with positive hepatitis B core antibody (especially in some countries), and that these donors transmit HBV infection to recipients without HBM in a significant number of cases. Thus, vaccination against HBV in patients who are candidates for liver transplantation is fundamental to avoid cases of de novo hepatitis B. (Am J Gastroenterol 2002;97: 2398 –2401. © 2002 by Am. Coll. of Gastroenterology)
INTRODUCTION Transmission of de novo hepatitis B from liver donors with hepatitis B virus serum markers (HBM) to their recipients has recently been described (1–5). On the other hand, the frequency of HBM (hepatitis B core antibody [anti-HBc] with or without hepatitis B surface antibody [anti-HBs]) in the adult western population is quite high and varies greatly according to country. For example, the incidence is 0.5% in Ireland (6), 8.7% in Germany (7), 7.9% in Portugal (8), 10 –20% in Spain (9 –11), and 5.5–24% in the United States (12, 13). Thus, elimination of anti-HBc positive donors
would lead to a significant loss of organs in many countries. It is unclear whether the presence of anti-HBc in the recipient protects against infection, although some retrospective studies seem to indicate that this is possible (2). We have retrospectively reviewed 108 patients who underwent liver transplantation because of nonviral disease and whose survival rate was ⬎1 yr to determine the risk of de novo hepatitis B based on the pretransplantation HBM.
MATERIALS AND METHODS Study Patients We retrospectively reviewed 108 orthotopic liver transplantations carried out in our center between 1994 and 1999, all of which were because of nonviral disease, with a survival rate was ⬎1 yr. None of the transplant recipients who died during year 1 had developed fibrosing cholestatic hepatitis from hepatitis B. Death was from other causes such as infections, renal failure, and surgical complications, among others. Therefore, no patients with de novo hepatitis B were excluded. There were 86 men (49.8 ⫾ 10 yr) and 22 women (47.8 ⫾ 12.2 yr) with a mean age was 49.4 ⫾ 11 yr. The reason for transplantation was: alcohol-induced chronic hepatic disease in 84 cases, primary biliary cirrhosis in six, hemochromatosis in five, autoimmune hepatitis in four, glycogenosis type 1b in one, and cryptogenetic cirrhosis in eight. Patients with C virus induced disease were not studied, as the presence of anti-HBc in this disease can be due to previous or present B virus infection, but also to false reactions caused by the technique that was being used in our laboratory, which could alter the results. Since the initiation of the liver transplantation program in our center, those candidates on the list who had no HBMs were vaccinated against hepatitis B virus (HBV). Because the waiting list was very small initially so that the time on the list was short, and because we also received patients from different sites of the country, only a portion of the patients were vaccinated. Of the latter, only a minority received the three doses before transplantation. In all, 19 (17.6%) of the 108 patients studied presented with anti-HBc and anti-HBs before transplantation and therefore were not
AJG – September, 2002
Prevention of HBV in Liver Transplant Recipients
2399
Table 1. Pretransplantation Status of Recipients Pretransplantation Status Rejections CMV infection de novo Hepatitis B
HBM⫹ (n ⫽ 27)
HBM⫺ (n ⫽ 67)
Difference
9 3 0
26 8 10
ns ns p ⬍ 0.005
vaccinated. Of the remaining 89, 38 were vaccinated. Of these 38 patients, 14 received only one or two doses and their anti-HBs levels were not determined before transplantation, and they have not been considered in the study. The remaining 24 patients (aged 50.4 ⫾ 9.6 yr) received the three doses; eight of these patients (33.3%) developed protective titers. In all, 27 patients presented with positive anti-HBs titers from vaccination or past infection, and the remaining 67 patients did not. Of these patients, 21 were men, with a mean age of 50.1 ⫾ 10 yr. Mean follow-up was 22 months (range 13–72 months). After transplantation, hepatitis B surface antigen (HBsAg), anti-HBc, and anti-HBs were determined in archive serum corresponding to 3 and 12 months as well as to the most recent serum drawn. ELISA techniques (Abbott Diagnostics, North Chicago, IL) were used to analyze HBV (HBsAg, anti-HBc, anti-HBs) serum markers and HBV DNA was determined with the hybridation technique. Biopsy specimens were examined with hematoxylin-eosin staining and immunohistochemical techniques for HBsAg and anti-HBc. The diagnosis of HBV infection was established by the presence of HBsAg and positive B virus DNA in serum. The de novo hepatitis B diagnosis was determined by an alteration compatible with the transaminase values, hepatitis data from the biopsy specimen, and positive immunohistochemistry for HBsAg and HBcAg. Statistical Analysis The PRESTA program was used for the statistical study. The 2 test was used to compare qualitative variable percentages. For the quantitative variable study, the Wilcoxon test for paired data and Student’s t test for nonpaired data were used. A p value of ⬍0.005 was considered to be statistically significant. Results are expressed as mean ⫾ standard deviation.
RESULTS Ten of the 108 patients developed HBV infection. No case (0%) of de novo hepatitis B was found in the 27 patients with HBM from vaccination or past infection, whereas there were 10 cases (14.5%) among the 67 patients without antiHBs, a significant difference (p ⬍ 0.005). One of the 10 cases occurred among the 16 patients vaccinated without response (6.25%), and nine occurred among the 51 nonvaccinated patients (17.6%; p ⫽ ns). There were no significant differences regarding reason for transplantation, age, sex,
pretransplantation Child stage, frequency of cytomegalovirus infection, or rejection episodes in both groups (Table 1). The mean age of the 10 patients who developed hepatitis B was 48.1 ⫾ 11.9 yr, and that of the patients who did not develop it was 52 ⫾ 6.9 (p ⫽ 0.068, ns). Of the patients who developed hepatitis B, eight patients were male and two were female.
DISCUSSION Subjects with anti-HBc and anti-HBs in serum have always been considered noninfective for both blood as well as organ donation, although cases of posttransfusion hepatitis in HBsAg negative donors have sporadically been described (14). The appearance of de novo B virus infection has recently been reported in patients undergoing transplantation with positive anti-HBc donor organs, either with or without antiHBs (1). These results have been confirmed in other studies (2– 4, 9). Infection transmission frequency varies according to the report; however, it is generally very high, reaching values of ⬎75% and, in some of the studies, close to 100% (4, 9). This indicates that complete or reproducible forms of the HBV remain in the liver—perhaps permanently—in patients who have previously had this disease, so transplantation of organs from these patients to susceptible or immunodepressed patients would precipitate a new HBV infection in these transplant recipients. This form of occult or latent infection has already been described in isolated cases of HIV-infected patients in whom, coincident with the development of AIDS, there had been reactivation (demonstrated by sequential analysis of both viruses) of previous B virus infection that had already been cured; thus, in these patients, anti-HBs titers had developed years earlier (15). In addition, the presence of HBV DNA in serum (16, 17) and/or in the liver (18, 19) had been described in patients with past infection from HBV with the presence of anti-HBs serum. This occurrence, which was considered rare, seems to be quite frequent. In a recent study involving 15 patients with chronic hepatitis B who had lost HBsAg, Loriot et al. found HBV DNA by polymerase chain reaction in 100% of cases and hybridation in situ in 40% (17). Very recently, replicative intermediates of HBV as well as covalently closed circular DNA or pregenomic RNA have been found in hepatic tissues of 13 of 14 healthy donors with anti-HBc and anti-HBs in serum. This indicates that the virus is maintained as a latent or occult infection in individuals with past HBV infection markers (20). The livers of these indi-
2400
Ba´rcena Maruga´n et al.
viduals transmit HBV infection in almost all cases, at least if the recipient is susceptible. In contrast, in individuals with anti-HBs as the only HBM, these replicative forms of the HBV are not found (20), and these grafts do not seem to transmit the infection (2, 9). The prevalence of positive anti-HBc in the Spanish adult population is very high at 15–25% (6 –13, 21–27). Among adult organ donors, anti-HBc prevalence is also high (2) and increases with donor age, reaching values of ⬎25% in adults and/or donors ⬎60 yr of age (7, 9, 11). Whether the presence of anti-HBc and/or anti-HBs due to past infection or vaccination (28, 29) protects liver recipients with anti-HBc has not been established, although the few retrospective studies that have been carried out seem to indicate that there was no infection in this type of recipient (2, 9). The high prevalence (⬎15%) of donors with positive anti-HBc as well as the high mortality of those on the waiting list (⬎7%) prevent us from eliminating this type of grafts, at least in countries with such a high hepatitis B marker prevalence among donors. In our country, the probability that a liver recipient can receive a graft with anti-HBc is approximately 30% (9), which is the same among those who present previous or nonprevious HBMs. If, as it seems to be demonstrated, infectivity is very high among non-HBM recipients, the value of 14.5% infectivity is not high and would correspond to about half of the non-HBM recipients. If the presence of anti-HBs did not protect against de novo infection, we would have found this same percentage among the HBM patients; consequently, the lack of any case among this population probably means that its presence protects against the infection. Thus, our study seems to indicate that the HBM patients can receive donor livers with anti-HBc with or without anti-HBs. Based on these results, we believe that grafts with negative HBsAg HBMs can be used in recipients with HBM from past infection or from vaccinations with response, and we have acted accordingly. These patients should be followed periodically to detemine anti-HBs titers and, in the case of vaccinated patients, to revaccinate them if the titers decrease, as we have observed that patients with transplants can respond to intensive HBV vaccination when they are receiving monotherapy and 2 yr after the transplantation (30). Almost one third of the patients have developed antiHBs and anti-HBc naturally from past infection and could receive this type of grafts, and this number could be increased by vaccinating all liver transplantation candidates without HBM against HBV. In our present study, 33.3% of patients were vaccinated with only one double dose cycle; however, in a larger series, we have found even better results, with 44% of seroconversion to anti-HBs with only one cycle and 66% with two cycles (31). Given that the waiting list for liver transplantation in our country is presently ⬎4 months, a large portion of the candidates could receive two vaccination cycles if necessary while being
AJG – Vol. 97, No. 9, 2002
studied as candidates or while on the waiting list. The best option would be to vaccinate all patients with liver disease before they develop cirrhosis, because in this latter condition the response, as we observe, is less (32). In conclusion, the presence of anti-HBs in the antipositive HBc donor liver recipient seems to protect against de novo HBV. All candidates for transplantation should be vaccinated while on the list, or— even better—all patients with liver disease who could potentially require liver transplantation in the future should be vaccinated. The donor organs with positive anti-HBc could be used in recipients with anti-HBs from past infection (i.e., recipients in whom antiHBs is present in addition to anti-HBc) or effective vaccination. Reprint requests and correspondence: Rafael Ba´ rcena Maruga´ n, M.D., Servicio de Gastroenterologı´a, Hospital Ramo´ n y Cajal, Carretera de Colmenar Km 9,1, Madrid 28034, Spain. Received July 30, 2001; accepted Mar. 4, 2002.
REFERENCES 1. Dickson RC, Everhart JE, Lake JR, 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 transplantation database. Gastroenterology 1997;113:1668 –74. 2. Dodson FS, Issa S, Araya V, et al. Infectivity of hepatic allograft with antibodies to hepatitis B virus. Transplantation 1997;64:1582– 4. 3. Uemoto S, Sugiyama K, Marusawa H, et al. Transmission of hepatitis B virus from hepatitis B core antibody-positive donors in living related liver transplants. Transplantation 1998; 65:494 –9. 4. Wachs M. The risk of transmission of hepatitis B from HBsAg(⫺), HBcAb(⫹), HBcIgM(⫺) organ donors. Transplantation 1995;59:230 – 4. 5. Delmonico FL. Organ donors screening for infectious disease. Transplantation 1998;65:603– 61. 6. O’Connell T, Thornton L, O’Flanagan D, et al. Prevalence of hepatitis B anti-core antibody in the Republic of Ireland. Epidemiol Infect 2000;125:701– 4. 7. Jilg W, Hottentrager B, Weinberger K, et al. Prevalence of markers of hepatitis B in the adult German population. J Med Virol 2001;63:96 –102. 8. Santos A, Carvalho A, Tomas J, et al. Prevalence of markers of hepatitis B infection in the adult population of the district of Coimbra. Acta Med Port 2000;13:167–71. 9. Ba´ rcena Maruga´ n R, Garcı´a Garzo´ n S, Lo´ pez San Roma´ n A, et al. Riesgo de transmisio´ n de virus de hepatitis B de donantes de hı´gado anti-HBc positivos. Med Clin 2001;116:125– 8. 10. Pascasio JM, Ba´ rcena R, Zamora C, et al. Prevalencia de ALAT elevada y marcadores serolo´ gicos del virus de la hepatitis B en donantes incriminados en transmisio´ n de hepatitis no A no B. Rev Clin Esp 1987;180:142– 6. 11. Prieto M, Go´ mez MD, Berenguer M, et al. De novo hepatitis B after liver transplantation from hepatitis B core antibodypositive donors in an area with high prevalence of anti-HBc positivity in the donors population. Liver Transplant 2001;7: 51– 8. 12. McQuillan GM, Coleman PJ, Kruszon-Moran D, et al. Prevalence of hepatitis B infection in the United States: The Na-
AJG – September, 2002
13. 14. 15. 16. 17.
18. 19. 20. 21. 22.
tional Health and Nutrition Examination Surveys, 1976 through 1994. Am J Public Health 1999;89:14 – 8. Chien NT, Dunddo G, Horani MH, et al. Seroprevalence of viral hepatitis in an older nursing home population. J Am Geriatr Soc 1999;47:1110 –3. Larsen J. Posttransfusion hepatitis B transmited by blood from a B surface antigen-negative virus carrier. Transfusion 1990; 30:431–2. Vento S, di Perri G, Luzzati R, et al. Clinical reactivation of hepatitis B in anti-HBs positive patients with AIDS. Lancet 1989;1:332–3. Michalk TI, Pasquinelli C, Guilhot S, et al. Hepatitis B virus persistence after recovery from acute viral hepatitis. J Clin Invest 1994;94:907. Loriot MA, Marcellin P, Walker F, et al. Persistence of hepatitis B virus DNA in serum and liver from patients with chronic hepatitis B after loss of HBsAg. J Hepatol 1997;27: 251– 8. Fong TL, Di Bisceglie AM, Gerber MA, et al. Persistence of hepatitis B virus DNA in the liver after loss of HBsAg in chronic hepatitis B. Hepatology 1993;18:1313– 8. Kuhns M, McNamara A, Mason A, et al. Serum and liver hepatitis B after sustained loss of surface antigen. Gastroenterology 1992;103:1649 –56. Marusawa H, Uemoto S, Hijikata M, et al. Latent hepatitis B virus infection in healthy individuals with antibodies to hepatitis B core antigen. Hepatology 2000;31:88 –95. Domı´nguez A, Bruguera M, Vidal J, et al. Changes in the seroepidemiology of hepatitis B infection in Catalonia 1989 – 1996. Vaccine 2000;18:2345–50. Sua´ rez A, Rodrı´guez M, Riestra S, et al. Prevalencia de la positividad del anti-HBc entre donantes de sangre en Asturias. Un estudio clinicoepidemiolo´ gico. Med Clin 1994;103:606 – 10.
Prevention of HBV in Liver Transplant Recipients
2401
23. Garcı´a-Fulgueiras A, Tormo MJ, Rodrı´guez T, et al. Prevalence of hepatitis B and C markers in the south-east of Spain: An unlinked community-based serosurvey of 2203 adults. Scand J Infect Dis 1996;28:17–20. 24. Panizo Delgado A, Martı´nez de Artola V, Panizo Santos C. Seroprevalence of hepatitis B virus markers in pregnant women attending a public hospital in Navarra. Rev Clin Esp 1994;194:891– 6. 25. Resina RA, Fahim Zawati Z, Domı´nguez Grandal C. Prevalencia de marcadores serolo´ gicos del virus de hepatitis B en pacientes ambulantes de la ciudad de Vigo. Aten Primaria 1992;10:1028 –9. 26. Gonza´ lez L, Roses A, Alomar P, et al. The maternal-infant center in the control of hepatitis B. Acta Obstet Gynecol Scand 1988;67:421–7. 27. Dal-Re R, Aguilar L, Coronel P. Current prevalence of hepatitis B, A and C in a healthy Spanish population. A seroepidemiological study. Infection 1991;19:409 –13. 28. Keeffe EB. Vaccination against hepatitis A and B in chronic liver disease. Viral Hepatitis Rev 1999;5:77– 88. 29. Hadler SC, Francis DP, Maynard JE, et al. Long term inmunogenicity of hepatitis B vaccine in homosexual men. N Engl J Med 1986;315:209 –14. 30. Ba´ rcena R, Ferna´ ndez-Braso M, Urman J, et al. Response to hepatitis B virus vaccine in patients transplanted for HBVrelates liver disease under specific gammaglobulin prophylaxis. Transplant Proc 1999;31:2459 – 60. 31. Dodson SF, Bonham CA, Geller DA, et al. Prevention of de novo hepatitis B infection in recipients of hepatic allografts from anti-HBc positive donors. Transplantation 1999;68: 1058 – 61. 32. Domı´nguez M, Ba´ rcena R, Garcı´a M, et al. Vaccination against hepatitis B virus in cirrhotic patients on liver transplant waiting list. Liver Transplant 2000;6:440 –2.
Vol. 97, No. 9, 2002 ISSN 0002-9270/02/$22.00 PII S0002-9270(02)04351-4
Prevention of de novo Hepatitis B Infection in Liver Allograft Recipients With Previous Hepatitis B Infection or Hepatitis B Vaccination R. Ba´rcena Maruga´n, M.D., F. Garcı´a-Hoz, M.D., M. Va´zquez Romero, M.D., R. Nash, M.D., M. Mateos, M.D., R. Gonza´lez Alonso, M.D., M. Garcı´a Gonza´lez, M.D., and A. Garcı´a Plaza, M.D. Gastroenterology Service and Microbiology and Virology Service, Hospital Ramo´n y Cajal, Madrid, Spain
OBJECTIVES: To assess de novo hepatitis B virus (HBV) transmission from liver donors with HBV serum markers (HBM) to their recipients and the need for HBV vaccination before liver transplantation. METHODS: A total of 108 orthotopic liver transplantations for nonviral disease and the risk of developing de novo hepatitis B based on HBMs before transplantation have been studied. Of the 108 patients, 94 met the study criteria and were divided into two groups: 27 who had HBMs before transplantation (from past infection or by previous vaccination) and 67 who had no HBM. Development of de novo hepatitis B was determined by analytical, serological, and histological parameters. RESULTS: No case (0%) of de novo hepatitis B was detected in the pretransplantation HBM group, whereas there were 10 cases (14.5%) in the other group (p ⬍ 0.005). CONCLUSIONS: The presence of pretransplantation HBM in liver transplant recipients protects these patients against the development of de novo hepatitis B. This is especially important considering that there is a high prevalence of donors with positive hepatitis B core antibody (especially in some countries), and that these donors transmit HBV infection to recipients without HBM in a significant number of cases. Thus, vaccination against HBV in patients who are candidates for liver transplantation is fundamental to avoid cases of de novo hepatitis B. (Am J Gastroenterol 2002;97: 2398 –2401. © 2002 by Am. Coll. of Gastroenterology)
INTRODUCTION Transmission of de novo hepatitis B from liver donors with hepatitis B virus serum markers (HBM) to their recipients has recently been described (1–5). On the other hand, the frequency of HBM (hepatitis B core antibody [anti-HBc] with or without hepatitis B surface antibody [anti-HBs]) in the adult western population is quite high and varies greatly according to country. For example, the incidence is 0.5% in Ireland (6), 8.7% in Germany (7), 7.9% in Portugal (8), 10 –20% in Spain (9 –11), and 5.5–24% in the United States (12, 13). Thus, elimination of anti-HBc positive donors
would lead to a significant loss of organs in many countries. It is unclear whether the presence of anti-HBc in the recipient protects against infection, although some retrospective studies seem to indicate that this is possible (2). We have retrospectively reviewed 108 patients who underwent liver transplantation because of nonviral disease and whose survival rate was ⬎1 yr to determine the risk of de novo hepatitis B based on the pretransplantation HBM.
MATERIALS AND METHODS Study Patients We retrospectively reviewed 108 orthotopic liver transplantations carried out in our center between 1994 and 1999, all of which were because of nonviral disease, with a survival rate was ⬎1 yr. None of the transplant recipients who died during year 1 had developed fibrosing cholestatic hepatitis from hepatitis B. Death was from other causes such as infections, renal failure, and surgical complications, among others. Therefore, no patients with de novo hepatitis B were excluded. There were 86 men (49.8 ⫾ 10 yr) and 22 women (47.8 ⫾ 12.2 yr) with a mean age was 49.4 ⫾ 11 yr. The reason for transplantation was: alcohol-induced chronic hepatic disease in 84 cases, primary biliary cirrhosis in six, hemochromatosis in five, autoimmune hepatitis in four, glycogenosis type 1b in one, and cryptogenetic cirrhosis in eight. Patients with C virus induced disease were not studied, as the presence of anti-HBc in this disease can be due to previous or present B virus infection, but also to false reactions caused by the technique that was being used in our laboratory, which could alter the results. Since the initiation of the liver transplantation program in our center, those candidates on the list who had no HBMs were vaccinated against hepatitis B virus (HBV). Because the waiting list was very small initially so that the time on the list was short, and because we also received patients from different sites of the country, only a portion of the patients were vaccinated. Of the latter, only a minority received the three doses before transplantation. In all, 19 (17.6%) of the 108 patients studied presented with anti-HBc and anti-HBs before transplantation and therefore were not
AJG – September, 2002
Prevention of HBV in Liver Transplant Recipients
2399
Table 1. Pretransplantation Status of Recipients Pretransplantation Status Rejections CMV infection de novo Hepatitis B
HBM⫹ (n ⫽ 27)
HBM⫺ (n ⫽ 67)
Difference
9 3 0
26 8 10
ns ns p ⬍ 0.005
vaccinated. Of the remaining 89, 38 were vaccinated. Of these 38 patients, 14 received only one or two doses and their anti-HBs levels were not determined before transplantation, and they have not been considered in the study. The remaining 24 patients (aged 50.4 ⫾ 9.6 yr) received the three doses; eight of these patients (33.3%) developed protective titers. In all, 27 patients presented with positive anti-HBs titers from vaccination or past infection, and the remaining 67 patients did not. Of these patients, 21 were men, with a mean age of 50.1 ⫾ 10 yr. Mean follow-up was 22 months (range 13–72 months). After transplantation, hepatitis B surface antigen (HBsAg), anti-HBc, and anti-HBs were determined in archive serum corresponding to 3 and 12 months as well as to the most recent serum drawn. ELISA techniques (Abbott Diagnostics, North Chicago, IL) were used to analyze HBV (HBsAg, anti-HBc, anti-HBs) serum markers and HBV DNA was determined with the hybridation technique. Biopsy specimens were examined with hematoxylin-eosin staining and immunohistochemical techniques for HBsAg and anti-HBc. The diagnosis of HBV infection was established by the presence of HBsAg and positive B virus DNA in serum. The de novo hepatitis B diagnosis was determined by an alteration compatible with the transaminase values, hepatitis data from the biopsy specimen, and positive immunohistochemistry for HBsAg and HBcAg. Statistical Analysis The PRESTA program was used for the statistical study. The 2 test was used to compare qualitative variable percentages. For the quantitative variable study, the Wilcoxon test for paired data and Student’s t test for nonpaired data were used. A p value of ⬍0.005 was considered to be statistically significant. Results are expressed as mean ⫾ standard deviation.
RESULTS Ten of the 108 patients developed HBV infection. No case (0%) of de novo hepatitis B was found in the 27 patients with HBM from vaccination or past infection, whereas there were 10 cases (14.5%) among the 67 patients without antiHBs, a significant difference (p ⬍ 0.005). One of the 10 cases occurred among the 16 patients vaccinated without response (6.25%), and nine occurred among the 51 nonvaccinated patients (17.6%; p ⫽ ns). There were no significant differences regarding reason for transplantation, age, sex,
pretransplantation Child stage, frequency of cytomegalovirus infection, or rejection episodes in both groups (Table 1). The mean age of the 10 patients who developed hepatitis B was 48.1 ⫾ 11.9 yr, and that of the patients who did not develop it was 52 ⫾ 6.9 (p ⫽ 0.068, ns). Of the patients who developed hepatitis B, eight patients were male and two were female.
DISCUSSION Subjects with anti-HBc and anti-HBs in serum have always been considered noninfective for both blood as well as organ donation, although cases of posttransfusion hepatitis in HBsAg negative donors have sporadically been described (14). The appearance of de novo B virus infection has recently been reported in patients undergoing transplantation with positive anti-HBc donor organs, either with or without antiHBs (1). These results have been confirmed in other studies (2– 4, 9). Infection transmission frequency varies according to the report; however, it is generally very high, reaching values of ⬎75% and, in some of the studies, close to 100% (4, 9). This indicates that complete or reproducible forms of the HBV remain in the liver—perhaps permanently—in patients who have previously had this disease, so transplantation of organs from these patients to susceptible or immunodepressed patients would precipitate a new HBV infection in these transplant recipients. This form of occult or latent infection has already been described in isolated cases of HIV-infected patients in whom, coincident with the development of AIDS, there had been reactivation (demonstrated by sequential analysis of both viruses) of previous B virus infection that had already been cured; thus, in these patients, anti-HBs titers had developed years earlier (15). In addition, the presence of HBV DNA in serum (16, 17) and/or in the liver (18, 19) had been described in patients with past infection from HBV with the presence of anti-HBs serum. This occurrence, which was considered rare, seems to be quite frequent. In a recent study involving 15 patients with chronic hepatitis B who had lost HBsAg, Loriot et al. found HBV DNA by polymerase chain reaction in 100% of cases and hybridation in situ in 40% (17). Very recently, replicative intermediates of HBV as well as covalently closed circular DNA or pregenomic RNA have been found in hepatic tissues of 13 of 14 healthy donors with anti-HBc and anti-HBs in serum. This indicates that the virus is maintained as a latent or occult infection in individuals with past HBV infection markers (20). The livers of these indi-
2400
Ba´rcena Maruga´n et al.
viduals transmit HBV infection in almost all cases, at least if the recipient is susceptible. In contrast, in individuals with anti-HBs as the only HBM, these replicative forms of the HBV are not found (20), and these grafts do not seem to transmit the infection (2, 9). The prevalence of positive anti-HBc in the Spanish adult population is very high at 15–25% (6 –13, 21–27). Among adult organ donors, anti-HBc prevalence is also high (2) and increases with donor age, reaching values of ⬎25% in adults and/or donors ⬎60 yr of age (7, 9, 11). Whether the presence of anti-HBc and/or anti-HBs due to past infection or vaccination (28, 29) protects liver recipients with anti-HBc has not been established, although the few retrospective studies that have been carried out seem to indicate that there was no infection in this type of recipient (2, 9). The high prevalence (⬎15%) of donors with positive anti-HBc as well as the high mortality of those on the waiting list (⬎7%) prevent us from eliminating this type of grafts, at least in countries with such a high hepatitis B marker prevalence among donors. In our country, the probability that a liver recipient can receive a graft with anti-HBc is approximately 30% (9), which is the same among those who present previous or nonprevious HBMs. If, as it seems to be demonstrated, infectivity is very high among non-HBM recipients, the value of 14.5% infectivity is not high and would correspond to about half of the non-HBM recipients. If the presence of anti-HBs did not protect against de novo infection, we would have found this same percentage among the HBM patients; consequently, the lack of any case among this population probably means that its presence protects against the infection. Thus, our study seems to indicate that the HBM patients can receive donor livers with anti-HBc with or without anti-HBs. Based on these results, we believe that grafts with negative HBsAg HBMs can be used in recipients with HBM from past infection or from vaccinations with response, and we have acted accordingly. These patients should be followed periodically to detemine anti-HBs titers and, in the case of vaccinated patients, to revaccinate them if the titers decrease, as we have observed that patients with transplants can respond to intensive HBV vaccination when they are receiving monotherapy and 2 yr after the transplantation (30). Almost one third of the patients have developed antiHBs and anti-HBc naturally from past infection and could receive this type of grafts, and this number could be increased by vaccinating all liver transplantation candidates without HBM against HBV. In our present study, 33.3% of patients were vaccinated with only one double dose cycle; however, in a larger series, we have found even better results, with 44% of seroconversion to anti-HBs with only one cycle and 66% with two cycles (31). Given that the waiting list for liver transplantation in our country is presently ⬎4 months, a large portion of the candidates could receive two vaccination cycles if necessary while being
AJG – Vol. 97, No. 9, 2002
studied as candidates or while on the waiting list. The best option would be to vaccinate all patients with liver disease before they develop cirrhosis, because in this latter condition the response, as we observe, is less (32). In conclusion, the presence of anti-HBs in the antipositive HBc donor liver recipient seems to protect against de novo HBV. All candidates for transplantation should be vaccinated while on the list, or— even better—all patients with liver disease who could potentially require liver transplantation in the future should be vaccinated. The donor organs with positive anti-HBc could be used in recipients with anti-HBs from past infection (i.e., recipients in whom antiHBs is present in addition to anti-HBc) or effective vaccination. Reprint requests and correspondence: Rafael Ba´ rcena Maruga´ n, M.D., Servicio de Gastroenterologı´a, Hospital Ramo´ n y Cajal, Carretera de Colmenar Km 9,1, Madrid 28034, Spain. Received July 30, 2001; accepted Mar. 4, 2002.
REFERENCES 1. Dickson RC, Everhart JE, Lake JR, 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 transplantation database. Gastroenterology 1997;113:1668 –74. 2. Dodson FS, Issa S, Araya V, et al. Infectivity of hepatic allograft with antibodies to hepatitis B virus. Transplantation 1997;64:1582– 4. 3. Uemoto S, Sugiyama K, Marusawa H, et al. Transmission of hepatitis B virus from hepatitis B core antibody-positive donors in living related liver transplants. Transplantation 1998; 65:494 –9. 4. Wachs M. The risk of transmission of hepatitis B from HBsAg(⫺), HBcAb(⫹), HBcIgM(⫺) organ donors. Transplantation 1995;59:230 – 4. 5. Delmonico FL. Organ donors screening for infectious disease. Transplantation 1998;65:603– 61. 6. O’Connell T, Thornton L, O’Flanagan D, et al. Prevalence of hepatitis B anti-core antibody in the Republic of Ireland. Epidemiol Infect 2000;125:701– 4. 7. Jilg W, Hottentrager B, Weinberger K, et al. Prevalence of markers of hepatitis B in the adult German population. J Med Virol 2001;63:96 –102. 8. Santos A, Carvalho A, Tomas J, et al. Prevalence of markers of hepatitis B infection in the adult population of the district of Coimbra. Acta Med Port 2000;13:167–71. 9. Ba´ rcena Maruga´ n R, Garcı´a Garzo´ n S, Lo´ pez San Roma´ n A, et al. Riesgo de transmisio´ n de virus de hepatitis B de donantes de hı´gado anti-HBc positivos. Med Clin 2001;116:125– 8. 10. Pascasio JM, Ba´ rcena R, Zamora C, et al. Prevalencia de ALAT elevada y marcadores serolo´ gicos del virus de la hepatitis B en donantes incriminados en transmisio´ n de hepatitis no A no B. Rev Clin Esp 1987;180:142– 6. 11. Prieto M, Go´ mez MD, Berenguer M, et al. De novo hepatitis B after liver transplantation from hepatitis B core antibodypositive donors in an area with high prevalence of anti-HBc positivity in the donors population. Liver Transplant 2001;7: 51– 8. 12. McQuillan GM, Coleman PJ, Kruszon-Moran D, et al. Prevalence of hepatitis B infection in the United States: The Na-
AJG – September, 2002
13. 14. 15. 16. 17.
18. 19. 20. 21. 22.
tional Health and Nutrition Examination Surveys, 1976 through 1994. Am J Public Health 1999;89:14 – 8. Chien NT, Dunddo G, Horani MH, et al. Seroprevalence of viral hepatitis in an older nursing home population. J Am Geriatr Soc 1999;47:1110 –3. Larsen J. Posttransfusion hepatitis B transmited by blood from a B surface antigen-negative virus carrier. Transfusion 1990; 30:431–2. Vento S, di Perri G, Luzzati R, et al. Clinical reactivation of hepatitis B in anti-HBs positive patients with AIDS. Lancet 1989;1:332–3. Michalk TI, Pasquinelli C, Guilhot S, et al. Hepatitis B virus persistence after recovery from acute viral hepatitis. J Clin Invest 1994;94:907. Loriot MA, Marcellin P, Walker F, et al. Persistence of hepatitis B virus DNA in serum and liver from patients with chronic hepatitis B after loss of HBsAg. J Hepatol 1997;27: 251– 8. Fong TL, Di Bisceglie AM, Gerber MA, et al. Persistence of hepatitis B virus DNA in the liver after loss of HBsAg in chronic hepatitis B. Hepatology 1993;18:1313– 8. Kuhns M, McNamara A, Mason A, et al. Serum and liver hepatitis B after sustained loss of surface antigen. Gastroenterology 1992;103:1649 –56. Marusawa H, Uemoto S, Hijikata M, et al. Latent hepatitis B virus infection in healthy individuals with antibodies to hepatitis B core antigen. Hepatology 2000;31:88 –95. Domı´nguez A, Bruguera M, Vidal J, et al. Changes in the seroepidemiology of hepatitis B infection in Catalonia 1989 – 1996. Vaccine 2000;18:2345–50. Sua´ rez A, Rodrı´guez M, Riestra S, et al. Prevalencia de la positividad del anti-HBc entre donantes de sangre en Asturias. Un estudio clinicoepidemiolo´ gico. Med Clin 1994;103:606 – 10.
Prevention of HBV in Liver Transplant Recipients
2401
23. Garcı´a-Fulgueiras A, Tormo MJ, Rodrı´guez T, et al. Prevalence of hepatitis B and C markers in the south-east of Spain: An unlinked community-based serosurvey of 2203 adults. Scand J Infect Dis 1996;28:17–20. 24. Panizo Delgado A, Martı´nez de Artola V, Panizo Santos C. Seroprevalence of hepatitis B virus markers in pregnant women attending a public hospital in Navarra. Rev Clin Esp 1994;194:891– 6. 25. Resina RA, Fahim Zawati Z, Domı´nguez Grandal C. Prevalencia de marcadores serolo´ gicos del virus de hepatitis B en pacientes ambulantes de la ciudad de Vigo. Aten Primaria 1992;10:1028 –9. 26. Gonza´ lez L, Roses A, Alomar P, et al. The maternal-infant center in the control of hepatitis B. Acta Obstet Gynecol Scand 1988;67:421–7. 27. Dal-Re R, Aguilar L, Coronel P. Current prevalence of hepatitis B, A and C in a healthy Spanish population. A seroepidemiological study. Infection 1991;19:409 –13. 28. Keeffe EB. Vaccination against hepatitis A and B in chronic liver disease. Viral Hepatitis Rev 1999;5:77– 88. 29. Hadler SC, Francis DP, Maynard JE, et al. Long term inmunogenicity of hepatitis B vaccine in homosexual men. N Engl J Med 1986;315:209 –14. 30. Ba´ rcena R, Ferna´ ndez-Braso M, Urman J, et al. Response to hepatitis B virus vaccine in patients transplanted for HBVrelates liver disease under specific gammaglobulin prophylaxis. Transplant Proc 1999;31:2459 – 60. 31. Dodson SF, Bonham CA, Geller DA, et al. Prevention of de novo hepatitis B infection in recipients of hepatic allografts from anti-HBc positive donors. Transplantation 1999;68: 1058 – 61. 32. Domı´nguez M, Ba´ rcena R, Garcı´a M, et al. Vaccination against hepatitis B virus in cirrhotic patients on liver transplant waiting list. Liver Transplant 2000;6:440 –2.