Vaccination to Prevent De Novo Hepatitis B: Are There Patients Who Don’t Need Antiviral Prophylaxis?
Elizabeth C. Verna, MD, MSc
Columbia University Center for Liver Disease and Transplantation, New York, NY
Corresponding Author: Elizabeth C. Verna, MD, MSc Assistant Professor of Medicine Center for Liver Disease and Transplantation Division of Digestive and Liver Diseases Columbia University email: [email protected] office: 212-305-0914
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/lt.24858 This article is protected by copyright. All rights reserved.
Liver Transplantation
Page 2 of 6
The use of isolated hepatitis B core antibody (anti-HBc) positive liver allografts is an important strategy to expand the organ donor pool. These grafts are especially important in regions with a high prevalence of HBV exposure. In the most recent National Health and Nutrition Examination Survey (2007-2012) in the United States, while the overall prevalence of resolved infection (anti-HBc positive) was 3.7%, it increased to 6.7% among people over 50 years and was as high as 20.5% among non-Hispanic Asians in the US.1 However, unacceptably high rates of acquisition of HBV infection in previously uninfected recipients of these organs have led to a variety of prophylaxis strategies including hepatitis B immunoglobulin (HBIG) administration and/or indefinite use of antiviral agents, which are expensive and are associated potential long term toxicities and antiviral resistance.2 The risk of de novo HBV among liver transplant recipients without prophylaxis is significant, in a systematic review 58% among HBV naïve recipients of these grafts, compared with 11% when HBIG and/or lamivudine was given.3 However, for recipients with detectable hepatitis B surface antibody (antiHBs) prior to LT, the rate of de novo HBV was intermediate at 14% without prophylaxis and 3% with prophylaxis. Thus, antiviral prophylaxis is recommended for recipients of anti-HBc positive liver allografts in recipients that are anti-HBc negative, even if they have mounted anti-HBs with vaccination.4 The current recommendations are less clear among transplant recipients with anti-HBc and anti-HBs antibodies, as there are conflicting data whether prophylaxis significantly reduces the incidence of de novo HBV in this group. While these
John Wiley & Sons, Inc. This article is protected by copyright. All rights reserved.
2
Page 3 of 6
Liver Transplantation
patients are thought to be at the lowest risk overall2, many centers utilize indefinite prophylaxis even in this immune population. In this issue of Liver Transplantation, Wang and colleagues describe a cohort of 71 adult living donor liver transplant recipients of isolated anti-HBc positive grafts who underwent active HBV vaccination with anti-HBs titer targets before and after transplant facilitating prevention of de novo HBV without antiviral prophylaxis.5 A remarkable 71/153 (46%) of their living donor transplants in this period were from anti-HBc positive organs, reflecting the importance of this study in high prevalence communities. The cohort was treated in 3 groups depending of vaccine response: (1) those with sufficient response to vaccination pretransplant (anti-HBs levels >1000 IU/ml) who were followed without any posttransplant prophylaxis, (2) those without sufficient pretransplant response who received lamivudine prophylaxis but then responded to repeated vaccination with anti-HBs levels >100 IU/ml post-transplant and were taken off antiviral medications after a minimum of 2 years, and (3) those who never responded adequately to vaccination and continued lamivudine indefinitely. Booster vaccinations were given to maintain posttransplant anti-HBs > 100 IU/ml. Notably, almost a quarter of patients were in the third category and required indefinite therapy, thus this approach is not universally successful. In addition, 72% of recipients in the cohort had anti-HBc pre-transplant indicating that this population was largely patients with prior infection conferring immunity at baseline, and were perhaps at a lower risk of de novo HBV overall.
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3
Liver Transplantation
Page 4 of 6
The strengths of this report include the longterm follow up provided, with a median overall follow-up of almost 8 years. In this period, there were only 3 (4%) cases of de novo HBV, all in the third group who required persistent prophylaxis, none of whom had flares significant enough to require liver biopsy or impact graft outcomes. In addition, serial monitoring and vaccination are clearly cheaper than lifelong antiviral therapy, especially if newer generation medications are used for prophylaxis, such as tenofovir or entecavir. However, several questions remain unanswered. The antibody level required to confer protection against de novo HBV is unknown, and as high levels likely achieve greater benefit, whether 100 IU/ml is sufficient for longterm protection post-transplant is uncertain. While there were no patients with de novo HBV in the groups that reached these anti-HBs titer targets either pretransplant or posttransplant in this study, the overall small numbers and low-risk baseline population limit the ability to draw definitive conclusions about the safety with these cutoffs. A significant limitation to this approach is the importance of vaccination with immune response in the pretransplant period. Not only are vaccines less likely to be effective in cirrhosis, but the timing can be difficult to predict and vaccination can take months. Thus, the protocol is most elegantly applied in the case of living rather than deceased donation. While all nonimmune liver transplant candidates should be vaccinated for HBV prior to transplant,4 it is clear that this is not always feasible, and it is not possible to predict which patients will be offered an anti-HBc positive deceased donor in advance. Even in this living
John Wiley & Sons, Inc. This article is protected by copyright. All rights reserved.
4
Page 5 of 6
Liver Transplantation
donor study, only 89% received at least one dose of vaccination pretransplant, and among the vaccinated patients, only 38% achieved the target pretransplant anti-HBs level. In addition, a fairly large number of vaccines were required throughout the study to maintain immunity (median of 4 doses, range 1-9), and 9 patients were never vaccinated posttransplant due to their medical condition. Thus, while cheaper, this approach is more complex, requiring monitoring and compliance with intermittent vaccination, and will not be applicable to a significant proportion of patients who don’t achieve anti-HBs targets for a variety of reasons. Safe expansion of the organ donor pool remains crucial. In the United States, the optimal management strategy for recipients of anti-HBc positive donors, as well as HCV RNA positive or Public Health Service (PHS) increased risk organs, is of increasing importance in the current opioid epidemic. While this study by Wang and colleagues may be too small to recommend this approach universally, the possibility of prevention through vaccination without costly indefinite antiviral medications would further encourage the use of these organs and should be a focus of ongoing study.
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5
Liver Transplantation
Page 6 of 6
References 1.
2.
3.
4.
5.
Roberts H, Kruszon-Moran D, Ly KN, et al. Prevalence of chronic hepatitis B virus (HBV) infection in U.S. households: National Health and Nutrition Examination Survey (NHANES), 1988-2012. Hepatology. 2016;63(2):388397. Saab S, Waterman B, Chi AC, Tong MJ. Comparison of different immunoprophylaxis regimens after liver transplantation with hepatitis B core antibody-positive donors: a systematic review. Liver Transpl. 2010;16(3):300-307. Skagen CL, Jou JH, Said A. Risk of de novo hepatitis in liver recipients from hepatitis-B core antibody-positive grafts - a systematic analysis. Clin Transplant. 2011;25(3):E243-249. Huprikar S, Danziger-Isakov L, Ahn J, et al. Solid organ transplantation from hepatitis B virus-positive donors: consensus guidelines for recipient management. Am J Transplant. 2015;15(5):1162-1172. Wang SH, Loh PY, Lin TL, et al. Active Immunization for Prevention of De Novo HBV infection after Adult Living Donor Liver Transplantation with HBc(+) Graft. Liver Transpl. 2017.
John Wiley & Sons, Inc. This article is protected by copyright. All rights reserved.
6
Elizabeth C. Verna, MD, MSc
Columbia University Center for Liver Disease and Transplantation, New York, NY
Corresponding Author: Elizabeth C. Verna, MD, MSc Assistant Professor of Medicine Center for Liver Disease and Transplantation Division of Digestive and Liver Diseases Columbia University email: [email protected] office: 212-305-0914
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/lt.24858 This article is protected by copyright. All rights reserved.
Liver Transplantation
Page 2 of 6
The use of isolated hepatitis B core antibody (anti-HBc) positive liver allografts is an important strategy to expand the organ donor pool. These grafts are especially important in regions with a high prevalence of HBV exposure. In the most recent National Health and Nutrition Examination Survey (2007-2012) in the United States, while the overall prevalence of resolved infection (anti-HBc positive) was 3.7%, it increased to 6.7% among people over 50 years and was as high as 20.5% among non-Hispanic Asians in the US.1 However, unacceptably high rates of acquisition of HBV infection in previously uninfected recipients of these organs have led to a variety of prophylaxis strategies including hepatitis B immunoglobulin (HBIG) administration and/or indefinite use of antiviral agents, which are expensive and are associated potential long term toxicities and antiviral resistance.2 The risk of de novo HBV among liver transplant recipients without prophylaxis is significant, in a systematic review 58% among HBV naïve recipients of these grafts, compared with 11% when HBIG and/or lamivudine was given.3 However, for recipients with detectable hepatitis B surface antibody (antiHBs) prior to LT, the rate of de novo HBV was intermediate at 14% without prophylaxis and 3% with prophylaxis. Thus, antiviral prophylaxis is recommended for recipients of anti-HBc positive liver allografts in recipients that are anti-HBc negative, even if they have mounted anti-HBs with vaccination.4 The current recommendations are less clear among transplant recipients with anti-HBc and anti-HBs antibodies, as there are conflicting data whether prophylaxis significantly reduces the incidence of de novo HBV in this group. While these
John Wiley & Sons, Inc. This article is protected by copyright. All rights reserved.
2
Page 3 of 6
Liver Transplantation
patients are thought to be at the lowest risk overall2, many centers utilize indefinite prophylaxis even in this immune population. In this issue of Liver Transplantation, Wang and colleagues describe a cohort of 71 adult living donor liver transplant recipients of isolated anti-HBc positive grafts who underwent active HBV vaccination with anti-HBs titer targets before and after transplant facilitating prevention of de novo HBV without antiviral prophylaxis.5 A remarkable 71/153 (46%) of their living donor transplants in this period were from anti-HBc positive organs, reflecting the importance of this study in high prevalence communities. The cohort was treated in 3 groups depending of vaccine response: (1) those with sufficient response to vaccination pretransplant (anti-HBs levels >1000 IU/ml) who were followed without any posttransplant prophylaxis, (2) those without sufficient pretransplant response who received lamivudine prophylaxis but then responded to repeated vaccination with anti-HBs levels >100 IU/ml post-transplant and were taken off antiviral medications after a minimum of 2 years, and (3) those who never responded adequately to vaccination and continued lamivudine indefinitely. Booster vaccinations were given to maintain posttransplant anti-HBs > 100 IU/ml. Notably, almost a quarter of patients were in the third category and required indefinite therapy, thus this approach is not universally successful. In addition, 72% of recipients in the cohort had anti-HBc pre-transplant indicating that this population was largely patients with prior infection conferring immunity at baseline, and were perhaps at a lower risk of de novo HBV overall.
John Wiley & Sons, Inc. This article is protected by copyright. All rights reserved.
3
Liver Transplantation
Page 4 of 6
The strengths of this report include the longterm follow up provided, with a median overall follow-up of almost 8 years. In this period, there were only 3 (4%) cases of de novo HBV, all in the third group who required persistent prophylaxis, none of whom had flares significant enough to require liver biopsy or impact graft outcomes. In addition, serial monitoring and vaccination are clearly cheaper than lifelong antiviral therapy, especially if newer generation medications are used for prophylaxis, such as tenofovir or entecavir. However, several questions remain unanswered. The antibody level required to confer protection against de novo HBV is unknown, and as high levels likely achieve greater benefit, whether 100 IU/ml is sufficient for longterm protection post-transplant is uncertain. While there were no patients with de novo HBV in the groups that reached these anti-HBs titer targets either pretransplant or posttransplant in this study, the overall small numbers and low-risk baseline population limit the ability to draw definitive conclusions about the safety with these cutoffs. A significant limitation to this approach is the importance of vaccination with immune response in the pretransplant period. Not only are vaccines less likely to be effective in cirrhosis, but the timing can be difficult to predict and vaccination can take months. Thus, the protocol is most elegantly applied in the case of living rather than deceased donation. While all nonimmune liver transplant candidates should be vaccinated for HBV prior to transplant,4 it is clear that this is not always feasible, and it is not possible to predict which patients will be offered an anti-HBc positive deceased donor in advance. Even in this living
John Wiley & Sons, Inc. This article is protected by copyright. All rights reserved.
4
Page 5 of 6
Liver Transplantation
donor study, only 89% received at least one dose of vaccination pretransplant, and among the vaccinated patients, only 38% achieved the target pretransplant anti-HBs level. In addition, a fairly large number of vaccines were required throughout the study to maintain immunity (median of 4 doses, range 1-9), and 9 patients were never vaccinated posttransplant due to their medical condition. Thus, while cheaper, this approach is more complex, requiring monitoring and compliance with intermittent vaccination, and will not be applicable to a significant proportion of patients who don’t achieve anti-HBs targets for a variety of reasons. Safe expansion of the organ donor pool remains crucial. In the United States, the optimal management strategy for recipients of anti-HBc positive donors, as well as HCV RNA positive or Public Health Service (PHS) increased risk organs, is of increasing importance in the current opioid epidemic. While this study by Wang and colleagues may be too small to recommend this approach universally, the possibility of prevention through vaccination without costly indefinite antiviral medications would further encourage the use of these organs and should be a focus of ongoing study.
John Wiley & Sons, Inc. This article is protected by copyright. All rights reserved.
5
Liver Transplantation
Page 6 of 6
References 1.
2.
3.
4.
5.
Roberts H, Kruszon-Moran D, Ly KN, et al. Prevalence of chronic hepatitis B virus (HBV) infection in U.S. households: National Health and Nutrition Examination Survey (NHANES), 1988-2012. Hepatology. 2016;63(2):388397. Saab S, Waterman B, Chi AC, Tong MJ. Comparison of different immunoprophylaxis regimens after liver transplantation with hepatitis B core antibody-positive donors: a systematic review. Liver Transpl. 2010;16(3):300-307. Skagen CL, Jou JH, Said A. Risk of de novo hepatitis in liver recipients from hepatitis-B core antibody-positive grafts - a systematic analysis. Clin Transplant. 2011;25(3):E243-249. Huprikar S, Danziger-Isakov L, Ahn J, et al. Solid organ transplantation from hepatitis B virus-positive donors: consensus guidelines for recipient management. Am J Transplant. 2015;15(5):1162-1172. Wang SH, Loh PY, Lin TL, et al. Active Immunization for Prevention of De Novo HBV infection after Adult Living Donor Liver Transplantation with HBc(+) Graft. Liver Transpl. 2017.
John Wiley & Sons, Inc. This article is protected by copyright. All rights reserved.
6
