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HBV-positive and HIV-positive organs in transplantation: A clinical guide for the hepatologist

  • Author Footnotes
    † These authors contributed equally.
    Francesco Paolo Russo
    Footnotes
    † These authors contributed equally.
    Affiliations
    Department of Surgery, Oncology and Gastroenterology, University of Padua, Italy

    Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale Università-Padova, Italy
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  • Author Footnotes
    † These authors contributed equally.
    Mauro Viganò
    Footnotes
    † These authors contributed equally.
    Affiliations
    Division of Hepatology, San Giuseppe Hospital, MultiMedica IRCCS, Milan, Italy
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  • Peter Stock
    Affiliations
    Department of Surgery, University of California at San Francisco, San Francisco, California, USA
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  • Alberto Ferrarese
    Affiliations
    Unit of Gastroenterology, Borgo Trento University Hospital of Verona, Verona, Italy
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  • Nicola Pugliese
    Affiliations
    Department of Biomedical Sciences, Humanitas University, Milan, Italy

    Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Research Hospital IRCCS, Milan, Italy
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  • Patrizia Burra
    Correspondence
    Corresponding author. Address: Via Giustiniani 2, 35128 Padova, Italy. Tel.: 049.8212892.
    Affiliations
    Department of Surgery, Oncology and Gastroenterology, University of Padua, Italy

    Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale Università-Padova, Italy
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  • Alessio Aghemo
    Affiliations
    Department of Biomedical Sciences, Humanitas University, Milan, Italy

    Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Research Hospital IRCCS, Milan, Italy
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  • Author Footnotes
    † These authors contributed equally.
Published:April 07, 2022DOI:https://doi.org/10.1016/j.jhep.2022.03.007

      Summary

      Organ transplantation is a life-saving treatment for patients with end-stage organ disease, a severe condition associated with a high risk of waitlist mortality. It is primarily limited by a shortage of available organs. Maximising available donors can increase access to transplantation. Transplantation from donors positive for HBV and HIV has increased in many countries. However, antiviral therapies need to be readily available for recipients after transplantation to prevent possible reactivation of the virus following the administration of immunosuppressive therapies. Furthermore, the intentional transmission of a virus has practical, ethical, and clinical implications. In this review, we summarise the current research, focusing on grafts from donors positive for the HBV surface antigen, antibodies against the HBV core antigen, and HIV, to help hepatologists and physicians interested in transplantation to select the best antiviral and/or prophylactic regimens for after transplantation.

      Keywords

      Introduction

      Organ transplantation is the best and most cost-effective therapy for patients with end-stage organ failure.
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      • Koukoura A.
      • Tsianos G.I.
      • Gargavanis A.A.
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      Organ donation in the US and Europe: the supply vs demand imbalance.
      Despite improvements in post-transplant outcomes through refinements in perioperative management and surgical techniques, waitlist mortality remains high.
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      Changing trends in liver transplantation: challenges and solutions.
      As the number of donors is considerably lower than that of potential recipients, the use of expanded criteria grafts has increased.
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      • Burra P.
      Current challenges and future directions for liver transplantation.
      Following a patient-tailored treatment strategy, transplantation programmes aim to offer the most suitable graft for the benefit of the individual recipient, while also expanding the criteria for organ acceptance and allocation.
      Owing to powerful antiviral therapies, problems of organ shortage can be overcome by using grafts affected by HCV, HBV, or HIV.
      Following a review on liver transplantation (LT) from HCV+ donors,
      • Weinfurtner K.
      • Reddy K.R.
      Hepatitis C viraemic organs in solid organ transplantation.
      this manuscript summarises current research on grafts from donors positive for hepatitis B surface antigen (HBsAg), antibodies against the HBV core antigen (HBcAb), and HIV, to help hepatologists and physicians to select the best antiviral and/or prophylactic regimen for follow-up after transplantation. In the first part of this review, we discuss LT from HBV+ donors; in the second part, we discuss non-liver solid organ transplantation and cell transplantation from HBV+ donors; finally, in the last part, we discuss LT from HIV+ donors.

      HBV+ donors in the LT setting

      HBsAg+ donors

      Transplanting livers from HBsAg+ donors might be an option to increase the number of liver donors, especially in endemic areas, such as the Far East and the Mediterranean basin. The prevalence of potential HBsAg+ donors (ranging from 0.5% to 7% of all potential donors) might cause the heterogenous spreading of such an infection worldwide.
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      • Chen D.
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      • Zhao Y.
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      • Shi H.
      • et al.
      Long-term outcome and recurrence of hepatitis B virus following liver transplantation from hepatitis B surface antigen-positive donors in a Chinese population.
      ,
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      • Fan J.G.
      • Zhang Z.
      • Gao B.
      • Wang H.Y.
      The global burden of liver disease: the major impact of China.
      A recent study from the US reported a prevalence of 0.7% among 38,166 potential donors and highlighted the net benefit of routine nucleic acid testing.
      • Theodoropoulos N.
      • Kroll-Desrosiers A.
      • Ison M.G.
      Utilization of deceased organ donors based on HIV, hepatitis B virus, and hepatitis C virus screening test results.
      The number of potential good-quality grafts from HBsAg+ donors might increase in the future following the increased availability of high-barrier nucleos(t)ide analogues (NAs) that can arrest HBV disease progression.
      Conversely, regarding HBcAb+ donors, only a few studies on LT, where grafts from HBsAg+ donors were used, have been published since the first report in 1994
      • Wei L.
      • Chen D.
      • Zhang B.
      • Zhao Y.
      • Liu B.
      • Shi H.
      • et al.
      Long-term outcome and recurrence of hepatitis B virus following liver transplantation from hepatitis B surface antigen-positive donors in a Chinese population.
      ,
      • González-Peralta R.P.
      • Andres J.M.
      • Tung F.Y.
      • Fang J.W.
      • Brunson M.E.
      • Davis G.L.
      • et al.
      Transplantation of a hepatitis B surface antigen-positive donor liver into a hepatitis B virus-negative recipient.
      • Franchello A.
      • Ghisetti V.
      • Marzano A.
      • Romagnoli R.
      • Salizzoni M.
      Transplantation of hepatitis B surface antigen-positive livers into hepatitis B virus-positive recipients and the role of hepatitis delta coinfection.
      • Ho J.K.
      • Harrigan P.R.
      • Sherlock C.H.
      • Steinbrecher U.P.
      • Erb S.R.
      • Mo T.
      • et al.
      Utilization of a liver allograft from a hepatitis B surface antigen positive donor.
      • Hwang S.
      • Lee S.G.
      • Park K.M.
      • Kim K.H.
      • Ahn C.S.
      • Oh H.B.
      • et al.
      Five-year follow-up of a hepatitis B virus-positive recipient of hepatitis B surface antigen-positive living donor liver graft.
      • Soejima Y.
      • Shimada M.
      • Taketomi A.
      • Yoshizumi T.
      • Uchiyama H.
      • Ikegami T.
      • et al.
      Successful living donor liver transplantation using a graft from a hepatitis B surface antigen-positive donor.
      • Loggi E.
      • Bihl F.
      • Chisholm J.V.
      • Biselli M.
      • Bontadini A.
      • Vitale G.
      • et al.
      Anti-HBs re-seroconversion after liver transplantation in a patient with past HBV infection receiving a HBsAg positive graft.
      • Bahde R.
      • Hölzen J.P.
      • Wolters H.H.
      • Schmidt H.H.
      • Bock C.T.
      • Lügering A.
      • et al.
      Course of a HBsAg positive liver transplantation in a hepatitis B and D virus coinfected recipient.
      • Jiao Z.
      • Zhang Y.
      • Han L.
      • Zeng Y.
      • Yan L.
      Four-year follow-up of two chronic hepatitis B recipients of hepatitis B surface antigen-positive cadaveric liver grafts from asymptomatic carriers.
      • Jiang L.
      • Yan L.
      • Li B.
      • Wen T.
      • Zhao J.
      • Yang J.
      • et al.
      Successful use of hepatitis B surface antigen-positive liver grafts in recipients with hepatitis B virus-related liver diseases.
      • Loggi E.
      • Micco L.
      • Ercolani G.
      • Cucchetti A.
      • Bihl F.K.
      • Grazi G.L.
      • et al.
      Liver transplantation from hepatitis B surface antigen positive donors: a safe way to expand the donor pool.
      • Ju W.
      • Chen M.
      • Guo Z.
      • Wang D.
      • Zhu X.
      • Huang J.
      • et al.
      Allografts positive for hepatitis B surface antigen in liver transplant for disease related to hepatitis B virus.
      • Saidi R.F.
      • Jabbour N.
      • Shah S.A.
      • Li Y.F.
      • Bozorgzadeh A.
      Liver transplantation from hepatitis B surface antigen-positive donors.
      • Choi Y.
      • Choi J.Y.
      • Yi N.J.
      • Lee K.
      • Mori S.
      • Hong G.
      • et al.
      Liver transplantation for HBsAg-positive recipients using grafts from HBsAg-positive deceased donors.
      • Krishnamoorthi R.
      • Manickam P.
      • Cappell M.S.
      Liver transplantation of hepatitis B surface antigen positive donors to hepatitis B core antibody recipients: analysis of 27 patients.
      • Li Z.
      • Hu Z.
      • Xiang J.
      • Zhou J.
      • Yan S.
      • Wu J.
      • et al.
      Use of hepatitis B surface antigen-positive grafts in liver transplantation: a matched analysis of the US National database.
      • Yu S.
      • Yu J.
      • Zhang W.
      • Cheng L.
      • Ye Y.
      • Geng L.
      • et al.
      Safe use of liver grafts from hepatitis B surface antigen positive donors in liver transplantation.
      • Jeng L.B.
      • Thorat A.
      • Yang H.R.
      • Yeh C.C.
      • Chen T.H.
      • Hsu C.H.
      • et al.
      Successful use of hepatitis B surface antigen-positive liver grafts-an effective source for donor organs in endemic areas: a single-center experience.
      • Ballarin R.
      • Cucchetti A.
      • Russo F.P.
      • Magistri P.
      • Cescon M.
      • Cillo U.
      • et al.
      Long term follow-up and outcome of liver transplantation from hepatitis B surface antigen positive donors.
      • Lee W.C.
      • Chou H.S.
      • Lee C.S.
      • Wu T.H.
      • Wang Y.C.
      • Cheng C.H.
      • et al.
      Viral activity and outcome of hepatitis B surface antigen-positive grafts in deceased liver transplantation.
      • Lee T.C.
      • Kaiser T.E.
      • Luckett K.
      • Wima K.
      • Winer L.K.
      • Morris M.C.
      • et al.
      Use, safety, and effectiveness of viremic hepatitis B virus donor livers: a potential opportunity to expand the donor pool.
      (Table S1). HBsAg+ grafts used to be considered marginal organs due to active viral infection and the high risk of viral transmission without treatment. However, recently they have been shown to be safe, with good postoperative outcomes, especially when good-quality organs were transplanted through proper donor-to-recipient matching.
      • Huprikar S.
      • Danziger-Isakov L.
      • Ahn J.
      • Naugler S.
      • Blumberg E.
      • Avery R.K.
      • et al.
      Solid organ transplantation from hepatitis B virus-positive donors: consensus guidelines for recipient management.
      The HDV status of the donor is unknown during donor assessment. In case the status of HBsAg+/HDV+ coinfected livers is known, they are not allocated due to the high risk of HDV recurrence after transplantation.
      • Duvoux C.
      • Belli L.S.
      • Fung J.
      • Angelico M.
      • Buti M.
      • Coilly A.
      • et al.
      2020 position statement and recommendations of the European Liver and Intestine Transplantation Association (ELITA): management of hepatitis B virus-related infection before and after liver transplantation.
      HBsAg+ and HCV viraemic coinfected donor livers may be considered for transplantation after proper (histological) assessment of graft quality. The advent of direct-acting antivirals (DAAs) against HCV has enabled the transplantation of HCV viraemic livers, expanding the donor pool significantly, even for HCV- recipients.
      • Weinfurtner K.
      • Reddy K.R.
      Hepatitis C viraemic organs in solid organ transplantation.
      Donor-derived HBV transmission, often undiagnosed during transplantation because of the window period, should be carefully evaluated in such cases.
      • Bixler D.
      • Annambhotla P.
      • Montgomery M.P.
      • Mixon-Hayden T.
      • Kupronis B.
      • Michaels M.G.
      • et al.
      Unexpected hepatitis B virus infection after liver transplantation-United States, 2014–2019.

      Recipients of HBsAg+ donors

      Allocating HBsAg+ grafts to HBsAg+ recipients is the most reasonable choice since it does not significantly change postoperative management regarding prophylaxis against viral recurrence.
      • Duvoux C.
      • Belli L.S.
      • Fung J.
      • Angelico M.
      • Buti M.
      • Coilly A.
      • et al.
      2020 position statement and recommendations of the European Liver and Intestine Transplantation Association (ELITA): management of hepatitis B virus-related infection before and after liver transplantation.
      Transplantation of HBsAg+ grafts into HBsAg- recipients is performed only during emergencies.
      • Saidi R.F.
      • Jabbour N.
      • Shah S.A.
      • Li Y.F.
      • Bozorgzadeh A.
      Liver transplantation from hepatitis B surface antigen-positive donors.
      ,
      • Yu S.
      • Yu J.
      • Zhang W.
      • Cheng L.
      • Ye Y.
      • Geng L.
      • et al.
      Safe use of liver grafts from hepatitis B surface antigen positive donors in liver transplantation.
      There have been a couple of reported cases of HCV viraemic, HBsAg- patients, with decompensated cirrhosis and high model for end-stage liver disease (MELD) scores, receiving an HBsAg+ graft without developing rapidly progressive cholestatic hepatitis.
      • Ho J.K.
      • Harrigan P.R.
      • Sherlock C.H.
      • Steinbrecher U.P.
      • Erb S.R.
      • Mo T.
      • et al.
      Utilization of a liver allograft from a hepatitis B surface antigen positive donor.
      ,
      • Loggi E.
      • Bihl F.
      • Chisholm J.V.
      • Biselli M.
      • Bontadini A.
      • Vitale G.
      • et al.
      Anti-HBs re-seroconversion after liver transplantation in a patient with past HBV infection receiving a HBsAg positive graft.
      Due to limited data, strong conclusions cannot be made; the risk is less pronounced following the introduction of DAAs. The available information suggests that transplantation of HBsAg+ grafts into HBsAg- recipients is safe, especially in endemic areas and in cases of emergency,
      • Lee T.C.
      • Kaiser T.E.
      • Luckett K.
      • Wima K.
      • Winer L.K.
      • Morris M.C.
      • et al.
      Use, safety, and effectiveness of viremic hepatitis B virus donor livers: a potential opportunity to expand the donor pool.
      as the high-barrier NAs used for prophylaxis are highly effective. Effective therapeutic options for HDV might enable transplantation from HBsAg+ donors to this subgroup of patients, who cannot be provided grafts due to the risk of viral recurrence and subsequent graft loss.
      • Duvoux C.
      • Belli L.S.
      • Fung J.
      • Angelico M.
      • Buti M.
      • Coilly A.
      • et al.
      2020 position statement and recommendations of the European Liver and Intestine Transplantation Association (ELITA): management of hepatitis B virus-related infection before and after liver transplantation.

      Prophylaxis after receiving HBsAg+ grafts

      Retrospective studies from around the world provided optimal survival curves for patients who received good-quality HBsAg+ grafts when they maintained a persistently negative viremia postoperatively.
      • Bortoluzzi I.
      • Gambato M.
      • Albertoni L.
      • Mescoli C.
      • Pacenti M.
      • Cusinato R.
      • et al.
      Use of grafts from anti-HBc-positive donors in liver transplantation: a 5-year, single-center experience.
      Case-control studies
      • Saidi R.F.
      • Jabbour N.
      • Shah S.A.
      • Li Y.F.
      • Bozorgzadeh A.
      Liver transplantation from hepatitis B surface antigen-positive donors.
      ,
      • Li Z.
      • Hu Z.
      • Xiang J.
      • Zhou J.
      • Yan S.
      • Wu J.
      • et al.
      Use of hepatitis B surface antigen-positive grafts in liver transplantation: a matched analysis of the US National database.
      ,
      • Jeng L.B.
      • Thorat A.
      • Yang H.R.
      • Yeh C.C.
      • Chen T.H.
      • Hsu C.H.
      • et al.
      Successful use of hepatitis B surface antigen-positive liver grafts-an effective source for donor organs in endemic areas: a single-center experience.
      did not find any difference in survival after transplantation of HBsAg+ or HBsAg- grafts, although a short follow-up time and the absence of granular data on the grafts allocated to the controls prevented any strong conclusion from being drawn.
      Increasing liver transplantation from HBV+ donors, with adequate prophylactic antiviral therapy, in positive and negative recipients can decrease the national organ shortage.
      The reappearance of serum HBsAg after LT needs to be managed; therefore, antiviral prophylaxis, preferably with high-barrier NAs, is important. Several cases reported the development of lamivudine-resistance post-LT, but such cases can be reduced significantly after applying high-barrier NAs. The benefits of the administration of long-term hepatitis B immune globulin (HBIG) and the timing of withdrawal are debated. Theoretically, HBIG is not useful because it lacks a neutralising effect after the reappearance of HBsAg,
      • González-Peralta R.P.
      • Andres J.M.
      • Tung F.Y.
      • Fang J.W.
      • Brunson M.E.
      • Davis G.L.
      • et al.
      Transplantation of a hepatitis B surface antigen-positive donor liver into a hepatitis B virus-negative recipient.
      ,
      • Hwang S.
      • Lee S.G.
      • Park K.M.
      • Kim K.H.
      • Ahn C.S.
      • Oh H.B.
      • et al.
      Five-year follow-up of a hepatitis B virus-positive recipient of hepatitis B surface antigen-positive living donor liver graft.
      ,
      • Soejima Y.
      • Shimada M.
      • Taketomi A.
      • Yoshizumi T.
      • Uchiyama H.
      • Ikegami T.
      • et al.
      Successful living donor liver transplantation using a graft from a hepatitis B surface antigen-positive donor.
      ,
      • Loggi E.
      • Micco L.
      • Ercolani G.
      • Cucchetti A.
      • Bihl F.K.
      • Grazi G.L.
      • et al.
      Liver transplantation from hepatitis B surface antigen positive donors: a safe way to expand the donor pool.
      ,
      • Ballarin R.
      • Cucchetti A.
      • Russo F.P.
      • Magistri P.
      • Cescon M.
      • Cillo U.
      • et al.
      Long term follow-up and outcome of liver transplantation from hepatitis B surface antigen positive donors.
      and thus, it is not recommended (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Prophylactic strategies after liver transplantation using an HBsAg+ graft.
      The dark-green arrows indicate that LT is safe and effective; the light-green arrow indicates that LT is generally safe and effective but should be considered in specific cases (e.g., urgent cases) or in endemic areas. The red arrow indicates that LT is not recommended. ∗Living donation should be carefully evaluated in specific cases, and HDV+ grafts should not be used for transplantation; §donor graft quality should be routinely assessed by liver biopsy; °the HBsAg appearance is highly expected after liver transplantation; therefore, HBIG should not be used when HBsAg reappearance is confirmed. HBIG, hepatitis B immune globulin; LT, liver transplantation; NA, nucleos(t)ide analogue.
      Treatment using tenofovir disoproxil fumarate, tenofovir alafenamide, and entecavir is currently preferred, depending on local availability, costs, pre-transplant treatments, renal function, and bone health. Potential worsening of renal function after the co-administration of tenofovir disoproxil with nephrotoxic drugs (e.g., aminoglycosides, ganciclovir), as well as potential interactions between tenofovir alafenamide and some antifungal/antimycobacterial agents, should be carefully considered, especially in the early postoperative phase. The risk of viral resistance to high-barrier NAs might be an issue in recipients with HBsAg reappearance after transplantation. Thus, such cases should be carefully evaluated and managed following the recommendations currently adopted for patients with chronic hepatitis B.
      [email protected] EAftSotLEa, Liver EAftSot
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      The seroconversion to HBsAb was observed during follow-up. Loggi et al.
      • Loggi E.
      • Bihl F.
      • Chisholm J.V.
      • Biselli M.
      • Bontadini A.
      • Vitale G.
      • et al.
      Anti-HBs re-seroconversion after liver transplantation in a patient with past HBV infection receiving a HBsAg positive graft.
      showed an HBsAg-, HBcAb+/HBsAb+ patient who turned HBsAg+ 3.5 months after receiving an HBsAg+ graft due to a reduced HBsAb titre; however, at month 18 post-LT, HBsAg clearance occurred concomitantly with the reappearance of a high HBsAb titre. The previous viral exposure might have elicited the immune response to HBV after LT, but this hypothesis was not confirmed in other studies.
      • Yu S.
      • Yu J.
      • Zhang W.
      • Cheng L.
      • Ye Y.
      • Geng L.
      • et al.
      Safe use of liver grafts from hepatitis B surface antigen positive donors in liver transplantation.
      More studies need to be performed to confirm this pathogenetic hypothesis.
      Regarding postoperative follow-up, patients receiving HBsAg+ grafts have to be carefully monitored through per-protocol biopsies or by using non-invasive tools/serum biomarkers, with scheduled biochemical and sero-virological assessments (every 3 months in the first year, and then, every 3–6 months indefinitely, with liver ultrasound every 6–12 months).
      • Theodoropoulos N.
      • Kroll-Desrosiers A.
      • Ison M.G.
      Utilization of deceased organ donors based on HIV, hepatitis B virus, and hepatitis C virus screening test results.
      Moreover, they should be provided life-long prophylaxis, which is associated with an unavoidable increase in costs. Fortunately, some studies have recently confirmed the cost-effectiveness of this procedure, especially for patients with high MELD scores and HBsAg- recipients who have received livers from HBV+ donors.
      • Lee T.C.
      • Eckman M.H.
      • Shah S.A.
      Cost-effectiveness of utilization of hepatitis B virus-positive liver donors for HBV-negative transplant recipients.
      Additional studies are required to confirm this preliminary report.
      Other important issues also need to be addressed. Further assessment is required to determine whether these patients are at a higher risk of de novo or recurrent postoperative hepatocellular carcinoma, given that HBV is oncogenic. The relatives of such patients must be informed about the risk of infectious disease transmission, especially if the patient becomes viraemic. Specific methods of treatment (e.g., HBV vaccination) should be recommended. Viraemic grafts should be offered to adherent patients only when a strict follow-up by the local transplant team is guaranteed, and there is a certainty that the prescribed therapy will be available throughout life.
      The transplantation of organs from HBsAg+ living donors has been proposed in very few cases. For good outcomes, donors should be selected carefully, and the histological/functional status of the graft should be extensively evaluated before surgery.

      HBcAb+ donors in LT

      The HBcAb+ condition requires prior exposure to HBV and causes a lifelong hepatocyte infection due to the presence of covalently closed circular DNA (cccDNA) in the hepatocyte that cannot be cleared by the host immune response.
      • Raimondo G.
      • Locarnini S.
      • Pollicino T.
      • Levrero M.
      • Zoulim F.
      • Lok A.S.
      • et al.
      Update of the statements on biology and clinical impact of occult hepatitis B virus infection.
      Therefore, HBcAb+ grafts were viewed as marginal organs. However, due to the worsening global organ shortage, the allocation of HBcAb+ livers has increased substantially in endemic countries like those in the Far East (where the prevalence is roughly 50% of all organs),
      • Lo C.M.
      • Fan S.T.
      • Liu C.L.
      • Yong B.H.
      • Wong Y.
      • Ng I.O.
      • et al.
      Safety and outcome of hepatitis B core antibody-positive donors in right-lobe living donor liver transplantation.
      ,
      • Wong T.C.
      • Fung J.Y.
      • Cui T.Y.
      • Lam A.H.
      • Dai J.W.
      • Chan A.C.
      • et al.
      Liver transplantation using hepatitis B core positive grafts with antiviral monotherapy prophylaxis.
      the Mediterranean basin (where HBcAb+ grafts comprise about 15% of all organs),
      • Angelico M.
      • Nardi A.
      • Marianelli T.
      • Caccamo L.
      • Romagnoli R.
      • Tisone G.
      • et al.
      Hepatitis B-core antibody positive donors in liver transplantation and their impact on graft survival: evidence from the Liver Match cohort study.
      and in low-endemic countries, like the USA (where the prevalence increased from 1.8% in 1994 to 6% in 2006).
      • Yu L.
      • Koepsell T.
      • Manhart L.
      • Ioannou G.
      Survival after orthotopic liver transplantation: the impact of antibody against hepatitis B core antigen in the donor.

      Determining the optimal allocation of HBcAb+ grafts

      The development of HBV recurrence or a de novo viral infection significantly affects the survival of the graft and the patient. After the introduction of a high-barrier NA, such risks are minimised considerably. Moreover, since the risk varies with the serostatus of the pre-LT recipient, the current guidelines recommend tailored prophylactic algorithms.
      • Duvoux C.
      • Belli L.S.
      • Fung J.
      • Angelico M.
      • Buti M.
      • Coilly A.
      • et al.
      2020 position statement and recommendations of the European Liver and Intestine Transplantation Association (ELITA): management of hepatitis B virus-related infection before and after liver transplantation.
      ,
      • Cholongitas E.
      • Papatheodoridis G.V.
      • Burroughs A.K.
      Liver grafts from anti-hepatitis B core positive donors: a systematic review.
      Transplanting an HBcAb+ graft into an HBsAg+ recipient might be safe and effective, given that post-transplant prophylaxis remains the same. A study showed that HBcAb positivity increased the risk of post-LT viral recurrence by twofold; however, in that study, more than 60% of patients received HBIG monoprophylaxis.
      • Joya-Vazquez P.P.
      • Dodson F.S.
      • Dvorchik I.
      • Gray E.
      • Chesky A.
      • Demetris A.J.
      • et al.
      Impact of anti-hepatitis Bc-positive grafts on the outcome of liver transplantation for HBV-related cirrhosis.
      HBV-naive recipients are at the greatest risk of de novo infection without prophylaxis, followed by HBcAb+/HBsAb- and HBcAb-/HBsAb+ patients (47%, 13%, and 9%, respectively). Conversely, HBcAb+/HBsAb+ recipients have a negligible risk of de novo infection (1.4%), making antiviral prophylaxis unnecessary (Fig. 2).
      Figure thumbnail gr2
      Fig. 2Prophylactic strategies after liver transplantation using an HBcAb+ graft.
      Circles indicate the probability of de novo infection without prophylaxis. NA monoprophylaxis should be proposed to adherent patients with persistently negative HBV DNA and HBsAg for the long-term follow-up after liver transplantation. HBIG, hepatitis B immune globulin; NA, nucleos(t)ide analogue.
      A recent hypothesis suggested considering the prognostic value of the HBsAb serostatus of recipients during patient selection for lifelong prophylaxis.
      • Fallahzadeh M.A.
      • Trotter J.F.
      An experiment of nature: HBV-naive recipients receiving liver grafts with HBV core antibody-positive donors without antiviral prophylaxis.
      While an aforementioned systematic review
      • Cholongitas E.
      • Papatheodoridis G.V.
      • Burroughs A.K.
      Liver grafts from anti-hepatitis B core positive donors: a systematic review.
      showed that HBsAb detectability through vaccination reduces, but does not abolish, the risk of de novo HBV infection, a recent study on the recipients of LTs from living donors showed that active pre-operative immunisation can effectively prevent de novo HBV infection, provided high HBsAb serum levels are maintained after surgery.
      • Wang S.H.
      • Loh P.Y.
      • Lin T.L.
      • Lin L.M.
      • Li W.F.
      • Lin Y.H.
      • et al.
      Active immunization for prevention of De novo hepatitis B virus infection after adult living donor liver transplantation with a hepatitis B core antigen-positive graft.

      Determining the best prophylaxis after LT

      A monoprophylaxis regimen might be the most reasonable option for HBsAg- recipients receiving an HBcAb+ graft. Unlike when receiving HBsAg+ donors, no circulating HBsAg-coated virions requiring neutralisation by HBIG will be present in HBsAg- recipients of HBcAb+ grafts. No randomised, comparative studies are available regarding the choice of NA. Lamivudine has been used as a cost-effective treatment in patients receiving HBcAb+ grafts. The increased global availability of high-barrier NAs at low cost has made this a safer treatment option.
      • Wong T.C.
      • Fung J.Y.
      • Cui T.Y.
      • Lam A.H.
      • Dai J.W.
      • Chan A.C.
      • et al.
      Liver transplantation using hepatitis B core positive grafts with antiviral monotherapy prophylaxis.
      ,
      • Terrault N.A.
      • Lok A.S.F.
      • McMahon B.J.
      • Chang K.M.
      • Hwang J.P.
      • Jonas M.M.
      • et al.
      Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.
      A complete withdrawal of prophylaxis is not recommended and requires the evaluation (and monitoring) of intrahepatic cccDNA; it might be performed when serum biomarkers, which are reliable surrogates of intranuclear DNA,
      • Testoni B.
      • Lebossé F.
      • Scholtes C.
      • Berby F.
      • Miaglia C.
      • Subic M.
      • et al.
      Serum hepatitis B core-related antigen (HBcrAg) correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients.
      are available.

      The impact of HBcAb+ grafts on survival

      The impact of HBcAb+ grafts on post-transplant survival is debated. The development of good prophylactic strategies has reduced the risk of de novo infection after LT. Moreover, such occurrences can be safely and effectively treated with high-barrier NAs. Therefore, the attention has shifted from HBV recurrence to the hypothesis that HBcAb+ status might reflect suboptimal graft quality. This hypothesis was proposed in a large prospective study, where the effect of organs transplanted from HBcAb+ donors on the postoperative survival of recipients was only considered after they were allocated to HBsAg- recipients (mainly hepatitis C recipients).
      • Angelico M.
      • Nardi A.
      • Marianelli T.
      • Caccamo L.
      • Romagnoli R.
      • Tisone G.
      • et al.
      Hepatitis B-core antibody positive donors in liver transplantation and their impact on graft survival: evidence from the Liver Match cohort study.
      A recent study from a highly endemic HBV-prevalent area demonstrated a similar 10-year graft survival status (76.8% vs. 74.8%, respectively) for HBcAb+ grafts, without any difference in primary non-function, graft dysfunction, or hepatocellular carcinoma.
      • Wong T.C.
      • Fung J.Y.
      • Cui T.Y.
      • Lam A.H.
      • Dai J.W.
      • Chan A.C.
      • et al.
      Liver transplantation using hepatitis B core positive grafts with antiviral monotherapy prophylaxis.
      This study considered both living and deceased donor LTs, including young donors. Studies have suggested that HBcAb+ grafts should not be discarded, especially at times of organ shortage.
      Kidneys from HBV viraemic donors should only be transplanted to recipients with protective HBV immunity (HBsAb >10 IU/L) during transplantation, and the antibody titre should be monitored immediately after transplantation, one month after transplantation, and then, every three months to verify the necessity of a booster dose of vaccine or antiviral prophylaxis until HBsAb levels are above 10 IU/L.

      HBV+ donors in non-liver solid organ transplantation

      HBsAg+ donors

      Transplanting an HBsAg+ graft into an HBsAg- recipient is associated with a significant risk of de novo infection. In areas endemic for HBV infection, where HBsAg+ rates are high (10–20%), the exclusion of HBsAg+ donors would considerably reduce the donor pool.
      [email protected] EAftSotLEa
      EASL clinical practice guidelines: liver transplantation.
      This issue is less significant in western countries where organs from HBsAg+ donors are not transplanted regularly. The successful transplantation of deceased-donor or living-donor HBsAg+ kidneys has been reported in several studies, including in recipients with pre-existing immunity through vaccination or previous HBV infection (Table 1). A retrospective study compared the outcomes between kidney transplant (KT) recipients with HBsAb titres above 10 IU/L, who received either HBsAg+ (with absent or minimal viral replication; n = 43) or HBsAg- (n = 86) grafts. Regardless of the status of the HBsAg donors, there were neither cases of de novo HBV infection nor significant differences in graft and patient survival after a median follow-up of 58 months. Moreover, recipients who received kidneys from HBsAg+ donors with no HBV prophylaxis (n = 20) showed outcomes comparable to those treated with lamivudine only (n = 21) or lamivudine along with HBIG (n = 2).
      • Chancharoenthana W.
      • Townamchai N.
      • Pongpirul K.
      • Kittiskulnam P.
      • Leelahavanichkul A.
      • Avihingsanon Y.
      • et al.
      The outcomes of kidney transplantation in hepatitis B surface antigen (HBsAg)-negative recipients receiving graft from HBsAg-positive donors: a retrospective, propensity score-matched study.
      Tuncer et al. highlighted the importance of HBsAb titre >10 IU/L in recipients and did not find cases of HBV infection in 35 HBV-immune patients who underwent KT from HBsAg+ living donors (with undetectable serum HBV DNA) without antiviral prophylaxis or HBIG administration.
      • Tuncer M.
      • Tekin S.
      • Yücetin L.
      • Şengül A.
      • Demirbaş A.
      Hepatitis B surface antigen positivity is not a contraindication for living kidney donation.
      The protective role of immunisation was further demonstrated in a recent study performed in a large Chinese cohort. HBsAg- individuals (n = 83), including 20 without a protective HBsAb titre, underwent KT from HBsAg+ donors. Although all patients received antiviral prophylaxis (average duration 1–3 months), after a mean follow-up of 36 months, 2 recipients (2.4%; n = 83) became HBsAg+ and tested positive for HBV DNA. The 2 patients lacked a protective HBsAb titre.
      • Wang X.D.
      • Liu J.P.
      • Song T.R.
      • Huang Z.L.
      • Fan Y.
      • Shi Y.Y.
      • et al.
      Kidney transplantation from hepatitis B surface antigen (HBsAg)-positive living donors to HBsAg-negative recipients: clinical outcomes at a high-volume center in China.
      These results confirmed that protective immunity is crucial to prevent de novo HBV infection.
      Table 1Studies on non-liver solid organ transplantation with HBsAg+ donors.
      StudyOrgan transplantedDonor(s) characteristicsRecipient(s) characteristicsAntiviral treatmentPost-transplant outcomeRelevant findings
      Tuncer et al., 2012Retrospective studyKidney35 HBsAg+ living donors (with undetectable serum HBV-DNA)35 HBsAg– recipients with anti-HBs titres above 10 IU/LNo use of antiviral prophylaxis or HBIGNo cases of HBV de novo infection
      Chancharoenthana W et al., 2014Retrospective, longitudinal studyKidney43 HBsAg+ donors (with absent or minimal viral replication) and 86 HBsAg- donors129 HBsAg- recipients with anti-HBs titres above 100 IU/L21 HBsAg+ organ recipients were treated with lamivudine.2 HBsAg+ organ recipients received lamivudine in combina-tion with HBIGNo cases of HBV de novo infectionRegardless of the HBsAg donor status, no significant differences in graft and patient survival after a median follow-up of 58.2 months.
      Wang et al., 2021Retrospective studyKidney83 HBsAg+ donors (viraemia not reported; histology not reported)83 HBsAg– recipients, including 20 without a protective anti-HBs titreAll recipients received antiviral prophylaxis (average duration 1–3 months)Two recipients became HBsAg+ and tested positive for HBV-DNAThe 2 patients who became HBsAg+ did not have a protective anti-HBs titre
      Wang et al., 2004Retrospective studyHeart32 HBsAg+ donors2 HBsAg- recipients without a docume-nted protective anti-HBs titre

      4 HBsAg+ recipients

      26 anti-HBs+ recipients
      Only 1 HBsAg- and anti-HBs- recipient received post-operative HBIG

      All HBsAg+ recipients received antiviral prophylaxis
      One of the 2 patients who did not have previous HBV infection or anti-HBs titre experienced a hepatitis infection

      Becoming HBsAg+
      Chen et al., 2012Retrospective studyHeart3 HBsAg+ donors3 HBsAg- recipients (no information about anti-HBs titre)Perioperative HBIGOne recipient became HBsAg+
      Shin et al., 2014Retrospective studyHeart6 HBsAg+ donors6 HBsAg- recipients with a documented anti-HBs titre (except for 1 patient whose serologic data was missing)Perioperative HBIGNo cases of HBV de novo infection
      Eichenberger et al., 2020Case reportLung1 HBsAg+ viraemic deceased donor1 HBsAg- recipient with anti-HBs titres above 100 IU/LHBIG immediately before and after transplantation daily for 5–7 days. Antiviral prophylaxis was started immediately after surgery.No de novo HBV infection (duration of the follow-up not mentioned)
      Belga et al., 2020Case reportLung1 HBsAg+ with low-level HBV-DNA1 HBsAg-recipient without a protective anti-HBs titreHBIG immediately before and after transplantation daily for 5–7 days. Antiviral prophylaxis was started immediately after surgeryHBV serology after 12 months showed positive anti-HBc and anti-HBs, but negative HBsAg and HBV-DNA
      HBIG, hepatitis B immunoglobulin.
      Based on the available data, although they were from studies that differed in pre-and post-transplant patient management, we suggest that KT from HBV viraemic allografts should only be considered for recipients with protective HBV immunity (HBsAb >10 IU/L) at the time of transplantation. The antibody titre should also be monitored immediately after transplantation, 1 month after transplantation, and then, every 3 months to verify the necessity of a booster dose of vaccine or antiviral prophylaxis until HBsAb levels are above 10 IU/L. Moreover, the aforementioned data suggest that antiviral prophylaxis is not mandatory in all HBsAg+ graft recipients, but the assessment of the status of immunosuppression should be performed, especially for desensitisation using T cell- and/or B cell-depleting agents.
      • Chancharoenthana W.
      • Leelahavanichkul A.
      Kidney transplantation from hepatitis B surface antigen (HBsAg)-positive living donors to HBsAg-negative recipients: benefits and risks.
      Data on the transplantation of thoracic organs from HBsAg+ donors is limited (Table 1). Most of the available data are related to heart transplantation from overlapping cohorts living in Korea. From an analysis of HBsAg+ heart transplants (n = 41 recipients), only 2 recipients (4.8%) were reported to be HBsAg+. One out of 3 HBsAb- recipients and 1 out of 7 recipients who were HBcAb+ before transplantation became HBsAg+; neither of the patients had received HBIG or antiviral prophylaxis. No case of HBsAg positivity was observed in the group of HBsAb+ recipients.
      • Chen Y.C.
      • Chuang M.K.
      • Chou N.K.
      • Chi N.H.
      • Wu I.H.
      • Chen Y.S.
      • et al.
      Twenty-four year single-center experience of hepatitis B virus infection in heart transplantation.
      • Wang S.S.
      • Chou N.K.
      • Ko W.J.
      • Yu H.Y.
      • Chen Y.S.
      • Hsu R.B.
      • et al.
      Heart transplantation using donors positive for hepatitis.
      • Shin H.S.
      • Cho H.J.
      • Jeon E.S.
      • Hwang H.Y.
      • Kim J.J.
      • Kim K.B.
      • et al.
      The impact of hepatitis B on heart transplantation: 19 years of national experience in Korea.
      Data on lung transplantation from HBsAg+ donors came from 2 case reports that described emergency transplantation from 2 HBsAg+ donors with variable levels of serum HBV DNA to an HBsAg- and an HBcAb- recipient, with no documented immunisation before transplantation in 1 case. In both cases, the recipients received HBIG daily for 5–7 days immediately before and after transplantation; entecavir administration was started immediately after surgery. After 12 months, the HBsAg- recipient was positive for HBcAb and HBsAb, but negative for HBsAg and HBV DNA. In the HBcAb- patient, de novo HBV infection was not detected, but the length of the follow-up was not mentioned.
      • Eichenberger E.M.
      • Vece G.R.
      • Kakoullis S.
      • Steinbrink J.M.
      • Reynolds J.M.
      • Wolfe C.R.
      Viremic hepatitis B donors: a case of why it's time to further expand the donor pool for thoracic transplant.
      ,
      • Belga S.
      • Kabbani D.
      • Doucette K.
      Hepatitis B surface antigen-positive donor to negative recipient lung transplantation.
      However, the use of HBsAg+ grafts during lung and heart transplantation is currently restricted and generally limited to emergency cases. Given the paucity of data on the transplantation of thoracic organs from HBsAg- donors, no specific suggestions can be made.

      HBcAb+ donors

      Ideally, HBcAb+ organs should be transplanted into HBcAb+ and/or HBsAg+ recipients, but this strategy would yield a small donor pool. Assuming the appropriate management of recipients, the risk of HBV transmission from HBcAb+/HBsAg- grafts to HBV-naïve patients is low/moderate in KT and even lower in thoracic organ transplantations.
      • Huprikar S.
      • Danziger-Isakov L.
      • Ahn J.
      • Naugler S.
      • Blumberg E.
      • Avery R.K.
      • et al.
      Solid organ transplantation from hepatitis B virus-positive donors: consensus guidelines for recipient management.
      ,
      • Te H.
      • Doucette K.
      Viral hepatitis: guidelines by the American society of transplantation infectious disease community of practice.
      ,
      • Fabrizio F.
      • Bunnapradist S.
      • Martin P.
      Transplanting kidneys from donors with prior hepatitis B infection: one response to the organ shortage.
      Immunisation against HBV infection and HBsAb titre levels before transplantation are key ways to minimise the risk of HBV transmission from HBcAb+ grafts.
      • Huprikar S.
      • Danziger-Isakov L.
      • Ahn J.
      • Naugler S.
      • Blumberg E.
      • Avery R.K.
      • et al.
      Solid organ transplantation from hepatitis B virus-positive donors: consensus guidelines for recipient management.
      The most robust evidence on the risk of transmission, and related outcomes with HBcAb- recipients is in KT. However, studies on KT are generally characterised by a lack of information on the pre-transplant HBV serological status of the recipients and considerable heterogeneity in recipient management. In a systematic review of 9 studies comprising 1,385 patients who received KT from HBsAg+/HBcAb+ donors, HBV serological markers developed in only 45 patients (3.24%), and 4 patients turned HBsAg+ (rate of seroconversion was 0.28%) with no evidence of symptomatic hepatitis. Although they did not investigate the impact of HBsAb status or the use of antiviral prophylaxis in recipients, they reported similar transplant outcomes in patients with HBsAg or HBcAb seroconversion as for HBsAb+ recipients.
      • Mahboobi N.
      • Tabatabaei S.V.
      • Blum H.E.
      • Alavian S.M.
      Renal grafts from anti-hepatitis B core-positive donors: a quantitative review of the literature.
      The largest study that evaluated the status of HBsAg- kidney recipients from the United Network for Organ Sharing database between 1994 and 1999 – reported a similar rate of HBsAg acquisition in 763 recipients of HBcAb+ grafts compared to 24,661 recipients of HBcAb- organs (0.001 vs. 0.003, p = 0.23). In that study, no difference in survival was found between the recipients of HBcAb+ and HBcAb- organs after conducting a multivariable-adjusted analysis.
      • Fong T.L.
      • Bunnapradist S.
      • Jordan S.C.
      • Cho Y.W.
      Impact of hepatitis B core antibody status on outcomes of cadaveric renal transplantation: analysis of United network of organ sharing database between 1994 and 1999.
      In most centres, kidneys are transplanted from HBcAb+ donors to candidates with documented immunity to HBV, i.e. with HBsAb >10 IU/L through vaccination or previous exposure. This titre confers immunity against de novo HBV infection. In 3 recent studies, no cases of HBsAg seroconversion were found in 236 HBcAb+ kidney recipients with protective HBV immunity (HBsAb >10 IU/L) during transplantation.
      • Abrão J.M.
      • Carvalho M.F.
      • Garcia P.D.
      • Contti M.M.
      • Andrade L.G.
      Safety of kidney transplantation using anti-HBc-positive donors.
      • De Feo T.M.
      • Grossi P.
      • Poli F.
      • Mozzi F.
      • Messa P.
      • Minetti E.
      • et al.
      Kidney transplantation from anti-HBc+ donors: results from a retrospective Italian study.
      • Madayag R.M.
      • Johnson L.B.
      • Bartlett S.T.
      • Schweitzer E.J.
      • Constantine N.T.
      • McCarter R.J.
      • et al.
      Use of renal allografts from donors positive for hepatitis B core antibody confers minimal risk for subsequent development of clinical hepatitis B virus disease.
      Therefore, vaccination can prevent the risk of transmission in KT. However, many patients with renal failure have an impaired immune response, resulting in a suboptimal response to standard recombinant vaccines.
      • Pesanti E.L.
      Immunologic defects and vaccination in patients with chronic renal failure.
      Thus, antiviral prophylaxis might still play a role in non-immune recipients of HBcAb+ grafts, as suggested by the guidelines.
      • Huprikar S.
      • Danziger-Isakov L.
      • Ahn J.
      • Naugler S.
      • Blumberg E.
      • Avery R.K.
      • et al.
      Solid organ transplantation from hepatitis B virus-positive donors: consensus guidelines for recipient management.
      The optimal duration of antiviral prophylaxis is unknown, but the risk is generally restricted to the early post-transplantation period (6–12 months).
      The administration of HBIG is an alternative to antiviral prophylaxis. One study reported no cases of HBsAg seroconversion following the administration of a single dose of HBIG in 18 KT recipients with HBcAb+ grafts.
      • Veroux M.
      • Corona D.
      • Ekser B.
      • Giaquinta A.
      • Tallarita T.
      • De Martino C.
      • et al.
      Kidney transplantation from hepatitis B virus core antibody-positive donors: prophylaxis with hepatitis B immunoglobulin.
      However, further studies are needed to confirm that the use of HBIG is a safe and effective alternative to antiviral prophylaxis in non-immune recipients of HBcAb+ grafts.
      Studies on HBV in thoracic transplantation are limited. An analysis of a large cohort of lung and heart-lung transplants was performed to compare the results of 13,233 recipients of organs from HBcAb- donors with 333 recipients of organs from HBcAb+ donors. Although 1-year mortality was higher in the latter group in an unadjusted analysis, there was no significant difference in 5-year mortality, and HBcAb status did not affect mortality 1 and 5 years after transplantation.
      • Dhillon G.S.
      • Levitt J.
      • Mallidi H.
      • Valentine V.G.
      • Gupta M.R.
      • Sista R.
      • et al.
      Impact of hepatitis B core antibody positive donors in lung and heart-lung transplantation: an analysis of the United Network for Organ Sharing Database.
      In 2 other studies, no case of de novo HBV infection was reported among 36 recipients of HBcAb+ lungs who were vaccinated against HBV before transplantation or received antiviral prophylaxis after transplantation.
      • Hartwig M.G.
      • Patel V.
      • Palmer S.M.
      • Cantu E.
      • Appel J.Z.
      • Messier R.H.
      • et al.
      Hepatitis B core antibody positive donors as a safe and effective therapeutic option to increase available organs for lung transplantation.
      ,
      • Shitrit A.B.
      • Kramer M.R.
      • Bakal I.
      • Morali G.
      • Ben Ari Z.
      • Shitrit D.
      Lamivudine prophylaxis for hepatitis B virus infection after lung transplantation.
      Early studies, including those on patients who underwent heart transplantation from HBcAb+ donors without prophylaxis, did not report any incidence of HBV transmission in cohorts of more than 80 patients; however, some of the patients were vaccinated before transplantation.
      • Horan J.L.
      • Stout J.E.
      • Alexander B.D.
      Hepatitis B core antibody-positive donors in cardiac transplantation: a single-center experience.
      • Kuczaj A.
      • Warwas S.
      • Przybyłowski P.
      • Zembala M.
      Heart retransplantation from an hepatitis B core antibody (Anti-HBcore)-positive donor: a case report.
      • Radzi Y.
      • Shezad M.F.
      • Danziger-Isakov L.
      • Morales D.L.S.
      • Zafar F.
      Using hepatitis C and B virus-infected donor organs for pediatric heart transplantation.
      • Pinney S.P.
      • Cheema F.H.
      • Hammond K.
      • Chen J.M.
      • Edwards N.M.
      • Mancini D.
      Acceptable recipient outcomes with the use of hearts from donors with hepatitis-B core antibodies.
      The indications for prophylaxis in recipients of non-liver HBV+ solid organs are summarised in Table 2.
      Preliminary data suggested that antiviral prophylaxis should also be provided to the hematopoietic stem cell transplant (HSCT) recipients if they receive transplants from HBcAb+ve donors, regardless of the HBcAb status of the recipient.
      Table 2Indications for the management of recipients of HBV+ grafts in non-liver solid organ transplantation.
      Donor statusRecipient status
      HBsAg-/HBsAb-HBsAg+HBsAg-/HBsAb+/HBcAb±
      HBsAg+Not recommendedHigh-barrier NA prophylaxisCan be used without high-barrier NA prophylaxis, only if careful monitoring and antiviral therapy at the earliest sign of HBV recurrence
      HBsAg-/HBcAb+High-barrier NAHigh-barrier NAprophylaxisCan be used without high-barrier NA prophylaxis with careful monitoring and antiviral therapy at the earliest sign of HBV recurrence
      NA, nucleos(t)ide analogue.

      Allogeneic haematopoietic stem cell transplantation

      The treatment of haematological malignancies has changed substantially in recent decades, and haematopoietic stem cell transplantation (HSCT) has become very common. HBV can be transmitted by HBsAg+ grafts to HBV-naïve recipients or those who have lost protective immunity. Such transmission is generally fatal because of the primary disease of the patients and the immunodeficiency associated with pre-transplant conditioning therapy and immunosuppressive drugs used after transplantation to prevent the onset of graft-vs.-host disease. A high HBV viral load in the donor and the absence of HBsAb in the recipients are important risk factors associated with the development of HBV-related hepatitis post-HSCT.
      • Locasciulli A.
      • Vossen J.
      • Bacigalupo A.
      • Hows J.
      • VanLint M.T.
      • Gluckman E.
      • et al.
      Allogeneic bone marrow transplantation (BMT) for acquired severe aplastic anaemia (SAA) in children.
      ,
      • Lau G.K.
      • Lie A.K.
      • Kwong Y.L.
      • Lee C.K.
      • Hou J.
      • Lau Y.L.
      • et al.
      A case-controlled study on the use of HBsAg-positive donors for allogeneic hematopoietic cell transplantation.
      In HBV endemic areas, excluding HBsAg+ donors significantly limits the use of allogeneic HSCT, especially when an HBsAg+ donor might be the only option. A 3-level approach was proposed to manage HBsAg+ donor transplantation at the Fifth European Conference on Infections in Leukaemia (ECIL-5), which established the possibility of using organs from such a donor pool provided that HBsAg- recipients were vaccinated before transplantation and that both the donor and the recipient underwent antiviral therapy to reduce HBV DNA before HSCT in the donors and suppress HBV DNA after HSCT in the recipients.
      • Mallet V.
      • van Bömmel F.
      • Doerig C.
      • Pischke S.
      • Hermine O.
      • Locasciulli A.
      • et al.
      Management of viral hepatitis in patients with haematological malignancy and in patients undergoing haemopoietic stem cell transplantation: recommendations of the 5th European Conference on Infections in Leukaemia (ECIL-5).
      Following these recommendations, Hui et al. showed that HBV-related hepatitis occurred in 2 recipients (6.9%; n = 29) who received stem cells from HBsAg+ donors, whereas, in the control group that underwent HSCT without antiviral prophylaxis, the incidence was 48% (12 of 25 recipients).
      • Hui C.K.
      • Lie A.
      • Au W.Y.
      • Ma S.Y.
      • Leung Y.H.
      • Zhang H.Y.
      • et al.
      Effectiveness of prophylactic Anti-HBV therapy in allogeneic hematopoietic stem cell transplantation with HBsAg positive donors.
      Another study performed in an Asian cohort, showed a similar 5-year cumulative incidence of HBV-related hepatitis among patients who received stem cells from HBsAg+ donors and matched control recipients who received stem cells from HBsAg- donors (8.5% [95% CI −0.9% to 17.9%] vs. 7.9% [95% CI −0.9% to 16.7%]; p = 0.939). The HBsAg+ donors received antiviral treatment, and HBIG was administered to the HBsAg- recipients.
      • Wu Y.
      • Shi J.
      • Tan Y.
      • Zhao Y.
      • Yu J.
      • Lai X.
      • et al.
      A novel strategy for the prevention of hepatitis B virus-related hepatitis following allogeneic hematopoietic stem cell transplantation from hepatitis B surface antigen-positive donors.
      Moreover, Shen et al. demonstrated that HBIG, combined with long-term antiviral prophylaxis, effectively prevented de novo HBV infection in 67 HBsAg- patients who received grafts from double-positive HBsAg and HBcAb donors. None of the HBsAg- patients developed HBV infection after HSCT.
      • Shen Y.
      • Qi J.
      • Wang Y.
      • Chen J.
      • Fan Y.
      • Wu D.
      • et al.
      Hepatitis B immunoglobulin (HBIG) combined with long-term entecavir prophylaxis for hepatitis B virus infection in allogeneic hematopoietic stem cell transplantation with hepatitis B surface antigen-positive donors.
      Therefore, through appropriate management of donors and recipients, the risk of HBV-related hepatitis following HSCT from HBsAg+ stem cells can be reduced. This might enable patients in need to receive allo-HSCT in HBV-endemic areas. However, considering the paucity of data, clinical trials are needed to establish the most effective management methods when accepting stem cells from HBsAg+ donors.
      Information on the effects of HSCT from HBcAb+ donors to HBV- recipients is lacking. A study reported the absence of HBV transmission in a cohort of HBV-naïve children undergoing prophylaxis through vaccination and/or HBIG administration when receiving HSCT from HBcAb+ donors.
      • Frange P.
      • Leruez-Ville M.
      • Neven B.
      • Mascard L.
      • Moshous D.
      • Touzot F.
      • et al.
      Safety of hematopoietic stem cell transplantation from hepatitis B core antibodies-positive donors with low/undetectable viremia in HBV-naïve children.
      Another study showed that HBV- recipients receiving stem cells from HBcAb+ donors had a 10.5% higher risk of developing HBV-related hepatitis after transplantation compared to the recipients receiving transplants from HBV- donors.
      • Hui C.K.
      • Sun J.
      • Au W.Y.
      • Lie A.K.
      • Yueng Y.H.
      • Zhang H.Y.
      • et al.
      Occult hepatitis B virus infection in hematopoietic stem cell donors in a hepatitis B virus endemic area.
      In a more recent study from Italy, 11 out of 15 HBV- patients undergoing allo-HSCT with stem cells from HBcAb+/HBsAg- donors were treated with lamivudine. One of the remaining 4 patients who did not receive lamivudine experienced HBV reactivation.
      • Cerva C.
      • Colagrossi L.
      • Maffongelli G.
      • Salpini R.
      • Di Carlo D.
      • Malagnino V.
      • et al.
      Persistent risk of HBV reactivation despite extensive lamivudine prophylaxis in haematopoietic stem cell transplant recipients who are anti-HBc-positive or HBV-negative recipients with an anti-HBc-positive donor.
      Therefore, the transmission of HBV infection from HBcAb+/HBsAg- donors is possible. The ECIL-5 had suggested that antiviral prophylaxis should also be provided to recipients if they receive transplants from this pool of donors, regardless of the HBcAb status of the recipient; however, further studies are needed regarding this. The current indications from a few published studies are summarised in Table 3.
      Table 3Indications for the management of recipients of HBV+ grafts in hematopoietic stem cell transplantation.
      Donor statusRecipient status
      HBsAg-/HBsAb-HBsAg+HBsAg-/HBsAb+/ HBcAb±
      HBsAg+Not recommended (In urgent cases: pre transplant vaccination+ life-long high-barrier NA +HBIG at transplant in recipients and pre transplant high-barrier NA in living donor)High-barrier NA prophylaxisCan be used without high-barrier NA prophylaxis, only if careful monitoring and antiviral therapy at the earliest sign of HBV recurrence
      HBsAg-/HBcAb+Pre-transplant vaccination+ high-barrier NA+ HBIG at transplantHigh-barrier NA prophylaxisCan be used without high-barrier NA prophylaxis if HBcAb-. NA prophylaxis if HBcAb+
      HBIG, hepatitis B immunoglobulin; NA, nucleos(t)ide analogue.

      HIV donors in transplantation

      A new source of donors for the HIV+ recipient

      Combination antiretroviral therapy (cART) has increased the survival of HIV+ individuals and changed the status of AIDS from a fatal disease to a chronic condition. The transplant community has been relatively slow in recognising this change,
      • Halpern S.D.
      • Asch D.A.
      • Shaked A.
      • Stock P.G.
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      This has significantly increased the number of HIV+ candidates on the waiting lists, which highlights the importance of new donor sources for HIV+ individuals waiting for solid organ transplants, as well as the need to expand the donor pool to new sources of HIV-infected donor organs.

      The increasing demand for solid organ transplantation in HIV+ recipients

      As the status of HIV has changed from a fatal disease to a chronic condition, the number of people with well-controlled HIV who are candidates for solid organ transplants has increased considerably.
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      Coinfection with hepatitis B is associated with membranous nephropathy, and IgA nephropathy might be directly associated with an HIV infection.
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      Progression to end-stage renal failure is further exacerbated by nephrotoxicity associated with cART and prophylaxis. Unfortunately, waiting times for KT are long, and dialysis is associated with poorer allograft and patient survival.
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      Lengthy waiting times might be even more problematic for HIV-infected recipients. Although more recent studies have shown an improvement in the survival duration for HIV-infected patients on dialysis,
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      A national study of outcomes among HIV-infected kidney transplant recipients.
      earlier transplantation from HIV-infected donors can greatly benefit HIV+ patients. In the US, the HIV Organ Policy Equity Act (HOPE), which was made a part of federal law in 2013, has enabled such early transplantations.
      Health Resources and Services Administration (HRSA) DpoHaHSH
      Organ procurement and transplantation: implementation of the HIV Organ Policy Equity Act. Final rule.
      After the status of an HIV infection changed to a chronic condition, liver diseases became a leading cause of death among HIV+ patients with non-alcoholic fatty liver disease, co-infected with HBV and/or HCV.
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      Unfortunately, HIV-infected candidates with ESLD, who are on the waiting list for transplantation, are often at a high risk of death.
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      ,
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      Pretransplant survival is shorter in HIV-positive than HIV-negative subjects with end-stage liver disease.
      With an increase in the number of all potential recipients on LT waiting lists, poor survival is even more problematic since the MELD scores necessary for the allocation of a liver are high. By the time the HIV+ candidate achieves the MELD score required for allocation of the liver of a deceased donor, clinical deterioration might be so severe that they might not meet the inclusion/exclusion criteria of most transplant centres based on CD4 counts and HIV viral load. By providing access to HIV+ donors, the HOPE Act has enabled transplantation from deceased donors at a lower MELD score, thus increasing the likelihood of better post-transplant outcomes.
      Transplantation of HIV+ donor organs is increasing since they are as efficacious and safe as their HIV- counterparts.

      The early experience with HIV-infected deceased donors

      The transplantation of organs from HIV+ deceased donors (D+) was pioneered by Dr Elmi Muller in Cape Town, South Africa, in 2008
      • Muller E.
      • Kahn D.
      • Mendelson M.
      Renal transplantation between HIV-positive donors and recipients.
      ,
      • Muller E.
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      • Mendelson M.
      • Kahn D.
      Renal transplantation between HIV-positive donors and recipients justified.
      in response to the lack of funding for haemodialysis in HIV+ recipients (R+) in the public sector. Based on the early success of KT of HIV- donor organs into HIV+ individuals,
      • Stock P.G.
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      Outcomes of kidney transplantation in HIV-infected recipients.
      Dr Muller recognised that organs from HIV+ donors, who were on life support and met the criteria for brain death, could potentially be used for transplantation. South Africa has an extremely high incidence of HIV infection, with a prevalence of 19% and over 7 million HIV+ people. Since the HIV+ recipients were largely in the public sector, transplantation was the only survival option; HIV-infected donors permitted early access to donor organs due to the high prevalence of HIV. In a pilot study, the first 4 HIV D+/R+ deceased donor transplants were associated with excellent outcomes, and no evidence of superinfection with more resistant strains of HIV or opportunistic infections transmitted by the D(+) organ was found following kidney transplantation.
      • Muller E.
      • Kahn D.
      • Mendelson M.
      Renal transplantation between HIV-positive donors and recipients.
      ,
      • Muller E.
      • Barday Z.
      • Mendelson M.
      • Kahn D.
      Renal transplantation between HIV-positive donors and recipients justified.
      In follow-up studies, long-term detection of the donor-strain virus was not observed in 25 HIV D(+)/R(+) recipients in the South African study, although the donor-strain virus was sporadically detected in 32% of recipients.
      • Selhorst P.
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      • Manning K.
      • Botha F.C.J.
      • Labuschagne J.P.L.
      • Anthony C.
      • et al.
      Longer-term outcomes of HIV-positive-to-HIV-positive renal transplantation.
      The safety and efficacy of kidney transplantation in South Africa prompted US centres to change federal laws, which had prohibited the utilisation of tissue or organs from HIV-infected recipients. Based on the 500–600 viable HIV-infected recipients in the US annually,
      • Boyarsky B.J.
      • Hall E.C.
      • Singer A.L.
      • Montgomery R.A.
      • Gebo K.A.
      • Segev D.L.
      Estimating the potential pool of HIV-infected deceased organ donors in the United States.
      the team from Johns Hopkins facilitated the rapid passage of the HOPE Act to permit the transplantation of organs procured from HIV-infected donors.
      • Boyarsky B.J.
      • Segev D.L.
      From bench to bill: how a transplant nuance became 1 of only 57 laws passed in 2013.
      This increased the donor pool substantially, which was necessary to meet the demand for organs and reduce the disproportionate mortality observed among HIV+ individuals on the transplant waiting lists. A report on HIV+ deceased donor organs in the US described 92 HIV+ donors between March 2016 and March 2020, with 177 organs donated (131 kidneys and 46 livers).
      • Werbel W.A.
      • Brown D.M.
      • Kusemiju O.T.
      • Doby B.L.
      • Seaman S.M.
      • Redd A.D.
      • et al.
      National landscape of HIV+ deceased organ donors in the United States.
      There were no restrictions on donor HIV viral load or CD4 counts, although the presence of an opportunistic infection suggested a contraindication. Most of the HIV+ donors (90%) were on cART. Major mutations for drug resistance were present in 42% of donors. Importantly, integrase strand transfer inhibitors were present in only 4% of donors, which was fortunate since antiretroviral therapy in the HIV+ recipients is most frequently based on the integrase inhibitor to minimise the inter-drug interactions between antiretroviral agents and immunosuppressive agents.
      The first NIH multicentre clinical trials (D+/R+) were initiated for KT recipients in 2018 (NCT03500315) and LT recipients in 2019 (NCT03734393) and included 160 HIV+ KT recipients and 80 HIV+ LT recipients. Although results on safety and efficacy are pending, the OPTN registry reported the trends during the first 2 years after the HOPE Act was passed. The 1-year patient and graft survival of 71 (D+/R+) KT and 31 (D+/R+) LT recipients were comparable to the outcomes of D-/R+ kidney and liver transplant recipients.
      • Wilk A.R.
      • Hunter R.A.
      • McBride M.A.
      • Klassen D.K.
      National landscape of HIV+ to HIV+ kidney and liver transplantation in the United States.
      The chance of superinfection from the donor HIV strain, donor-derived infections, and HIV-associated disease in the donor liver or kidney remains a concern, but the safety and efficacy data from the US pilot trials performed with HIV+ donors for liver
      • Durand C.M.
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      • Brown D.
      • Ostrander D.
      • Yu S.
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      and kidney
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      transplantation showed promising results. Importantly, both pilot studies showed that there was no loss of viral control following transplantation with an HIV+ donor. The HIV+ KT recipients showed excellent outcomes after receiving transplants from HIV+ and HIV- donors, although there was a higher incidence of rejection in the HIV+ cohort. There were also no statistical differences in the 1-year outcome following LT from either HIV+ or HIV- donors, but the incidences of opportunistic infections, infectious hospitalisations, and cancers were higher in the cohort transplanted from HIV+ donors. More definitive data should be available from the HOPE trials conducted by the NIH in the future. The results of those trials might help to formulate informed consent. Outside South Africa and the US, there have been scattered reports of excellent early outcomes following D+/R+ deceased donor kidney and liver transplantation.
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      Liver and kidney transplantations from HIV-infected living donors can greatly minimise the time spent on dialysis in ESRD and maximise outcomes. Similarly, HIV+ donors provide the opportunity for LT in recipients with lower MELD scores before a significant deterioration in patient health, which could terminate transplant candidacy. Unfortunately, HIV+ candidates have a 47% lower chance of receiving a living donation KT compared to non-affected candidates on the waiting list.
      • Locke J.E.
      • Mehta S.
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      • Reed R.D.
      • et al.
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      Since many HIV-infected potential recipients have HIV-infected partners, the opportunity for transplantations from living donors can increase if people with well-controlled HIV serve as donors. Importantly, the HOPE Act also changed federal laws to permit living HIV+ donors to donate a kidney or a liver lobe. Although a prospective clinical trial with HIV+ living kidney donors was initiated in 2018 (NCT03408106), there are concerns that HIV-infected donors might have a higher risk of ESRD after donation due to HIV-associated diseases in the remaining kidney. Muzaale et al.
      • Muzaale A.D.
      • Althoff K.N.
      • Sperati C.J.
      • Abraham A.G.
      • Kucirka L.M.
      • Massie A.B.
      • et al.
      Risk of end-stage renal disease in HIV-positive potential live kidney donors.
      assessed the cumulative incidence of ESRD in people with well-controlled HIV and no diabetes, hypertension, or hepatitis C and compared it to matched HIV- people. Although there was a slightly higher risk of ESRD in people with HIV, it was comparable to other risk factors that were not contraindications to donation, such as tobacco use. In the US, the first 2 living donor operations between HIV- kidney donors and recipients were performed at Johns Hopkins University in 2019, with excellent early outcomes., The first living donor liver operation between an HIV+ donor (mother) and her 11-month-old HIV- child with ESLD, secondary to biliary atresia, was conducted in South Africa in 2017. The early outcomes, in this case, were favourable for the donor and the recipient, and HIV was undetectable in the child – who received cART – 1 year after transplantation.
      • Botha J.
      • Conradie F.
      • Etheredge H.
      • Fabian J.
      • Duncan’s M.
      • Haeri Mazanderani A.
      • et al.
      Living donor liver transplant from an HIV-positive mother to her HIV-negative child: opening up new therapeutic options.
      In conclusion, the inclusion of HIV+ deceased donors was initiated in the US by the HOPE Act, which facilitated earlier transplantation of organs to the increasing number of HIV+ people suffering from ESRD and ESLD. Such candidates face higher waitlist mortality and can greatly benefit from earlier transplantation made possible by increasing the donor pool to include HIV+ donors (Fig. 3). Long-term results from the initial trials in South Africa and the US are pending, but the early outcomes of HIV+ donations demonstrated that the transplantations were safe and efficacious, comparable to the transplantations of their HIV- counterparts. Although transplantations from HIV+ living donors are permitted in the US, the incidences of such transplantations are relatively low, perhaps due to the greater availability of and good early outcomes observed with HIV+ deceased donors.
      Figure thumbnail gr3
      Fig. 3The proposed algorithm for management of the HIV-positive solid organ transplantation.
      cART, combination antiretroviral therapy.

      Ethical point of view

      Regarding the ethical point of view, the 4 basic principles that we should consider when assessing a procedure include autonomy, beneficence, non-maleficence, and justice.
      • Anwar N.
      • Sherman K.E.
      Transplanting organs from hepatitis B positive donors: is it safe? Is it ethical?.
      By obtaining the patient’s informed consent (autonomy),
      OPTN
      Organ Procurement and Transplant Network policies.
      removing the cause of morbidity, decreasing the mortality, increasing the patient’s quality of life (beneficence), using an effective antiviral therapy after transplantation (non-maleficence), and increasing the size of the organ pool to reduce the suffering of patients with end-stage organ dysfunction (justice), all the above principles are met. We recommend that full informed consent, including detailed information on the benefits and potential harms, should be discussed with the transplant candidate and their family. They should be informed about the potential risk of transmission of infectious diseases. This consent should be obtained during waiting list registration.

      Conclusions

      The disparity between the availability of organs and the need for them can be addressed by broadening the criteria for the donation of organs and expanding the size of the donor pool. Owing to the development of reliable antiviral therapies, problems of organ shortage can be overcome by using grafts affected by HCV, HBV, or HIV. In this review, we summarised all the data published to date on the use of these organs, except those positive for HCV, as mentioned in the introduction. Transplantations from HBV-+ donors are regularly performed with the appropriate prophylaxis schemes prescribed by expert hepatologists from the transplant centres. However, the donation of HIV- organs is uncommon, although the safety and efficacy of such transplantations are comparable to those from HIV- donors. A multidisciplinary approach with trained hepatologists and infectious disease specialists in the local transplant team is essential to determine the optimal allocation of infected organs, prescribe the best prophylactic treatment after transplantation, assess patient’s adherence, and treat recurrent/de novo infection, if it occurs. This resembles a tailored approach that can be implemented as part of modern personalised transplantation strategies.

      Abbreviations

      cART, combination antiretroviral therapy; cccDNA, covalently closed circular DNA; ESLD, end stage liver disease; ESRD, end-stage renal disease; HBcAb, antibodies against the HBV core antigen; HBIG, hepatitis B immune globulin; HBsAb, antibodies against HBsAg; HBsAg, HBV surface antigen; HOPE, HIV Organ Policy Equity; HSCT, haematopoietic stem cell transplantation; KT, kidney transplant; LT, liver transplantation; MELD, model for end-stage liver disease; NA, nucleos(t)ide analogues.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors' contributions

      FPR, MV, PB and AG were involved in the concept, design, and writing the manuscript; AF, NP, and PS were involved in writing the manuscript. All authors were involved in the revision and approved the final draft of the manuscript.

      Conflict of interest

      The authors of this manuscript have no conflicts of interest to disclose.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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