Assessment of organ transplants from donors with markers of hepatitis B.

Organ transplantation (TX) is currently a therapeutic alternative in the management of end-stage or lethal diseases and, in some cases, for improving the quality of life and reducing the complications of chronic conditions. The scarcity of organ grafts or donors due to the limited number of deceased donors or to a lack of compatible living donors is one of the main limitations for the execution of organ TX. In Brazil, there is a great disparity between the number of patients on waiting lists and TX procedures, especially for liver and kidney TX. As a result of this inequality, grafts from donors who are considered marginal or not ideal have been used, including those with higher risk of failure following TX or those with potentially transmissible infections, involving donors with positive serologic markers for the hepatitis B virus (HBV).

Donors who are positive for HBV markers have been routinely used in some TX centers. Four aspects should be considered for the assessment of the risk-benefit ratio of this procedure: 1. donor serologic profile, 2. recipient serologic profile, 3. TX variety and 4. the use of preventive therapy with human-specific HBV immunoglobulin and/or antiviral drugs. To establish recommendations, our group held discussions based on the data available in the medical literature and on the accumulated experience of the TX units at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. The definitions of serologic profiles for donors and recipients are described in Tables 1 and 2, respectively. The following transplants have been evaluated: liver, kidney, heart, lung, and hematopoietic stem cell transplants (HSCT). The IDSA (Infectious Diseases Society of America) rating system was used to assess the quality of evidence for graft acceptance and to identify the appropriate preventive strategy.

Table 1

Definitions of HBV serologic profiles – Donors.

Table 2

Definitions of HBV serologic profiles – Recipients.

HBc-Ab*)	HBs-Ab**)	HBsAg***)	Definition
-	-	-	Naïve
+	-	+	Positive HBsAg
-	+	-	Isolated HBs-Ab/Vaccinated
+	-	-	Isolated HBc-Ab
+	+	-	HBc-Ab and HBs-Ab

anti-core hepatitis B antibody,

anti-hepatitis B surface antigen antibody,

hepatitis B surface antigen.

1. Liver TX

HBsAg-positive donor: few reports are available, under particular circumstances, and there is a high risk of “de novo” HBV infection.

HBc-Ab-positive donor:

HBsAg-positive recipient: regardless of the donor's serologic profile, this recipient must be administered combined prophylaxis with HBIG and an antiviral drug. The risk of viral reactivation does not seem to be increased by the involvement of an HBc-Ab-positive donor.

Recipients who are positive for HBc-Ab and HBs-Ab: there are no reports of “de novo” HBV infection, with or without prophylaxis.

Recipients with isolated HBc-Ab or a history of vaccination: the risk of “de novo” HBV is reduced in case series that described lamivudine and/or HBIG prophylaxis.

Naïve recipient: group at highest risk; case series that described lamivudine and HBIG prophylaxis have demonstrated a reduction in risk.

Kidney TX

The largest case series of donors with positive serologic markers for HBV were published in kidney TX. However, some studies describe only the post-TX clinical course and fail to assess HBV serology.

HBsAg-positive donor: among 48 donors, “de novo” HBV infection has been detected in three recipients with variable pre-TX serologic profiles, while liver enzyme elevation has been detected in nine recipients.

HBc-Ab-positive donor:

HBsAg-positive recipient: when lamivudine is used as preventive therapy, the clinical evolution is similar to that of recipients whose donors have negative HBV serology.

Recipients with isolated HBc-Ab: without any prophylaxis, the seroconversion of HBsAg has been observed in 0.5% of recipients after TX. No reports have described seroconversion under lamivudine prophylaxis.

Vaccinated or Naïve recipient: after TX, without any prophylaxis, seroconversion of HBc-Ab occurs in 2% of cases, and seroconversion of HBsAg occurs in less than 0.5% - without any impact on the clinical course. No reports have described seroconversion under lamivudine prophylaxis.

Heart TX

There are two case series on heart TX that report lamivudine prophylaxis in some recipients. Only one case of “de novo” HBV infection is reported in a naïve recipient with an HBsAg-positive donor.

Lung TX

In two small case series of HBc-Ab-positive donors, no cases of recipient post-TX seroconversion were described. Among the two case series, one involved lamivudine prophylaxis.

Hematopoietic Stem Cell Transplant

In HSCT, the most relevant consideration is the risk of reverse seroconversion (loss of HBs-Ab after TX).

HBsAg-positive donor: in a study of HBsAg-negative recipients with a historical control group, the risk of “de novo” HBV was significantly reduced with lamivudine prophylaxis.

HBc-Ab-positive donor: when the bone marrow donor is naturally immunized (HBc-Ab and HBs-Ab positive), there is an unmistakable reduction in the risk of reverse seroconversion.

Assessment of organ transplants from donors with hepatitis B-positive markers

Recommendations:

General recommendations

Potential TX recipients should receive HBV vaccination before TX, if possible (AII).

HSCT donors should receive HBV vaccination before TX, if possible (BII).

HSCT recipients who are negative for HBsAg must be directed to HBV vaccination, starting six months after TX (BIII).

Liver TX recipients who are HBsAg positive must be prescribed an antiviral drug and HBIG as preventive therapy, regardless of the donor's serologic profile, due to the risk of post-TX recurrence (AII).

TX recipients (except for those undergoing liver TX) who are HBsAg positive must be prescribed an antiviral drug, due to the risk of viral replication following TX (AII).

HSCT donors who are HBsAg positive with active viral replication (positive polymerase chain reaction) must start on antiviral treatment before TX (BIII).

Specific recommendations:

Liver TX (B1).

Kidney TX (B2).

Heart and Lung TX (B3).

Hematopoietic Stem Cell Transplantation TX (B4).

ACKNOWLEDGMENTS

We thank the Clinical Directors from Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (Prof. José Otavio Costa Auler Junior, Prof. Tarcísio Eloi Pessoa de Barros Filho and Prof. Eloísa Bonfá) for all their support.

Tabela 1

Definições para perfis sorológicos para o vírus da hepatite B – Doadores.

Tabela 2

Definições para perfis sorológicos para o vírus da hepatite B – Receptor.

Anti-HBc	Anti-HBs	AgHBs	Definição
-	-	-	Naïve
+	-	+	AgHBs positivo
-	+	-	Anti-HBs isolado/Vacinado
+	-	-	Anti-HBc isolado
+	+	-	Anti-HBc e Anti-HBs

Anticorpo anti-core vírus hepatite B, ** anticorpo anti-antígeno de superfície do vírus da hepatite B, ***Antígeno de superfície do vírus da hepatite B.

B1

Transplante de Fígado: Recomendações Específicas

Doador	Receptor
	AgHBs +	Anti-HBc+ Anti-HBs+	Anti-HBc- Anti-HBs+	Anti-HBc+ isolado	Naive
AgHBs+	Não (DII)	Não (DII)	Não (DII)	Não (DII)	Não (EI)
Anti-HBc+	Sim (BII)	Sim (BII)	Sim (BIII)	Sim (BIII)	Não (DII)
Profilaxia	LAM + HBIG*) (AII)	LAM (BIII)**	LAM (BIII)**	LAM (BIII)**	_

HBIG por 1 ano, lamivudina indefinidamente; **Por pelo menos 1 ano.

Obs.: outro antiviral pode ser utilizado, no lugar da lamivudina.

B2

Transplante de Rim: Recomendações Específicas

Doador	Receptor
	AgHBs +	Anti-HBc+ Anti-HBs+	Anti-HBc- Anti-HBs+	Anti-HBc+ isolado	Naive
AgHBs+	Situações excepc.*) (CIII)	Situações excepc.*) (CIII)	Situações excepc.*) (CIII)	Situações excepc.*) (CIII)	Não (DIII)
Profilaxia	LAM (AII)**	LAM (BIII)***	LAM (BIII)***	LAM (BIII)***	-
Anti-HBc+	Sim (BII)	Sim (BII)	Sim (BII)	Sim (BII)	Não (DIII)
Profilaxia	LAM (AII)**	LAM (CIII)****	LAM (CIII)****	LAM (CIII)****	_

Situações excepcionais, definidas pelo grupo de transplante; **Indefinidamente; ***Por pelo menos 1 ano; ****Uso opcional.

Obs.: outro antiviral pode ser utilizado, no lugar da lamivudina.

B3

Transplantes de Coração e de Pulmão: Recomendações Específicas

Doador	Receptor
	AgHBs +	Anti-HBc+Anti-HBs+	Anti-HBc-Anti-HBs+	Anti-HBc+ isolado	Naive
AgHBs+	Situações excepc.*) (CIII)	Situações excepc.*) (CIII)	Situações excepc.*) (CIII)	Situações excepc.*) (CIII)	Não (DIII)
Profilaxia	LAM (AII)**	LAM (BIII)***	LAM (BIII)***	LAM (BIII)***	-
Anti-HBc+	Sim (BII)	Sim (BII)	Sim (BII)	Sim (BII)	Não (DIII)
Profilaxia	LAM (AII)**	LAM (CIII)****	LAM (CIII)****	LAM (CIII)****	_

Situações excepcionais, definidas pelo grupo de transplante; **Indefinidamente; ***Por pelo menos 1 ano; ****O Núcleo sugere o uso, por pelo menos 1 ano.

Obs.: outro antiviral pode ser utilizado, no lugar da lamivudina.

B4

Transplantes de Células Tronco-Hematopoiéticas: Recomendações Específicas

Doador	Receptor
	AgHBs +	Anti-HBc+Anti-HBs+	Anti-HBc-Anti-HBs+	Anti-HBc+ isolado	Naive
AgHBs+	Sim (BII)	Sim (BII)	Sim (BII)	Sim (BII)	Situações especiais (CIII)
Profilaxia	LAM (AII)*)	LAM (AII)**	LAM (AII)**	LAM (AII)**	LAM (AII)**
Anti-HBc+ Anti-HBs-	Sim (BII)	Sim (BII)	Sim (BII)	Sim (BII)	Sim (BII)
Profilaxia	LAM (AII)*)	***	***	***	***
Anti-HBc+ Anti-HBs+	Sim (AII)	Sim (AII)	Sim (AII)	Sim (AII)	Sim (AII)
Profilaxia	LAM (AII)	#	-	-	-

Indefinidamente; **Por pelo menos 1 ano; ***fazer PCR do doador – se positivo, tratar como doador AgHBs+, se negativo, tratar como doador Anti-HBc+ e Anti-HBs+; #Acompanhar com sorologia a cada 3 meses.

Obs.: outro antiviral pode ser utilizado, no lugar da lamivudina.

B1

Liver TX: Specific Recommendations

Donor	Recipient
	HBsAg +	HBc-Ab+ HBs-Ab+	HBc-Ab- HBs-Ab+	Isolated HBc-Ab+	Naïve
HBsAg+	No (DII)	No (DII)	No (DII)	No (DII)	No (EI)
HBc-Ab+	Yes (BII)	Yes (BII)	Yes (BIII)	Yes (BIII)	No (DII)
Prophylaxis	LAM + HBIG* (AII)	LAM (BIII)**	LAM (BIII)**	LAM (BIII)**	_

LAM = lamivudine

HBIG for one year, lamivudine indefinitely; **For at least one year.

Obs.: lamivudine may be replaced by an alternative antiviral.

B2

Kidney TX: Specific Recommendations

Donor	Recipient
	HBsAg+	HBc-Ab+HBs-Ab+	HBc-Ab-HBs-Ab+	IsolatedHBc-Ab+	Naïve
HBsAg+	Exceptional circumstances*) (CIII)	Exceptional circumstances*) (CIII)	Exceptional circumstances*) (CIII)	Exceptional circumstances*) (CIII)	No (DIII)
Prophylaxis	LAM (AII)**	LAM (BIII)***	LAM (BIII)***	LAM (BIII)***	-
HBc-Ab+	Yes (BII)	Yes (BII)	Yes (BII)	Yes (BII)	No (DIII)
Prophylaxis	LAM (AII)**	LAM (CIII)****	LAM (CIII)****	LAM (CIII)****	_

Exceptional circumstances, defined by the TX group; **Indefinitely; ***For at least one year; ****Optional use.

Obs.: lamivudine may be replaced by an alternative antiviral.

B3

Heart and Lung TX: Specific Recommendations

Donor	Recipient
	HBsAg+	HBc-Ab+HBs-Ab+	HBc-Ab-HBs-Ab+	IsolatedHBc-Ab+	Naïve
AgHBs+	Exceptional circumstances*) (CIII)	Exceptional circumstances*) (CIII)	Exceptional circumstances*) (CIII)	Exceptional circumstances*) (CIII)	No (DIII)
Prophylaxis	LAM (AII)**	LAM (BIII)***	LAM (BIII)***	LAM (BIII)***	-
Anti-HBc+	Yes (BII)	Yes (BII)	Yes (BII)	Yes (BII)	No (DIII)
Prophylaxis	LAM (AII)**	LAM (CIII)***	LAM (CIII)***	LAM (CIII)***	-

Exceptional circumstances, defined by the TX group; **Indefinitely; ***For at least one year.

Obs.: lamivudine may be replaced by an alternative antiviral.

B4

Hematopoietic Stem Cell Transplantation: Specific Recommendations

Donor	Recipient
	HBsAg+	HBc-Ab+HBs-Ab+	HBc-Ab-HBs-Ab+	IsolatedHBc-Ab+	Naïve
HBsAg+	Yes (BII)	Yes (BII)	Yes (BII)	Yes (BII)	Special circumstances (CIII)
Prophylaxis	LAM (AII)*)	LAM (AII)**	LAM (AII)**	LAM (AII)**	LAM (AII)**
HBc-Ab+ HBs-Ab-	Yes (BII)	Yes (BII)	Yes (BII)	Yes (BII)	Yes (BII)
Prophylaxis	LAM (AII)*)	***	***	***	***
HBc-Ab+ HBs-Ab+	Yes (AII)	Yes (AII)	Yes (AII)	Yes (AII)	Yes (AII)
Prophylaxis	LAM (AII)	#	-	-	-

Indefinitely; **For at least one year; ***Request donor PCR – If positive, treat as if donor HBsAg+; if negative, treat as if donor HBc-Ab+ and HBs-Ab+; #Follow up with serologic assessment every three months.

Obs.: lamivudine may be replaced by an alternative antiviral.