Hepatitis B virus (HBV) is a highly infectious blood-borne pathogen that can be transmitted by a solid organ allograft and result in substantial morbidity and mortality. Recent advances in the management of HBV infection prompt a reappraisal of the approach to the management of allograft recipients from cadaver donors previously exposed to HBV, because of the ongoing shortage of organ donors. This report reviews current knowledge regarding the risk of HBV transmission by an organ from cadaver donors testing positive for markers of HBV infection and makes recommendations for the evaluation, treatment, and surveillance of the allograft recipients.
The detection of hepatitis B virus (HBV) in the blood sample of a prospective organ donor has historically limited the utilization of organs recovered from such individuals. The transmission of this blood-borne pathogen via organ transplants is hazardous to allograft recipients for two reasons: first, HBV has a remarkably high infectivity rate; and second, HBV replication is enhanced by immunosuppression (1,2). Acquisition of HBV infection has been associated with rapidly progressive liver disease, leading to high rates of liver failure and mortality (3).
The administration of hepatitis B immunoglobulin (HBIg) with or without lamivudine has improved the outcome of liver transplantation for end-stage liver disease due to chronic HBV infection by decreasing the rate of HBV recurrence (4–6). Significant advances in the understanding, diagnosis, prevention, and treatment of HBV infection now permit a reappraisal of our approach to the transplantation of organs from cadaver donors previously exposed to HBV and to the management of allograft recipients from such donors.
Serologic History of HBV Infection
After infection with HBV, hepatitis B surface antigen (HBsAg) is the first marker to appear in the serum, typically 4 weeks after exposure (Figure 1). Circulating HBsAg, which precedes appearance of clinical symptoms and elevation of serum aminotransferases, remains detectable throughout the entire symptomatic phase of acute illness. Antibody to hepatitis B core antigen (anti-HBc) is detectable in the serum 1–2 weeks after the appearance of HBsAg and precedes detectable anti-HBs by weeks or months. The IgM class of anti-HBc predominates during the first 6 months after acute infection, whereas the IgG class of anti-HBc predominates thereafter. Thus, IgM anti-HBc indicates current or recent infection and IgG anti-HBc reflects more remote infection. With clearance of HBV, antibody to HBs (anti-HBs), which is exclusively IgG, becomes detectable ≈ 6 months after exposure and persists indefinitely. In general, anti-HBs and anti-HBc both persist in those who have recovered from HBV infection. Isolated anti-HBc may occur in the infrequent (< 5%) person whose HBsAg level drops below the detection threshold of currently available immunoassays. HBsAg persists in those who fail to clear virus, and these individuals develop chronic hepatitis B. Recipients of HBV immunization can be identified by isolated anti-HBs. However, in a few individuals who have recovered from natural HBV infection, anti-HBc may wane below the limits of detection of conventional assays, producing a picture of isolated anti-HBs. The presence of serum HBV DNA is generally indicative of circulating virus. HBV DNA can be detected prior to appearance of HBsAg in acute HBV infection. However, the most common application of assays for HBV DNA is in the diagnosis of chronic, replicative HBV infection.
Hepatitis B Surface Antigen (HBsAg+) Donor
The greatest risk of HBV transmission occurs with organs procured from a donor who is positive for HBsAg. HBsAg is detected by an enzyme-linked immunoassay (EIA), which has a low false-positive rate. Our organ procurement organization (OPO) laboratory performs the EIA in triplicate, and any positive result prompts a confirmatory EIA with pedigreed positive and negative controls. If the EIA is consistently reactive or borderline and the confirmatory test is positive, a positive result is reported. If the EIA result is borderline positive and the confirmatory test is negative, the assay is reported as borderline positive. If the initial EIA is negative, the result is reported as negative. In the event of a positive result, the donor is infected with HBV, either recently or chronically, and can transmit HBV to organ recipients (Figure 2).
Because HBV transmission occurs through organ transplantation and can result in the death of allograft recipients, historically, organs from HBsAg+ donors have been used for recipients with extenuating circumstances of medical necessity (Table 1). Liver allografts from HBsAg+ donors have been transplanted to critically ill HBsAg– recipients without deleterious outcome (7). Renal transplants from HBsAg+ donors to HBsAg– recipients have also been performed without development of HBV infection; however, the satisfactory outcome in these cases may have been influenced by the history of prior HBV immunization (8).
Table 1. : Relative risk of hepatitis B virus (HBV) transmission by donor HBV serology
Management of the Allograft Recipient of an Organ from an HBsAg+ Donor
Although the risk of HBV infection may be reduced in recipients who are positive for anti-HBs (by virtue of immunization or natural immunity), infection has been well documented after transplantation of abdominal and thoracic organs from a donor positive for HBsAg irrespective of the recipient's immunization status. Therefore, the regimen outlined below should be applied to all recipients of organs from HBsAg+ donors.
If the clinical circumstances necessitate transplantation of an organ from an HBsAg+ donor, the recipient should be prophylactically treated with HBIg and antiviral therapy. We recommend HBIg 10 000 U i.v. daily for the first 7 d after transplant, followed by monthly infusions of HBIg for at least 1 year to maintain adequate anti-HBs levels (> 100 IU/mL) (9), although some centers recommend maintenance of anti-HBs at even higher levels. Alternatively, many centers employ a fixed-dose regimen in the first year post-transplantation (10). HBIg is combined with lamivudine 100 mg p.o. daily for at least 1 year. We recommend frequent surveillance of the allograft recipient for liver function tests, HBsAg, anti-HBs, and HBV DNA (see Table 2).
Table 2. : Suggested management of solid organ transplant recipients by donor hepatitis B virus (HBV) serology status
HBsAg, hepatitis B surface antigen; anti-HBc, antibody to hepatitis B core antigen; anti-HBs, antibody to hepatitis B surface antigen; LFTs, liver function tests; HBIg, hepatitis B immunoglobulin;
Some centers have used lamivudine alone.
The use of donor HBV DNA testing is suggested given the potential risk for transmission with detectable HBV DNA. Refinements in the use of HBV DNA testing in the transplant setting await the results of further study.
If donor DNA(+), frequent (q. 3 months) surveillance LFTs, HBsAg, anti-HBs, and HBV DNAb If donor DNA(–), sporadic (q. 6 months) surveillance LFTs, HBsAg, anti-HBs, and HBV DNAb
HBsAg–, anti-HBc– anti-HBs+ or –
Follow LFTs; consider investigation for HBV with elevations
Anti-HBc+ Donor (anti-HBs+/–; HBsAg–)
All organs from donors who test positive for anti-HBc can transmit hepatitis B to allograft recipients; this is particularly true for the liver. Antibodies detected in the donor serum against hepatitis B core antigen are only present after HBV infection; they cannot be the result of previous HBV vaccination (which evokes immunity only to the HBsAg).
Anti-HBc assays, which have historically been performed as EIAs, have been associated with high false-positive rates (as high as 75%), particularly in individuals with isolated anti-HBc positivity (11–13). More recently, a radioimmunoassay (RIA) has become the standard anti-HBc test in most OPO laboratories. Although the RIA has been associated with considerably lower false-positive rates, a precise figure is difficult to arrive at in the absence of a gold standard (12). In general, a positive RIA is repeated and confirmed before the result is reported by the OPO laboratory.
In donors who test positive for anti-HBc, other serologic results may provide clinical context. For the positive anti-HBc result, the result should be further defined by determining whether the antibody is of the IgM or the IgG class. The presence of IgM anti-HBc indicates recent infection with HBV; in general, anti-HBs will not yet be detectable. The presence of IgG anti-HBc represents more remote infection that may or may not be accompanied by anti-HBs. Although the presence of anti-HBs has been traditionally interpreted as evidence of recovery, immunity, and lack of infectivity, more recently, it has been shown that the presence of donor immunity (anti-HBs+) does not eliminate the risk of hepatitis B transmission (see below). Therefore, we suggest that OPOs assay only for HBsAg and anti-HBc in the initial serologic assessment of the prospective donor (Figure 2). If the donor is reactive for anti-HBc, the result should be further defined by testing for IgM and IgG anti-HBc to identify donors with either recent HBV exposure or current HBV infection. If the anti-HBc is of the IgM class, then there is a high risk of HBV transmission with transplantation of any of the donor's organs. Therefore, the recipient should be managed according to the guidelines for HBsAg+ organs. If the anti-HBc is of the IgG class, then there is high risk of HBV transmission with transplantation of the liver but significantly lower risk of HBV transmission by transplantation of other organs. The management strategy for the recipient is discussed below. When a donor tests positive for anti-HBc, the OPO laboratory may proceed to determine the anti-HBs status. However, since donor immunity does not alter the risk of HBV transmission, the presence of anti-HBs is only helpful to indicate that the positive anti-HBc result is not falsely positive. Similarly, during organ procurement, a liver biopsy should be obtained for all anti-HBc+ donors, since it can provide immediately useful information for all organ recovery surgeons. The finding of persistent or active hepatitis or cirrhosis has obvious implications for liver donation. This biopsy finding confirms that the positive anti-HBc result is not falsely positive and may ultimately help guide the post-transplant anti-HBV treatment plan for recipients of other organs from the same donor. Finally, serum should also be sent for HBV DNA and the results, when available, distributed to the transplant centers of all organ recipients. While it should be emphasized that the optimal use of HBV DNA levels in guiding the post-transplant management of anti-HBc(+) allograft recipients has yet to be defined, it is reasonable to conjecture that these assays can be useful in dictating the initial approach as well as intensity of postoperative surveillance (see below).
Recent reports have emphasized the importance of anti-HBc positivity regardless of the anti-HBs result, especially for the liver allograft recipient. Long after apparent serologic clearance of infection, HBV may reside in the donor patient's liver. The NIH Liver Transplant Database confirms that the majority (18/23) of anti-HBc+ livers have transmitted HBV (14). Graft hepatitis occurred irrespective of either donor or recipient anti-HBs status, including previously immunized recipients. Thus, in the donor, serologic markers suggesting disease resolution may mask latent HBV infection. This may be explained in part by the existence of defective viral genomes harboring deletions that affect the production of HBsAg (15). Furthermore, HBV DNA sequences have been identified in the liver (16,17) of most anti-HBc-positive donors, regardless of anti-HBs status. Overall, the risk of transmission of HBV by a liver graft procured from a donor positive for anti-HBc to a HBsAg– recipient ranges from 25 to 94% (14,18–20).
Other organs such as kidney or heart from an anti-HBc+ donor have demonstrated a much lower rate of HBV transmission. Combining the results of four separate series, only one of 132 kidney recipients and zero of 19 heart recipients from anti-HBc+ donors became HBsAg+ (18,21–23). A recent analysis of UNOS data was performed to determine the impact of donor anti-HBc positivity on the development of antibodies to HBV in kidney and heart recipients within 1 year of transplant. A stepwise multivariate logistic regression analysis of cadaveric kidney and heart transplants between 1994 and 1996 was performed from the UNOS database. The analysis showed that 12–15% of kidney and heart allograft recipients from an anti-HBc+ donor were reported to develop antibodies to HBV by 1 year following transplantation, in contrast to only 2–3% of recipients from an anti-HBc– donor (p = 0.001). When donors were positive for anti-HBc, the odds ratio for developing HBV antibodies within 1 year of transplant was 5.16 for kidney recipients and 6.16 for heart recipients. Although the UNOS database did not provide information regarding the development of recipient hepatitis or mortality in either the kidney or heart recipient group, the findings suggest that transmission of HBV may occur in these groups. Further study is warranted to determine the true rate of clinically significant HBV transmission, but collectively the data indicate that transmission of active HBV with kidney and heart transplant is uncommon. Although there are no data with regard to HBV transmission through lung or pancreas transplantation, it is reasonable to assume comparable risk with kidney and heart transplants.
Highly sensitive amplification-based assays for HBV DNA (PCR, bDNA, hybrid-capture amplification) now permit detection of HBV well below the threshold of currently available HBsAg assays. Indeed, a significant portion of persons positive only for anti-HBc tested positive for low-level serum HBV DNA in one study (24). It remains unclear what level of donor HBV DNA is associated with viral replication or risk of transmission with an organ; this will need clarification by future studies which correlate risk of HBV transmission with HBV DNA levels in anti-HBc+ donors. Nonetheless, determination of donor HBV DNA status will likely assist management of kidney and thoracic recipients following transplantation, especially if the result is negative.
In summary, a positive donor anti-HBc result should be interpreted as a potential risk for transmission of HBV to allograft recipients, but the risk is greatest for the liver allograft because the liver is likely to harbor HBV.
Management of the Allograft Recipient of an Organ from an Anti-HBc+ Donor
The IgM anti-HBc+ donor (any organ)
Because this serology is indicative of recent or ongoing acute infection, recipients of any organ from a donor testing positive for IgM anti-HBc should be treated in a manner analogous to allograft recipients from an HBsAg+ donor. Thus, we recommend the administration of HBIg and lamivudine as detailed above.
The IgG anti-HBc+ donor: liver recipients
In view of the significant risk for HBV transmission, the approach to transplantation of the liver from an IgG anti-HBc+ donor should be as aggressive as that from a HBsAg+ donor. We therefore recommend the same intravenous HBIg regimen in combination with oral lamivudine (Table 2). HBsAg, anti-HBs, and HBV DNA should be closely monitored to detect active infection. It should be noted that several centers have described successful prevention of graft HBV using therapy with lamivudine alone, although lamivudine resistance and graft failure have occurred (25,26). The optimal and most cost-effective regimen in preventing HBV infection in the allograft from an anti-HBc positive liver donor awaits the result of randomized controlled trials. While emergence of lamivudine resistance has been described with increasing frequency with prolonged therapy of established HBV infection (27), the implementation of this agent as part of prophylactic regimens has still been successful in preventing detectable infection (4–6,28). Even in the event of emergence of lamivudine resistance, an increasing array of antiviral agents active against lamivudine-resistant HBV should soon be available to address this problem (27).
The IgG anti-HBc+ donor: thoracic and other abdominal organ recipients
Since HBsAg–, anti-HBc+ donors are capable of transmitting HBV infection to any allograft recipient, we suggest that recipients of thoracic or other abdominal organs obtained from an IgG anti-HBc+ cadaver donor be preferentially considered for recipients who have been immunized to HBV, who have evidence of prior HBV infection, or who have an extenuating need.
Thoracic and other abdominal organ recipients who have evidence of active or passive HBV immunity do not require any additional treatment at the time of transplantation. We recommend a postoperative surveillance strategy with determination of liver enzymes, HBsAg, anti-HBs, and an HBV DNA amplification assay. Since immunosuppression diminishes necroinflammatory activity, viral replication may proceed unchecked after transplantation without elevation of the liver enzymes. Furthermore, reduction or withdrawal of immunosuppression may precipitate significant liver injury. Thus, normal serum aminotransferases do not exclude active HBV infection. These tests can be performed sporadically (every 6 months) for recipients of organs from donors who are HBV DNA– and intensified (every 3 months) for recipients of organs from donors who are HBV DNA+(Table 2). At present, there are no data to validate this use of donor HBV DNA information, but our recommendation makes the assumption that the risk of viral transmission increases in the presence of detectable HBV DNA. The results of studies aimed at quantifying risk and establishment of infective cut-offs will further inform these recommendations.
Recipients without evidence of HBV immunity who have been selected to receive a kidney or heart from an anti-HBc+ donor because of medical need should receive a short course (7 d) of i.v. HBIg, beginning at the time of the operation and continuing into the immediate postoperative period (Table 2). We suggest that the donor HBV DNA status dictate subsequent management. If the donor HBV DNA is detectable (and the theoretical risk of transmission of infection remains), then the course of daily HBIg should be completed and continued for a short course (3–6 months). If the donor HBV DNA is undetectable, then the daily HBIg course may be discontinued. If the donor HBV DNA is unavailable, then the donor should be treated as HBV DNA+. A reasonable and possibly more cost-effective alternative approach would have recipients treated at the time of the operation with lamivudine until the HBV DNA result is known, with continuation for 12 months in the event of HBV DNA positivity and discontinuation with undetectable HBV DNA. While the theoretical risk exists for selection of lamivudine-resistant HBV, the frequency of this phenomenon would be expected to be rare given the very low levels of transmitted virus in this setting. In either scenario, we recommend routine postoperative monitoring of the recipient's liver enzymes, HBsAg, anti-HBs, and HBV DNA (Table 2). If the HBsAg or the HBV DNA become positive, then antiviral therapy with lamivudine should be given.
HBsAg– and Anti-HBc– Donor (Anti-HBs+ or –)
The lowest risk of HBV transmission occurs when the donor is negative for both HBsAg and anti-HBc, as this is taken as evidence of no active infection (Figure 2). The transplant community generally regards this serologic profile as ideal for the recovery of all organs. If the OPO tests for anti-HBs, this group of donors can be divided into those positive or negative for anti-HBs.
A positive result for anti-HBs may result from several clinical scenarios. The donor may have been vaccinated against HBV, received HBIg or a blood product from an individual with anti-HBs, or had previous HBV infection. Although this serologic profile does not suggest active viral replication, in rare instances transmission of HBV by a liver allograft has been observed (29). It has been shown that the liver may harbor latent HBV indefinitely, even in the presence of neutralizing antibody (17,30,31). In rare instances, even donors who are negative for all markers of HBV (HBsAg–, anti-HBc–, anti-HBs–) have transmitted HBV to liver allograft recipients (32).
Management of Recipients of an Organ from HBsAg–, Anti-HBc– donors
Since transmission of HBV is extremely rare (< 1%) from donors with this profile (33) we do not recommend prophylactic treatment of any organ recipients, including the liver allograft recipient. Furthermore, we do not advocate prospective testing of the donor for HBV DNA. Thoracic or other abdominal allograft recipients should have periodic liver function testing. Abnormalities in liver function tests in all allograft recipients should prompt thorough investigation, including the possibility of HBV transmission by the allograft. At that point in time, the donor's serum may be retrospectively interrogated for the presence of additional markers of HBV infection, particularly HBV DNA.
Advances in the understanding of the biology and natural history of HBV infection have led to successful immunoprophylactic and antiviral approaches that can prevent HBV infection in the organ transplant recipient. These approaches have, in turn, led to the development of a rational approach to the transplantation of organs from cadaver donors with previous exposure to HBV. The recipient of organs from donors harboring active HBV infection (HBsAg+ or IgM anti-HBc+) should be treated aggressively with HBIg and lamivudine, pending the outcome of clinical trials. Organs from donors testing positive for IgG anti-HBc should be considered in clinical context. The liver from such a donor should be considered at high risk for transmission of HBV and treated as if actively infected, whereas the kidney or heart appears to be at low risk for transmission. The judicious use of donor liver biopsy and HBV DNA amplification assays should assist decision-making pertinent to the anti-HBc+ donor, especially in the low-risk scenario. We can anticipate that forthcoming analyses employing these adjunctive studies will help to optimize treatment decisions further and maximize the use of organs from cadaver donors previously exposed to HBV. It is also anticipated that the forthcoming availability of additional antiviral chemotherapies for HBV will further swing the pendulum toward employment of antiviral rather than immunoprophylactic strategies.