Utilization of hepatitis B virus-positive allografts in liver transplantation: a new arrow to the bowstring for expanding the donor pool?

Liver disease accounts for approximately 2 million deaths per year worldwide, including 1 million due to complications of cirrhosis and 1 million due to viral hepatitis and hepatocellular carcinoma (HCC) (1). Liver transplantation (LTx) is the definitive management for end-stage liver disease and HCC in both children and adults. However, the number of liver transplant candidates on the waiting list exceeds that of available allografts. Approximately one-third of the global population has serological evidence of past or current hepatitis B virus (HBV) infection, including 250 million people with chronic HBV infection. The concept of using HBV-positive liver allografts has been implemented to expand the organ pool worldwide (2). Especially in regions with high or intermediate prevalence of HBV infection, these allografts can be an optimal choice for LTx recipients. Over the decades, LTx from HBV-exposed allografts has shifted from the first case in the 1980s to expanded practice supported by positive outcomes, particularly with the availability of safe and effective clinical therapies (3).

Currently, both the American Society of Transplantation and the British Transplantation Society have developed consensus guidelines indicating that the utilization of liver allografts from HBV-positive donors is acceptable (4,5). To date, some early studies have investigated differences in the risk of HBV transmission from liver donors to recipients by serologic status (6-8). The results revealed that hepatitis B surface antigen (HBsAg)-positive liver donors were at a high risk of transmission, whereas anti-hepatitis B core (HBc)-positive/HBsAg-negative liver donors had a lower risk (6,7). In addition, given that HBV resides in the form of covalently closed circular DNA within the nucleus of hepatocytes, compared with other solid organ transplants such as the kidney and lung, LTx recipients have the highest risk of HBV transmission (9,10). Currently, the availability of clinical prophylactic therapies, such as hepatitis B immunoglobulin (HBIG), and long-term nucleos(t)ide analogues (NAs), such as entecavir and tenofovir, for suppressing HBV replication have been widely used in clinical treatment. Unlike hepatitis C virus infection, there is no direct antiviral drug for the treatment of HBV infection; however, the current treatments have allowed the application of HBV-positive allografts in LTx.

In this context, Delman et al. reported the short-term outcomes of HBV nucleic acid test (HBV NAT)-positive liver allografts in HBV seronegative recipients in Annals of Surgery (10). In their prospective study, 33 LTx patients received HBV NAT-positive allografts and all recipients were HBV NAT-negative and HBsAg-negative at the time of LTx. With a median follow-up of 1 year, laboratory post-transplant monitoring per the protocol revealed that 9 (27.3%) LTx recipients had detectable HBV DNA on HBV NAT testing. At the end of the study period, 31 (93.9%) LTx recipients were HBV NAT-negative, whereas 8 (24.2%) recipients were HBsAg-positive, indicating chronic infection. Nevertheless, there were no HBV-related complications in the 33 HBV NAT-negative recipients, as defined by clinically significant HBV hepatitis. With a median follow-up of 13 months, LTx patient and allograft survival did not differ between HBV NAT-positive and HBV NAT-negative recipients on Kaplan-Meier analysis (P>0.05) (10).

Unlike other reported cases of HBV-positive donors focusing on HBV serological markers, this is the first study with a large sample size on the utilization of liver donors with hepatitis B viremia in HBV seronegative recipients. At present, LTx policies require that organ procurement organizations (OPOs) perform deceased donor testing for HBV to guide decisions about organ donation. If the donor is HBV NAT-positive, many OPOs and transplant centers typically discard such liver allografts for donation due to concern for HBV infection. Very recently, however, it has been noted that HBV NAT-positive allografts will now be included in the eligible donor pool with recent changes in the Organ Procurement and Transplantation Network (OPTN) policy 1.2 (11). The emergence of NAs and many optimistic research results have provided a promising beginning for the utilization of HBV-positive liver allografts. However, at this time, we should be more cautious about this issue.

It is important to fully evaluate allografts before LTx, especially for HBV-positive donors. Although current studies have shown that HBV-positive donors do not increase the risk of donor dysfunction, liver fibrosis does. Since HBV infection is an independent risk factor for liver fibrosis and cirrhosis, preoperative liver function should be evaluated carefully in HBV-positive donors. Comprehensive laboratory and imaging tests should be performed. In addition, the importance of liver biopsy should never be ignored as the gold standard for the diagnosis of liver fibrosis. In our view, the utilization of HBV-positive allografts should only be considered when significant allograft disease has been ruled out by histological examination. Regrettably, Delman et al. did not include this in the preoperative evaluation routine. This shortcoming may increase the risk of postoperative liver dysfunction for HBV-negative recipients. Recently, noninvasive evaluation of liver fibrosis, including liver elastography and magnetic resonance imaging, has been promoted and has yielded satisfactory results (12). We believe that this will help upgrade our evaluation scheme for HBV-positive liver allografts in the future.

Previous studies have emphasized the dismal outcomes of HBsAg-negative recipients who received liver allografts from anti-HBc-positive donors without prophylaxis, with 25–94% of recipients experiencing HBV transmission (13,14). More recently, post-transplant recipient and graft survival have dramatically improved with effective antiviral therapy. Owing to the required post-LTx immunosuppressive therapy, the risk of de novo HBV infection becomes the most important issue after receiving HBV-positive allografts. At present, because of the limited existing data on the use of grafts from HBV-positive donors, few recommendations in clinical guidelines can be applied for consistent management of such recipients. Indeed, some attempts have been made to use HBV-positive allografts to extend the donor pool in our transplant center (7,8). Based on our therapeutic experience, management treatment protocols for LTx recipients from HBV-positive donors have been developed in our center, including medical management, education programs, and intensive follow-up schedules (Figure 1). For unvaccinated HBV-negative LTx recipients, pre-transplant HBV vaccination provides significant protection against HBV infection, particularly in HBV-negative recipients who achieve protective antibody response before HBV exposure. Prophylaxis protocols, in addition to HBV vaccination, the use of HBIG, antiviral drugs such as lamivudine, entecavir, and tenofovir, or a combination of HBIG and antiviral therapy, have been used in our center to decrease the risk of donor-transmitted HBV. Improved adherence to prophylaxis therapy has also been associated with a decreased risk of de novo HBV infection. We also conducted a specific education program for recipients and their families, including lifestyle and HBV vaccine recommendations, to decrease the transmission risk to family members.

Figure 1 The management strategy for HBV-negative recipients receiving HBV-positive donor livers in West China Hospital. Antiviral prophylaxis: entecavir and tenofovir. HBV, hepatitis B virus; anti-HBc (HBcAb), hepatitis B core antibody; anti-HBs (HBsAb), hepatitis B surface antibody; HDV, hepatitis delta virus; HBsAg, hepatitis B surface antigen; HBIG, hepatitis B virus immunoglobulin; HBV NAT, hepatitis B virus nucleic acid test.

As demonstrated by Delman et al., de novo HBV infection occurred in only 8 LTx (24.2%) recipients, with a median follow-up of 13 months (10). Additionally, the 30-day, 90-day, and 1-year survival rates of patients and allografts were similar between recipients of liver allografts from HBV NAT-positive donors and patients who received allografts from HBV NAT-negative donors (10). However, de novo HBV infection may be challenging because the onset of infection is not predictable and may be delayed for up to 5 years (15). Furthermore, the lifelong intake of immunosuppressive regimens in LTx patients increases the risk of de novo HCC. It is unclear at this stage whether recipients of HBV-positive liver allografts will have an increased risk of HCC development after a longer follow-up. Moreover, several direct-acting antiviral approaches with new mechanisms of action that may cure HBV infection are being developed (Table 1). We believe that the combination of novel therapies may further aid in the availability of HBV-positive allografts in LTx.

Collectively, the work of Delman et al. points to a bright future, where HBV NAT-positive allografts can be used to expand the donor pool in LTx with prophylaxis therapies and informed consent, especially in endemic regions. At the very least, the long-term outcomes associated with HBV NAT-positive allografts in LTx merit further investigation.

Acknowledgments

Funding: This study was supported by the Sichuan Science and Technology Program (2019YFG0036), the Major National Science and Technology Special Projects (No. 2017ZX10203205-005-002 and No. 2017ZX10203205-001-004), and the National Natural Science Foundation of China (No. 81470037 and No. 81770653).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Hepatobiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-21-543/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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