Transplanting hepatitis B surface antigen–positive livers in the United States: Outcomes and opportunities

Abstract

Livers from donors with positive hepatitis B surface antigens (HBsAg+) have been used to expand the donor pool; however, outcome data are limited. We aim to evaluate survival following liver transplant (LT) from HBsAg+ donors. Using the United Network for Organ Sharing registry, we identified HBsAg+ donors used for LT from 2009 to 2020. We used Kaplan-Meier survival and Cox proportional hazards regression to compare post-LT survival in hepatitis B virus-negative recipients who utilized HBsAg+ donors to propensity-matched cohorts who utilized other types of donors. From 2009-2020, 70 patients received HBsAg+ livers, and 58 of them did not carry a diagnosis of chronic hepatitis B virus. The 1- and 3-year post-LT survival for hepatitis B virus-negative patients who received livers from HBsAg+ donors were 96.6% and 91.4%, respectively, with no statistical differences compared with patients who received livers from hepatitis C virus viremic donors (96.5%/93.0%, P = .961/.427), donation after cardiac death donors (93.0%/86.0%, P = .651/.598), average-risk donors (89.5%/86.0%, P = 0.264/0.617), and a combination of extended-criteria donors, including donation after cardiac death, donor age over 70, and graft with greater than 30% steatosis (93.0%/91.2%, P = .621/.785). Recipients of HBsAg+ livers have similar post-LT survival compared with those receiving other types of grafts. Increasing the utilization of HBsAg+ livers could safely expand the donor pool.

1. Introduction

Given the ongoing organ shortage in liver transplantation (LT), donor pool expansion has become one of the most important topics in the field of transplantation. The use of previously deemed increased-risk or extended-criteria donors, including donors with advanced age, donation after deceased cardiac death (DCD), and increased macrosteatosis in the graft has been increasing over time with promising outcomes.^1–3 Liver grafts from donors with current hepatitis B virus (HBV) infection were previously deemed not safe for transplant given the concern of HBV transmission and reactivation posttransplant.^4–6 However, current antiviral treatments for HBV, such as entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide, are well tolerated and effective in suppressing HBV with minimal risk of drug resistance. Given the improvements in HBV therapy and ongoing organ shortage, there has been increased interest from transplant centers in utilizing livers from donors with positive hepatitis B surface antigens (HBsAg+). However, the data regarding the outcomes of patients who received these organs are scarce, especially in the United States. Our study aims to compare the utilization and posttransplant patient survival of HBsAg+ liver donors to other extended-criteria donors.

2. Materials and Methods

2.1. Data collection

Using the United Network for Organ Sharing (UNOS) and Organ Procurement and Transplantation Network registry, we identified all adult patients listed for LT in the United States between January 1, 2009, and December 31, 2020, with follow-up through June 30, 2020. The study was approved by the institutional review board at Baylor College of Medicine.

2.2. Identifying donors and recipients with HBV

Donors with positive HBsAg were identified at the time of procurement in the UNOS database. Recipients with HBV as an indication for LT were identified using primary or secondary diagnostic codes for acute and/or chronic HBV in the UNOS database, and all others were categorized as non-HBV recipients. Since 2015, UNOS has collected data regarding antibodies to hepatitis B surface antigens (anti-HBs). Concordantly, recipients were stratified by anti-HBs status when they underwent LT between 2015 and 2020.

2.3. Primary outcomes

We evaluated 1- and 3-year patient survival following LT in those who received HBsAg+ livers. We also examined the utilization and discarded rate of livers from HBsAg+ donors according to UNOS data.

2.4. Secondary outcomes

Survival among HBV− recipients who received liver allografts from HBsAg+ donors was compared with separate propensity score-matched (PSM) cohorts of recipients who received grafts from (1) hepatitis C virus nucleic acid test (HCV NAT)+ donors, (2) DCD donors, (3) extended-criteria donors, including DCD donors aged over 70, and donors with greater than 30% macrovesicular steatosis in the liver,^2,3 and (4) donors with average risk, defined as those with the 40^th to 60th percentile donor risk index (DRI). DRI is a metric of donor quality calculated from donor age, race, height, cause of death, type of graft, regional/national share, and cold ischemia time.⁷ We estimated the propensity score for the conditional probability of receiving an HBsAg+ liver graft given each recipient’s pretransplant characteristics. Characteristics in the PSM analysis include recipient and donor pretransplant clinical information, such as recipient age, sex, race/ethnicity, transplant year, etiology of liver disease, hepatocellular carcinoma (HCC) status, as well as donor age and cold ischemia time. Observations from the treatment and control groups were matched based on a single composite propensity score using nearest-neighbor matching methods with replacement. Information on patient and donor characteristics for the PSM survival analyses can be found in the Supplementary Table.

We compared 1- and 3-year post-LT survival outcomes between propensity-matched groups. Post-LT survival rates were reported using the Kaplan-Meier method and log-rank testing for equality of survivor functions. Cox regression was also used to estimate the hazard ratio (HR) in 1- and 3-year post-LT survival between propensity-matched groups. A P value of <.05 was used for statistical significance. All statistical analyses were performed using STATA 16.0.

3. Results

3.1. Utilization of HBsAg+ livers in the United States

The overall utilization of HBsAg+ donor livers increased from 6 per year to 19 per year (Fig. 1). In total, more than 50% of HBsAg+ livers were discarded in 2020 and 2021.

Figure 1.

Utilization of liver graft from hepatitis B-positive org in the United States. The number of utilized and discarded livers from donors with positive hepatitis B surface antigen (HBsAg+) over time.

3.2. Clinical characteristics of donors and recipients

Between 2009 and 2020, 70 patients received liver transplants from HBsAg+ donors. The mean age of these recipients was 56.2 years, and 61.4% were male, with an average Model for End-Stage Liver Disease (MELD) score of 20.7 (Table 1). Most (82.9%, n = 58) of these recipients did not have a diagnosis of acute or chronic hepatitis B virus in the UNOS database and were classified as HBV−. In terms of HBV vaccination in the recipients, only 17 (40.5%) HBV− recipients had positive anti-HBs. The rest of the demographic information of these recipients and donors is summarized in Table 1.

Table 1.

Clinical characteristics of hepatitis B surface antigen (HBsAg)+ donors and the recipients.

	Recipients	Donors
Demographic factors
Age, mean (SD) y	56.2 (9.8)	40.4 (14.5)
Sex, male (%)	61.4 (n = 43)	54.3 (n = 38)
Race/ethnicity, (%)
White	71.4 (n = 50)	52.9 (n = 37)
Black	4.3 (n = 3)	22.9 (n = 16)
Hispanic	11.4 (n = 8)	8.6 (n = 6)
Asian	7.1 (n = 5)	14.3 (n = 10)
Other	5.7 (n = 4)	1.4 (n = 1)
Cold ischemia time, h, mean (SD)		5.9 (2.5)
MELD laboratory score, mean (SD)	20.7 (11.1)
Etiology of liver disease (%)
HBV	17.1 (n = 12)
HCV	20 (n = 14)
NASH	15.7 (n = 11)
Alcohol	22.9 (n = 16)
AIH/PBC/PSC	10(n = 7)
HBV-negative recipients	82.9 (n = 58)
*Anti-HBs+ (%)	40.5 (n = 17)
*Missing anti-HBs status (%)	2.4 (n = 1)

^*The anti-HBs status is only available in patients who received a transplant after 2015 (n = 42). SD, standard deviation; HBV, hepatitis B virus; HCV, hepatitis C virus; NASH, non-alcoholic steatotic hepatitis; AIH, autoimmune hepatitis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; anti-HBs, anti-hepatitis B surface antibody.

3.3. Posttransplant patient survival of those who received HBsAg+ livers

Survival rates of recipients of livers from HBsAg+ donors are provided in Table 2. The 1- and 3-year survival rates for all recipients of livers from HBsAg+ donors were 95.7% (95% confidence interval [CI]: 88.0, 99.1) and 91.4% (95% CI: 82.3, 96.8). For HBV+ recipients, the 1- and 3-year survival rates were 91.7% (95% CI: 61.5, 99.8) and 91.7% (95% CI: 61.5, 99.8), respectively. For HBV− recipients, the 1- and 3-year survival rates were 96.6% (95% CI: 88.1, 99.6) and 91.4% (95% CI: 81.0, 97.1). HBV+ and HBV− recipients did not have statistically different 1- and 3-year survival rates (P = .447 and .974, respectively).

Table 2.

One- and 3-year posttransplant survival in recipients of hepatitis B surface antigen (HBsAg)+ livers.

	Number of patients (percentage)	1-year survival (95% confidence interval [CI])	3-year survival (95% CI)
All recipients	70	95.7% (88.0, 99.1)	91.4% (82.3, 96.8)
Hepatitis B virus-positive (HBV+) recipients	12 (17.1%)	91.7% (61.5, 99.8)	91.7% (61.5, 99.8)
HBV-negative (HBV−) recipients	58 (82.9%)	96.6% (88.1, 99.6)	91.4% (81.0, 97.1)

3.4. Posttransplant survival compared with those who received livers from other types of donors

3.4.1. Survival compared with HCV NAT+ donors

Liver transplant recipient survival outcomes after propensity-matching HBsAg+ donors to HCV NAT+ donors are summarized in Figure 2A. Propensity-matched patients who received livers from HCV NAT+ donors had corresponding 1- and 3-year survival rates of 96.5% and 93.0%, respectively. Cox regression showed no statistical difference in survival between the 2 groups at 1 year (HR: 1.051, 95% CI: 0.148-7.459, P = .961)and 3 years (HR: 1.711, 95% CI: 0.455-6.433, P =.427).

Figure 2.

Post liver transplant (LT) survival of hepatitis B virus (HBV)-negative recipients utilized positive hepatitis B surface antigen (HBsAg+) livers compared with the propensity-matched groups. (A) Post-LT survival of HBV-negative recipients utilized HBsAg+ livers versus those who received livers from donors with positive nucleic acid amplification testing for hepatitis C. (B) Post-LT transplant survival of HBV-negative recipients utilized HBsAg+ livers versus those who received livers from donation after cardiac death (DCD) donors. (C) Post-LT survival of HBV-negative recipients utilized HBsAg+ livers versus those who received livers from extended-criteria donors, including DCD, donor age over 70, or graft with greater than 30% macrovesicular steatosis. (D) Post-LT transplant survival of HBV-negative recipients utilized HBsAg+ livers versus those who received livers from average-risk donors, defined by donors with the 40th to 60th percentile donor risk index (DRI). HCV NAT+, hepatitis C virus nucleic acid test positive.

3.4.2. Survival compared with DCD donors

Propensity-matched patients who received livers from DCD donors had 1- and 3-year post-LT survival rates of 93.0% and 86.0%, respectively. There was no statistical difference in survival between the 2 groups at 1 year (HR: 0.661, 95% CI: 0.110-3.958, P =.651) and 3 years (HR: 0.734, 95% CI: 0.233-2.315, P = .598, Fig. 2B).

3.4.3. Survival compared to extended-criteria donors

In propensity-matched groups, the 1- and 3-year survival rates for recipients of extended-criteria donors, including DCD, donor age over 70, or graft with greater than 30% macrovesicular steatosis, are shown in Figure 2D. In propensity-matched groups, the 1- and 3-year survival rates for recipients of extended-criteria donors were 93.0% and 91.2%, respectively. There was no statistical difference in survival between the 2 groups at 1 year (HR: 0.636, 95% CI: 0.106-3.810, P = .621) and 3 years (HR: 1.201, 95% CI: 0.322-4.476, P =.785, Fig. 2C).

3.4.4. Survival compared to average-risk donors

The 1- and 3-year survival rates of recipients of propensity-matched 40th to 60th percentile DRI donors were 89.5% and 86.0%, respectively. There was no statistical difference in survival between the 2 groups at 1 year (HR: 0.392, 95% CI: 0.076-2.024, P =.264) and 3 years (HR: 0.746, 95% CI: 0.236-2.352, P = .617, Fig. 2D).

4. Discussion

Our study demonstrated good posttransplant patient survival outcomes in recipients of livers from HBsAg+ donors, even in those without chronic HBV infection prior to transplant. In propensity-matched analyses, HBV− patients who received HBsAg+ livers had overall similar 1- and 3-year post-LT survival compared with those who received livers from DCD donors, HCV NAT+ donors, extended-criteria donors, and average-risk donors.

There are a limited number of studies detailing the posttransplant outcome of patients who received HBsAg+ grafts. In a single-center retrospective study from China, which included 42 HBsAg+ donors and 237 HBsAg− donors, there were no differences in patient and graft survival.⁸ However, most recipients (91%) had HBV-related liver disease, and hence the results cannot be generalized to US patients. A previous study from Li et al⁹ compared 78 patients who received HBsAg+ grafts versus 312 matched controls who received HBsAg− grafts using earlier (1987-2010) data from the Scientific Registry of Transplant Recipients (SRTR) database. This study also showed comparable patient and graft survival in recipients of HBsAg+ and HBsAg− liver grafts. However, these data predate the new generation of nucleoside analogs (NA), such as entecavir and tenofovir, and up to 20% of the recipients have HBV-related diseases. Our data, which were based on an updated national transplant registry, support using HBsAg+ liver for transplant, even in recipients without HBV. Furthermore, the posttransplant outcome was comparable to that of those who received livers from average-risk or extended-criteria donors.

Our study demonstrated that the utilization of HBV+ organs had been slowly increasing. However, the overall utilization of these organs remains suboptimal.¹⁰ From a clinical perspective, there remain several challenges that need to be addressed. First, the optimal strategy to reduce the risk of HBV transmission is unclear. Historically, all recipients of such organs were given hepatitis B immune globulin (HBIG) in addition to indefinite NA post-LT.¹¹ However, the role of HBIG has become less clear with the newer generation of NA. Delman et al¹² recently published their single-center experience of using HBV NAT+ donors. According to their protocol, recipients were not given HBIG when they already had a positive anti-HBs antibody prior to transplant. For HBV− transplant candidates who had negative anti-HBs, only one dose of HBIG (10,000 units IV) was given to prevent HBV activation during the immediate postoperative period. In their study, 8 out of 33 HBsAg− recipients became HBsAg+ in 1 year, but only 1 had an acute HBV infection post-LT in the setting of noncompliance to NA. The short-term survival of recipients of HBV NAT+ liver was good and comparable to that of recipients of HBsAg− liver. However, long-term data on such an approach is needed, and having an evidence-based protocol will be crucial.

Additionally, it can be difficult to assess the quality of HBsAg+ livers using noninvasive tests, especially with a time constraint. Many transplant centers still require biopsies before utilizing HBsAg+ livers, which is a reasonable approach until a better noninvasive test is available. Further studies, including developing a multicenter cohort with potential serum and tissue banking, might be helpful in identifying potential biomarkers. It is also important to mention that the risk of developing de novo HCC in recipients of HBsAg+ liver remains unclear, especially in those who received grafts from donors who may have had prolonged HBV exposure (ie, donors who acquired HBV through vertical transmission). Although some studies from Asia have shown that treatment with NA can reduce the HCC by up to 80% in noncirrhotic patients, such findings are not universal, and there is a lack of data in countries outside Asia.¹³ Furthermore, important information from the donor, such as the timing of acquiring the HBV infection and the HBV treatment period, may not be available, which makes it difficult to determine the HCC risk. Although awaiting more long-term data regarding this topic, we believe it is reasonable to perform routine HCC screening, such as abdominal ultrasound every 6 months with or without alpha fetoprotein (AFP) in all recipients of HBsAg+ liver post-LT. The potential risk of developing HCC in the long term should be balanced with the benefit of the transplant and needs to be discussed with the recipients, especially for younger LT candidates. However, many waitlisted patients have high short-term mortality or morbidity from cirrhosis but are disadvantaged by low MELD scores. Transplanting HBsAg+ liver is a reasonable option for these patients, supported by the good 1- and 3-year post-LT mortality shown in our study.

From a recipient’s standpoint, one of the most important strategies to reduce HBV transmission is HBV vaccination. According to our study, less than half of the HBV− recipients had positive hepatitis B surface antibody prior to receiving HBsAg+ livers. Although we were unable to differentiate the HBV vaccine nonresponders from those that were not vaccinated in the UNOS system, the low positive anti-HBs rate remains concerning and needs to be improved. Interventions that could increase the vaccination rate include providing routine transplant infection disease screening visits for all transplant candidates,¹⁴ and initiating the hepatitis B vaccine series during hospitalization or in hepatology clinics.^15,16

Finally, it can be challenging for transplant centers to discuss with patients and their families the possible pros and cons of using such organs, given the complexity of the issue and the stigmatization of HBV infection. It can be even more difficult if the discussion happens at the last minute before the organ offer. Transplant centers should be encouraged to routinely discuss with the patient about using these organs before or at the time of listing, especially for those suffering from cirrhosis complications who are disadvantaged by low MELD scores. Last but not least, it is critical to monitor NA compliance and HBV status posttransplant. Further studies are also needed to assess the possible long-term post-LT complications of these recipients, such as graft function and de novo HCC.

There are several limitations to our study. First, the number of HBV-negative recipients may be overestimated, given that their HBV status might not be well captured in the UNOS system. Posttransplant HBV serology and NAT status were not captured in the UNOS database either, so the HBV transmission rate cannot be assessed. The follow-up period in our study may not be long enough to observe outcomes regarding de novo HCC. Long-term studies with more granular data collection will be needed to answer these important questions. Furthermore, only a small number of HBsAg+ donors were transplanted during our study period. These are highly selected recipients who were transplanted in certain centers in the United States, so the results may not be generalizable to all transplant candidates. With the small number of patients, it can also be difficult to show statistically significant differences. However, the observed survival rates are mostly similar to or better than the recipients of the average risk of extended-criteria donors in our well-defined PSM cohorts. Our study proves the concept that transplanting HBsAg+ liver to selected HBV− recipients can have a similar outcome compared with those who received extended-criteria or average-risk grafts. We hope the promising results of our study can not only encourage more utilization of HBsAg+ livers but also inspire more future studies on this specific topic.

Using the UNOS database, we demonstrated that recipients of HBsAg+ livers had a good posttransplant outcome with a similar survival rate when compared with those who received livers from extended-criteria and average-risk donors. Utilization of HBsAg+ livers could safely expand the donor pool, especially for patients who are suffering from cirrhosis complications but do not have a high MELD score. The utilization of HBsAg+ liver remains low in the United States. Transplant centers and organ procurement organizations should be encouraged to procure and utilize these organs. Furthermore, transplant centers should develop protocols to vaccinate and consent potential recipients’ pretransplant and to monitor for possible complications posttransplant. Future studies should focus on the long-term post-LT outcome of the recipients of HBsAg+ livers, including graft function and the risk of HCC development.

Abbreviations:

AFP

alpha fetoprotein

AIH

autoimmune hepatitis

anti-HBs

antibody to hepatitis B surface antigen

CI

confidence interval

DCD

deceased cardiac death

DRI

donor risk index

HBV

hepatitis B virus

HBIG

hepatitis B immune globulin

HCC

hepatocellular carcinoma

HCV

hepatitis C virus

HCV NAT

hepatitis C virus nucleic acid test

HBsAg

hepatitis B surface antigen

LT

liver transplant

MELD

model for end-stage liver disease

NA

nucleoside analogs

NASH

Non-alcoholic steatohepatitis

PBC

primary biliary cholangitis

PSC

primary sclerosing cholangitis

PSM

propensity score-matched

SD

standard deviation

UNOS

united network for organ sharing

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.ajt.2023.04.024.

Data availability

Data sharing is not applicable to this article as no new data were created or analyzed in this study.