The scarcity of available donor organs is the key challenge in orthotopic liver transplantation A viable way to expand the donor pool is the use of liver grafts from hepatitis B virus surface antigen (HBsAg) positive donors. To date, data on OLT using HBsAg-positive liver grafts are limited. Using the Scientific Registry of Transplant Recipients (SRTR) database (1987-2010), seventy-eight patients undergoing OLTs with HBsAg-positive grafts were matched each one for urgent status, gender of donor and recipient, age of donor and recipient, transplant date, Model for End-Stage Liver Disease (MELD) score, and warm ischemia time with four patients receiving HBsAg-negative grafts. Demographics and outcome of all included patients were assessed. Overall graft and patient survival was similar between recipients with HBsAg-positive grafts and the matched controls (5-year survival: 66% versus 64%, P = 0.954 and 71% versus 71%, P = 0.870, respectively).Cox proportional regression analysis adjusting for other variables showed no impact of the donor HBsAg status on the graft and patient survival. The causes of graft loss and patient mortality were also similar in the two groups. Further analysis shown that the use of hepatitis B immunoglobulin (HBIG) was independently associated with better post-transplant patient survival among recipients with HBsAg-positive grafts (HR = 0.21, 95% CI = 0.04-0.96). Conclusion: The use of HBsAg-positive liver grafts did not reduce post-transplant graft and patient survival. Matching these donors to recipients with HBIG administration simultaneously may be especially safe.
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Orthotopic liver transplantation (OLT) is now well establishedÂ as a definitive treatment for patients with end-stage liver disease (ESLD) and/or hepatocellular carcinoma (HCC). Despite the tremendous advances in OLT, there is a growing gap between the number of organs available and the number of organs needed. In 2009, more than 15000 patients were on the waiting list while only 5975 of them (38.2%) received OLTs. At the same time, 2396 patients were died while on the waiting list and 327 were too sick to transplant in United State (US) . The high waiting list mortality has made us to modify the criteria of an acceptable liver donor to expand the donor pool.
The use of marginal donors, including organs from donation after cardiac death (DCD), aged donors, or donors infected with hepatitis B (HBV) or C virus (HCV), is becoming a viable alternative to reduce the organ deficit . Liver grafts from HBV core antibody (anti-HBc) positive but HBV surface antigen (HBsAg) negative donors, so called "anti-HBc positive donors", are increasing applied, and these liver grafts are rather common in countries of increased HBV endemicity, such as Asia and the Mediterranean region. A number of studies have suggested that the use of anti-HBc positive graft does not adversely impact on clinical outcome and shows a low risk of HBV reactivation when treated with hepatitis B immunoglobulin (HBIG) and/or nucleos(t)ide analogues for prophylaxis . In contrast to anti-HBc positive donors, the use of HBsAg positive liver grafts is far more limited. To date, only a few studies exist regarding the effect of donor HBsAg positivity on survival, all of which are case reports or short series. These available reports yield conflicting results and are limited by small sample sizes and short follow-up . The potential use of HBsAg positive grafts would have public policy implications, as it will extremely expand the donor pool for OLT, especially in high prevalence areas.
Based on a national registry database, we used a matched analysis to define whether one could safely expand the donor pool by using HBsAg-positive liver grafts for patients with ESLD. We aimed to assess the post-liver transplantation outcomes of patients who received HBsAg-positive liver grafts and compared the results with those who received HBsAg-negative liver grafts.
Materials and methods
Source of data
This study was based on the Scientific Registry of Transplant Recipients (SRTR). The SRTR data system includes current and past information about the full continuum of transplant activity, from organ donation and waiting list candidates to transplant recipients and survival statistics in the US, submitted by the Organ Procurement and Transplantation Network (OPTN) from hospitals and organ procurement organizations (OPOs) across the country. The SRTR is administered by the Chronic Disease Research Group (CDRG) of the Minneapolis Medical Research Foundation (MMRF) under contract with Health and Human Services (HHS) / Health Resources and Services Administration (HRSA). The whole study was reviewed and approved by the Ethical Committee at Zhejiang University.
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All liver transplant patients who received a first liver transplantation between October 1987 and January 2010 were eligible in this study cohort. Donors were considered HBsAg positive if the variable "donor HBsAg status" was reported as "positive". Donors who were not HBsAg positive and with "negative" results recorded for the variable were considered HBsAg negative. Recipients for which donor HBsAg status was unknown were excluded. Among patients with HBsAg-negative grafts, we also excluded those with anti-HBc positive donor grafts to avoid the influence of donor's prior HBV exposure. A total of 92,157 patients met the inclusion criteria and 78 of them received HBsAg-positive liver grafts.
Each patient who underwent OLT and received an HBsAg-positive liver graft was matched to four corresponding patients who received an HBsAg-negative graft. The characteristics used for matching were those previously found to be associated with patient and graft outcome. Matching was completed in sequential steps. In the first step, patients were matched by urgent status (urgent and nonurgent), gender of donor and recipient, age of donor and recipient at transplant (Â±5 years), transplant date(Â±1 year), Model for End-Stage Liver Disease (MELD) score (Â±5 points), and warm ischemia time(Â±15 minutes). Patients waiting for OLT were considered as urgent or nonurgent candidates according to their medical conditions before transplantation, as defined by United Network for Organ Sharing (UNOS) categories. Before November 1994, urgent recipients were categorized as status 4, while nonurgent recipients included status 1, 2, and 3. After November 1994, the status designation was modified by UNOS. Urgent recipients included either status 1 or 2A, and nonurgent recipients included status 2B, 3, or 4, according to the designated UNOS criteria at the time of transplantation. Since February 2002, UNOS status is determined by either status 1 designation or the MELD score system, which is based on the values of serum total bilirubin, creatinine, and INR ; these values were included for analysis as well. From the group of patients who received an HBsAg-positive graft with the value of continuous variables (age, MELD, warm ischemia time) in the matched range, we selected four patients who received an HBsAg-negative graft with the closest value on these variables. By this method, 67 of the 78 HBsAg-positive graft recipients (85.9%) had acceptable matched controls. The remaining 14.1% of HBsAg-positive graft recipients were successfully matched with HBsAg-negative graft recipients in the next step by relaxing the transplant date range (Â±2 years). As all the cases received deceased donor liver transplants (DDLT), controls were selected only for DDLT.
The main outcomes were patient survival and graft function. Both the current status and time to outcome were included as outcome measures. Patient follow-up was defined as time from transplantation until date of death or last known follow-up. The occurrence and the date of death were obtained from data reported by the transplant centers and were completed by data from the US Social Security Administration and the OPTN. The causes of death or graft failure in recipients were acquired from the dataset for patients achieving these outcomes.
The 78 cases and the 312 matched controls were compared for baseline recipient and donor characteristics. Statistical analyses were performed utilizing Student-t tests for continuous variables, and Chi-square tests for categorical variables. Survivals were assessed using Kaplan-Meier curves and compared with log-rank tests. Cox proportional hazard models were created for the time to survival and time to graft loss, respectively, to evaluate potential predictors on the outcome measures. Variables that were significantly different at baseline comparison as well as those clinically relevant even if similar at baseline were included in the models. The results were expressed as hazard ratio (HR) with 95% confidence interval (CI). The causes of graft loss and patient death were analyzed and compared between cases and matched controls. Results were listed as mean Â± standard deviation (SD) unless otherwise indicated. Standard alpha level of 0.05 indicated statistical significance. All statistical tests were two-sided. Analyses were conducted using SPSS 15.0 (SPSS, Chicago, IL).
Among the 92,157 patients who underwent a first liver transplantation during the study period, seventy-eight patients received HBsAg-positive liver grafts. These patients were matched to four corresponding patients according to the above-described procedures. A total of 312 patients were included in the matched control group. For the cohorts of HBsAg-positive graft and HBsAg-negative graft recipients, the mean follow-ups of which were both 52 months. Most patients underwent OLTs with HBsAg-positive donor grafts after 1993, with a peak around the year 2005 (Fig. 1).
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The baseline characteristics of HBsAg-positive graft recipients (n = 78) and HBsAg-negative graft recipients (n = 312) are listed in Table 1. Recipient characteristics included age, sex, race, history of diabetes mellitus, history of HCC, retransplantation, urgent status, days on waiting list, whether on ventilator, whether on dialysis last 1 week, history of previous abdominal surgery, incidental tumor at OLT, MELD score, serum creatitine, serum bilirubin and cause of liver disease. Causes of liver disease were categorized as follows: HBV, HCV, alcohol, nonalcoholic steatohepatitis, autoimmune (including autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis), and other. Patients who were listed with HCV in addition to other diagnosis were included under a listing diagnosis of HCV. Patients who had a listing diagnosis of HCC were included in the cohort under their primary cause of liver disease. Donor variables included age, sex, race, body mass index (BMI), donor risk index (DRI) , non-heart-beating donor, warm ischemia time, cold ischemia time and cause of death.
Since the two groups were well matched prior to analysis as per protocol, there were no statistical differences in most donor and recipient characteristics between recipients with HBsAg-positive grafts and those with HBsAg-negative grafts. However, some differences were noted between the two groups. Recipients with HBsAg-positive grafts were more likely to have received previous abdominal surgery (32.7% versus 20.5%; P = 0.039) prior to transplant. A higher proportion of patients who received an HBsAg-positive graft were infected with HBV infection (19.2% versus 7.2%, P=0.002).
Graft and patient survival
A total of 28 (35.9%) HBsAg-positive graft recipients and 113 (36.2%) HBsAg-negative graft recipients lost their grafts. At 1, 5, and 10 years, graft survival rates were 82%, 66%, and 49% for recipients with HBsAg-positive grafts and 81%, 64%, 51% for recipients with HBsAg-negative grafts, respectively (Log rank P=0.954) (Fig. 2A).
A total of 24 (30.7%) HBsAg-positive graft recipients and 95 (30.4%) HBsAg-negative graft recipients died on follow-up. The 1-, 5-, and 10-year patient survival rates were 86%, 71%, and 53% for recipients with HBsAg-positive grafts and 86%, 71%, and 56% for recipients with HBsAg-negative grafts, respectively (P=0.870) (Fig. 2B).
As the HBV infection rate was significantly higher among HBsAg-positive graft recipients compared with HBsAg-negative graft recipients (19.2% versus 7.2%, P=0.002), we additionally analyzed the graft and patient survival at 5 years after excluding HBV-positive recipients. In this subgroup, graft and patient survival were also similar comparing recipients with HBsAg-positive grafts as well as those with HBsAg-negative grafts (63% versus 63%; P = 0.926 and 67% versus 71%; P = 0.702, respectively).
Predictors of graft and patient survival
Cox proportional hazard regression analysis models showed no effect of the donor HBsAg status on the graft or patient survival (Table 2). Variables that were included in the model were: recipient characteristics (age, gender, race, MELD score, HCC, abdominal surgery prior to transplant, being on ventilator at the time of transplantation, dialysis 1 week prior to transplant, incidental tumor at the time of transplantation, days on waiting list, and HBV infection); and donor characteristics (age, DRI, and non-heart-beating donor).
Recipient age is the independent predictor of both graft and patient survival. There was a 3% increased risk of losing the graft and 4% increased risk of patient mortality perÂ yearÂ ofÂ increaseÂ inÂ recipient age. Besides, independent predictors of graft survival were: DRI (HR = 2.27, 95% CI = 1.17-4.40) and recipient with HCC (HR = 1.94, 95% CI = 1.08-3.46) (Table 2), while which of patient survival were: on dialysis prior to transplant and recipient with HBV infection (Table 2). A patient on dialysis prior to transplant was about 4 times more likely to die on follow-up compared with patients not on dialysis. Otherwise, for patients with HBV infection, there was a 77% decreased risk of mortality.
Causes of graft loss and patient mortality
The causes of graft loss were available in 21 of 28 (75.0%) recipients with HBsAg-positive grafts and 96 of 113 (85.0%) recipients with HBsAg-negative grafts (Table 3). The causes were similar in the two groups, with the most common ones being primary graft failure and hepatitis. The causes of patient mortality were available in 19 of 24 (79.2%) recipients with HBsAg-positive grafts and 71 of 95 (74.7%) recipients with HBsAg-negative grafts. The common causes were graft failure, infection, and cardiovascular problems. The causes of patient mortality were similar in the two groups except for a likely trend for a higher proportion of deaths due to infection in HBsAg-positive graft recipients compared with HBsAg-negative graft recipients (25.0% versus 11.6%; P = 0.11).
The effect of HBIG on recipients with HBsAg-positive grafts
Among recipients with HBsAg-positive grafts for whom data on HBIG use were available, we also assess the potential effect of HBIG on graft and patient survival. Patient survival rate was significantly higher in recipients with HBIG prophylaxis than those without HBIG prophylaxis (89% versus 57% at 5 years, P=0.028) (Fig 3B), while there was a trend toward a significant association between the increased graft survival and the use of HBIG (81% versus 54% at 5 years, P=0.060) (Fig 3A).
A multivariate cox analysis was computed to determine which variable could best predict outcome in recipients with HBsAg-positive grafts. Only the use of HBIG in HBsAg-positive graft recipients independently predicted the post-transplant graft and patient survival rates (HR = 0.25, 95% CI = 0.63-0.96, and HR = 0.21, 95% CI = 0.04-0.96, respectively). The result was corrected for other variables including recipient characteristics (age, gender, race, MELD score, HCC, abdominal surgery prior to transplant, being on ventilator at the time of transplantation, dialysis prior to transplant, incidental tumor at the time of transplantation, days on waiting list, and HBV infection); and donor characteristics (age, DRI, and non-heart-beating donor).
Using comprehensive clinical data from SRTR database, we did not find a significant association between use of HBsAg-positive donors and post-transplant graft or patient survival after adjusting for other predictors of post-transplant survival. This indicates that the use of HBsAg-positive grafts is safe and comparable in outcome even for long-term survival to using HBsAg-negative grafts. Furthermore, our study demonstrated clearly that the use of HBIG can improve post-transplant survival in recipients with HBsAg-positive grafts.
Though the number of patients on the waiting list continues to grow, the donor organs remains in short supply. Steps have been taken over the past years to increase the number of organs available for OLT, which include using split liver transplantation and introducing living donor liver transplant programs. Moreover, the use of marginal donor grafts has also been explored with the improvements in surgical techniques and immunosuppression. These marginal donors include steatotic livers, aged donors, DCD donors, and donors infected with HBV or HCV . Recent studies showed that DCD recipients also could enjoy satisfactory post-transplant survivals (over 70% at 3 years) with some intervening measures. While in a study using UNOS database recently, Yu et al. found that patient survival of recipients with anti-HBc positive grafts was similar with those with anti-HBc positive grafts (HR = 1.09; 95% CI = 0.97-1.24) . The use of these marginal donor grafts are gradually regarded as safe. Expansion of acceptable donor criteria has become a significant source of transplantable organs. In our study, 5-year patient and graft survival were not significantly different between the HBsAg-positive graft recipients and the matched controls (71% versus 71%, and 66% versus 64%, respectively).
The management of patients who underwent OLT for HBV-related liver disease has changed significantly in the last two decades. Important innovations took place to improve the outcome of patients receiving OLT for HBV-related liver disease during this period, such as HBIG and lamivudine. Immunoprophylaxis using HBIG alone began to be used widely in the early 1990s in the United States , while immunoprophylaxis using HBIG combined with lamivudine was introduced in late 1990s . The time points are consistent with our observation about the year distribution of patients undergoing OLT with HBsAg-positive grafts: began in early 1990s while most OLT were performed in late 1990s (Fig. 1). Although the use of HBIG in recipients with HBV infection has become a consensus, the use of HBIG in recipients with HBV infective donors remains unclear. Previous studies have suggested using HBIG as an effective approach to prevent hepatitis B recurrence and improve outcomes in recipients with anti-HBc positive grafts .
Nevertheless, the use of HBsAg positive liver grafts is currently precluded in most transplant centers because of the high risk of de novo HBV infection or HBV recurrence after OLT. To date, liver transplantation from HBsAg positive donors has rarely been performed. Gonzalez-Peralta et al. first reported a successful OLT of an HBsAg-positive graft into a recipient without HBV infection . Despite HBIG prophylaxis, the patient was seropositive for HBsAg shortly after OLT. However, the patient never encountered severe HBV-related liver disease and even eliminated active HBV replication subsequently. Several other case reports also reported their experience of using HBIG and antiviral drugs against HBV such as lamivudine , adefovir dipivoxil and tenofovir in recipients with HBsAg-positive grafts . Recently, Loggi et al. reported a small sample study of 10 patients successfully using HBsAg-positive grafts with HBIG and nucleos(t)ide analogues prophylaxis . However, there was no comparison of outcome between HBsAg-positive graft recipients with and without HBIG prophylaxis. The present study, which consisted of 78 patients, clearly showed that HBsAg-positive graft recipients with HBIG prophylaxis had significantly higher patient and graft survival that reached about 30% advantages by 5 years (89% versus 57%, and 81% versus 54%, respectively) than those without HBIG prophylaxis. Furthermore, multivariate analyses identified the use of HBIG in HBsAg-positive graft recipients to be an independent predictor of mortality and graft loss.
Graft failure, malignancy, and infection were common causes of death in liver transplant population . In a prior study, Yu et al. found that the common causes of death in recipients with anti-HBc positive grafts was infection (20%),malignancy (12.8%), and hepatitis (9.3%) . In our study, graft failure, infection and cardiovascular problems were common causes of patient mortality on follow-up, contributing to 15%, 14% and 11% deaths, respectively. While primary graft failure (8%) and hepatitis (7%) were the most frequent causes of graft loss in both groups. Moreover, there was no significant difference in the causes of patient mortality and graft loss between recipients with HBsAg-positive and -negative grafts. This further corroborates that the use of HBsAg-positive grafts does not increase the risk of patient death or losing the graft due to hepatitis related liver disease.
HBsAg-positive donor grafts may not lead to worse survival because post-transplant HBV infection has a mild clinical course and is treatable. The severity of post-transplant HBV infection was first described by Gonzalez-Peralta et al., who reported that, the recipient who was seronegative for HBsAg pre-transplantation developed HBV infection after OLT. Although the recipient suffered mild liver dysfunction, liver function normalized after treatment. The recipient finally eliminated active HBV replication and was seronegative for HBsAg and HBV DNA. Subsequent case reports and studies also have suggested an optimistic outcome. Loggi el al. reported the use of HBsAg-positive grafts for OLT in 10 patients with serological evidence of past hepatitis B infection. During a mean follow-up of 36.8 months, only 1 patient died due to HCV recurrence. Despite 8 of 10 patients were seropositive for HBsAg after OLT, no patient ever had any sign of active HBV hepatitis.
Due to the registry-based nature, there are a number of limitations of this study, which are mainly related to the data. The most important one is the inability to assess the rate of post-transplant HBV infection on follow-up. We presume this was not very high, as the cause of patient death or graft loss due to hepatitis was not higher in recipients with HBsAg-positive grafts than those with HBsAg-negative grafts where this cause was known. Second, any large database is subject to reporting bias, data entry errors, and inaccuracies. Although the SRTR database is not immune to this problem, these issues may be less worrying in studies using the SRTR database because of the mandatory participation for all transplant centers and the electronic editing system to minimize data entry errors . Moreover, lack of information on viral load, previous and present use of oral antiviral drugs, liver biopsy details limits generalizability of the present study results. Finally, given the high missing rate of the variable of lamivudine use, we are technically unable to assess the effect of lamivudine use on post-transplant survival.
Our study also has several extremely important strengths. Our study includes the largest population of patients who received HBsAg-positive liver grafts with the longest follow-up available based on the SRTR database, which represents the entire transplant population in the US. The large sample size allows a firmer conclusion to be drawn in comparison with prior case reports of small sample size. Moreover, the present study is the first survival analysis study concerning post-transplant graft and patient survival of HBsAg-positive graft recipients. SRTR database collects detailed pre-transplant variables that are known predictors of post-transplant survival. And adjusting for these variables provides a less confounded assessment of the true effect of donor HBsAg positivity on post-transplant outcome. Furthermore, we perform a matched analysis of recipients with HBsAg-positive and -negative liver grafts to reduce the effect of confounding variable and display a more intuitive comparison. It is also the first study assessing the effect of HBIG on post-transplant survival among HBsAg-positive graft recipients. Although the aforementioned limitations affected our ability to confirm reasons behind our findings, they do not affect the validity of our primary analysis of patient and graft survival.
In summary, using the largest dataset available for analysis and the longest follow-up available to date, our study shows that the graft and patient survival in recipients with HBsAg-positive grafts are similar to those with HBsAg-negative grafts when other predictors of post-transplant survival are taken into account. There does not appear to be an increased risk of post-transplant patient mortality and graft loss in HBsAg-positive graft recipients. Use of HBIG in recipients with HBsAg-positive grafts could improve post-transplant outcomes. Our results will have some implication for expansion of the donor pool. With careful implementation and informed consent from the recipients, a significant pool of extended criteria liver donors could be created with a potential for decreasing waiting list mortality and improving post-transplant outcomes, mainly in high prevalence areas. Future prospective studies of this population are warranted.