Successful Use of Hepatitis B Surface
Antigen- Positive Liver Grafts – An
Effective Source for Donor Organs in
Endemic Areas: A Single-Center
Experience
Long-Bin Jeng1,2,5, Ashok Thorat1,5, Horng-Ren Yang1,2,5, Chun-Chieh Yeh1,2,5, Te-Hung Chen1,2,6 , Chia-Hao Hsu1,2,6, Shih-Chao Hsu1,2,6, Kin-Shing Poon 3,5, Ping-Chung Li1,2,5, Hsueh-Chou Lai4,5, Wen-Pang Su4,6, Cheng-Yuan Peng4,6
1. Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan. 2. Department of Surgery, China Medical University Hospital, Taichung, Taiwan.
3. Department of Anesthesiology, China Medical University Hospital, Taichung, Taiwan. 4. Division of Hepatogastroenterology, Department of Internal Medicine, China Medical
University Hospital, Taichung, Taiwan.
5. College of Medicine, China Medical University, Taichung, Taiwan. 6. China Medical University, Taichung, Taiwan.
Correspondence to Long-Bin Jeng. Email: otc@mail.cmuh.org.tw
Organ Transplantation Center, China Medical University Hospital, 2, Yuh-Der Road, Taichung, Taiwan, 40447. TEL：04-22052121 Ext.1765, FAX：04-22029083
Authors’ emails:
Ashok Thorat: ashsurg@gmail.com, Horng-Ren Yang: er.sun@msa.hinet.net,
Chun-Chieh Yeh: b8202034@gmail.com, Te-Hung Chen: d13001@mail.cmuh.org.tw, Chia-Hao Hsu: d10759@mail.cmuh.org.tw, Shih-Chao Hsu: d12722@mail.cmuh.org.tw, Kin-Shing Poon: d7568@mail.cmuh.org.tw, Ping-Chun Li: d6789@mail.cmuh.org.tw, Hsueh-Chou Lai: d3145@mail.cmuh.org.tw, Wen-Pang Su: d13845@mail.cmuh.org.tw, Cheng-Yuan Peng: cypeng@mail.cmuh.org.tw
Key words: Hepatocellular carcinoma, End-stage liver disease, hepatitis B immunoglobulin, Entecavir, Acute liver failure.
liver transplantation; HCC, hepatocellular carcinoma; ESLD, end-stage liver disease; HCV, hepatitis C virus; ALF, acute liver failure; LT, liver transplantation; HBIG, hepatitis B immunoglobulin; MELD, model for end-stage liver disease; AST, aspartate aminotransferase; ALT, alanine aminotransferase; INR, international normalized ration; AFP, alpha-fetoprotein.
Abstract:
Background: Due to high prevalence of hepatitis B virus (HBV) infection in Taiwan, liver grafts from donors that are positive for hepatitis B surface antigen (HBsAg) without progressive disease can be effective alternative source of donor organs. This study aims to prove the safety of living donor liver transplantation (LDLT) using HBsAg positive liver grafts and its long term outcome. Methods: We studied 14 consecutive LDLT recipients that received HBsAg positive grafts from November 2009 to December 2013. Indications were HBV related hepatocellular carcinoma (HCC) in 8 patients, HBV-end-stage liver disease (ESLD) in 2, hepatitis C virus (HCV)-ESLD in 1 & acute liver failure (ALF) in 4 patients. 1 patient of HCC presented with ALF. All donors were chronic HBsAg carriers with normal liver function tests. Median follow up was 46 months (range, 35-59). Results: All the donors & recipients recovered well post-transplant with no reactivation of HBV till date. All the recipients were positive for HBsAg & 2 of the recipients (14.28%) had HBsAg >250 IU/ml & HBV deoxyribonucleic acid (DNA)>1Million IU/ml prior to the
transplantation; however, both the patients recovered well with undetectable HBV-DNA levels at post-transplant year 1. Two of the recipients died due to extrahepatic recurrence of HCC. At median follow up of 46 months, 4 years cumulative survival of recipients was 77.38%.
Conclusion: Use of HBsAg positive grafts in LDLT is safe for donors as well as recipients. HBV disease reactivation does not appear to be a threat even with HBIG-free antiviral monoprophylaxis regimen. This study thus proves the safety and feasibility of the option of using HBsAg positive grafts in high prevalence areas.
Introduction:
As liver transplantation (LT) emerged as a definite therapeutic treatment option for the patients with ESLD and/or HCC, the transplant community continues to face challenges in the form of increased demand with less availability of donor organs (1). Due to scarcity of deceased donation, living donation is the major means to expand the organ pool in Asia.
As prevalence of HBV infection is high in Asian countries like Taiwan and the ratio of HBsAg positive donors to the whole donor population is higher compared to western countries (2, 3), liver allografts from chronic HBV carriers without progressive liver disease can certainly expand the donor organ pool, especially in recipients with HBV related ESLD. This can also overcome the organ shortage in HCC patients with underlying HBV related cirrhosis, who otherwise have high chances of drop out in absence of suitable donor due to progression of underlying liver disease. Liver grafts from the hepatitis B core antibody (HBcAb) positive donors have been transplanted frequently in recipients with chronic HBV disease with promising outcome (4-6). The experience of using HBcAb positive liver allografts in HBV-naïve patients, however, shows that such transplantation carries the risk of transmitting de novo HBV infection to the recipients which is as high as 16%-95% in absence of effective antiviral prophylaxis (4, 5).
Despite of these studies of HBcAb positive liver grafts, experience of using HBsAg positive liver grafts remains less and in LDLT it is even rare (7-15). This is probably due to high concern of reactivation and recurrence of HBV in allograft as well as safety of donor that has precluded transplant community from using liver allografts from healthy HBV carriers. But, majority of the LT recipients in Asia are chronic HBV carriers and in emergency situations the chances of getting deceased organs are dismal. Thus, exclusion of HBsAg liver grafts from living donors is unwise provided that the donors lack progressive liver disease with negative HBeAg status, which is hallmark of high infectivity (16).
However, HBsAg positive grafts should never be transplanted in HBV-naïve recipients due to high risk of acquiring HBV infection in recipients and is historically prohibited. Also, it is suggested that all the recipients should receive some form of prophylaxis against HBV such as hepatitis B immunoglobulin (HBIG) and/or oral antivirals, with close monitoring of HBV serological tests (15).
Herein we present our successful experience of 14 recipients that underwent LDLT using HBsAg positive liver grafts. In this non-randomized retrospective study, we evaluated the clinical, virological & serological outcome in LT recipients as well as donors and the long term liver graft functioning in such patients. We also proposed the role of HBIG-free entecavir-only monoprophylaxis regimen in preventing HBV recurrence & disease reactivation.
Materials and Methods:
From November 2009 to December 2013, 371 patients underwent LDLT at our institute China medical University Hospital, Taiwan. Among these, 16 patients that received grafts from HBsAg positive donors without progressive liver disease were retrospectively studied. However, 2 patients were excluded from the study as their longest follow up was less than 12 months after liver transplantation and remaining 14 patients were enrolled for this study.
Demographic data, medical records, pretransplant laboratory data and virological markers of the recipients & donors were analyzed. The laboratory viral markers included HBsAg, HBeAg, anti-HBe, anti-HBc, anti-HBs and HBV DNA levels. HBV DNA levels were measured by analytical measurement by polymerase chain reaction (PCR) assay (ROCHE Cobas Ampliprep, Roche ®
Diagnostic Systems Inc., Bronnchburg, NJ; lower level of detection 2.6 log copy/ml).
Donor evaluation& Follow up protocol:
Pre-transplant donor evaluation was done adhering strict institutional protocol considering donor safety all the time. Liver functions and viral markers were assessed followed by radiological imaging studies that included ultrasonography, computerized tomography (CT) scan and/or magnetic resonance imaging (MRI). No evidence of hepatic parenchymal changes noted.
The donors with HBsAg positive serology were required to meet following virological criteria to be considered as safe for donation;
1. Negative for HBeAg
2. Reactive Anti-HBe antibodies. 3. No detectable HBV-DNA levels.
4. Normal liver function profile prior to surgery.
After the surgery all donors were followed up closely and required to undergo ultrasound study of liver in first week after surgery and every 3rd month thereafter for 1 year and 6 monthly for second year. In addition, serum virological data was assessed at 3 months, 6 months after transplantation and yearly thereafter. Donors were also followed up routine liver enzyme assays. At our center, we do not perform protocol liver biopsy. Liver biopsy is performed only in donors with clinical indications that require histopathological analysis.
All the donors received oral entecavir 0.5mg once daily for two years after surgery.
The risk of the procedure was explained to donor and recipient in each case. The detailed risk regarding the recurrence of HBV disease in recipient and potential risk of HBV flare up in donors in post-operative period was explained and signed consent was taken from donor and recipient in
every case. The study was approved by internal review board and ethical committee prior to LDLT.
Immunosuppression and anti-viral prophylaxis in recipients:
Our institute immunosuppressive protocol is mentioned in previous study (17). Primary immunosuppressive regimen was tacrolimus with addition of mycophenolate mofetil and/or everolimus. Tacrolimus trough levels were maintained between 8-10 ng/ml while everolimus, when used, trough levels were maintained between 3-5 ng/ml.
No HBIG was administered in any of the recipients who received HBsAg positive grafts. Monoprophylaxis was given with entecavir 0.5 mg once daily as lifelong treatment in recipients. Donor characteristics & serovirological analysis:
The donor cohort comprised of 8 males and 6 females with a mean age of 34.3 years (range, 24 to 55 years) (Table 1). All Donors were positive for HBsAg antigen and IgG anti-HBc with undetectable HBV DNA levels. Liver function profile prior to surgery was normal in all the donors.
Recipient characteristics & serovirological analysis:
Recipient characteristics are as shown in Table 2. In this present study, 11 males & 3 females underwent LDLT with a mean age 51.9 years (range, 31 to 64 years). Primary indication for liver transplant was HBV related HCC in 8 patients, ALF due to HBV flare-up in 4 patients, HBV related ESLD in 2 patients and HCV related cirrhosis in 1 patient. One patient with HCC had acute flare-up of underlying HBV infection.
Out of 8 HCC patients, five patients were within UCSF criteria while remaining 3 were beyond UCSF criteria. Two of the patients (Case 3& 11) had co-infection with hepatitis B and hepatitis C virus. Model for end-stage liver disease (MELD) score ranged from 7 to 40 (median=21). Six patients had MELD score more than 25. Five of these patients had grade II to grade III hepatic encephalopathy before transplantation. All the patients with HCC (n=8) & ESLD (n=3) had child score C.
All recipients except one were chronic hepatitis B carrier with positive HBsAg & anti-HBc antibodies (Table 2). None of the patients had hepatitis D virus co-infection. One patient (Case 11) was HCV related ESLD with positive serum profile for IgG anti-HBc antibody, which indicates recent acute HBV infection with absent HBsAg.
Six of the recipients had undetectable HBV-DNA prior to transplantation. Two recipients (14.28%) had HBV-DNA levels < 2000 IU/ml while 4 recipients (28.57%) had HBV-DNA levels between 10,000 to 30,000 IU/ml. Heavy HBV load was noted in two patients (Case 2 & 9) with HBV-DNA levels more than 1million IU/ml.
Alpha-fetoprotein (AFP) levels were as shown in Table 2. One recipient (Case 8) with HCC had AFP levels of 3854 ng/ml while it was <200ng/ml in remaining recipients.
Results:
Donor outcome
All donors underwent right hepatectomy and recovered well post operatively without any complications. The average hospital stay was 7 days in all the donors. The mean aspartate aminotransferase (AST), alanine aminotransferase (ALT), total Bilirubin & international
normalized ratio (INR) at 15th day post-donor surgery were 28.78 IU/ml, 28.07 IU/ml, 0.96 mg/dl & 1.09 respectively (Table 3). All the donors showed undetectable levels in the post hepatectomy period and continued to remain undetectable at the longest follow up period. The post operative ultrasound study of all the donors at median follow up of 46 months showed no evidence of cirrhosis or progressive liver disease.
Recipient outcome
14 patients received grafts from HBsAg positive donors and followed up for a period of 35 to 59 months (median 46 months). Two patients (14.3%) (Case 4 and Case 7 as shown in order in
table 2 &4) died at 13th and 33rd month respectively due to extrahepatic recurrence of HCC. For both of these patients, the liver function profile was normal as shown in Table 4 and HBV-DNA levels were undetectable at 1 year. Remaining 12 patients (85.71%) showed no signs of HBV disease reactivation during their follow-up till date. One episode of acute rejection occurred in 1 patient (7.1%) in 2nd week after surgery (Case 10) which was successfully treated with steroid pulse therapy. Graft failure requiring re-transplantation occurred in none of the patients.
Serovirological outcome of recipients
All patients continued to be positive for HBsAg and none of them practically cleared the HBV infection, although HBV DNA levels were undetectable in all the surviving recipients. HBV-DNA undetectability in recipients at 3, 6, 12 and 24 months were 57.14%, 85.71%, 100% and 100%, respectively.
The case 3 in this series had HCC as primary indication with HBV & HCV coinfection. But, post transplant viral activity remained quiescent till the longest follow up period (Table 2).
Case 11 presented with HCV related ESLD had presented with acute decompensation with grade 3 encephalopathy & MELD score 33 (Table 2). This patient was negative for HBsAg, but showed presence of IgG anti-HBc antibodies indicating past exposure to HBV infection and positive seroconversion was noted in post-operative period with HBsAg levels <250 IU/ml. But, no HBV replication noted in post-LT period and HBV-DNA levels remained undetectable. However, this
patient had universal recurrence of HCV infection after transplantation with altered liver functions. Liver function profile of case 11 at 1 year post-LT: AST 149 IU/ml, ALT 145 IU/ml, total Bilirubin 1.85 mg/dl and INR 1.1 (Table 4).
Two patients (14.28%) had HBeAg positivity at the time of transplantation indicating acute replicating HBV infection (Case 13 & 14). Post-operative recovery was good and HBeAg became undetectable at 6 weeks after transplantation in both the patients. HBV DNA showed gradual decline before becoming undetectable at the end of 1 year post-LT in both of these recipients. Liver function profile of both these patients at the end 1 year post-LT was AST 57 & 22 IU/ml, ALT 53 & 22 IU/ml, total bilirubin 0.42 & 0.59 mg/ml and INR 1.1 & 1 respectively (Table 4).
Relation between underlying liver disease and post transplant serovirological outcome
All the patients with acute liver failure (n=4) had HBsAg levels >250 IU/ml and increased HBV-DNA levels to more than 30000 IU/ml (2 patients had HBV HBV-DNA >1 million IU/ml). All these patients had smooth postoperative course with normal liver functions. At the end of 1 year post-LT, liver functions of the recipients with ALF were (Table 4): AST 41.5 IU/ml (range, 16-149), ALT 48.6 IU/ml (range, 13-150), total bilirubin 0.87mg/dl (range, 0.32-2.4) and INR 1.05. The HBV-DNA levels showed gradual decline and became undetectable at the end of 1 year (<12 IU/ml). No reactivation of the HBV infection was noted and graft functioning was stable at the end of follow up.
All the 8 patients with HCC had chronic underlying HBV infection. Among these, 2 patients had HBV DNA levels more than 10000 IU/ml and 1 patient had HBV-DNA < 2000 IU/ml. Remaining HCC patients had quiescent activity of HBV with undetectable HBV-DNA levels prior transplantation. Post operatively all these patients showed good graft functions with steady fall in HBV DNA levels till its disappearance at 1 year post LT. Liver function profile of HCC cohort at 1 year post-LT was: AST 37.12 IU/ml (range, 19-102), ALT 52.12 IU/ml (range, 29-150), total bilirubin 0.96 mg/ml (range, 0.32-2.4) & INR 1.02 (Table 5).
Post transplant outcome and overall survival in HCC & non-HCC subgroups
The recipients were further analyzed by categorizing them in two subgroups: HCC subgroup (n=8) & non-HCC subgroup (n=6). The characteristics and liver functions of both the subgroups are as shown in Table 5. The long term overall survival was reduced in HCC subgroup. The overall survival of HCC subgroup at median follow-up of 46 months was 75% (n=6) and for non-HCC subgroup it was 100%. Thus, underlying disease process had more impact on the long term survival of recipients than the mere HBsAg positivity of liver graft.
The liver function profile of all the recipients is shown in Table 6. At the end of the 1 year post transplant the mean AST, ALT, total bilirubin and INR were 41.5 IU/ml, 48.64 IU/ml, 0.87 mg/dl and 1.05 respectively (Figure 1a & 1b). The AST & ALT though initially were above normal (<2 upper limit of normal) showed gradual decline to within normal by 6 months.
Five patients developed biliary anastomotic stenosis requiring intervention. Acute rejection episode occurred in one patient and one patient developed upper gastrointestinal bleeding due to duodenal ulcer that was treated successfully with no further complications. Patient with HCV related ESLD had universal recurrence of HCV infection at 12th post-operative month with increased liver enzymes (Table 4).
Overall patient survival
1, 2 and 4-year overall survival at median follow-up of 46 months was 100%, 92.86% & 77.38% respectively (Figure 2). The survival of 14 recipients who underwent LDLT using HBsAg positive grafts from November 2009 to November 2011 was compared to 159 LDLT recipients that received healthy liver grafts (HBsAg-negative) in the same time period by using logrank test. 4-years survival achieved in study cohort (n=14) was 77.38% while in patients who received HBsAg negative grafts (n=173) it was 75.32% (p=0.43).
Discussion:
This retrospective analysis describes the safety of LDLT using HBsAg positive grafts in donors as well as recipients, and a practical solution to expand donor organ source in high prevalence areas. This is so far the largest population of patients who have received HBsAg-positive liver grafts from living donors with favorable long term outcome.
Due to the high prevalence of HBV infection in Taiwan (3) and as HBsAg-positive patients have mainly comprised the adult liver transplant recipient population, exclusion of such HBsAg positive donors does not appear to be practical especially in presence of severe underlying liver disease with deteriorating clinical condition. Six recipients had MELD score more than 25 and five of these patients had grade II to grade III hepatic encephalopathy before transplantation. All the recipients with ESLD (n=3) had child score C. Hence, in absence of suitable donor, we opted to use HBsAg positive donor allografts. But, while using HBsAg positive liver grafts, HBV disease reactivation in recipients always was a concern. However, the serum HBV load was undetectable in all the recipients at follow up period that ranged from 35 to 59 months, although all of them remained HBsAg positive after transplantation.
No signs of HBV hepatitis noted clinically in any of the recipients. We do not perform protocol biopsy either before or after liver transplantation unless clinical condition demands tissue diagnosis or in case of persistent rejection even after steroid therapy. As the follow up study of
studied cohort did not have any clinical evidence of underlying viral hepatitis, biopsy was not performed in any of the patients. Although, the histological grade of chronic hepatitis shows hepatitis activity and its progression to cirrhosis, this scoring system may be affected by sampling and observer variability. Also, a liver biopsy sample taken at one point will not fully demonstrate the liver disease status as chronic HBV hepatitis is slowly progressive disease. Serovirological and biochemical profile of both donors & recipients were followed up at regular intervals as per institute protocol. That demonstrated normal underlying liver functions.
Recent analysis of 10 recipients by Loggi et al. (13) & 78 studied recipients by Li et al. (15) who received HBsAg positive grafts, has shown similar favorable outcomes and stated that disease reactivation did not occur to be a threat. However, these studies were conducted in cohort population who received deceased donor liver transplantation. Also, both of these studies were conducted in areas (Europe & North America) with low prevalence (3% to 4%) of HBV infection as compared to 8.6% prevalence in south Asia (18). In addition, data from national registry may carry reporting bias, data entry errors, and inaccuracies. In our experience these all confounding factors were excluded due to small patient population and detail follow up of recipients & donors as per protocol.
Immunoprophylaxis regimens such as HBIG, antivirals and/or vaccination are recommended to minimize the risk for transmission of HBV to HBsAg-negative recipients and/or its reactivation in chronic HBV recipients (19). However, in our series, we precluded the use of HBIG and used oral entecavir 0.5 mg once daily as monoprophylaxis to prevent the reactivation of HBV. In donors, oral entecavir was continued for 2 years after surgery while in recipients it is given as lifelong therapy. In the donors as well as recipients we start oral entecavir therapy as early as 1st postoperative day. After 2years of follow up after stopping the entecavir treatment in donors showed no increased activity hepatitis B virus and HBV DNA levels remained undetectable. Theoretically, clinical flare up of HBV can happen during first few weeks after donor hepatectomy due to hepatocyte regeneration. Hence, HBV DNA levels were strictly monitored in all the donors after donor hepatectomy as per protocol. But, none of the donors showed any detectable activity of HBV replication postoperatively confirming the safety of donor hepatectomy.
With no viral reactivation in study cohort, we highlight the possibility of HBIG-free entecavir monoprophylaxis regimen in preventing HBV disease reactivation in post-LT period. The safety and adequacy of HBIG-free regimen of entecavir monotherapy after LT for chronic hepatitis B is also proven by Fung et al (20). In their study, 91% of studied patients lost HBsAg, with 98.8% achieving undetectable levels of HBV DNA at 1 year after transplantation and at the end
of 3 years of their study 78% of the recipients continued to have undetectable HBV DNA. Above all, the fact that entecavir (0.5 mg daily) is a potent anti-HBV agent that is superior to lamivudine or adefovir in rendering HBV-DNA undetectable and has a very good resistance profile, with < 2% cumulative 5-year resistance rate in nucleos(t)ide-naïve chronic hepatitis B patients (21). Although newer potent antiviral drugs such as tenofovir, adefovir dipivoxil are available, the antiviral efficacy of entecavir monotherapy is comparable. In one recent study entecavir monotherapy was equally effective to that of entecavir plus tenofovir in a mixed population of nucleos(t)ide-naïve patients of chronic hepatitis B with 70% of them being HBeAg positive (22)
In previous studies, we noted that HBIG has failed to show beneficial role in long term disease-free survival in all chronically infected HBV recipients receiving HBsAg positive liver grafts. Franchello et al. (7) in their study recommended against the use of HBIG as it failed to achieve measurable anti-HBs levels. Bahde et al. (11) in their single case experience suspended the use of HBIG after 6 months due to lack of efficacy in preventing replication of HBV as shown by elevation of HBsAg post-transplant & anti-HBs below the therapeutic range.
The lack of efficacy of HBIG can be attributed to the ability of an HBsAg-positive graft to continuously produce such large amounts of HBsAg that HBIG cannot by itself neutralize the circulating and intracellular HBsAg (23). Complete omission of HBIG after LDLT in chronic HBV recipients has been described recently (24). Hence, with the advent of more potent oral antivirals, the need for HBIG in the post-transplant setting needs to be re-evaluated.
HBV recurrence after LT is influenced by the severity of pre-transplant liver disease and patient's long term viraemic status (25). Patients transplanted for hepatitis B virus-related liver disease with undetectable or low (< 2000–20 000 IU/ml) serum HBV-DNA before antiviral therapy are considered to be at a low risk. However, those with a serum HBV-DNA levels ≥ 20000 IU/ml before antiviral therapy are at high risk for post-transplant HBV recurrence (26). Only four patients in this series had HBV-DNA levels ≥ 20,000 IU/ml (2 patients with >1M IU/ml) in pre-operative period, but all these patients were successful in suppressing the post-transplant viral activity. This confirms the fact that the patients whose serology showed controlled HBV infection for long duration in past were able to prevent HBV recurrence all the time after LT (13). Thus, the underlying pre-transplant disease severity affects the prognosis more than the mere HBsAg positivity of donor liver grafts. Also, the reason for the lack of a negative impact of HBsAg-positive donor grafts on survival may be that posttransplant HBV infections have a mild clinical course and are treatable (27).
Safety of living donors is top priority in all the LDLT programs. As major hepatectomy is a significant insult even for the healthy donor, risk of HBV flare-up in post hepatectomy period was the prime concern. But, postoperative course of the studied donors did not show any detrimental consequences. None of the donors in study cohort suffered from any complications. All donors were discharged on postoperative day 7 and followed up regularly. We do not perform protocol liver biopsy and/or CT; MRI studies unless there is underlying clinical suspicion warranting liver biopsy & imaging studies. Chronic hepatitis B is slowly progresses to cirrhosis; hence, a liver biopsy sample taken at one point will not fully demonstrate the liver disease status. Also, the scoring system may be affected by sampling and observer variability.
As maximal hepatocyte DNA synthesis occurs 24 to 36 hours after partial hepatectomy, and maximal DNA synthesis of the other cell types occurs 48 to 72 hours later (28), there were practical concerns of HBV flare up in first week after donor surgery. But, no such HBV replicative activity was noted in any of the donors. However, entecavir 0.5 mg as an antiviral prophylaxis was given in every donor for 2 years post surgery. HBV-DNA levels were assessed every 3 months for 1 year and every 6 months thereafter. Before the surgery all the donors were explained about the possible risks and theoretical possibility of HBV flare up in postoperative period due to hepatocyte regenerative activity. Also, no available reports have suggested the association between hepatectomy & hepatitis flare-ups in healthy HBsAg carriers (10). Although ethical dilemma of donor safety and saving the recipient exists, we state that the donor hepatectomy is feasible for HBsAg-positive healthy carrier under antiviral prophylaxis. However, ethical considerations are essential before considering HBsAg-positive donors.
This study thus confirms effectiveness of the LDLT in emergency situations using HBsAg positive liver grafts. Both, donors and recipients, showed no activity of increased HBV replication at their longest follow up and proved to be safe for donors as well as recipients. But, there are limitations of this study of being a non-randomized, single center non-comparative study, & small patient number. Also, as we stated the success of entecavir monoprophylaxis; the future study is required to include control group in strengthening this finding.
Conclusions:
With 4-years cumulative survival in 77.38% of LDLT recipients, this study thus proves the safety and feasibility of the option of using HBsAg positive grafts in high prevalence areas. Donor hepatectomy is safe for HBsAg-positive healthy carrier under antiviral prophylaxis. This study also highlights the role of HBIG free regimen in chronic HBsAg positive recipients, proving it to be cost effective. However, more studies are warranted to further strengthen the safety of donor and better outcome in recipients receiving HBsAg positive grafts.
References:
1. Pomfret EA, Sung RS, Allan J, Kinkhabwala M, Melancon JK, Roberts JP. Solving the organ shortage crisis: The 7th annual American society of transplant surgeons' state-of-the-art winter symposium. Am J Transplant 2008; 8: 745-752.
2. Merican I, Guan R, Amarapuka D, Alexander M, Chutaputti A, Xu D et al. Chronic hepatitis B virus infection in Asian countries. J Gastroenterol Hepatol 2000; 15:1356– 1361.
3. Liu CJ, Chen DS, Chen PJ. Epidemiology of HBV infection in Asian blood donors: emphasis on occult HBV infection and the role of NAT. J Clin Virol 2006; 36:S33–S44. 4. Prieto M, Gömez MD, Berenguer M, Cordoba J, Rayon JM, Berenguer J et al. De novo
hepatitis B after liver transplantation from hepatitis B core antibody-positive donors in an area with high prevalence of anti-HBc positivity in the donor population. Liver Transpl 2001; 7:51–58.
5. Cholongitas E, Papatheodoridis GV, Burroughs AK. Liver grafts from anti-hepatitis B core positive donors: A systemic review. J Hepatol 2010; 52: 272-279.
6. Donataccio D, Roggen F, De Reyck C, Verbaandert C, Bodeus M, Lerut J et al. Use of anti-HBc positive allografts in adult liver transplantation: Toward a safer way to expand the donor pool. Transpl Int 2006; 19:38-43.
7. Franchello A, Ghisetti V, Marzano A, Romagnoli R, Salizzoni M. Transplantation of hepatitis B surface antigen–positive livers into hepatitis B virus–positive recipients and the role of hepatitis delta coinfection. Liver Transpl 2005; 11: 922–928.
8. Ho JK, Harrigan PR, Sherlock CH, Steinbrecher UP, Erb SR, Yoshida EM et al. Utilization of a liver allograft from a hepatitis B surface antigen positive donor. Transplantation 2006; 81: 129-131.
9. Hwang S, Lee SG, Park KM, Kim KH, Ahn CS, Jung DH et al. Five-year follow-up of a hepatitis B virus-positive recipient of hepatitis B surface antigen-positive living donor liver graft. Liver Transpl 2006; 12: 993-997.
10. Soejima Y, Shimada M, Taketomi A, Yoshizumi T, Uchiyama H, Maehara Y et al. Successful living donor liver transplantation using graft from a hepatitis B surface antigen positive donor. Liver Int 2007; 27: 1282-1286.
11. Bahde R, Holzen JP, Wolters HH, Schmidt HH, Bock CT, Brockmann JG et al. Course of a HBsAg positive liver transplantation in a hepatitis B and D virus coinfected recipient. Ann Hepatol 2011; 10: 355-360.
antigen–positive liver grafts in recipients with hepatitis B virus–related liver diseases. Liver Transpl 2011; 17: 1236–1238.
13. Loggi E, Micco L, Ercolani G, Cucchetti A, Bihl F, Andreone P et al. Liver transplantation from hepatitis B surface antigen positive donors: A safe way to expand the donor pool. J Hepatol 2012; 56: 579-585.
14. Ju W, Chen M, Guo Z, Wang D, Zhu X, He X et al. Allografts positive for hepatitis B Antigen in Liver Transplant for Disease Related to Hepatitis B Virus. Exp Clin Transpl 2013; 11: 245-249.
15. Li Z, Hu Z, Xiang J, Zhou J, Yan S, Zheng S et al. Use of hepatitis B surface antigen– positive grafts in liver transplantation: A matched analysis of the US national database. Liver Transpl 2014; 20: 35–45.
16. Nguyen MH, Keeffe EB. Are hepatitis B e antigen (HBeAg)–positive chronic hepatitis B and HBeAg-Negative chronic hepatitis B distinct Diseases? Clin Infect Dis 2008; 47: 1312-1314.
17. Jeng LB, Thorat A, Hsieh YW, Yang HR, Yeh CC, Hsu CH et al. Experience of using everolimus in the early stage of living donor liver transplantation. Transplant proc. 2014; 46: 744-748.
18. Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: New estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine 2012; 30: 2212-2219.
19. Saab S, Waterman B, Chi AC, Tong MJ. Comparison of different immunoprophylaxis regimens after liver transplantation with hepatitis B core antibody-positive donors: A systematic review. Liver Transpl 2010; 16:300-7.
20. Fung J, Cheung C, Chan SC, Yuen MF, Chok KS, Lo CM et al. Entecavir monotherapy is effective in suppressing hepatitis B virus after liver transplantation. Gastroenterology 2011; 141: 1212-1219.
21. Chang TT, Lai CL, Kew Yoon S, Lee SS, Coelho HSM, Iloeje U et al. Entecavir treatment for up to 5 years in patients with hepatitis B e antigen–positive chronic hepatitis B. Hepatol 2010; 51: 422–430.
22.Lok AS, Trinh H, Carosi G, Akarca US, Gadano A, Habersetzer F et al. Efficacy of entecavir with or without tenofovir disoproxil fumarate for nucleos(t)ide-naïve patients with chronic hepatitis B. Gastroenterology 2012; 143: 619-28.
23. Van Nunen AB, De Man RA, Schalm SW. Passive immunization of chronic hepatitis B patients on lamivudine therapy: A feasible issue? J Viral Hepatitis 2002; 9:221-228.
24. Wadhawan M, Gupta S, Goyal N, Taneja S, Kumar A. Living related liver transplantation for hepatitis B–related liver disease without hepatitis B immune globulin prophylaxis. Liver Transpl 2013; 19: 1030–1035.
25. Lake J. Do we really need long-term hepatitis B hyperimmune globulin? What are the alternatives? Liver Transpl 2008; 14: S23–26.
26. Angus PW, Patterson SJ. Liver transplantation for hepatitis B: What is the best hepatitis B immune globulin/antiviral regimen? Liver Transpl 2008; 14: S15–22.
27. Yu L, Koepsell T, Manhart L, Ioannou G. Survival after orthotopic liver transplantation: The impact of antibody against hepatitis B core antigen in the donor. Liver Transpl 2009; 15: 1343-1350.
28. Taub, R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol. 2004; 5: 836–847.
Legend of figures:
Figure 1: 1a- ALT levels in recipients after liver transplantation. 1b- AST levels in recipients after liver transplantation.
