The scarceness of available donor variety meats is the cardinal challenge in orthotopic liver organ transplant A feasible manner to spread out the giver pool is the usage of liver transplants from hepatitis B virus surface antigen ( HBsAg ) positive givers. To day of the month, informations on OLT utilizing HBsAg-positive liver transplants are limited. Using the Scientific Registry of Transplant Recipients ( SRTR ) database ( 1987-2010 ) , 78 patients undergoing OLTs with HBsAg-positive transplants were matched each one for pressing position, gender of giver and receiver, age of giver and receiver, graft day of the month, Model for End-Stage Liver Disease ( MELD ) mark, and warm ischaemia clip with four patients having HBsAg-negative transplants. Demographics and result of all included patients were assessed. Overall transplant and patient endurance was similar between receivers with HBsAg-positive transplants and the matched controls ( 5-year endurance: 66 % versus 64 % , P = 0.954 and 71 % versus 71 % , P = 0.870, severally ) .Cox relative arrested development analysis seting for other variables showed no impact of the giver HBsAg position on the transplant and patient endurance. The causes of transplant loss and patient mortality were besides similar in the two groups. Further analysis shown that the usage of hepatitis B Ig ( HBIG ) was independently associated with better post-transplant patient endurance among receivers with HBsAg-positive transplants ( HR = 0.21, 95 % CI = 0.04-0.96 ) . Decision: The usage of HBsAg-positive liver transplants did non cut down post-transplant transplant and patient endurance. Matching these givers to receivers with HBIG disposal at the same time may be particularly safe.
Orthotopic liver organ transplant ( OLT ) is now good establishedA as a unequivocal intervention for patients with end-stage liver disease ( ESLD ) and/or hepatocellular carcinoma ( HCC ) . Despite the enormous progresss in OLT, there is a turning spread between the figure of variety meats available and the figure of variety meats needed. In 2009, more than 15000 patients were on the waiting list while lone 5975 of them ( 38.2 % ) received OLTs. At the same clip, 2396 patients were died while on the waiting list and 327 were excessively ill to transfer in United State ( US ) . The high waiting list mortality has made us to modify the standards of an acceptable liver giver to spread out the giver pool.
The usage of fringy givers, including variety meats from contribution after cardiac decease ( DCD ) , aged givers, or givers infected with hepatitis B ( HBV ) or C virus ( HCV ) , is going a feasible option to cut down the organ shortage. Liver transplants from HBV nucleus antibody ( anti-HBc ) positive but HBV surface antigen ( HBsAg ) negative givers, so called “ anti-HBc positive givers ” , are increasing applied, and these liver transplants are instead common in states of increased HBV endemicity, such as Asia and the Mediterranean part. A figure of surveies have suggested that the usage of anti-HBc positive transplant does non adversely impact on clinical result and shows a low hazard of HBV reactivation when treated with hepatitis B Ig ( HBIG ) and/or nucleos ( T ) ide parallels for prophylaxis. In contrast to anti-HBc positive givers, the usage of HBsAg positive liver transplants is far more limited. To day of the month, merely a few surveies exist sing the consequence of giver HBsAg positiveness on endurance, all of which are instance studies or short series. These available studies output conflicting consequences and are limited by little sample sizes and short followup. The possible usage of HBsAg positive transplants would hold public policy deductions, as it will highly spread out the giver pool for OLT, particularly in high prevalence countries.
Based on a national register database, we used a matched analysis to specify whether one could safely spread out the giver pool by utilizing HBsAg-positive liver transplants for patients with ESLD. We aimed to measure the post-liver organ transplant results of patients who received HBsAg-positive liver transplants and compared the consequences with those who received HBsAg-negative liver transplants.
Materials and methods
Beginning of informations
This survey was based on the Scientific Registry of Transplant Recipients ( SRTR ) . The SRTR information system includes current and past information about the full continuum of graft activity, from organ contribution and waiting list campaigners to transfer receivers and survival statistics in the US, submitted by the Organ Procurement and Transplantation Network ( OPTN ) from infirmaries and organ procurance organisations ( OPOs ) across the state. 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 survey was reviewed and approved by the Ethical Committee at Zhejiang University.
All liver transplant patients who received a first liver organ transplant between October 1987 and January 2010 were eligible in this survey cohort. Donors were considered HBsAg positive if the variable “ donor HBsAg position ” was reported as “ positive ” . Donors who were non HBsAg positive and with “ negative ” consequences recorded for the variable were considered HBsAg negative. Recipients for which giver HBsAg position was unknown were excluded. Among patients with HBsAg-negative transplants, we besides excluded those with anti-HBc positive giver transplants to avoid the influence of giver ‘s anterior HBV exposure. A sum of 92,157 patients met the inclusion standards and 78 of them received HBsAg-positive liver transplants.
Each patient who underwent OLT and received an HBsAg-positive liver transplant was matched to four matching patients who received an HBsAg-negative transplant. The features used for fiting were those antecedently found to be associated with patient and transplant result. Matching was completed in consecutive stairss. In the first measure, patients were matched by pressing position ( pressing and nonurgent ) , gender of giver and receiver, age of giver and receiver at graft ( A±5 old ages ) , transplant day of the month ( A±1 twelvemonth ) , Model for End-Stage Liver Disease ( MELD ) mark ( A±5 points ) , and warm ischaemia clip ( A±15 proceedingss ) . Patients waiting for OLT were considered as pressing or nonurgent campaigners harmonizing to their medical conditions before organ transplant, as defined by United Network for Organ Sharing ( UNOS ) classs. Before November 1994, pressing receivers were categorized as position 4, while nonurgent receivers included position 1, 2, and 3. After November 1994, the position appellation was modified by UNOS. Urgent receivers included either position 1 or 2A, and nonurgent receivers included position 2B, 3, or 4, harmonizing to the designated UNOS standards at the clip of organ transplant. Since February 2002, UNOS position is determined by either position 1 appellation or the MELD mark system, which is based on the values of serum entire hematoidin, creatinine, and INR ; these values were included for analysis every bit good. From the group of patients who received an HBsAg-positive transplant with the value of uninterrupted variables ( age, MELD, warm ischaemia clip ) in the matched scope, we selected four patients who received an HBsAg-negative transplant with the closest value on these variables. By this method, 67 of the 78 HBsAg-positive transplant receivers ( 85.9 % ) had acceptable matched controls. The staying 14.1 % of HBsAg-positive transplant receivers were successfully matched with HBsAg-negative transplant receivers in the following measure by loosen uping the graft day of the month scope ( A±2 old ages ) . As all the instances received asleep giver liver grafts ( DDLT ) , controls were selected merely for DDLT.
The chief results were patient endurance and transplant map. Both the current position and clip to outcome were included as result steps. Patient followup was defined as clip from organ transplant until day of the month of decease or last known followup. The happening and the day of the month of decease were obtained from informations reported by the graft centres and were completed by informations from the US Social Security Administration and the OPTN. The causes of decease or transplant failure in receivers were acquired from the dataset for patients accomplishing these results.
The 78 instances and the 312 matched controls were compared for baseline receiver and giver features. Statistical analyses were performed utilizing Student-t trials for uninterrupted variables, and Chi-square trials for categorical variables. Survivals were assessed utilizing Kaplan-Meier curves and compared with log-rank trials. Cox relative jeopardy theoretical accounts were created for the clip to survival and clip to graft loss, severally, to measure possible forecasters on the result steps. Variables that were significantly different at baseline comparing every bit good as those clinically relevant even if similar at baseline were included in the theoretical accounts. The consequences were expressed as jeopardy ratio ( HR ) with 95 % assurance interval ( CI ) . The causes of transplant loss and patient decease were analyzed and compared between instances and matched controls. Consequences were listed as average A± criterion divergence ( SD ) unless otherwise indicated. Standard alpha degree of 0.05 indicated statistical significance. All statistical trials were reversible. Analysiss were conducted utilizing SPSS 15.0 ( SPSS, Chicago, IL ) .
Among the 92,157 patients who underwent a first liver organ transplant during the survey period, 78 patients received HBsAg-positive liver transplants. These patients were matched to four corresponding patients harmonizing to the above-described processs. A sum of 312 patients were included in the matched control group. For the cohorts of HBsAg-positive transplant and HBsAg-negative transplant receivers, the average followups of which were both 52 months. Most patients underwent OLTs with HBsAg-positive giver transplants after 1993, with a extremum around the twelvemonth 2005 ( Fig. 1 ) .
The baseline features of HBsAg-positive transplant receivers ( n = 78 ) and HBsAg-negative transplant receivers ( n = 312 ) are listed in Table 1. Recipient features included age, sex, race, history of diabetes mellitus, history of HCC, retransplantation, pressing position, yearss on waiting list, whether on ventilator, whether on dialysis last 1 hebdomad, history of old abdominal surgery, incidental tumour at OLT, MELD mark, serum creatitine, serum hematoidin and cause of liver disease. Causes of liver disease were categorized as follows: HBV, HCV, intoxicant, nonalcoholic steatohepatitis, autoimmune ( including autoimmune hepatitis, primary bilious cirrhosis and primary sclerosing cholangitis ) , and other. Patients who were listed with HCV in add-on to other diagnosing were included under a listing diagnosing of HCV. Patients who had a listing diagnosing of HCC were included in the cohort under their primary cause of liver disease. Donor variables included age, sex, race, organic structure mass index ( BMI ) , donor hazard index ( DRI ) , non-heart-beating giver, warm ischaemia clip, cold ischaemia clip and cause of decease.
Since the two groups were good matched prior to analysis as per protocol, there were no statistical differences in most giver and receiver features between receivers with HBsAg-positive transplants and those with HBsAg-negative transplants. However, some differences were noted between the two groups. Recipients with HBsAg-positive transplants were more likely to hold received old abdominal surgery ( 32.7 % versus 20.5 % ; P = 0.039 ) prior to transfer. A higher proportion of patients who received an HBsAg-positive transplant were infected with HBV infection ( 19.2 % versus 7.2 % , P=0.002 ) .
Graft and patient endurance
A sum of 28 ( 35.9 % ) HBsAg-positive transplant receivers and 113 ( 36.2 % ) HBsAg-negative transplant receivers lost their transplants. At 1, 5, and 10 old ages, transplant endurance rates were 82 % , 66 % , and 49 % for receivers with HBsAg-positive transplants and 81 % , 64 % , 51 % for receivers with HBsAg-negative transplants, severally ( Log rank P=0.954 ) ( Fig. 2A ) .
A sum of 24 ( 30.7 % ) HBsAg-positive transplant receivers and 95 ( 30.4 % ) HBsAg-negative transplant receivers died on followup. The 1- , 5- , and 10-year patient endurance rates were 86 % , 71 % , and 53 % for receivers with HBsAg-positive transplants and 86 % , 71 % , and 56 % for receivers with HBsAg-negative transplants, severally ( P=0.870 ) ( Fig. 2B ) .
As the HBV infection rate was significantly higher among HBsAg-positive transplant receivers compared with HBsAg-negative transplant receivers ( 19.2 % versus 7.2 % , P=0.002 ) , we to boot analyzed the transplant and patient endurance at 5 old ages after excepting HBV-positive receivers. In this subgroup, transplant and patient endurance were besides similar comparing receivers with HBsAg-positive transplants every bit good as those with HBsAg-negative transplants ( 63 % versus 63 % ; P = 0.926 and 67 % versus 71 % ; P = 0.702, severally ) .
Forecasters of transplant and patient endurance
Cox relative jeopardy arrested development analysis theoretical accounts showed no consequence of the giver HBsAg position on the transplant or patient endurance ( Table 2 ) . Variables that were included in the theoretical account were: receiver features ( age, gender, race, MELD mark, HCC, abdominal surgery prior to transfer, being on ventilator at the clip of organ transplant, dialysis 1 hebdomad prior to transfer, incidental tumour at the clip of organ transplant, yearss on waiting list, and HBV infection ) ; and donor features ( age, DRI, and non-heart-beating giver ) .
Recipient age is the independent forecaster of both transplant and patient endurance. There was a 3 % increased hazard of losing the transplant and 4 % increased hazard of patient mortality perA yearA ofA increaseA inA receiver age. Besides, independent forecasters of transplant endurance were: DRI ( HR = 2.27, 95 % CI = 1.17-4.40 ) and receiver with HCC ( HR = 1.94, 95 % CI = 1.08-3.46 ) ( Table 2 ) , while which of patient endurance were: on dialysis prior to transfer and recipient with HBV infection ( Table 2 ) . A patient on dialysis prior to transfer was about 4 times more likely to decease on follow-up compared with patients non on dialysis. Otherwise, for patients with HBV infection, there was a 77 % decreased hazard of mortality.
Causes of transplant loss and patient mortality
The causes of graft loss were available in 21 of 28 ( 75.0 % ) recipients with HBsAg-positive transplants and 96 of 113 ( 85.0 % ) recipients with HBsAg-negative transplants ( Table 3 ) . The causes were similar in the two groups, with the most common 1s being primary transplant failure and hepatitis. The causes of patient mortality were available in 19 of 24 ( 79.2 % ) recipients with HBsAg-positive transplants and 71 of 95 ( 74.7 % ) recipients with HBsAg-negative transplants. The common causes were graft failure, infection, and cardiovascular jobs. The causes of patient mortality were similar in the two groups except for a likely tendency for a higher proportion of deceases due to infection in HBsAg-positive transplant receivers compared with HBsAg-negative transplant receivers ( 25.0 % versus 11.6 % ; P = 0.11 ) .
The consequence of HBIG on receivers with HBsAg-positive transplants
Among receivers with HBsAg-positive transplants for whom informations on HBIG usage were available, we besides assess the possible consequence of HBIG on transplant and patient endurance. Patient endurance rate was significantly higher in receivers with HBIG prophylaxis than those without HBIG prophylaxis ( 89 % versus 57 % at 5 old ages, P=0.028 ) ( Fig 3B ) , while there was a tendency toward a important association between the increased transplant endurance and the usage of HBIG ( 81 % versus 54 % at 5 old ages, P=0.060 ) ( Fig 3A ) .
A multivariate cyclooxygenase analysis was computed to find which variable could outdo predict result in receivers with HBsAg-positive transplants. Merely the usage of HBIG in HBsAg-positive transplant receivers independently predicted the post-transplant transplant and patient endurance rates ( HR = 0.25, 95 % CI = 0.63-0.96, and HR = 0.21, 95 % CI = 0.04-0.96, severally ) . The consequence was corrected for other variables including receiver features ( age, gender, race, MELD mark, HCC, abdominal surgery prior to transfer, being on ventilator at the clip of organ transplant, dialysis prior to transfer, incidental tumour at the clip of organ transplant, yearss on waiting list, and HBV infection ) ; and donor features ( age, DRI, and non-heart-beating giver ) .
Using comprehensive clinical informations from SRTR database, we did non happen a important association between usage of HBsAg-positive givers and post-transplant transplant or patient endurance after seting for other forecasters of post-transplant endurance. This indicates that the usage of HBsAg-positive transplants is safe and comparable in result even for long-run endurance to utilizing HBsAg-negative transplants. Furthermore, our survey demonstrated clearly that the usage of HBIG can better post-transplant endurance in receivers with HBsAg-positive transplants.
Though the figure of patients on the waiting list continues to turn, the giver organs remains in short supply. Stairss have been taken over the past old ages to increase the figure of variety meats available for OLT, which include utilizing split liver organ transplant and presenting populating giver liver graft plans. Furthermore, the usage of fringy giver transplant has besides been explored with the betterments in surgical techniques and immunosuppression. These fringy givers include steatotic livers, aged givers, DCD givers, and givers infected with HBV or HCV. Recent surveies showed that DCD receivers besides could bask satisfactory post-transplant endurances ( over 70 % at 3 old ages ) with some intervening steps. While in a survey utilizing UNOS database late, Yu et Al. found that patient endurance of receivers with anti-HBc positive transplant was similar with those with anti-HBc positive transplants ( HR = 1.09 ; 95 % CI = 0.97-1.24 ) . The usage of these fringy giver transplants are bit by bit regarded as safe. Expansion of acceptable giver standard has become a important beginning of transplantable variety meats. In our survey, 5-year patient and transplant endurance were non significantly different between the HBsAg-positive transplant receivers and the matched controls ( 71 % versus 71 % , and 66 % versus 64 % , severally ) .
The direction of patients who underwent OLT for HBV-related liver disease has changed significantly in the last two decennaries. Important inventions took topographic point to better the result of patients having OLT for HBV-related liver disease during this period, such as HBIG and 3TC. Immunoprophylaxis utilizing HBIG entirely began to be used widely in the early 1990s in the United States, while immunoprophylaxis utilizing HBIG combined with 3TC was introduced in late ninetiess. The clip points are consistent with our observation about the twelvemonth distribution of patients undergoing OLT with HBsAg-positive transplants: began in early 1990s while most OLT were performed in late ninetiess ( Fig. 1 ) . Although the usage of HBIG in receivers with HBV infection has become a consensus, the usage of HBIG in receivers with HBV morbific givers remains ill-defined. Previous surveies have suggested utilizing HBIG as an effectual attack to forestall hepatitis B return and better results in receivers with anti-HBc positive transplants.
However, the usage of HBsAg positive liver transplants is presently precluded in most transplant centres because of the high hazard of de novo HBV infection or HBV return after OLT. To day of the month, liver organ transplant from HBsAg positive givers has seldom been performed. Gonzalez-Peralta et Al. foremost reported a successful OLT of an HBsAg-positive transplant into a receiver without HBV infection. Despite HBIG prophylaxis, the patient was seropositive for HBsAg shortly after OLT. However, the patient ne’er encountered terrible HBV-related liver disease and even eliminated active HBV reproduction later. Several other instance studies besides reported their experience of utilizing HBIG and antiviral drugs against HBV such as 3TC, adefovir dipivoxil and tenofovir in receivers with HBsAg-positive transplants. Recently, Loggi et Al. reported a little sample survey of 10 patients successfully utilizing HBsAg-positive transplants with HBIG and nucleos ( T ) ide parallels prophylaxis. However, there was no comparing of result between HBsAg-positive transplant receivers with and without HBIG prophylaxis. The present survey, which consisted of 78 patients, clearly showed that HBsAg-positive transplant receivers with HBIG prophylaxis had significantly higher patient and transplant endurance that reached about 30 % advantages by 5 old ages ( 89 % versus 57 % , and 81 % versus 54 % , severally ) than those without HBIG prophylaxis. Furthermore, multivariate analyses identified the usage of HBIG in HBsAg-positive transplant receivers to be an independent forecaster of mortality and transplant loss.
Graft failure, malignance, and infection were common causes of decease in liver transplant population. In a anterior survey, Yu et Al. found that the common causes of decease in receivers with anti-HBc positive transplant was infection ( 20 % ) , malignance ( 12.8 % ) , and hepatitis ( 9.3 % ) . In our survey, transplant failure, infection and cardiovascular jobs were common causes of patient mortality on followup, lending to 15 % , 14 % and 11 % deceases, severally. While primary transplant failure ( 8 % ) and hepatitis ( 7 % ) were the most frequent causes of transplant loss in both groups. Furthermore, there was no important difference in the causes of patient mortality and transplant loss between receivers with HBsAg-positive and -negative transplants. This farther corroborates that the usage of HBsAg-positive transplants does non increase the hazard of patient decease or losing the transplant due to hepatitis related liver disease.
HBsAg-positive giver transplants may non take to worse endurance because post-transplant HBV infection has a mild clinical class and is treatable. The badness of post-transplant HBV infection was foremost described by Gonzalez-Peralta et al. , who reported that, the receiver who was seronegative for HBsAg pre-transplantation developed HBV infection after OLT. Although the receiver suffered mild liver disfunction, liver map normalized after intervention. The receiver eventually eliminated active HBV reproduction and was seronegative for HBsAg and HBV DNA. Subsequent instance studies and surveies besides have suggested an optimistic result. Loggi el Al. reported the usage of HBsAg-positive transplants for OLT in 10 patients with serological grounds of past hepatitis B infection. During a average followup of 36.8 months, merely 1 patient died due to HCV return. Despite 8 of 10 patients were seropositive for HBsAg after OLT, no patient of all time had any mark of active HBV hepatitis.
Due to the registry-based nature, there are a figure of restrictions of this survey, which are chiefly related to the information. The most of import one is the inability to measure the rate of post-transplant HBV infection on follow-up. We presume this was non really high, as the cause of patient decease or transplant loss due to hepatitis was non higher in receivers with HBsAg-positive transplants than those with HBsAg-negative transplants where this cause was known. Second, any big database is capable to describing prejudice, informations entry mistakes, and inaccuracies. Although the SRTR database is non immune to this job, these issues may be less worrying in surveies utilizing the SRTR database because of the compulsory engagement for all graft centres and the electronic redaction system to minimise informations entry mistakes. Furthermore, deficiency of information on viral burden, old and present usage of unwritten antiviral drugs, liver biopsy inside informations limits generalizability of the present survey consequences. Finally, given the high losing rate of the variable of 3TC usage, we are technically unable to measure the consequence of 3TC usage on post-transplant endurance.
Our survey besides has several highly of import strengths. Our survey includes the largest population of patients who received HBsAg-positive liver transplants with the longest follow-up available based on the SRTR database, which represents the full graft population in the US. The big sample size allows a firmer decision to be drawn in comparing with anterior instance studies of little sample size. Furthermore, the present survey is the first endurance analysis survey refering post-transplant transplant and patient endurance of HBsAg-positive transplant receivers. SRTR database collects detailed pre-transplant variables that are known forecasters of post-transplant endurance. And seting for these variables provides a less baffled appraisal of the true consequence of giver HBsAg positiveness on post-transplant result. Furthermore, we perform a matched analysis of receivers with HBsAg-positive and -negative liver transplants to cut down the consequence of confusing variable and expose a more intuitive comparing. It is besides the first survey measuring the consequence of HBIG on post-transplant endurance among HBsAg-positive transplant receivers. Although the aforesaid restrictions affected our ability to corroborate grounds behind our findings, they do non impact the cogency of our primary analysis of patient and transplant endurance.
In drumhead, utilizing the largest dataset available for analysis and the longest follow-up available to day of the month, our survey shows that the transplant and patient endurance in receivers with HBsAg-positive transplants are similar to those with HBsAg-negative transplants when other forecasters of post-transplant endurance are taken into history. There does non look to be an increased hazard of post-transplant patient mortality and transplant loss in HBsAg-positive transplant receivers. Use of HBIG in receivers with HBsAg-positive transplants could better post-transplant results. Our consequences will hold some deduction for enlargement of the donor pool. With careful execution and informed consent from the receivers, a important pool of drawn-out standards liver givers could be created with a potency for diminishing waiting list mortality and bettering post-transplant results, chiefly in high prevalence countries. Future prospective surveies of this population are warranted.