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Increased Risk of Severe Recurrence of Hepatitis C Virus in Liver Transplant Recipients of Donation After Cardiac Death Allografts

Hernandez-Alejandro, Roberto1,2,4; Croome, Kris P.1,2; Quan, Douglas1,2; Mawardi, Mohamed1,3; Chandok, Natasha1,3; Dale, Cheryl1; McAlister, Vivian1,2; Levstik, Mark A.1,3; Wall, William1,2; Marotta, Paul1,3

doi: 10.1097/TP.0b013e31822a79d2
Clinical and Translational Research
Free
SDC

Background. In hepatitis C virus (HCV) recipients of donation after cardiac death (DCD) grafts, there is suggestion of lower rates of graft survival, indicating that DCD grafts themselves may represent a significant risk factor for severe recurrence of HCV.

Methods. We evaluated all DCD liver transplant recipients from August 2006 to February 2011 at our center. Recipients with HCV who received a DCD graft (group 1, HCV+ DCD, n=17) were compared with non-HCV recipients transplanted with a DCD graft (group 2, HCV− DCD, n=15), and with a matched group of HCV recipients transplanted with a donation after brain death (DBD) graft (group 3, HCV+ DBD, n=42).

Results. A trend of poorer graft survival was seen in HCV+ patients who underwent a DCD transplant (group 1) compared with HCV− patients who underwent a DCD transplant (group 2) (P=0.14). Importantly, a statistically significant difference in graft survival was seen in HCV+ patients undergoing DCD transplant (group 1) (73%) as compared with DBD transplant (group 3) (93%)(P=0.01). There was a statistically significant increase in HCV recurrence at 3 months (76% vs. 16%) (P=0.005) and severe HCV recurrence within the first year (47% vs. 10%) in the DCD group (P=0.004).

Conclusions. HCV recurrence is more severe and progresses more rapidly in HCV+ recipients who receive grafts from DCD compared with those who receive grafts from DBD. DCD liver transplantation in HCV+ recipients is associated with a higher rate of graft failure compared with those who receive grafts from DBD. Caution must be taken when using DCD grafts in HCV+ recipients.

1 Multi-Organ Transplant Program, London Health Sciences Centre, University Hospital, London, ON, Canada.

2 Division of General Surgery, The Department of Surgery, The University of Western Ontario, London, ON, Canada.

3 Division of Gastroenterology, The Department of Surgery, The University of Western Ontario, London, ON, Canada.

The authors declare no funding or conflicts of interest.

4 Address correspondence to: Roberto Hernandez-Alejandro, M.D., London Health Sciences Centre, University Hospital, 339 Windermere Rd., London, ON, Canada N6A 5A5.

E-mail: roberto.hernandezalejandro@lhsc.on.ca

R.H.-A., K.P.C., P.M., D.Q., and W.W. participated in the research design. R.H.-A., K.P.C., P.M., and M.A.L participated in the writing of the manuscript. R.H.-A., K.P.C., M.M., C.D., and V.M.A participated in the performance of the research. R.H.-A. and K.P.C. participated in data analysis.

Received 3 January 2011. Revision requested 27 April 2011.

Accepted 21 June 2011.

Donation after cardiac death (DCD) has become a significant source of transplantable organs in an attempt to bridge the gap between the limited organ supply and the increasing pool of liver transplant candidates (1–4). Over the last decade, there has been over a 100% increase in DCD donations in the United States (5). It has clearly been shown that recipients who are hepatitis C virus (HCV) positive, and are transplanted with organs from donation after brain death (DBD) organs have a worse outcome compared with non-HCV recipients (6). However, the outcomes in HCV+ patients receiving DCD grafts have not yet been well described. Liver allografts from extended criteria donors such as those with advanced age have been shown to be a significant risk factor for earlier HCV recurrence which impacts both patient and graft outcomes (7, 8). Prolonged cold ischemia time (CIT) and, more importantly, warm ischemia time (WIT) are additional risk factors contributing to the poorer clinical outcomes in HCV recipients due to enhanced recurrence of the virus (9–11). Furthermore, other authors have suggested that HCV+ transplant recipients with early preservation injury have poorer survival outcomes than HCV transplant patients without preservation injury (12). By their very nature, DCD allografts typically suffer from these and other insults, suggesting that perhaps they are less than ideal organs for use in the delicate HCV recipient. We hypothesize that HCV+ patients receiving DCD allografts will have more severe recurrence and poorer clinical outcomes compared with HCV recipients of DBD allografts. Our center, London Health Sciences Centre, has the largest Canadian experience in liver transplantation using DCD grafts and in HCV recipients of these grafts we have observed a trend toward worsening clinical outcomes prompting further study. Thus, we set out to examine the outcomes of DCD liver transplant in HCV+ and HCV− recipients, and a control group of DBD liver transplants in HCV+ patients was also analyzed.

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RESULTS

A total of 32 patients underwent DCD LT from August 2006 to February 2011. All DCD donors were from hospitals within Ontario, Canada. Donor characteristics are summarized in Table 1. Of the 32 recipients, 17 patients were HCV+ (group 1) and 15 were HCV− (group 2). There were no significant differences in age, CIT, WIT between the HCV+ and HCV− groups, nor was there any significant difference in the recipients' age or MELD score. Diagnoses for recipients in group 2 included the following: alcoholic cirrhosis in five, autoimmune hepatitis in two, primary sclerosing cholangitis in two, non-alcoholic steatohepatitis in two, and other in 4. Recipient characteristics are summarized in Table 1.

TABLE 1

TABLE 1

Patient survival at 2 years was 80% in group 1 (HCV+ DCD) and 100% in group 2 (HCV− DCD) P=0.17. Graft survival at 2 years was 73% in group 1 and 93% in group 2 (P=0.14; Fig. 1). PNF occurred in one patient in group 1 (5.9%) and 1 patient in group 2 (6.6%). Disseminated IC occurred in 1 patient in group 1 (5.9%) and 1 patient in group 2 (6.6%). There were two deaths within the first year of transplantation in group 1, both secondary to severe HCV recurrence.

FIGURE 1.

FIGURE 1.

Group 1 (HCV+ DCD) were compared with a matched group of 42 HCV+ patients who underwent DBD LT during the same time period (group 3). The matched DBD liver transplant donors were also all from Ontario hospitals. Donor characteristics of the matched groups are summarized in Table 1. Recipient characteristics of the matched groups are summarized in Table 1.

Patient survival at 2 years was not statistically significant between group 1 and group 3, (80% vs. 92%), respectively. Graft survival was statistically significant between these groups, 73% vs. 92% (P=0.01; Fig. 2). There were no cases of PNF or IC in group 3 recipients. Causes of death in group 3 were HCV recurrence in 1 recipient, myocardial infarction in 1 recipient, and accidental death in 1 recipient.

FIGURE 2.

FIGURE 2.

Greater than 80% of patients in group 1 and group 3 were HCV genotype 1. HCV recurrence, determined by hepatic histology at 3 months, was present in 76% in group 1 and 16% in group 3 (P=0.005; Table 2). More impressively within the first year, histologic features of severe HCV recurrence (≥stage 2 fibrosis) was present in 47% of patients in group 1 and only 10% of patients in group 3 (P=0.004; Table 2). These findings were not associated with differences in genotype, viral load, cytomegalovirus status, episodes of rejection, or the tapering regimen of corticosteroids. Steroids were generally withdrawn after 3 months in a gradual fashion. Only one patient in the group 1 received antiviral therapy for hepatitis C within the first year of transplant and all the histologic comparisons are devoid of antiviral therapy such as interferon product or ribavirin. Antiviral therapy was held if patients were not felt to be well enough to tolerate it posttransplant.

TABLE 2

TABLE 2

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DISCUSSION

After transplantation into an HCV+ recipient, HCV recurrence is universal. Previous studies have shown that the duration of ischemic rewarming during DBD graft implantation is significantly associated with the severity of recurrent HCV and graft outcome (9, 10). Known risk factors for earlier HCV recurrence and decreased survival among HCV recipients include advanced donor age and steatosis (7, 8). It has also been suggested that liver transplantation after DCD in HCV recipients results in inferior patient and graft survival when compared with that after DBD (13, 14). Our analysis suggests that DCD graft is a risk factor for earlier and more aggressive HCV recurrence as revealed in the finding that 47% of our HCV+ recipients of DCD grafts were documented to have significant fibrosis (≥stage 2) within the first transplant year compared with significantly smaller number (10%) in the matched control group.

Organ cold/warm ischemia is believed to be a risk factor for increased severity of recurrence of HCV after liver transplantation (10–12). HCV+ recipients with evidence of graft reperfusion injury have been shown to have poorer survival outcomes when compared with non-HCV transplant patients with reperfusion injury. It is believed that with reperfusion injury there is associated hepatocyte death followed by cellular proliferation. In HCV+ patients, it is possible that the viral burden may increase dramatically by incorporating into these proliferating cells (15). The current study has shown nonsignificant but important trends of decreased patient and graft survival when comparing HCV+ with HCV− DCD recipients. We postulate that the WIT that is inherent to DCD transplant results in the rapid recurrence of HCV+ and subsequently leads to the higher rate of graft failure. Our findings may lack statistical power due to the small sample size; hence, a larger cohort will be required to substantiate these observations.

When comparing HCV+ DCD recipients with HCV+ DBD recipients, there was a trend of decreased patient survival in the DCD group, but a statistically significant decreased graft survival. Additionally, these differences correlated with a statically significant higher rate of HCV recurrence at 3 months and with a statically significant increased rate of severe HCV recurrence within the first year. These findings and the known increase in cold/warm ischemia seen with DCD transplants certainly lend support to the aforementioned theories that cold/warm ischemia may be the primary injury leading to the increased severity of recurrence of HCV after liver transplant. Moreover, the protocol biopsies performed in all HCV+ DCD liver transplant recipients showed histologic progression from time 0 to 3 months and then 1year, lending support that this was due to HCV progression and not a static process secondary to ischemia/reperfusion damage obtained at the time of liver procurement.

Cirrhosis from recurrent HCV after liver transplant has been shown to occur at a higher rate especially among patients infected with HCV genotype 1 (16). The HCV+ DCD and DBD groups had similar rates of HCV infection with genotype 1. Additionally, only one individual in group 1 and none of the individuals in group 3 received antiviral therapy specifically toward HCV within the first year of transplant. Given the observed rapid occurrence of fibrosis early after liver transplant in our HCV recipients of DCD grafts, we would suggest the early intervention of such products to reduce the potential for graft loss. Obviously any additional study evaluating DCD in hepatitis C recipient will have to be wary of the confounder that early introduction of antiviral therapy may have on the histologic outcomes.

A resent publication by Tao et al. (17) suggested that there is no significant difference in severe HCV recurrence between DCD (8%) and DBD (15%) allograft recipients. In the study by Tao et al., recipients who displayed biopsy-proven recurrence were treated with interferon-alpha and ribavirin for 48 weeks. In our study, one transplant recipient in group 1 and none of the transplant recipients in group 3 received antiviral therapy specifically toward HCV within the first year of transplant. It is possible that this could account for the difference in results seen between the two studies. These differences in results may indicate that antiviral therapy should be strongly considered in HCV+ recipients of DCD liver allografts.

A limitation of the present study is its small sample size and the single center nature of the study. A larger multicenter study would be valuable to further evaluate HCV recurrence in recipients of DCD liver transplants.

HCV recurrence was found to be more severe and progressed rapidly in HCV+ recipients who received grafts from DCD donors compared with those who received grafts from DBD donors. Additionally, this group had a trend towards a poorer graft survival. These findings highlight the negative impact of DCD grafts on hepatitis C liver transplant recipients and suggest a cautious approach for the ongoing use of these organs in these delicate recipients. In HCV+ recipients of DCD liver allografts, antiviral therapy should be strongly considered.

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MATERIALS AND METHODS

We performed a retrospective review on all patients who underwent DCD liver transplantation (LT) from August 2006 to February 2011 at our institution. Data on these patients were prospectively entered in our transplant database. Liver transplant recipients with hepatitis C and receiving a DCD graft (group 1, HCV+ DCD, n=17) were compared with transplant recipients without hepatitis C and receiving a DCD graft (group 2, HCV− DCD, n=15) and with a matched group of recipients with hepatitis C transplanted with a DBD graft (group 3, HCV+ DBD, n=42). This cohort was matched for year of transplantation, factors inherent in the donor risk index (donor age and donor height) and on CIT, recipient age, model for end stage liver disease (MELD) score, and previous liver transplant (18). Patients with hepatocellular carcinoma were listed because of synthetic decompensation and therefore the MELDs used in this study reflect their true MELDs and not the adjusted numbers. Primary outcomes were patient survival, graft survival, and HCV recurrence. Secondary outcomes were primary non-function (PNF) and biliary complications including ischemic cholangiopathy (IC). The study protocol received approval from our Institutional Review Board.

All DCD organs were procured in a controlled fashion. Patient withdrawal was performed in the intensive care unit in 29 (91%) patients and in the operating room in 3 (9%) patients. In all patients, a period of 5 min after cardiac arrest elapsed before declaration of death, as is the standard in Canada. Once in the operating room, a midline laparotomy incision was made. Canulation of the inferior vena cava was performed to exanguanate the abdominal organs. The aorta and superior mesenteric veins were then canulated and 4L histidine-trytophan-ketoglutarate cold perfusion fluid was used as preservation solution in the aorta and 3L histidine-trytophan-ketoglutarate was used in the superior mesenteric veins. Ice slurry was then poured into the abdominal cavity. A supraceliac aortic clamp was then placed after sternotomy. The common bile duct was transected and flushed immediately to drain bile as quickly as possible. The gallbladder was also opened to drain bile. Once the cold perfusate infusion was completed, the organ were removed from the abdomen and stored in cold preservation fluid. WIT and CIT were documented. WIT was defined as the time elapsed from withdrawal of life support until aortic cold perfusion was initiated. Implantation of the organs was performed using a classic bicaval anastomosis without veno-veno bypass. Standard immunosuppression included the use of tacrolimus, mycophenolate mofetil, and tapering corticosteroids.

All DCD recipients underwent a baseline liver biopsy at the time of transplantation (after arterial reperfusion). Protocol liver biopsies were also performed in HCV+ DCD liver transplant recipients. Protocol liver biopsies were started in all HCV+ DBD liver transplant recipients 7 months into the study period. Histologic HCV recurrence in recipients transplanted with DCD or DBD grafts was evaluated using protocol liver biopsies done at reperfusion, 3 months, and 1 year after transplantation and at other time points when clinically indicated. Recurrent HCV infection was defined as biochemical graft dysfunction with histologic findings consistent with HCV infection. Severe HCV recurrence was defined as HCV-related graft failure or death or a fibrosis stage more than or equal to 2 using the Metavir scoring system within 1 year from the date of transplantation (19). All HCV+ DCD and DBD liver recipients had positive HCV RNA before and after liver transplantation.

Differences between groups were analyzed using the unpaired t test for continuous variables and by the χ2 test or continuity correction method for categorical variables. Survival curves for patient and graft survival were generated using the Kaplan-Meier method and compared by the log-rank test. All statistical tests were two-sided and differences were considered significant when P is less than 0.05.

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REFERENCES

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Keywords:

Hepatitis C virus; Liver transplant; Donation after cardiac death

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