In the United Kingdom (UK) over 400 people die each year while waiting for a organ transplant, and approximately 1 in 6 people listed for a heart, lung, or liver transplant die or become too ill for transplantation before a graft is available.1
Currently around 200 000 people in the UK are infected with hepatitis C virus (HCV) and with increasing demand for organs for transplantation selected HCV seropositive donors (HCVpos) may represent an additional source of organs for transplantation.2,3
At present, organs from HCVpos deceased donors are usually declined for transplantation because of the high probability of disease transmission, with an accelerated risk of cirrhosis and liver failure; even in recipients who are HCV-positive, there is often reluctance to use organs from HCVpos donors. In many cases, HCV antibody-positive recipients have received treatment and cleared the virus.
National guidance in the US and UK cautions against the use of organs from HCVpos donors.4-6
Until recently, treatment of HCV in allograft recipients was expensive, toxic, and relatively ineffective.7 The advent of highly effective direct-acting antiviral (DAA) agents has greatly improved the outcome for HCV-infected patients, with sustained virological response (SVR) rates in excess of 95%.7-13 Hence, a large number of patients who would have required transplantation secondary to the end organ liver and/or kidney damage associated with chronic HCV infection are now being treated effectively before the need for transplantation.13 This means that the use of HCVpos donor organs for HCV negative recipients will need to be considered increasingly as the cohort of patients who could have received the HCVpos donor organs pre-DAA is reduced.13 However, the safety of using HCVpos donor organs varies depending on the organ being transplanted, with much of the current evidence demonstrating efficacy of DAA in the transplant population after donor transmission of HCV pertaining to kidney transplantation.1,14-16 There is concern regarding the use of livers from HCVpos donors because of the increased rate of progression to cholestatic hepatitis observed in liver transplant candidates with HCV.17,18 However, there is evidence to suggest that DAA use in this cohort also achieves SVR and reversal of hepatic decompensation.18,19 We hypothesized that there were a large number of nonproceeding HCVpos donors whose organs would otherwise have been considered of good quality for transplantation.
The aims of this study were to identify the seroprevalence of HCV in the UK deceased potential organ donor population, to determine the extent to which the presence of HCV impacted on their likelihood to proceed to organ donation, and to establish the quality of the donor organs that were not used for transplantation. We also aimed to estimate the impact that the use of organs from such donors would likely have in terms of additional transplants performed, transplant outcome, and specifically the cost benefit of using HCVpos donor kidneys for HCV negative recipients compared to a patient remaining on hemodialysis.
MATERIALS AND METHODS
Identification of Patients Dying in UK Critical Care Units Who Were Not Considered for Donation Because of the Risk of HCV Transmission
Many patients who die in critical care units and might be suitable organ donors are not considered for organ donation because the team caring for the patient do not consider donation as an option. To determine the number of patients who died in critical care and could have potentially donated organs but were not considered eligible as donors because of the presence of HCV or of an increased risk behavior posing an increased risk for HCV transmission (such as intravenous drug use), the UK national Potential Donor Audit (PDA) was examined. The PDA is a prospectively collected and validated registry of all patients younger than 80 years who died in critical care units in acute hospitals in the UK. A potential eligible donor is defined as a patient with no absolute contraindications to organ donation who met the requirements for brain-stem death testing or if death is thought likely to occur within 4 hours of withdrawal of treatment.20 The PDA was searched to identify deaths occurring from October 1, 2009 (when information in the PDA was made more comprehensive) to January 1, 2016. Patients with HCV were identified in the PDA by searching through the free text entries using the search terms “hepatitis,” “hepatitis C,” “HCV,” and “HepC.” All common abbreviations and misspellings of these search terms were also searched. Patients with a history of intravenous drug use (IVDU) were identified from the free text entries in the PDA using the search terms “intravenous drug use,” “IVDU,” “needle,” “heroin,” “overdose,” “injected,” “IVDA.” All common abbreviations, misspellings, synonymous terms, and colloquialisms of the above search terms were also searched.
Identification of Consented Potential and Proceeding Organ Donors in the UK Who Were Hepatitis C Positive
The UK Transplant Registry (UKTR) includes information on all deceased potential donors for whom consent for organ donation had been obtained, irrespective of whether or not they proceeded to donate organs for transplantation. The UKTR was examined to identify HCVpos potential and actual deceased donors in the UK between January 1, 2000, and January 1, 2016. HCVpos donors were identified by the presence of anti-HCV antibody in the serum at time of referral for organ donation; only a minority of the donor cohort had reported HCV RNA status in the UKTR as part of donor characterization. Consented potential donors were categorized as “nonproceeding organ donors” when, for whatever reason, organ donation did not occur, as “proceeding organ donors” when 1 or more of their solid organs were retrieved for transplantation irrespective of whether they were subsequently used for transplantation, and “actual organ donors” when 1 or more of their organs were used for transplantation.
Identifying Recipients of Organs From Hepatitis C–Positive Donors
The UKTR was used to identify all recipients of organs from deceased HCVpos donors and to obtain data on recipient survival, death-censored graft survival, and recipient HCV status.
Estimation of Nonproceeding Donor Organ Quality
The quality of nonproceeding donor organs, in terms of their suitability for transplantation, was assessed by estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease equation, liver tests, the UK Kidney Donor Risk Index (UKKDRI) and the UK Donor Liver Index (DLI).21-23 The UKKDRI and DLI are validated risk index scores that predict kidney and liver graft survival after transplantation in UK recipients.
Cost Analysis of Hemodialysis Versus Kidney Transplantation From a HCVpos Donor Together With Antiviral Therapy
To assess whether kidney transplantation along with the use of DAA to treat transmitted HCV would be cost-effective compared with hemodialysis, a cost analysis was carried out using the current estimated costs of renal transplantation in the UK (£53 288 first year plus £8,526 for each additional year), hemodialysis (£29,841) and a 12-week course of DAA therapy (sofosbuvir and ledipasvir +/− ribavirin, depending on the HCV genotype, £38 980).24,25 This combination of antiviral agents was selected based on the National Institute for Health and Care Excellence (NICE) recommendations published in 2015. Although the present study used only the combination of sofosbuvir and ledipasvir in the cost analysis, it is important to note that many more therapies have subsequently been approved by NICE.25,26
Continuous parametric variables were compared using Student t test and continuous nonparametric variables were compared using Mann-Whitney U test. Categorical variables were compared using χ2 test. Survival analysis was assessed using Kaplan-Meier tables. All analyses were performed using Statistical Analysis System (SAS) (version 9.3), and P values less than 0.05 were deemed to be statistically significant.27
Patients Dying in UK Critical Care Units Who Were Not Considered for Donation Because of the Risk of HCV Transmission
Between 2009 and 2016, 274 600 patients who died in UK critical care units and were not considered for organ donation for a variety of reasons were identified from the PDA, of which 780 (0.3%) patients were reported to have HCV infection and 882 (0.3%) had a history of IVDU. Of the 780 patients reported to have HCV, 277 (35.5%) also had a history of IVDU. Compared with all other patients not considered for donation in the PDA, those with reported HCV infection were younger (median, 48 years; interquartile range [IQR], 41-57 vs median, 68 years; IQR, 56-76, P < 0.001), were more likely to be male (69.5% male vs 59.3% male; P < 0.001), and were more likely to be of Asian descent compared to all other patients (7.3% vs 4.4%; P < 0.001) (Table 1).
Of the 780 patients with reported HCV infection, 370 had no other primary contraindication to organ donation, and met the requirements for brain stem death testing or could have been considered as a DCD donor. In 120 of the 370 patients, it was stated explicitly in free text entries of the PDA that the risk of HCV transmission was the reason that donation was considered not appropriate.
Proceeding and Nonproceeding Organ Donors Who Were HCVpos
Analysis of the UKTR for the period 2000 to 2015 identified 19 692 deceased potential organ donors. Of these, 244 (1.2%) were identified as anti-HCV antibody positive. Whereas only 98 (40.2%) of the HCVpos potential donors proceeded to become actual donors, 15 068 (76.5%) of the HCV seronegative (HCVneg) donors proceeded to donate 1 or more organs for transplantation (P < 0.001). Organs from 76 (77.6%) of the 98 HCVpos proceeding organ donors were used for transplantation, whereas organs from 14 458 (95.9%) of HCVneg donors were subsequently transplanted (P < 0.001). The number of potential HCVpos deceased donors increased over the study period, but the percentage proceeding to donate organs did not show any clear trend (Figure 1).
Over half (60.4%) of the 244 HCVpos potential organ donors had a history of increased-risk behavior for bloodborne viral disease. Only 6 (2.5%) consented HCVpos donors were co-infected with other bloodborne viruses (human immunodeficiency virus, n = 2; hepatitis B virus (HBV), n = 2; or human T-cell lymphotropic virus, n = 2).
The clinical characteristics of proceeding HCVpos donors were compared with those of nonproceeding HCVpos donors and to all proceeding HCVneg donors (Table 2). Proceeding HCVpos donors were significantly younger than nonproceeding HCVpos donors and all other proceeding HCVneg negative donors (median age [years], 41.5 [IQR, 32-51] vs 48.5 [IQR, 39-54] and 49.0 (IQR, 37-60), respectively, P = 0.010). Both proceeding and nonproceeding HCVpos donors were less likely to have a medical history of hypertension compared with all proceeding HCVneg donors (12 [12.2%], 24(16.4%) and 3717 (24.7%), respectively, P = 0.004). However, both proceeding and nonproceeding HCVpos had significantly higher reported rates of alcohol abuse, drug abuse, liver disease and smoking history compared to proceeding HCVneg donors (Table 2).
Outcomes of Recipients of HCVpos Donor Organs
Of the 98 HCVpos proceeding organ donors, organs were used from 76 donors and this resulted in a total of 92 solid organ transplants (63 liver, 27 kidneys, 2 heart). Patient and graft survival in recipients of livers and kidneys from HCVpos donors was no different to that observed in recipients of such organs from HCVneg deceased donors (Figure 2 and Figure 3). One of the heart transplant recipients died 7 years and 7 months after transplantation secondary to coronary occlusive disease, whereas the other heart transplant recipient is alive with a functioning graft (4 years, 8 months).
Of the liver transplant recipients, 96.8% (n = 61) were known to be or have been HCVpos. The 2 liver transplant recipients that were not known to have HCV required a liver transplant urgently. Of the 27 kidney transplant recipients, 8 (29.6%) were reported to be HCV antibody positive, 11 (40.7%) HCVneg, and 8 (29.6%) of unknown status. Of the heart transplant recipients, both recipients were recorded as being HCVneg. One of the heart transplant recipients fulfilled the criteria for super-urgent listing.
Estimation of Nonproceeding Donor Organ Quality
The most common reason given for consented HCVpos donors not proceeding to become actual organ donors was the presence of positive donor virology (76.0%); only 15 (8.9%) of such donors were declined because of poor organ function (Table 3).
The quality of organs in nonproceeding HCVpos consented donors was similar to that of HCVneg proceeding donors (Table 2). Of the nonproceeding HCVpos potential donors, 42% had an eGFR greater than 90 mL/min and a similar proportion had liver tests within normal range. UKKDRI calculated for nonproceeding HCVpos donors showed that half (49.9%) of the donors were in the best 2 UKKDRI quartiles. The DLI scores calculated indicated that 42 (28.7%) were in the 2 best DLI quartiles (Table 3).
We assessed if kidney transplantation and routine treatment with DAA would be cost effective compared with hemodialysis. As expected, kidney transplantation from an HCVneg donor was cost-effective compared with hemodialysis (Figure 4). Although the use of routine antiviral therapy in recipients of kidneys from HCVpos donors increased the cumulative cost of transplantation at 5 years by £38 979 per patient transplantation remained cost effective compared with hemodialysis at 5 years (Figure 4).
This study explored the opportunities for increasing organ donation and transplantation in the UK through the use of organs from HCVpos donors by analyzing the entire organ donation pathway from patients dying in critical care units who were not considered for donation through to donors whose organs were removed but subsequently declined for transplantation. Our findings confirm that many patients dying in UK critical care units are not considered as potential donors because of a history of HCV, and the majority of consented deceased potential donors with HCV do not proceed to organ donation because of the high risk of disease transmission.
The rationale for undertaking the present study was that the availability of DAA now provides a treatment that allows for safe transplantation of organs from HCVpos donors.16,28,29 DAA are small-molecule inhibitors of the HCV viral replication cycle that target nonstructural viral proteins.8,30,31 Genotypic coverage varies among the agents, but combination therapy permits the use of highly effective interferon-free regimens achieving SVR at 12 weeks in more than 95% of infected individuals. Several studies have shown successful HCV clearance using a variety of interferon-free, DAA-based regimens in genotypes 1 and 2 infected kidney and liver transplant recipients with preserved allograft function (The DAAs were safe, effective, and well tolerated.8,15,28-32 A recent open label, single group, pilot trial also demonstrated the feasibility of using HCVpos kidneys for HCVneg recipients.33 Studies are underway assessing the use of liver grafts from HCV viremic donors for HCVneg recipients but we are not aware of any published findings as yet. However, in terms of the DAA achieving SVR posttransplant several studies have demonstrated high rates of SVR in both cirrhotic and noncirrhotic liver transplant recipients, suggesting that if HCV was transmitted with the graft, treatment with combination DAA would likely achieve SVR also.8,18,19,34
An important consideration in the proposition to use organs from donors with HCV for HCV naive recipients is the possible legal implications of intentionally transmitting an infection. In the UK, the use of HCV infected organs is not prohibited, although guidance stipulates that recipients must give fully informed and specific consent and antiviral treatment must be made freely available. Similarly, in the US, federal law does not prohibit the use of HCV infected organs for transplantation.35
The PDA of patients dying in UK critical care units was established to identify patients that might be eligible to become organ donors but consent was not sought, and to examine the principal reasons for this. In the present study, analysis of the PDA identified 370 patients with a history of HCV over an 8-year period who were eligible to donate organs but consent for donation was not sought. In 120 of these, infection by HCV was stated explicitly as the reason for the patient not proceeding to become a potential donor. The patients identified from the PDA with a history of HCV/IVDU were significantly younger, and a greater proportion was of nonwhite ethnicity compared with all other patients identified in the PDA. These results are consistent with that reported by other studies investigating the clinical characteristics of deceased donors with HCV or a history of increased risk behavior for the transmission of bloodborne viral disease.13,36-39
The present study showed that for patients for whom consent for organ donation had been obtained, the presence of anti-HCV antibody was associated with a high likelihood (69%) that their organs would be declined for transplantation because of concern about disease transmission. In other respects, the declined HCVpos donors would have been considered satisfactory organ donors. They were of similar age to all other proceeding deceased donors and a significantly smaller proportion had a past medical history of hypertension. However, it is important to note that nonproceeding HCVpos donors were significantly more likely to be smokers, abuse alcohol, and have diabetes, all of which can detrimentally impact on allograft survival. Nevertheless, the use of organs from donors with such conditions is accepted in current transplant practice.
It is also important to note the possibility of coinfection of other bloodborne viral infections in HCVpos donors. In this cohort of nonproceeding deceased HCVpos donors, 6 (2.5%) were coinfected with HIV, HBV, or human T-lymphotropic virus. Although this represents a small proportion of the total, it is important to consider that if increased numbers of donors with HCV were to be consented and then used for transplantation, the risk of missing a recent HIV or HBV infection may possibly increase, although with current organ donor screening practice this risk is likely very small.40
Declined HCVpos donors often had good renal and liver function and based on validated UK Donor Risk Indices, 77% of kidneys and 80% of livers from the nonproceeding HCVpos donors would be predicted to be functioning at 5 years if they had been transplanted.
The majority of implanted HCVpos organs were livers and most of the liver recipients (96.8%) were known to already have had HCV infection before transplantation. Only a small minority of kidneys were used from proceeding HCVpos donors, yet were it not for the presence of HCV, they would generally be considered good quality kidney donors: compared with HCVneg donors, proceeding HCVpos donors were younger and a smaller proportion had hypertension. Although the number of transplant recipients of organs from HCVpos donors was small, their outcomes in terms of patient and graft survival were comparable with those in recipients of organs from HCVneg donors.
Although the routine use of HCVpos donors for transplantation would represent a major change in clinical practice, there are already precedents in the case of cytomegalovirus and Epstein-Barr virus, where it is accepted that transplantation may result in the transmission of viral disease and protocols are in place to mitigate their impact by prophylactic or preemptive therapy.40,41 With the use of DAA, acquisition of HCV through the transplanted graft, may become viewed in a similar light.42
The use of antiviral therapy of recipients of kidneys from HCVpos donors would add considerably to the cost of renal transplantation in the first 12 months. However, the cost analysis performed in the present study demonstrated that despite the high costs of combination sofosbuvir and ledispavir, their use to clear transmitted HCV from the renal allograft recipient would be cost effective compared to dialysis at 5 years. Similarly a recent US publication described the costs of hemodialysis being between US $40 000 and 73 000 and the cost of a combination of elbasvir/grazoprevir being US $63 000, indicating that similar cost benefit from transplanting HCVpos kidneys would be seen in the US.29,43 It is likely that the costs of DAA therapy will fall so the cost benefit may become greater in the future. Based on the last year of data in this study, and if the use of organs from HCVpos donors became part of UK practice, we could expect an additional 21 deceased donors with HCV. If each of these donors donated, on average, 2.3 organs for transplantation, like other UK deceased donors, we would expect 48 transplants of which 2 to 3 may be expected to fail treatment with current DAA therapy. However, it is important to note that many salvage therapies are in practice or in development, meaning that even those who do not clear the virus with first-line treatment will still likely achieve SVR.44
The UK Scientific Advisory Committee for the Safety of Blood, Tissues and Organs, the national committee that advises Ministers of the safety of organs for transplant (among other roles) has allowed use of organs from such donors in some circumstances and this advice has been accepted. A UK group, led by the British Transplantation Society and other bodies, is now drawing up clinical guidelines. We have proposed a pilot study in the UK to establish the impact that transplanting HCV viremic kidneys, hearts and lungs into HCV negative recipients followed by treatment of the recipients with combination DAA therapy. A pilot study in liver transplantation is underway.
There are limitations to the present analysis. The first concerns the determination of the HCV status of potential donors. Because the identification of HCVpos patients dying in critical care units through the PDA is based on entry of free text in the audit rather than a requirement to state the outcome of viral tests, it is likely that the number of patients classified as HCVpos is an underestimate. In the case of the UKTR of all consented potential donors, the presence of HCV infection was based on the results of serology and not on the presence of HCV RNA. In the UK, deceased donors who test positive for anti-HCV antibodies will be subsequently tested for HCV RNA with the result available after donation and transplantation. However, it is important to note that an increasing number of deceased organ donors who test positive for anti-HCV will be HCV RNA-negative secondary to increased use of DAA. Although centers in the UK may still not be able to test deceased donors for HCV RNA pretransplant, it is important to consider that a proportion of anti-HCV antibody-positive donors will not transmit HCV to the recipient.
Data from the UK blood donor service, where both HCV serology and NAT testing are performed on all blood donors, indicate that approximately 20% of the potential organ donors who are seropositive for HCV are likely to be RNA negative and therefore unlikely to transmit infection.3 The second limitation concerns the cost analysis of routine antiviral therapy in recipients of kidneys from HCVpos donors. The cost analysis performed was based on current costing by NICE using only the DAA currently recommended in their guidance in this rapidly moving field, many such treatments have now been approved.25,26 However, there are now a number of novel DAA, and these may be more or less cost effective in transplantation. Also, we have not been able to comment on the possible extra costs associated with routine testing of transplant recipients for the presence of HCV. Third, there is currently no information regarding the distribution of HCV genomes in the UK organ donor population as genotype determination is not part of routine organ donation screening. However, currently approved treatments include combinations that are active across all genotypes, with variable but usually high SVR greater than 95%. Data from the UK general population can be used to infer the expected proportion of different genotypes in the UK organ donor population. In the UK, 90% of infected strains belong to genotype 1 or 3 with the latter being more common than the former.3 The study cannot assess the likelihood of consent for transplantation in those potential donors where there was no attempt to determine their wishes. A further limitation of this study is not knowing the HCV status of all renal transplant recipients. However, given the period that these transplants were performed over, it is unlikely that these kidneys would have been transplanted into HCVneg recipients without confirmation of either recipient HCV status or further testing (not available in the UKTR) to confirm that the donor did not have HCV RNA.
In conclusion, the use of DAA raises the possibility that organs from HCVpos donors can be used with safety in HCVneg recipients. It is important to emphasize that experience of this practice is still limited, and although it appears safe and effective, some recipients may suffer adverse effects from antiviral therapy, and it cannot be assumed that antiviral treatment will invariably be effective. Nevertheless, as the present analysis demonstrates, the use of organs from donors with HCV offers considerable scope for increasing the number of organ transplants performed. Should such an approach be adopted, it is of course essential that the recipients gave fully informed consent before transplantation. These conclusions are in line with the recently published ASTS consensus conference statement on the use of HCV viremic donors.13 Although the present study was based on a detailed analysis of the UKTR and PDA, the US consensus guidelines focused on information from the Scientific Registry of Transplant Recipients and information available in the published literature; however, both the ASTS consensus report and this current article suggest the large scope available for using organs from donors with HCV.
The authors are grateful to the expert health economics advice we received from Professor John Cairns at the London School of Hygiene and Tropical Medicine and the Department of Health.
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