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Ian H Kerridge, Peter Saul and Robert G Batey
Current Australian policy prohibiting transplantation of organs from hepatitis C-infected donors raises questions about patient autonomy and medical paternalism.
MJA 1996; 165: 282-285
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Introduction - HCV infection - Transmission of HCV by organ transplantation - Implications of HCV infection after organ transplantation - Ethical issues - Conclusions - Acknowledgements - References - Authors' details
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A 42-year-old man presented to a liver clinic for assessment as he had
recently been found to be hepatitis C virus antibody (anti-HCV)
positive. Liver function test results had been normal in the two years
preceding this appointment, and the patient felt perfectly well.
There were no signs of chronic liver disease, and a liver biopsy
(undertaken at the patient's request) 12 months earlier had shown
minimal inflammatory damage and no fibrosis.
One of the main points for discussion at the outpatient clinic was that
this patient had been rejected as an organ donor by the
transplantation service. He was indignant that his offer of organs
was rejected, particularly as he felt that it would be appropriate in
the event of his death for his liver to be made available to another
HCV-positive patient. He asked for advice as to why HCV-positive
patients were unable to donate organs for transplantation.
A 48-year-old man presented with advanced alcohol-related liver
disease and is awaiting liver transplantation. His clinical
progress had improved slowly after cessation of alcohol intake but
his liver function had deteriorated in the preceding six months. He
had been advised that liver transplantation might be required within
12 months but had not yet been placed on the active transplantation
list.
This patient asked if he could have a liver transplant earlier if he
agreed to accept an HCV-antibody positive liver. This request was
motivated by his frustration at being unable to work and his awareness
that patients with hepatitis C were receiving transplants and
apparently doing well.
He was advised, that at present, there is a policy banning the use of
organs from all HCV-positive donors in Australia. He agreed to abide
by these rules but insisted that this issue be investigated further.
Introduction
D uring the past decade, advances in immunosuppression and
transplantation technology have increased the demand for organ
transplantation without a corresponding increase in the number of
donors. In June 1995, 1869 Australians were on waiting lists for
solid-organ transplantation, with a further 1435 awaiting corneal
transplants. Waiting-list numbers increased by 17% in the first six
months of 1995, while the Australian organ donation rate continued to
fall. 1 The relative donor
shortage and its impact on both waiting lists and the length of time
patients wait for transplantation highlights the importance of
efficient and effective organ procurement and use. 2
Viruses which may be transmitted by organ transplantation (such as cytomegalovirus, herpes simplex virus, Epstein-Barr virus, human immunodeficiency virus, hepatitis A virus, hepatitis B virus, hepatitis D virus and human T-cell lymphotropic virus type 1) have become one of the major causes of morbidity and mortality in organ transplant recipients. 3 For this reason, potential organ donors are routinely screened for the presence of viral infection. After the identification of the hepatitis C virus, and the recognition that it may be transmitted by organ transplantation, transplantation organisations have restricted the use of organs from anti-HCV-positive organ donors. 4
There is no international consensus about the use of HCV-positive organs in transplantation. Three recent studies from the United States highlight the variation in policies for the transplantation of organs from HCV-positive donors. Milfred et al. 5 found that, for heart and lung transplantation, 22% of the centres studied would accept organs from anti-HCV-positive donors irrespective of recipient HCV status, 45% would accept such donors only for anti-HCV-positive recipients, 27% would never accept these donors, 2% did not screen donors, and 4% did not have a defined policy. 5 By contrast, studies by Ramos et al. 6 and Schweitzer et al. 7 found that most US transplant centres would not accept organs from anti-HCV-positive donors for renal transplantation.
Part of the reason for the lack of consensus is that the consequences of transplantation of organs from anti-HCV donors (including the degree of HCV transmission, the prevalence of liver disease and the impact of HCV infection on survival) remain unclear. 8-11 Furthermore, any guidelines must incorporate ethical considerations relating to resource allocation, prognostic uncertainty, medical paternalism and limitation of patient autonomy.
In New South Wales, the Transplant Advisory Committee policy currently excludes transplant of all HCV-positive organs and tissues, including transplant to known HCV-positive recipients. The implications are that one in 50 potential organ donors are lost to the transplant program and that certain individuals therefore lose the right to choose potentially life-sustaining organ transplantation with an organ they know to be infected with HCV. These cases raise questions about the current Australian policy of excluding transplantation of HCV-positive organs and whether this constitutes unjustifiable paternalism. As with many questions of ethics in clinical practice, further understanding depends upon a number of factual issues concerning the transmission of HCV during transplantation and the consequences of HCV infection for the graft recipient. HCV infection HCV infection is now the most frequently reported notifiable disease in Australia. 12 Its true prevalence is unknown, but studies of Australian blood donors demonstrate a prevalence of 0.3%-0.7%. 13,14 Most estimates suggest that there are at least 100 000 cases in Australia. International studies reporting the incidence of HCV in cadaveric organ donors have shown wide variation (1.5%-16.7%), 15-17 probably reflecting both geographical variation in HCV prevalence and the different testing methods used for HCV identification.
Second generation enzyme-immunoassays used to detect anti-HCV have a sensitivity and specificity of about 90% and 99%, respectively, resulting in a positive predictive value in Australian blood and organ donors of less than 50%. 18 Confirmatory assays (e.g., radioimmunoblot assay [RIBA-2] and polymerase chain reaction techniques) can provide further evidence of actual HCV infection but may also give false positive or false negative results. 19 Genotyping assays are now available and may prove to be important for prognosis, determining epidemiological research and monitoring response to treatment.
Most cases of hepatitis C in Australia can be traced to a history of parenteral exposure through intravenous drug use (50% of cases) 20 or blood products (10%-15% of cases). 21 Since the introduction of routine donor screening for hepatitis C, the risk of transmission by infected blood products has reduced substantially. 22
Accurate information about the natural history of hepatitis C is extremely limited because diagnoses of acute hepatitis are rarely made, serum transaminase levels are poor predictors of liver disease and most studies of long-term outcome are limited to a 10-year follow-up. It is estimated that 50%-80% of infected patients develop chronic hepatitis C and 20%-30% of these will progress to cirrhosis. An unknown number (varying from 10%-75%) will develop hepatocellular carcinoma (HCC). 23 The mean interval between infection and diagnosis of cirrhosis is estimated to be 20 years.
The cornerstones of managing hepatitis C virus infection are education about its natural history and counselling to prevent transmission or worsening of the disease (e.g., avoiding the sharing of needles, restricting alcohol intake and practising "safe-sex"). Interferon alfa is available for treatment of chronic HCV under the Pharmaceutical Benefits Scheme but is extremely expensive; the long term response rate after a standard six-month course is approximately 20%-25%. 24
End-stage liver disease in patients with HCV can be managed medically or by liver transplantation. Reinfection of the graft is almost universal. Despite the need for immunosuppressive therapy, the resultant liver disease is generally benign and graft survival in the medium term (up to five years) is equivalent to that of other causes of liver disease requiring transplantation. Hepatitis C is now the most frequent indication for liver transplantation in Australia. 25 Transmission of HCV by organ transplantation There is conflicting evidence about the risk of transmission of HCV with organ transplantation. 26-30 Retrospective studies indicate that hepatitis is evident in approximately 50% of recipients of HCV-antibody-positive kidney transplants. 31 The type of solid organ transplanted (heart, lung, liver or kidney) does not appear to influence the transmission of HCV from an infected donor to a recipient. Recent studies have also demonstrated the transmission of HCV through bone marrow transplantation 32 and bone, ligament and tendon allografts. 33
Given the likely high degree of HCV transmission by organ transplantation, there is considerable interest in the work of Zucker et al., which suggests that washing donated kidneys can remove 99% of the viral burden. It is not known whether this has any significant impact on the transmission of HCV. 34 Implications of HCV infection after organ transplantation
There is evidence that liver disease is more frequent in recipients of anti-HCV-positive organs, 35 that immunosuppression may enhance HCV replication 36 and that immunocompromised patients infected with HCV may have a more aggressive course of infection. 37 A number of studies have also shown that, when HCV infection develops after renal transplantation, it will become chronic in approximately 85% of recipients and may progress to cirrhosis. 38 There is also evidence to suggest that HCV infection may increase the risk of rejection and infection; 39,40 however, no study has consistently demonstrated a significantly increased rate of mortality or graft loss in recipients of anti-HCV-positive organs. 41
The effects of HCV infection on transplanted livers in immunocompromised hosts can be partly surmised by examination of HCV-positive patients who receive HCV-negative liver transplants -- early reinfection occurs almost uniformly 42 and may range in severity from asymptomatic viraemia to cirrhosis and hepatic failure. A small number of patients develop fulminant hepatic failure after organ transplantation, but reinfection is usually not clinically significant, producing only mild inflammation. In general, primary infection with HCV and reinfection in a transplanted patient follow a similar course. 43
Growing awareness of the heterogeneous nature of HCV genotypes has led to suggestions that anti-HCV-positive organs could be safely made available for transplantation into anti-HCV-positive recipients. 44 Unfortunately, a number of studies have suggested that patients may become infected with multiple viral genotypes, 45 and there may not be sufficient cross-immunity between different HCV subtypes. 46 Furthermore, there is some evidence to suggest that repeated exposure to the virus may result in repeated bouts of hepatitis. 47,48 Thus, host seropositivity for HCV may provide no absolute assurance that a patient receiving an HCV-positive organ will have less risk of infection and liver disease.
In general terms it seems likely that transplant-related infection may follow a similar course to primary infection with hepatitis, 43 but the long term implications of HCV infection after organ transplantation remain unclear. Importantly, the use of interferon alfa for chronic hepatitis C does not appear to increase the risk of graft rejection. 49 Ethical issues With the increasing scarcity of organs, maximum use of donors is essential to realise the full potential of organ transplantation. However, in attempting to meet the health needs of both individuals and society, all attempts must be made to maximise the benefit and minimise the risks of transplantation to the recipient. The high probability of transmitting HCV by organ transplantation and the uncertain long term consequences of HCV infection in immunocompromised hosts have led the Transplantation Advisory Committee to ban the transplant of HCV-positive organs in New South Wales.
This policy is clearly medical paternalism; the question is, is it justifiable paternalism? Should informed patients be able to request transplantation of HCV-positive organs, in the light of their own wishes, beliefs and values, or do policies such as these constitute justifiable limits of autonomy? The uncertain risks of HCV may add to the mortality and morbidity associated with organ transplantation, but this is not in itself sufficient reason for preventing patients from choosing an HCV-positive organ.
It is well accepted that competent patients may have the right to choose medical interventions which have significant or uncertain side effects, provided they are aware of the nature and likelihood of such complications. This is especially the case when alternative forms of therapy are associated with high rates of morbidity and mortality. For example, young patients with acute myeloid leukaemia will always be offered bone-marrow transplantation, despite its significant risks, because other treatments for this condition have such poor outcomes.
This is not to suggest that patient autonomy is, or should be, unrestricted. Patients may not request treatment that is ineffective, that endangers others, or that is judged by health care professionals and, ultimately, by society to be of insufficient value to be allocated scarce health resources. It may well be that current policy should continue for non-life-threatening conditions (such as renal transplantation in chronic renal failure) because of the uncertain long-term consequences of HCV infection and the small number of donor organs that would be gained from relaxing the prohibition on the use of HCV-positive organs. On the other hand, for patients awaiting heart, lung or liver transplantation, the risk of liver disease after organ transplantation from an HCV-positive donor may well be more acceptable than the risk of death or poor quality of life without transplantation.
A further difficulty is that, whereas the transplantation of an HCV-positive organ may benefit the individual, this may be to the detriment of the wider community. The use of HCV-positive organs would clearly generate a potential source of preventable infection which may impact significantly on the lives of others (such as sexual partners) and inevitably demand further expensive treatment. The cost of a six-month course of interferon alfa is $3200 and the cost of liver transplantation for end-stage liver disease is $120 000, plus $7000-$10 000 per annum postoperatively. A conservative estimate of the cost of treating a patient with chronic hepatitis C (including hospitalisations) over five years is approximately $100 000.
The effects on the present system of waiting-lists of a separate pool of "sub-standard" HCV-positive organs may also become increasingly complicated. Should a patient be able to "jump the queue" to a position higher up the waiting list if they are willing to accept such an organ? Should a patient at the top of the queue have the right to refuse an HCV-infected organ? Should there be a separate list of patients who are eligible only for HCV-infected organs? Conclusions Much of the uncertainty about the significance of hepatitis C infection in organ transplantation will only be resolved by further research. Until then, the obligations suggested by the ethical principles of autonomy, non-maleficence, beneficence and justice suggest a number of alternative approaches to the management of HCV-positive donors, shown in the Box.
The decision to transplant an HCV-infected organ remains a complex issue in which benefit must be weighed against harm and individual choice against the wider demands of society and scarce health resources. Ultimately, such issues may only be resolved through an approach based on shared and informed decision-making between doctors and patients, recognising the many clinical and epidemiological uncertainties involved in these circumstances.
That there are organ recipients willing to accept HCV-positive organs, but prevented from doing so by current policy, reflects tension between professional guidelines and individual needs or between medical paternalism and patient autonomy. We believe that there are circumstances in which transplantation of HCV-infected organs may be indicated, particularly in the case of life-saving transplantation.
Decisions that deny choice to informed, competent patients are the subject of increasing scrutiny by the medical and legal professions and the community at large. If patients who are aware of the risks and complications are to be denied the choice of an HCV-infected organ, such denial must be carefully considered and explicitly justified. Acknowledgements We acknowledge the contributions of Dr Michael Lowe for his editorial assistance and of members of the John Hunter Hospital Clinical Ethics Committee for advice on the formulation of this paper. References
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