When Theory Becomes Reality: Navigating the Ethics of Transplanting Hepatitis C Virus–Positive Livers Into Negative Recipients

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Abbreviations

D⁺/R⁻

donor negative/recipient positive

DAA

direct‐acting antiviral

FCH

fibrosing cholestatic hepatitis

HCV

hepatitis C virus

LT

liver transplant

MELD

Model for End‐Stage Liver Disease

PHS IR

Public Health Service Increased Risk

RCT

randomized controlled trial

SVR

sustained virological response

UNOS

United Network for Organ Sharing

“Should organs from hepatitis C antibody positive donors be used for transplantation?” This question was posed in a Lancet editorial in 1995, in which its authors Sánchez‐Tapias and Rodés1 discussed the ethics of knowingly transmitting an infectious disease into an unexposed patient. Over the past 24 years, through progress and discovery in hepatology, infectious disease, and transplant medicine, hepatitis C virus (HCV) cure after transplant is safe and highly effective. Ethical questions of HCV transmission into negative donors persist, now not as a theoretical discussion but rather as an emerging aspect of standard of care in transplant medicine. Other ethical quandaries shaped by informed consent, organ donor scarcity, and health care delivery and economics exist as well (Fig. 1). These issues are discussed in the context of five principles of medical ethics: autonomy, nonmaleficence, beneficence, utility, and justice.2

Figure 1.

The interplay of medical considerations, patient preferences, quality‐of‐life concerns, and contextual features surrounding HCV D⁺/R⁻ LT.

Autonomy

Autonomy is defined as “deliberate self‐rule,” or having the ability to make one's own informed decisions.2 In medical ethics, the principle of autonomy often revolves around the issue of informed consent.2 The most important aspect of autonomy regarding HCV donor‐positive (i.e., viremic as measured by nucleic acid testing)/recipient‐negative (D⁺/R⁻) liver transplant (LT) is the informed consent process and institutional safeguards regarding therapies that are not yet standard of care. Currently, there are no standardized rules from the United Network for Organ Sharing (UNOS) regarding specialized informed consent specifically for HCV D⁺/R⁻ LT. In 2017, an American Society of Transplantation consensus conference released a report on HCV viremic donors in solid organ transplantation. The report recommended a multistep, unique informed consent process, involving the patient and his or her support system, that delves into HCV D⁺/R⁻ organ transplantation. The conference also specifically called for institutional review board–approved protocols for this informed consent process and the carrying out of HCV D⁺/R⁻ organ transplantation.3 Standardization and application of a specialized informed consent will be necessary to give patients impartial, complete information to make autonomous decisions regarding their care. Transplant societies may want to consider protocols outlining the specific components of the consent process in detail that would serve as a template for transplant centers. In addition, shared decision making involving the transplant team educating patients about direct‐acting antiviral (DAA) treatment and quality of HCV⁺ organs, and patients expressing their concerns about acquiring an infectious disease after LT, will be required.

A survey study of 422 transplant surgeons in the United States showed that only 52.7% of these providers used the UNOS special informed consent process required for Public Health Service Increased Risk (PHS IR) organs.4 Special informed consent use was significantly associated with greater use of PHS IR liver grafts.4 Moreover, another study showed that transplant surgeons who reported that medical risks of HCV infection disincentivized using PHS IR organ grafts were less likely to transplant HCV⁺ grafts (determined by antibody at that time).5 Although these data show provider concerns regarding PHS IR grafts and HCV⁺ grafts within the last 10 years but prior to the DAA era, further research is needed to determine whether DAA therapy and its well‐documented efficacy and safety profile have affected attitudes on this topic.6, 7, 8, 9, 10, 11

Nonmaleficence and Beneficence

“To provide net medical benefit to patients with minimal harm” is to balance beneficence with nonmaleficence.2 There has been a paucity of published data regarding outcomes of HCV D⁺/R⁻ LT. Two case reports of HCV D⁺/R⁻ LT were published in 2018, and both patients achieved sustained virological responses (SVRs) without adverse events.12, 13 Similarly, a case series analysis of 10 patients who underwent HCV D⁺/R⁻ LT between March 2017 and January 2018 with subsequent DAA treatment reported a 100% SVR rate without patient death or graft failure.14 In addition, a 2019 retrospective study by Cotter et al.15 comparing HCV D⁺/R⁻ LT with HCV D⁺/R⁺, D⁻/R⁺, and D⁻/R⁻ LT from 2014 to 2018 found that short‐term graft survival rates were not significantly different between all groups. The pertinent ethical issue of HCV D⁺/R⁻ LT regarding nonmaleficence and beneficence is whether the risks of knowingly infecting the patient with HCV—and exposing the patient to the sequelae of HCV infection, including the possibility of fibrosing cholestatic hepatitis (FCH), increased rates of graft rejection, and DAA side effects or treatment failure with resultant chronic HCV infection—outweigh the benefits, which may be preventing wait‐list dropout because of prolonged wait‐list times and patient death, particularly in an era of donor graft scarcity.14, 16, 17, 18, 19 Relevant precedents are cytomegalovirus D⁺/R⁻ and hepatitis B core antigen D⁺/R⁻ LT, which are accepted by the LT community.20, 21

Given that HCV D⁺/R⁻ LT is occurring without detailed, long‐term outcomes data, the LT community will benefit from robust, well‐designed randomized controlled trials (RCTs) assessing the outcomes of HCV D⁺/R⁻ LT. Although some may question whether carrying out RCTs is ethical given the promising short‐term preliminary data, to our knowledge, a reduction in wait‐list time, as well as acceptable long‐term outcomes data, in the DAA era with HCV D⁺/R⁻ LT have not yet been demonstrated. Although we believe that RCT data would be helpful in robustly evaluating HCV D⁺/R⁻ LT outcomes, and perhaps lead to universal adoption of HCV D⁺/R⁻ LT, absence of RCTs on HCV D⁺/R⁻ LT should not preclude this practice. Notably, the aforementioned case series of HCV D⁺/R⁻ LT had a median follow‐up time of 380 days.14 Further questions, such as proper protocols for DAA treatment post‐LT and best immunosuppression management to minimize drug‐drug interactions with DAA therapy, should be studied as well. Until more data are reported, the risk‐benefit calculus will have to be applied to each patient uniquely. The most pressing ethical dilemma for providers is what quantity and quality of evidence will be needed to either recommend or oppose HCV D⁺/R⁻ LT.

Utility

The role of the donor and the concept of utility, or the delivery of the most benefit to the largest number of individuals, must be examined. Two 2018 cost‐effectiveness studies showed better outcomes and less costs with HCV D⁺/R⁻ kidney transplantation compared with remaining on dialysis and waiting for a HCV⁻ kidney graft.22, 23 Similarly, a 2019 cost‐effectiveness study concluded that accepting either a HCV⁺ or HCV⁻ liver is cost‐effective beginning at a Model for End‐Stage Liver Disease (MELD) score of 22, as well as at any MELD score if a patient has a reduced quality of life compared with accepting only HCV⁻ livers.24 Another modeling study published in 2018 demonstrated that for patients with MELD scores ≥20, accepting either a HCV⁺ or HCV⁻ liver versus only HCV⁻ livers led to an increase in life expectancy, indicating that HCV D⁺/R⁻ LT may improve wait‐list survival.25 Additional studies should be carried out in the LT population to further demonstrate if and to what degree patients and society may benefit fiscally from HCV D⁺/R⁻ LT.

The opioid epidemic has led to an increase in the number of young donors who have died of drug overdoses, and the median age of HCV⁺ donors in 2016 was 35 years.26 Grafts from these donors are attractive to transplant providers and resulted in a 2‐fold increase in HCV⁺ LT from 2013 to 2016.26 Should these HCV⁺ organs, from not only otherwise suitable but often more favored donors, be discarded when preliminary, short‐term data show equivalent patient and graft survival data and excellent HCV SVR rates?12, 13, 14, 15

Justice

Justice in medical ethics means fairness, with impartiality and equity toward scarce resources, patients’ rights, and laws.2 Given that HCV D⁺/R⁻ LT is already occurring, ensuring its fairness nationwide and justice for patients in need of LT is paramount. LT providers need to ensure that providing HCV D⁺/R⁻ LT does not disadvantage patients or communities who may have been misinformed or have outdated information about HCV pathology and treatment after LT. One recent patient survey study showed that African Americans were less likely than whites to accept an HCV⁺ kidney graft.27 Although it is unclear whether this attitude extends to liver grafts, further studies are needed to determine whether disparities exist in beliefs toward HCV D⁺/R⁻ LT. Furthermore, to promote equity in liver graft allocation, transplant centers that do not provide HCV D⁺/R⁻ LT should inform their patients that other transplant centers may be performing HCV D⁺/R⁻ LT.

The aforementioned study by Cotter et al.15 of the Scientific Registry of Transplant Recipients data reported 87 instances of HCV D⁺/R⁻ LT from April 2014 to January 2018.15 HCV D⁺/R⁻ LT made up 1.1% of all HCV R⁻ LTs, and 1‐ and 2‐year graft survival was equivalent between HCV D⁺/R⁻ and HCV D⁻/R⁻ LTs.15 It is no longer a question of whether or not HCV D⁺/R⁻ LT should be occurring at all. The upcoming challenges for LT providers regarding HCV D⁺/R⁻ LT will be implementing ethical standards for informed consent, provider and patient education, the rigorous study of outcomes, and the equitable allocation of a scarce resource.