Over the last two decades, the iterative success of solid organ transplantation has hit a wall as a consequence of a plateau in organ donations. The result has been a fatal gap between an increasing need for transplantable organs and a ceiling in supply. That “ceiling” limited liver transplants to approximately 8,000 in 2017.[1] However, in 2016, there were more than 13,000 persons on the liver waitlist.[2] The overall number of organs transplanted in the U.S. has hovered in the 36,000 range.[3] Placing these numbers in a stark perspective, donations may be contrasted with a continually expanding organ waiting list. The list has exceeded 122,000 persons and increases 2–10% per year.[4] There is a human price to be paid for the disparity. In some instances, waiting list times may exceed 10 years, and in the context of kidney transplants, incurs a 25% mortality.[5] More than 1 out of every 10 persons on a waiting list dies annually—or is decimated.[6] In the future, this fatal imbalance will be exacerbated without more donors. The demand for livers is expected to expand further as a result of a contemporary epidemic of non-alcoholic steatosis—predicted to burden the waitlist with an increase of 170%![7] A similar increase is expected as a result of a burgeoning younger demographic with alcoholic cirrhosis.[8]
At this juncture, one is compelled to ask whether there an ethical way to increase the donor pool. A recent confluence of events has provided a unique possibility. Direct Acting Antiviral therapy (DAA) has “cured” previously incurable hepatitis C virus (HCV)-infected persons. In the past, potential, otherwise viable organs from an HCV-positive source would have been discarded. Such organs came from a category characterized as “Extended Criterion Grafts.” The category was comprised by a demographic of donated organs deemed inferior when compared with traditional donations. These organs have been deemed inferior because of their infectious risk to recipients. Until very recently, HCV-positive organs were presumed to transmit HCV to some recipients. Since HCV was incurable at that time, the infection could be fatal. Recently, there has been a veritable paradigm shift. HCV is now curable and this previously discarded pool of organs has the potential to dramatically increase donations. Opioid addiction, for example, will lead to a 200% increase in opioid-related deaths.[9] In Kentucky, the opioid addiction epicenter, 50% of users are HCV positive.[10]
Scrutiny of the escalating interest in HCV-positive grafts in an age of successful DAA treatment can engage important ethical questions in the context of transplantation’s next potential generation of donors. It has been estimated that organs from HCV-positive donors might increase the number of kidney transplants alone 500–1,000 or more per year.[11] Increases will also include hearts, livers, and other single organs. If reasonable ethical boundaries surrounding HCV-positive organ donations to HCV-negative recipients are met, the impact of this specific donor pool can be lifesaving for many. Exactly where should these boundaries be drawn? Unfortunately, there is no universal ethical standard for the utilization of HCV-positive grafts in this era of DAA. Although a reputable consensus conference has provided fundamental ethical direction, compliance with fundamental precepts has been lacking to date.
In 2017, an American Society of Transplantation (AST) Consensus Conference addressed the potential widespread utilization of HCV-positive donors for organ transplantation.[12] The committee was comprised by 23 members, all experts in the field of solid organ transplantation. This author’s reading of their “blueprint,” outlining an ethical approach to HCV-positive transplants, suggests that their constructs, designed to protect recipients of HCV-positive organs from harm, are a critical starting point. There were at least 4 that warrant consideration (from this author’s reading). In addition, a more recent publication and this author’s opinion respectively suggest fifth and sixth ethical considerations.[13]
1) At present, HCV-positive to negative transplantation is experimental and not standard of care. The conference concluded that a yellow light (proceed with caution), not a green light (characterize the enterprise as standard of care), should be given to the donation and transplantation of HCV-positive organs, and the group then proceeded to outline the conduct of future research protocols.
2) DAAs have to be guaranteed for all recipients and given early after transplantation as well as later (such as a “salvage regimen”) if they are deemed necessary for relapses. “Early” can be interpreted as either immediately pre- or post-transplant for all HCV-positive to negative recipients or as soon as possible after HCV positivity occurs in a previously negative recipient. This author favors immediately pre- or post-transplant for all. The ethics of “short” versus longer course DAA administration per se will not be discussed.
3) Informed consent has to be standardized, consistent, and evolving with new data obtained after longer-term follow-up. Ideally, it should be as centralized as feasible.
4) Monitoring of the cohort of organ recipients in trials should be extended.
5) Research results to date have to be interpreted with more scientific rigor.
6) Studies that are solely pharmaceutically sponsored should be prohibited.
The ethical consensus at the Conference proposed: “Until this practice [implanting HCV-positive organs into recipients without the infection] is clearly shown to be safe and efficacious in larger multiorgan studies, centers performing such transplants should continue to have IRB approved research protocols that have been vetted for safety and adequacy of the informed consent process.”[14] The experts’ concerns were safety, IRB oversight, and informed consent. Their conclusion left no doubt—the HCV positive to negative transplant enterprise, while promising, is experimental and should not be considered standard of care.
It is important to note that the consensus conference is not alone regarding this optimistic and yet cautious appraisal.[15] Their report in 2017 should have set ethical boundaries for the future, beginning with the agreement that efforts be characterized as experimental and therefore limited by the research direction drawn by the conference. Unfortunately, many studies since the conference have not heeded their conclusions. Additional caveats from the experts and concurring publications should have emphasized areas of concern that focus on safety (including DAA availability and potential complications without access to them), informed consent, unforeseen complications with longer follow up, and the addition of greater scientific rigor in the interpretation of HCV transplantation results—a degree of rigor that seems inconsistent with available studies performed with pharmaceutical sponsorship.
The consensus conference,[16] as well as others,[17] have identified a critical patient safety concern. DAAs should be uniformly available and initiated early after transplant in all HCV-negative recipients of HCV-positive organs. They should also be accessible later after transplant if they are deemed necessary. The “whys” for this recommendation and research compliance with the guideline will be detailed.
Sise and company have said: “Ensuring access to direct acting antiviral therapy in the first week post-transplant is an extremely important safety consideration.”[18] Shetty and coworkers likewise observed: “Results . . . suggest that the use of HCVpD [hepatitis C-positive donor] grafts is not completely risk free and can result in HCV infection and HCV hepatitis with progression to advanced fibrosis. However, with the help of DAA, we can overcome this drawback with early treatment of these grafts before HCV-related hepatitis or fibrosis occurs.”[19] Although early DAA treatment is ideal, but to date, has been running a dangerous gauntlet in the real world.
Goldberg and Reese expand upon this caveat.[20] Published trials implementing early DAA treatment have typically accessed the DAAs through donations from a pharmaceutical company. Otherwise, these expensive drugs must be subsidized by investigators, third-party payers, or be reimbursed by the patients themselves. But therein lies the rub. Certain third-party payers (in 2017, 65% of state Medicaid programs had hepatic fibrosis restrictions for approval of DAA therapy) will either not approve “early” (that is prior to explicit HCV injury) treatment (and so they require documentation of specific pathologies that occur later with chronic HCV infection) or approve DAAs only after a substantial delay.[21] With approval, co-pays can still approximate more than $1,000 per month.
From a medical and ethical perspective, what is the onus for early treatment, that is, DAAs, before transmission or damage from HCV are documented? After the consensus report, a study transplanting HCV-positive organs into C-negative individuals exposed a disconcerting reality.[22] First, despite the consensus recommendation to classify HCV-positive transplants as experimental, this protocol made the practice “standard” or a “real-world experience.”[23] As Durand and others observed: “Important practical, clinical, and ethical challenges emerge[ed] from this real-world experience. . . . DAAs were started a median of 76 days post-transplant, a significant delay compared to trials where DAAs were initiated pretransplant as prophylaxis or 3 days posttransplant.”[24] The ensuing complications—reflecting recipient infections with HCV—were unacceptable. One patient developed fibrosing cholestatic hepatitis (a serious post-transplant complication), 19% of these organ recipients experienced a tripling of liver enzymes (consequent to liver injury), some acute organ rejection, donor specific antibodies, BK viremia, and/or CMV viremia. It appears that the early development of HCV infection in these recipients not receiving timely DAAs creates an inflammatory environment followed by a cascade of serious and potentially fatal complications.[25]
Other investigators likewise highlight possible risks contingent on HCV infection (acquired without the organ transplant) in this demographic. They have reported a 1.56% greater risk of graft loss, a 1.79% relative risk for mortality (specifically in kidney recipients), more frequent rejection episodes compared to HCV-negative controls, chronic allograft nephropathy, diabetes, de novo glomerulonephritis, and fibrosing cholestatic hepatitis.[26] If any of these inflammatory complications occur, and DAAs are unavailable, recipients may be seriously harmed by the HCV-positive organ transplant. Sise and company also specifically express concern regarding the reported risk of focal glomerulosclerosis (FSGS) in recipients of HCV-positive kidneys.[27] In fact, in a study wherein a sustained viral response (SVR) was obtained, FSGS occurred six months later.[28]
An important General Guideline Summary outlining standard of care for HCV-infected individuals outside the realm of transplantation succinctly observed that DAA therapy “contribute[s] to dramatic reductions in all-cause mortality.”[29] The standard of care cannot and should not be applied to HCV infection in a non-transplant cohort and then jettisoned in a transplant population. Future studies should not proceed without a guarantee of early DAA access. Furthermore, if recurrence of HCV infection or any of the co-inflammatory complications occur later after transplant, DAAs must continue to be readily available and timely.
The consensus committee specifically emphasized the importance of informed consent. Since their opinion was published in 2017, this advice has also gone unheeded in some prominent publications. In the aforementioned study that was compromised by the early unavailability of DAAs, initial informed consent was by mail only.[30] The first face-to-face discussion was not held until the organ offer was made. This is hardly the ideal time to discuss such a complicated issue. Another study, in fact one of the largest (n = 55) specifically addressing liver transplants from HCV-positive donors, did not describe the informed consent process in any detail—merely summarizing that “informed consent was obtained in the office setting,” and any specifics of IRB supervision were ignored in the publication.[31] Furthermore, in this trial, “selection of antiviral therapy was based on provider preference and payer discretion” in contrast to the consensus committee’s recommendations. Editorials have noticed the same omission in other published studies.[32]
The informed consent and IRB shortfalls are becoming “rules” rather than “exceptions.” In another study, there was no IRB-approved protocol and there was no consent document.[33] Again, these investigators relied upon insurance coverage for DAAs without a guarantee.[34] The result was a delay in the initiation of DAAs for 43 days. As with the preceding study experiencing a delay in therapy, there were complications that may have been attributable to early HCV infection in the recipients.
On another level, how “informed” can the consent process be? Follow-up in most previous studies has been limited (usually in the range of six months to a year). Predicting later complications is therefore impossible. Further limiting accuracy, the studies are disparate in design. DAA administration has been prophylactic, in some instances given early after transplant or occasionally later, and then of variable durations. Valid consent has to emphasize complications incurred if DAAs are not administered early. As the consensus panel wrote: “If treatment is delayed beyond the early post-transplantation period, protocols that monitor infection, new-onset diabetes mellitus, glomerulonephritis, and severe chronic cholestasis should be put in place.”[35] To date, that important recommendation has been enforced inconsistently. A major study published in The New England Journal of Medicine decided to administer DAAs as a short course only.[36] What would have happened if an SVR was not achieved with this approach? The heterogeneity of studies to date precludes comprehensive counseling as to a veritable unlimited list of potential complications. If this complexity is confronted by a stressed patient and family for the first time when the organ is offered, is the process consonant with valid informed consent? With the lack of standardization and extreme variability of design in the published studies, “patient consent assumes a level of understanding about HCV infection that may not currently exist.”[37]
As alluded to above, the expense of research and DAAs in the area of HCV-positive to negative transplants have affected study designs. Not only has DAA access been a victim, but expense has also limited the duration of patient follow-up as noted in the previous section. As a result, potential immunological consequences of acute donor-derived HCV that may occur at a later date require further elucidation. As mentioned earlier, HCV infection has been associated with transplant glomerulopathy and chronic rejection. Alloimmunity is heightened by the viral infection.[38] Since chronic Hepatitis C infection is also associated with diabetes mellitus, glomerulonephritis, and liver cancer, rigorously performed clinical trials of appropriate design and duration are an ethical imperative.[39] Who is going to sponsor these “rigorous,” and therefore more expensive, trials? Are the designs again going to be disparate—as has been the model to date—so that firm conclusions and comparisons are precluded? The follow-up interval after transplant has to be extended considerably and the number of patients enrolled far greater. With these constraints, what else might be discovered later?
For example, it has been demonstrated that after transplant, the HCV virus can undergo a genotype change.[40] Thus far, this has not caused a problem with “pan-genotypic” DAAs. But will the safety in this regard be durable?
Goldberg and Reese also inquire as to whether other previously experienced HCV-mediated complications, such as immune related damage in the form of acute transplant glomerulopathy or acute and chronic vascular rejection can surface later.[41] If they do, will they be amenable to treatment? Will treatment even be available? Who is going to incur the cost? The same authors question whether the presence of tubuloreticular inclusions in HCV-transplanted kidneys may be a harbinger of untoward consequences in the transplanted organs at a later date—after the six months to a year interim typical of prior studies.
Finally, previous trials of HCV-positive heart transplants have been associated with graft coronary artery disease. This complication could be an issue long after the short follow up provided in extant trials for HCV-positive organs utilized for transplant.[42]
Does the Data Available Pass Muster at Journal Club?
Since the HCV-positive to negative transplant endeavor is experimental, it is on an evidence-based journey to verify safety and efficacy. Therefore, all data must be evaluated in an atmosphere of transparency—according to “Journal Club Rules.” How does the data to date fare under this scrutiny?
Blumberg mitigates some of the optimistic conclusions that have been drawn from a prominent study by Woolley and others. She then moves on to more general “evidence-based” considerations.[43] After noting that “early results are promising, with a 100% sustained viral response and generally excellent patient and allograft outcomes,” she says: “This trial has some unique features that must be considered.”[44] She infers that the excellent outcomes may reflect beneficial characteristics in both the donors and recipients that are absent in the typical transplant population. These include younger donors and recipients. Her critique suggests that current optimism regarding hepatitis C positive to negative transplants may be based on a selected cohort of younger individuals in both the recipient and donor groups. The donors were “surprisingly young.”[45] Since they represent donors usually dying from overdoses this is not unusual.
Recipients were also less critically ill, with shorter lengths of stay in the ICU and a cohort with better kidney function. As a result, Blumberg concludes, “there is still a lot to learn.”[46] Right now, “good” results are being garnered in a “healthier” donor and recipient population. However, comparing this cohort to a general transplantation demographic would be somewhat disingenuous. She also cautions that although an SVR has been obtained on short-term follow-up, a recently published report described a patient who later experienced a “severe relapse of HCV.”[47] Who would be responsible for this individual’s DAA costs? Firm scientific conclusions are being drawn with an inadequate number of subjects and a cohort that is different and healthier than a general transplant population.
Lastly, pharmaceutical sponsorship may place the proverbial “fox in charge of the chicken coop.” Two studies may be reviewed as examples. Pharmaceutically-funded studies tend to be one-dimensional in that the company’s DAA drug efficacy and safety appear to be the primary endpoints of the study. This choice of endpoints may lead to the potential exclusion of other important outcomes. The first of the 2 studies offered the following conclusions: “Pre- and post-transplantation HCV treatment was safe and prevented HCV infection in HCV D+/R- kidney transplant recipients. . . . This strategy should markedly expand organ options and reduce mortality for kidney transplant candidates without HCV infection.”[48] However to their credit, the authors were also frank about the study’s significant shortcomings as well. It was a single-center, non-randomized trial. There were few participants. Those recipients were older, predominantly male, and white, atypical for the transplant demographic at large. The trial follow up was limited to 12 weeks.[49] What about the myriad other potential complications heretofore mentioned? The second trial (with only 2 cohorts of 10 patients enrolled for a total of 20) observed: “The primary outcome was HCV cure.”[50] These trials were sponsored by pharmaceutical companies that stand to profit from DAA sales, so one may question whether they were primarily designed to look mainly at SVR from a patented DAA, minimizing other critical factors. Yes, SVR is important, but so are myriad other outcomes.
Unfortunately, the 2017 template proposed by the American Society of Transplantation Consensus Conference—regarding research conduct for safe and ethically sound practices with HCV-positive organs donated for transplantation—has been frequently ignored. What utility does a consensus have—reached by respected individuals in the field—if reasonable recommendations are repeatedly ignored or manipulated?
Future research—illuminated by a yellow light—has to be “centralized,” with standardized IRB guidance that is uniform for all trials. A different, or occasionally absent, IRB protocol for each and every small study is unacceptable. The process has to be face-to-face and iterative, evolving with data on more patients with longer follow-up. Early DAAs have to be de rigueur and guaranteed at no cost to the patient. Further delineation of short course options has to be studied. A safety monitoring committee has to be in place to report untoward issues from every center enrolling patients.
This author is optimistic that the future of HCV-positive donors may provide a “gift of life” for countless persons. However, if the present laxity in clinical research is allowed to continue unchecked, a red light may preclude innumerable benefits later for an extremely vulnerable population.
References
[1] Akshay Shetty, Adam Buch, and Sammy Saab, “Use of Hepatitis C-Positive Liver Grafts in Hepatitis C-Negative Recipients,” Digestive Diseases & Sciences 64 (2018), 1110–1118, https://doi.org/10.1007/s10620-018-5404-x.
[2] Keith Luckett et al., “Use of Hepatitis C Virus Antibody-Positive Donor Livers in Hepatitis C Nonviremic Liver Transplant Recipients,” Journal of the American College of Surgeons 228, no. 4 (2019): 560–569, https://doi.org/10.1016/j.jamcollsurg.2018.12.004.
[3] Emily A. Blumberg, “Organs from Hepatitis C Virus-Positive Donors,” The New England Journal of Medicine 380, no. 17 (2019): 1699–1670, https://doi.org/10.1056/NEJMe1901957.
[4] Meghan E. Sise et al., “Transplantation of Hepatitis C Virus Infected Kidneys into Hepatitis C Virus Uninfected Recipients,” Hemodialysis International 22, no. S1 (2018): S-71–S-80, https://doi.org/10.1111/hdi.12650.
[5] Sise et al., “Transplantation of Hepatitis C Virus Infected Kidneys into Hepatitis C Virus Uninfected Recipients,” S-71.
[6] Shetty, Buch, and Saab, “Use of Hepatitis C-Positive Liver Grafts in Hepatitis C-Negative Recipients,”1110.
[7] Shetty, Buch, and Saab, “Use of Hepatitis C-Positive Liver Grafts in Hepatitis C-Negative Recipients,”1110.
[8] Shetty, Buch, and Saab, “Use of Hepatitis C-Positive Liver Grafts in Hepatitis C-Negative Recipients,” 1110.
[9] David Goldberg and Peter P. Reese, “Risks, Benefits, and Ethical Questions Associated with Transplanting Kidneys from Hepatitis C Virus-Infected Donors into Hepatitis Virus-Negative Patients,” Seminars in Dialysis 32, no. 2 (2018): 179–186, https://doi.org/10.1111/sdi.12767.
[10] J. Levitsky et al, “The American Society of Transplantation Consensus Conference on the Use of Hepatitis C Viremic Donors in Solid Organ Transplantation,” American Journal of Transplantation 17, no. 1 (2017): 2790–2802, https://doi.org/10.1111/ajt.14381.
[11] David S. Goldberg and Josh Levitsky, “Transplanting Livers from HCV-Infected Donors into HCV-Negative Recipients: Promise but Mind the Pitfalls,” American Journal of Transplantation 19, no. 5 (2019): 1264–1265, https://doi.org/10.1111/ajt.15193.
[12] Levitsky et al., “The American Society of Transplantation Consensus Conference on the Use of Hepatitis C Viremic Donors in Solid Organ Transplantation,” 2790–802.
[13] Blumberg, “Organs from Hepatitis C Virus-Positive Donors,”1669–70.
[14] Levitsky et al., “The American Society of Transplantation Consensus Conference on the Use of Hepatitis C Viremic Donors in Solid Organ Transplantation,” 2796 (emphasis added).
[15] Blumberg, “Organs from Hepatitis C Virus-Positive Donors;” Goldberg and Levitsky, “Transplanting Livers from HCV-Infected Donors into HCV-Negative Recipients,”1669–70.
[16] Levitsky et al., “The American Society of Transplantation Consensus Conference on the Use of Hepatitis C Viremic Donors in Solid Organ Transplantation,” 2796–98.
[17] Shetty, Buch, and Saab, “Use of Hepatitis C-Positive Liver Grafts in Hepatitis C-Negative Recipients;” Goldberg and Levitsky, “Transplanting Livers from HCV-Infected Donors into HCV-Negative Recipients;” Meghan E. Sise et al., “Balancing the Risk and Rewards of Utilizing Organs from Hepatitis C Viremic Donors,” Current Opinion in Organ Transplantation 24, no. 3 (2019): 351–357, https://doi.org/10.1097/MOT.0000000000000651.
[18] Sise et al., “Balancing the Risk and Rewards of Utilizing Organs from Hepatitis C Viremic Donors,”352.
[19] Shetty, Buch, and Saab, “Use of Hepatitis C-Positive Liver Grafts in Hepatitis C-Negative Recipients,” 1114.
[20] Goldberg and Reese, “Risks, Benefits, and Ethical Questions Associated with Transplanting Kidneys from Hepatitis C Virus-Infected Donors into Hepatitis Virus-Negative Patients,” 182.
[21] Goldberg and Reese, “Risks, Benefits, and Ethical Questions Associated with Transplanting Kidneys from Hepatitis C Virus-Infected Donors into Hepatitis Virus-Negative Patients,” 182.
[22] Miklos Z. Molnar et al., “Transplantation of Kidneys from Hepatitis C-Infected Donors to Hepatitis C-Negative Recipients: Single Center Experience,” American Journal of Transplantation 19, no. 11 (2019): 3046–3057, https://doi.org/10.1111/ajt.15530.
[23] Molnar et al., “Transplantation of Kidneys from Hepatitis C-Infected Donors to Hepatitis C-Negative Recipients.”
[24] Christine M. Durand, Michael A. Chattergoon, and Niraj M. Desai, “Lessons from the Real World: HCV-Infected Donor Kidney Transplantation as Standard Practice,” American Journal of Transplantation 19, no. 11 (2019): 2969–2970, https://doi.org/10.1111/ajt.15582.
[25] Durand, Chattergoon, and Desai, “Lessons from the Real World,” 269.
[26] Sise et al., “Balancing the Risk and Rewards of Utilizing Organs from Hepatitis C Viremic Donors,” S-72.
[27] Sise et al., “Balancing the Risk and Rewards of Utilizing Organs from Hepatitis C Viremic Donors,”35–54.
[28] Goldberg and Reese, “Risks, Benefits, and Ethical Questions Associated with Transplanting Kidneys from Hepatitis C Virus-Infected Donors into Hepatitis Virus-Negative Patients,” 181.
[29] AASLD/IDSA HCV Guidance Panel, “Hepatitis C Guidance: AASLD-IDSA Recommendations for Testing, Managing, and Treating Adults Infected with Hepatitis C Virus,” Hepatology 62, no. 3 (2015): 932–954, https://doi.org/10.1002/hep.27950.
[30] Durand, Chattergoon, and Desai, “Lessons from the Real World,” 2969.
[31] Luckett et al, “Use of Hepatitis C Virus Antibody-Positive Donor Livers in Hepatitis C Nonviremic Liver Transplant Recipients,” 561.
[32] Goldberg and Levitsky, “Transplanting Livers from HCV-Infected Donors into HCV-Negative Recipients,” 1264.
[33] Allison J. Kwong et al., “Liver Transplantation for Hepatitis C Virus (HCV) Non-Viremic Recipients with HCV Viremic Donors, American Journal of Transplantation 19, no. 5 (2019): 1380–87, https://doi.org/10.1111/ajt.15162.
[34] Goldberg and Levitsky, “Transplanting Livers from HCV-Infected Donors into HCV-Negative Recipients, 1264.
[35] Levitsky et al, “The American Society of Transplantation Consensus Conference on the Use of Hepatitis C Viremic Donors in Solid Organ Transplantation,” 2795.
[36] Ann E. Woolley et al., “Heart and Lung Transplants from HCV-Infected Donors to Uninfected Recipients,” The New England Journal of Medicine 380, no. 17 (2019): 1606–1617, https://doi.org/10.1056/NEJMoa1812406.
[37] Blumberg, “Organs from Hepatitis C Virus-Positive Donors,” 1669.
[38] Goldberg and Reese, “Risks, Benefits, and Ethical Questions Associated with Transplanting Kidneys from Hepatitis C Virus-Infected Donors into Hepatitis Virus-Negative Patients,” 182.
[39] Sise et al., “Transplantation of Hepatitis C Virus Infected Kidneys into Hepatitis C Virus Uninfected Recipients,” S-72.
[40] R. Adekunle et al., “Hepatitis C Genotype Change after Transplantation Utilizing Hepatitis C Positive Donor Organs,” Transplant Infectious Disease 20, no. 4 (2018): e12925, https://doi.org/10.1111/tid.12925.
[41] Goldberg and Reese, “Risks, Benefits, and Ethical Questions Associated with Transplanting Kidneys from Hepatitis C Virus-Infected Donors into Hepatitis Virus-Negative Patients,” 182.
[42] Leanna B. Gasink et al., “Hepatitis C Virus Seropositivity in Organ Donors and Survival in Heart Transplant Recipients,” JAMA 296, no. 15 (2006): 1843–1850, https://doi.org/10.1001/jama.296.15.1843.
[43] Blumberg, “Organs from Hepatitis C Virus-Positive Donors;” Woolley et al., “Heart and Lung Transplants from HCV-Infected Donors to Uninfected Recipients,” 1669.
[44] Blumberg, “Organs from Hepatitis C Virus-Positive Donors,”1669 (emphasis added).
[45] Blumberg, “Organs from Hepatitis C Virus-Positive Donors,”1669.
[46] Blumberg, “Organs from Hepatitis C Virus-Positive Donors,”1669.
[47] Blumberg, “Organs from Hepatitis C Virus-Positive Donors,” 1669.
[48] Christine M. Durand et al., “Direct-Acting Antiviral Prophylaxis in Kidney Transplantation from Hepatitis C Virus–Infected Donors to Noninfected Recipients,” Annals of Internal Medicine 168, no. 8 (2018): 533–540, https://doi.org/10.7326/M17-2871. 533.
[49] Durand et al., “Direct-Acting Antiviral Prophylaxis in Kidney Transplantation from Hepatitis C Virus–Infected Donors to Noninfected Recipients,” 539.
[50] Peter P. Reese et al., “Twelve-Month Outcomes After Transplant of Hepatitis C–Infected Kidneys into Uninfected Recipients,” Annals of Internal Medicine 169, no. 5 (2018): 275, https://doi.org/10.7326/M18-0749.
Gregory R. Rutecki, “Green Light or Proceed with Caution? Has the Time Arrived for Hepatitis C-Positive Organ Donations?” Dignitas 27, no. 1–4 (2020): 3–8.
