Liberalizing transplantation of HCV positive donor organs into HCV negative recipients
Editorial Commentary

Liberalizing transplantation of HCV positive donor organs into HCV negative recipients

Dharani Guttikonda, Nancy Reau

Section of Hepatology, Rush University Medical Center, Chicago, IL, USA

Correspondence to: Nancy Reau, MD. Section of Hepatology, Division of Digestive Diseases, Department of Internal Medicine, Rush University Medical Center, 1725 West Harrison Street, Suite 319, Chicago, IL 60612, USA. Email: Nancy_Reau@rush.edu.

Comment on: Bethea ED, Gaj K, Gustafson JL, et al. Pre-emptive pangenotypic direct acting antiviral therapy in donor HCV-positive to recipient HCV-negative heart transplantation: an open-label study. Lancet Gastroenterol Hepatol 2019;4:771-80.


Received: 17 April 2020; Accepted: 09 May 2020; Published: 30 December 2020.

doi: 10.21037/dmr-20-52


In the United States, the demand for solid organ transplantation exceeds the availability of donor organs. As of April 14, 2020, an estimated 103,170 kidney, 12,960 liver, 3,682 heart, 1,283 lung transplant candidates are waiting transplantation with only 5,676 kidney, 2,198 liver, 874 heart, and 670 lung transplants being done thus far (1). Historically, HCV seropositive donor organs had been discarded due to concerns of transmission to recipients, poor graft function and increased mortality (2). This has resulted in prolonged wait times on transplant lists for all organs, including heart, lung, liver, and kidneys. However, with the recent surge in opioid overdose related deaths came a large pool of young, otherwise healthy, but HCV seropositive donors (3,4). This, coupled with the advent of curative direct acting antiviral (DAA) agents in the treatment of HCV, has opened up the potential of transplanting HCV donor organs into HCV negative recipients (D+R−). Adoption of this strategy has not only limited organ wastage, but also decreased the amount of time patients wait for organ availability (5-9). Although this sounds straightforward, controversy exists in determining if patients should undergo pre-emptive/prophylactic treatment as opposed to reactive treatment, as well as in determining duration of treatment.

Accumulating data is pushing the transplant community toward a shift in paradigm. In July 2019, The Lancet published a provocative article titled, “Pre-emptive pangenotypic DAA therapy in donor HCV-positive to recipient HCV-negative heart transplantation: an open-label study.” The study included 25 HCV positive donor hearts, 20 of which were viremic. Recipients of HCV viremic hearts were given pre-emptive glecaprevir/pibrentasvir (GP), with one dose given immediately prior to transplantation, and with subsequent once daily dosing for 8 weeks. In the 5 non-viremic HCV Ab positive organs, a reactive treatment strategy was adopted, with treatment only initiated if patient developed viremia, a phenomenon that did not occur during the span of the study. GP was selected due to fewer drug-drug interactions with amiodarone. The study, although relatively small, non-blinded, and with relatively short follow up of one year, determined that patients receiving an HCV positive donor heart received that organ more quickly, and that pre-emptive administration of GP led to rapid HCV suppression and prevention of chronic HCV without compromising allograft function (10). Historically, HCV positive solid organ transplant recipients were not treated post-transplant for fears of interferon induced organ rejection. Thus, solid organ recipients with HCV may have been treated pre-transplant or even considered ineligible for transplant due to active infection. To think that centers are now willing to infect recipients to facilitate transplant is truly monumental.

The risk of HCV transmission in D+R− solid organ transplantation will depend on both the donor viral load and the organ being transplanted. Thus, the post-transplant strategy may vary based on risk. Organs which are HCV Ab positive with a negative viral load have a very low risk of potential transmission to the recipient, even in liver transplantation (11-13). There may be a slightly higher transmission risk in HCV Ab positive, RNA negative “high risk donors” as identified by the US Public Health Service, and according to AASLD guidelines. Recipients of “high risk donor” organs should be monitored post transplantation for possible transmission (14-16). The highest risk of transmission is in Ab+, NAT+ donors, which can result in nearly 100% transmission in liver transplants, however was less so with other organs such as heart and kidney (17). A recent study by Kapila et al. of viremic donor organs (NAT+) transplanted into aviremic recipients showed that 95% kidney transplants, 100% of liver transplants, and 100% of heart transplants became viremic, however with use of DAA, all but one of 77 patients achieved sustained virologic response (SVR) (17).

The treatment of HCV after transplantation has proven safe and effective (16). Until recently, most post-transplant HCV was a result of transplanting an organ either HCV positive or negative into an HCV positive recipient. Even in this scenario, post-transplant protocols varied without consensus on when to initiate therapy, though most agree that early treatment is preferred.

Transplantation of a seropositive organ into a seronegative recipient has had relatively recent historical precedence. It has been trialed extensively in kidney and liver transplants, and more recently in lung and cardiac transplantations (2,7,8,10,18,19). Extending viremic HCV positive transplant to HCV negative recipients has viral induced risk including fibrosing cholestatic HCV (FCH) and extra-hepatic manifestations of HCV such as membranoproliferative glomerulonephritis (MPGN). Initiating DAA therapy also has well defined risk including drug interactions and potential toxicity. While studies have shown that the risks of transmission are low, there can be a risk of DAA related graft rejection and loss, although the long term adverse effects are yet to be understood (20-23).

Given that transmission may not be 100%, many early protocols deferred therapy until after post-transplant viremia was documented and the patient was considered appropriate for treatment. Unfortunately, there were rare but sometimes lethal consequences of delaying treatment.

Shortening duration of therapy from the standard 8–12 weeks is a potential strategy to limit treatment associated side effects. This has been effective is small trials of non-liver solid organ transplant, with Feld et al. presenting a preliminary data from of 25 D+R− patients given pre-emptive GP and the HCV entry blocker ezetimibe, followed by 7 post-operative daily doses (24).

In 2020, AASLD published updated guidance which supported either pre-emptive/prophylactic or reactive, pan-genotypic DAA treatment regimen for HCV negative recipients of an HCV viremic donor organ. Initiation of this can be done in two different strategies: prophylactic treatment at the time of transplant, or reactive treatment if the recipient develops HCV viremia (16). Some recent data, including that from Bethea et al., suggest that a prophylactic strategy reduces the risk of intra and extra hepatic complications and may even allow for a shorter course of therapy, with treatment regimens as short as one week being studied at present (10,19,25-27). Effective pan-genotypic treatment regimens include an 8-week course of GP, a 12-week course of sofosbuvir/velpatasvir (16). Drug choice should be carefully considered, especially in the setting of potential drug-drug interactions, most particularly with regards to concomitant calcineurin inhibitor use.

Although accumulating evidence is pushing the transplant community to consider HCV D+R− standard of care, more data is essential to identify which patients are most appropriate to receive HCV positive allografts and the ideal post-transplant treatment strategies (pre-emptive vs. prophylactic DAA administration), coupled with study into determining adequate duration of therapy to minimize “overtreatment.” In addition to identifying an ideal duration of therapy, long term follow-up of recipients of HCV positive donor organs will provide beneficial information regarding complications and allograft function.


Acknowledgments

Funding: None.


Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Digestive Medicine Research. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure from (available at http://dx.doi.org/10.21037/dmr-20-52). NR reports grants and other from Abbott, grants and other from AbbVie, grants and other from Gilead, outside the submitted work. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.


References

  1. Organ Procurement and Transplantation Network [database on the Internet] 2020. Available online: http://optn.transplant.hrsa.gov
  2. Cotter TG, Paul S, Sandikci B, et al. Increasing Utilization and Excellent Initial Outcomes Following Liver Transplant of Hepatitis C Virus (HCV)-Viremic Donors Into HCV-Negative Recipients: Outcomes Following Liver Transplant of HCV-Viremic Donors. Hepatology 2019;69:2381-95. [Crossref] [PubMed]
  3. Seth P, Scholl L, Rudd RA, et al. Overdose Deaths Involving Opioids, Cocaine, and Psychostimulants - United States, 2015-2016. MMWR Morb Mortal Wkly Rep 2018;67:349-58. [Crossref] [PubMed]
  4. Goldberg DS, Blumberg E, McCauley M, et al. Improving Organ Utilization to Help Overcome the Tragedies of the Opioid Epidemic. Am J Transplant 2016;16:2836-41. [Crossref] [PubMed]
  5. Bhamidimarri KR, Ladino M, Pedraza F, et al. Transplantation of kidneys from hepatitis C-positive donors into hepatitis C virus-infected recipients followed by early initiation of direct acting antiviral therapy: a single-center retrospective study. Transpl Int 2017;30:865-73. [Crossref] [PubMed]
  6. Scalea JR, Barth RN, Munivenkatappa R, et al. Shorter waitlist times and improved graft survivals are observed in patients who accept hepatitis C virus+ renal allografts. Transplantation 2015;99:1192-6. [Crossref] [PubMed]
  7. Sageshima J, Troppmann C, McVicar JP, et al. Impact of Willingness to Accept Hepatitis C Seropositive Kidneys Among Hepatitis C RNA-Positive Waitlisted Patients. Transplantation 2018;102:1179-87. [Crossref] [PubMed]
  8. Sawinski D, Forde KA, Lo Re V 3rd, et al. Mortality and Kidney Transplantation Outcomes Among Hepatitis C Virus-Seropositive Maintenance Dialysis Patients: A Retrospective Cohort Study. Am J Kidney Dis 2019;73:815-26. [Crossref] [PubMed]
  9. Shelton BA, Sawinski D, Mehta S, et al. Kidney transplantation and waitlist mortality rates among candidates registered as willing to accept a hepatitis C infected kidney. Transpl Infect Dis 2018;20:e12829. [Crossref] [PubMed]
  10. Bethea ED, Gaj K, Gustafson JL, et al. Pre-emptive pangenotypic direct acting antiviral therapy in donor HCV-positive to recipient HCV-negative heart transplantation: an open-label study. Lancet Gastroenterol Hepatol 2019;4:771-80. [Crossref] [PubMed]
  11. Bari K, Luckett K, Kaiser T, et al. Hepatitis C transmission from seropositive, nonviremic donors to non-hepatitis C liver transplant recipients. Hepatology 2018;67:1673-82. [Crossref] [PubMed]
  12. Selzner N, Berenguer M. Should organs from hepatitis C-positive donors be used in hepatitis C-negative recipients for liver transplantation? Liver Transpl 2018;24:831-40. [Crossref] [PubMed]
  13. Levitsky J, Formica RN, Bloom RD, et al. The American Society of Transplantation Consensus Conference on the Use of Hepatitis C Viremic Donors in Solid Organ Transplantation. Am J Transplant 2017;17:2790-802. [Crossref] [PubMed]
  14. Suryaprasad A, Basavaraju SV, Hocevar SN, et al. Transmission of Hepatitis C Virus From Organ Donors Despite Nucleic Acid Test Screening. Am J Transplant 2015;15:1827-35. [Crossref] [PubMed]
  15. Seem DL, Lee I, Umscheid CA, et al. PHS guideline for reducing human immunodeficiency virus, hepatitis B virus, and hepatitis C virus transmission through organ transplantation. Public Health Rep 2013;128:247-343. [Crossref] [PubMed]
  16. Ghany MG, Morgan TR. Panel A-IHCG. Hepatitis C Guidance 2019 Update: American Association for the Study of Liver Diseases-Infectious Diseases Society of America Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. Hepatology 2020;71:686-721. [Crossref] [PubMed]
  17. Kapila N, Menon KVN, Al-Khalloufi K, et al. Hepatitis C Virus NAT-Positive Solid Organ Allografts Transplanted Into Hepatitis C Virus-Negative Recipients: A Real-World Experience. Hepatology 2020;72:32-41. [Crossref] [PubMed]
  18. Potluri VS, Goldberg DS, Mohan S, et al. National Trends in Utilization and 1-Year Outcomes with Transplantation of HCV-Viremic Kidneys. J Am Soc Nephrol 2019;30:1939-51. [Crossref] [PubMed]
  19. Woolley AE, Singh SK, Goldberg HJ, et al. Heart and Lung Transplants from HCV-Infected Donors to Uninfected Recipients. N Engl J Med 2019;380:1606-17. [Crossref] [PubMed]
  20. Fernandez I, Munoz-Gomez R, Pascasio JM, et al. Efficacy and tolerability of interferon-free antiviral therapy in kidney transplant recipients with chronic hepatitis C. J Hepatol 2017;66:718-23. [Crossref] [PubMed]
  21. Fernandez-Ruiz M, Polanco N, Garcia-Santiago A, et al. Impact of anti-HCV direct antiviral agents on graft function and immunosuppressive drug levels in kidney transplant recipients: a call to attention in the mid-term follow-up in a single-center cohort study. Transpl Int 2018;31:887-99. [Crossref] [PubMed]
  22. Dharancy S, Coilly A, Fougerou-Leurent C, et al. Direct-acting antiviral agent-based regimen for HCV recurrence after combined liver-kidney transplantation: Results from the ANRS CO23 CUPILT study. Am J Transplant 2017;17:2869-78. [Crossref] [PubMed]
  23. Lubetzky M, Chun S, Joelson A, et al. Safety and Efficacy of Treatment of Hepatitis C in Kidney Transplant Recipients With Directly Acting Antiviral Agents. Transplantation 2017;101:1704-10. [Crossref] [PubMed]
  24. Feld J. editor. Transplantation from HCV-infected donors to HCV-uninfected recipients: Short course therapy to prevent transmission. AASLD; 2019; Boston, USA.
  25. Cypel M, Feld JJ, Galasso M, et al. Prevention of viral transmission during lung transplantation with hepatitis C-viraemic donors: an open-label, single-centre, pilot trial. Lancet Respir Med 2020;8:192-201. [Crossref] [PubMed]
  26. Kapila N, Al-Khalloufi K, Bejarano PA, et al. Fibrosing cholestatic hepatitis after kidney transplantation from HCV-viremic donors to HCV-negative recipients: A unique complication in the DAA era. Am J Transplant 2020;20:600-5. [Crossref] [PubMed]
  27. Martini S, Salizzoni M, David E, et al. Favorable short-term outcome of hepatitis C virus-positive liver graft with bridging fibrosis: A plea for very early viral eradication. Hepatology 2017;65:2116-8. [Crossref] [PubMed]
doi: 10.21037/dmr-20-52
Cite this article as: Guttikonda D, Reau N. Liberalizing transplantation of HCV positive donor organs into HCV negative recipients. Dig Med Res 2020;3:102.