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Hepatitis C viraemic organs in solid organ transplantation

  • Kelley Weinfurtner
    Affiliations
    Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania
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  • K. Rajender Reddy
    Correspondence
    Corresponding author. Address: Division of Gastroenterology and Hepatology, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104. Tel.: 215-662-4276.
    Affiliations
    Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania
    Search for articles by this author
Published:November 16, 2020DOI:https://doi.org/10.1016/j.jhep.2020.11.014

      Summary

      Although rates of organ donation and solid organ transplantation have been increasing over the last few decades, demand for organs still greatly exceeds supply. Several strategies have been utilised to increase organ supply, including utilisation of high-risk (e.g. HCV antibody-positive) donors. In this context, organs from HCV antibody-positive donors have been used in recipients with chronic HCV since the early 1990s. Recently, transplantation of HCV-viraemic organs into HCV-naïve recipients has garnered significant interest, owing to the development of safe and highly effective direct-acting antivirals and increased experience of treating HCV in the post-transplant setting. Preliminary studies based largely in the US have shown excellent outcomes in kidney, liver, heart, and lung transplantation. This practice has the potential to significantly increase transplantation rates and decrease waitlist mortality; however, intentionally transmitting an infectious disease to recipients has important practical and ethical implications. Further, the generalisability of the US experience to other countries is limited by significant differences in HCV-viraemic donor populations. This review summarises the current data on this practice, discusses barriers to implementation, and highlights areas that warrant further study.

      Keywords

      Introduction

      Despite increasing rates of organ donation and transplantation over the last few decades, the demand for organs still greatly exceeds the supply. In the US, there are currently over 120,000 candidates on the waitlist, but there were only 11,870 deceased donors in 2019 and over 5,000 patients died waiting for a transplant.
      Organ procurement and transplantation network.
      Similarly, there were over 150,000 candidates on the waitlist in Europe in 2018 with only 34,221 organ transplants that year.
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      Multiple strategies have been implemented to increase the donor pool: public health outreach to increase organ donation including opt out consent systems, use of living donors, donation after cardiac death, and increased utilisation of high-risk donors. Regarding high-risk donors, there is a well-established precedent for using organs exposed to viral infections, such as cytomegalovirus or HBV, in conjunction with prophylactic treatment to prevent infection and/or treatment following breakthrough infection; thus, there has been increasing interest in applying this strategy for HCV.
      Since the early 1990s, HCV antibody-positive (anti-HCV-positive) donor grafts have been used in recipients with chronic HCV, leading to comparable graft and patient outcomes for kidney and liver transplantation
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      Long-term experience with kidney transplantation from hepatitis C-positive donors into hepatitis C-positive recipients.
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      • et al.
      Shorter waitlist times and improved graft survivals are observed in patients who accept hepatitis C virus+ renal allografts.
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      Liver allografts from hepatitis C positive donors can offer good outcomes in hepatitis C positive recipients: a US National Transplant Registry analysis.
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      Long-term follow-up and outcome of liver transplantation from anti-hepatitis C virus-positive donors: a European multicentric case-control study.
      ; however, using these organs in anti-HCV-negative recipients prior to direct-acting antiviral (DAA) therapy led to high rates of HCV transmission and decreased patient and graft survival.
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      Elderly recipients of hepatitis C positive renal allografts can quickly develop liver disease.
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      Over the last decade, the development of highly effectively DAA agents has allowed for the safe and successful treatment of HCV, shrinking the number of recipients with chronic HCV.
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      Meanwhile, there has been a significant expansion of the HCV-positive donor pool in the US due to the opioid epidemic.
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      ,
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      Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study.
      combined with the increasing availability of anti-HCV-positive donors has led several US transplant centres to pursue transplantation of HCV-viraemic organs into nonviraemic recipients using various strategies for HCV prevention and/or treatment.
      • Goldberg D.S.
      • Abt P.L.
      • Blumberg E.A.
      • Van Deerlin V.M.
      • Levine M.
      • Reddy K.R.
      • et al.
      Trial of transplantation of HCV-infected kidneys into uninfected recipients.
      • Abdelbasit A.
      • Hirji A.
      • Halloran K.
      • Weinkauf J.
      • Kapasi A.
      • Lien D.
      • et al.
      Lung transplantation from hepatitis C viremic donors to uninfected recipients.
      • Durand C.M.
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      • Massaccesi G.
      • Bair N.
      • et al.
      Direct-acting antiviral prophylaxis in kidney transplantation from hepatitis C virus-infected donors to noninfected recipients an open-label nonrandomized trial.
      • Kwong A.J.
      • Wall A.
      • Melcher M.
      • Wang U.
      • Ahmed A.
      • Subramanian A.
      • et al.
      Liver transplantation for hepatitis C virus (HCV) non-viremic recipients with HCV viremic donors.
      • Reese P.P.
      • Abt P.L.
      • Blumberg E.A.
      • Van Deerlin V.M.
      • Bloom R.D.
      • Potluri V.S.
      • et al.
      Twelve-month outcomes after transplant of hepatitis C–infected kidneys into uninfected recipients a single-group trial.
      • Schlendorf K.H.
      • Zalawadiya S.
      • Shah A.S.
      • Wigger M.
      • Chung C.Y.
      • Smith S.
      • et al.
      Early outcomes using hepatitis C–positive donors for cardiac transplantation in the era of effective direct-acting anti-viral therapies.
      • Aslam S.
      • Yumul I.
      • Mariski M.
      • Pretorius V.
      • Adler E.
      Outcomes of heart transplantation from hepatitis C virus–positive donors.
      • Bethea E.
      • Gaj K.
      • Gustafson J.L.
      • Axtell A.
      • Lebeis T.
      • Schoenike M.
      • et al.
      Pre-emptive pangenotypic direct acting antiviral therapy in donor HCV-positive to recipient HCV-negative heart transplantation: an open-label study.
      • Gupta G.
      • Yakubu I.
      • Bhati C.S.
      • Zhang Y.
      • Kang L.
      • Patterson J.A.
      • et al.
      Ultra-short duration direct acting antiviral prophylaxis to prevent virus transmission from hepatitis C viremic donors to hepatitis C negative kidney transplant recipients.
      • McLean R.C.
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      • Atluri P.
      • Bermudez C.
      • Goldberg L.R.
      • et al.
      Transplanting hepatitis C virus–infected hearts into uninfected recipients: a single-arm trial.
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      • et al.
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      • Mallidi H.R.
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      Heart and lung transplants from HCV infected donors to uninfected recipients.
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      • Arvind A.
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      Immediate administration of antiviral therapy after transplantation of hepatitis C-infected livers into uninfected recipients: implications for therapeutic planning.
      • Cypel M.
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      • Marks N.
      • Kuczynski M.
      • et al.
      Prevention of viral transmission during lung transplantation with hepatitis C-viraemic donors: an open-label, single-centre, pilot trial.
      • Durand C.M.
      • Barnaba B.
      • Yu S.
      • Brown D.M.
      • Chattergoon M.A.
      • Bair N.
      • et al.
      Four-week direct-acting antiviral prophylaxis for kidney transplantation from hepatitis C-viremic donors to hepatitis C-negative recipients: an open-label nonrandomized study.
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      • Kumar D.
      • Dahari H.
      • Vanin Pinto Riberio R.
      • Marks N.
      • et al.
      Short-course, direct-acting antivirals and ezetimibe to prevent HCV infection in recipients of organs from HCV-infected donors: a phase 3, single-centre, open-label study.
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      • DuBray B.J.
      • Shawar S.
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      • et al.
      The effect of pulsatile pump perfusion on hepatitis C transmission in kidney transplantation: a prospective pilot study.
      • Kapila N.
      • Menon K.V.N.
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      • et al.
      Hepatitis C virus NAT-positive solid organ allografts transplanted into hepatitis C virus–negative recipients: a real-world experience.
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      • Kon Z.
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      • et al.
      Outcomes with treatment with glecaprevir/pibrentasvir following heart transplantation Utilizing hepatitis C viremic donors.
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      • Durand C.M.
      • et al.
      Multicenter study to transplant hepatitis C – infected kidneys ( MYTHIC ): an open-label study of combined glecaprevir and pibrentasvir to treat recipients of transplanted kidneys from deceased donors with Hepatitis C Virus Infect.
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      • Kon Z.N.
      • et al.
      Impact of early initiation of direct-acting antiviral therapy in thoracic organ transplantation from hepatitis C virus positive donors.
      Given that donors who die from drug overdose are generally younger with better organ function,
      • Goldberg D.S.
      • Blumberg E.
      • Mccauley M.
      • Abt P.
      • Levine M.
      Improving organ utilization to help overcome the tragedies of the opioid epidemic.
      this practice has the potential to significantly increase transplantation rates and decrease waitlist mortality in the US; however, intentionally transplanting patients with an infectious disease leads to important practical challenges and ethical considerations. Further, the generalisability of the US experience to other countries is limited by significant differences in HCV-viraemic populations. This review summarises the current data on this practice, discusses barriers to implementation, and highlights areas in need of further study.

      Defining “HCV-positive”

      HCV infection is detected by either serologic tests, which identify HCV antibodies (anti-HCV) 28–70 days post-exposure, or by HCV nucleic acid testing (NAT), which detects RNA 5–7 days post-exposure (Fig. 1). Historically, studies of “HCV-positive” organs only reported anti-HCV status, which can be negative in acute HCV infection during the “window period” and does not distinguish between resolved and active HCV infection. Beginning in August 2015, the United Network for Organ Sharing (UNOS) mandated HCV NAT in addition to HCV antibody testing for all potential organ donors, to better assess the risk of HCV transmission. There are 4 possible combinations with HCV antibody and NAT testing (Fig. 1): i) anti-HCV-positive NAT-positive consistent with active infection (acute or chronic depending on timing of exposure); ii) anti-HCV-negative NAT-negative consistent with HCV-naïve patient or hyperacute infection <5–7 days from exposure; iii) anti-HCV-negative NAT-positive consistent with acute HCV infection or chronic infection in immunocompromised patients; iv) anti-HCV-positive NAT-negative consistent with resolved or treated HCV infection (rarely hyperacute re-infection in patients with resolved prior infection). In each category, there is also the potential for false-positive and negatives; however, using both tests is estimated to miss only 10.5 donor cases of HCV per 100,000 person-years of recipient follow-up
      • Goldberg D.S.
      • Blumberg E.
      • Mccauley M.
      • Abt P.
      • Levine M.
      Improving organ utilization to help overcome the tragedies of the opioid epidemic.
      and the HCV NAT false-positive rate is estimated to be less than 0.2%.
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      • Formica R.N.
      • Bloom R.D.
      • Charlton M.
      • Curry M.
      • Friedewald J.
      • et al.
      The American Society of Transplantation Consensus Conference on the use of hepatitis C viremic donors in solid organ transplantation.
      Groups 1 and 3 are at high risk of HCV transmission and are referred to as HCV-viraemic patients for the purposes of this review.
      Despite increasing overall rates of organ transplantation, demand for organs still far exceeds the supply and HCV infection is a major reason for discarding organs.
      Figure thumbnail gr1
      Fig. 1Hepatitis C virus testing. ∗Rarely up to 9 months.
      ∗∗False-positives and negatives are possible for both anti-HCV and NAT. Anti-HCV, HCV antibody; NAT, nucleic acid testing.

      Underutilisation of anti-HCV-positive organs

      Pre-DAA era

      Historically, transplant centres were hesitant to use anti-HCV-positive donors due to high HCV transmission rates, unknown effects of immunosuppression on HCV, lack of effective HCV treatments, and concern regarding the consequences of untreated HCV, including fibrosing cholestatic hepatitis, cirrhosis, liver cancers, and extrahepatic manifestations of HCV such as glomerulonephritis.
      • Ciesek S.
      • Wedemeyer H.
      Immunosuppression, liver injury and post-transplant HCV recurrence.
      ,
      • Verna E.C.
      • Abdelmessih R.
      • Salomao M.
      • Lefkowitch J.
      • Moreira R.K.
      • Brown Jr., R.S.
      Cholestatic hepatitis C following liver transplantation: an outcome-based histological definition, clinical predictors, and prognosis.
      However, the high demand for organs and the high prevalence of chronic HCV among liver and kidney transplant candidates led to increasing interest in utilising anti-HCV-positive organs.
      • Kim W.R.
      The burden of hepatitis C in the United States.
      ,
      • Fabrizi F.
      • Poordad F.F.
      • Martin P.
      Hepatitis C infection and the patient with end-stage renal disease.
      Multiple studies in the 1990s and 2000s suggested that while using anti-HCV-positive kidneys in anti-HCV-positive recipients increased the incidence of clinical hepatitis and potentially decreased graft survival, this was likely offset by the decreased time on the waiting list and generally healthier organs donated, leading to improved survival from time of listing.
      • Morales J.M.
      • Campistol J.M.
      • Domínguez-Gil B.
      • Andrés A.
      • Esforzado N.
      • Oppenheimer F.
      • et al.
      Long-term experience with kidney transplantation from hepatitis C-positive donors into hepatitis C-positive recipients.
      ,
      • Scalea J.R.
      • Barth R.N.
      • Munivenkatappa R.
      • Philosophe B.
      • Cooper M.
      • Whitlow V.
      • et al.
      Shorter waitlist times and improved graft survivals are observed in patients who accept hepatitis C virus+ renal allografts.
      Among anti-HCV-positive liver transplant recipients, there was no difference in graft and patient survival with anti-HCV-positive vs. negative donors.
      • Northup P.G.
      • Argo C.K.
      • Nguyen D.T.
      • McBride M.A.
      • Kumer S.C.
      • Schmitt T.M.
      • et al.
      Liver allografts from hepatitis C positive donors can offer good outcomes in hepatitis C positive recipients: a US National Transplant Registry analysis.
      ,
      • Ballarin R.
      • Cucchetti A.
      • Spaggiari M.
      • Montalti R.
      • Di Benedetto F.
      • Nadalin S.
      • et al.
      Long-term follow-up and outcome of liver transplantation from anti-hepatitis C virus-positive donors: a European multicentric case-control study.
      In contrast, anti-HCV-negative recipients who received anti-HCV-positive organs in the pre-DAA era, including heart, lung, and kidneys, had increased liver-related complications and worse post-transplant survival, though the data on survival from time of listing for kidney transplant recipients were mixed due to significantly decreased wait times.
      • Gasink L.B.
      • Blumberg E.A.
      • Localio A.R.
      • Desai S.S.
      • Israni A.K.
      • Lautenbach E.
      Hepatitis C virus seropositivity in organ donors and survival in heart transplant recipients.
      • Flohr T.R.
      • Bonatti H.
      • Hranjec T.
      • Keith D.S.
      • Lobo P.I.
      • Kumer S.C.
      • et al.
      Elderly recipients of hepatitis C positive renal allografts can quickly develop liver disease.
      • Englum B.R.
      • Ganapathi A.M.
      • Speicher P.J.
      • Gulack B.C.
      • Snyder L.D.
      • Duane Davis R.
      • et al.
      Impact of donor and recipient hepatitis C status in lung transplantation.
      This data led to the growing use of anti-HCV-positive organs in anti-HCV-positive recipients, especially in liver and kidney transplants. Utilisation of anti-HCV-positive kidneys in anti-HCV-positive recipients increased from 20% to 38% between 1995 and 2008; however, still over 50% of anti-HCV-positive kidneys were still discarded during this period and at a 2.9-fold higher rate than comparable anti-HCV-negative kidneys.
      • Kucirka L.M.
      • Singer A.L.
      • Ros R.L.
      • Montgomery R.A.
      • Dagher N.N.
      • Segev D.L.
      Underutilization of hepatitis C-positive kidneys for hepatitis c-positive recipients.
      This discard rate remained relatively stable from 2005 to 2014, corresponding to nearly 500 discarded anti-HCV-positive kidneys per year.
      Organ procurement and transplantation network.
      ,
      • Reese P.P.
      • Abt P.L.
      • Blumberg E.A.
      • Goldberg D.S.
      Transplanting hepatitis C–positive kidneys.
      Similarly, anti-HCV-positive livers were 3x more likely than anti-HCV-negative livers to be discarded from 2005 to 2010, and, despite the use of of anti-HCV-positive livers in anti-HCV-positive recipients increasing from 7% to 17% between 2010 and 2015, anti-HCV-positive livers were still around 2x more likely to be discarded during this period.
      • Bowring M.G.
      • Kucirka L.M.
      • Massie A.B.
      • Luo X.
      • Cameron A.
      • Sulkowski M.
      • et al.
      Changes in utilization and discard of hepatitis C–infected donor livers in the recent era.

      DAA era

      Concurrent with the development of highly effective and safe DAAs,
      • Falade-Nwulia O.
      • Suarez-Cuervo C.
      • Nelson D.R.
      • Fried M.W.
      • Segal J.B.
      • Sulkowski M.S.
      Oral direct-acting agent therapy for hepatitis c virus infection: a systematic review.
      drug overdose deaths in the US substantially increased due to the opioid epidemic and, among overdose donors, the percentage who were anti-HCV-positive increased from 8% to 30%.
      • Durand C.M.
      • Bowring M.G.
      • Thomas A.G.
      • Kucirka L.M.
      • Massie A.B.
      • Cameron A.
      • et al.
      The drug overdose epidemic and deceased-donor transplantation in the United States: a national registry study.
      In this context, anti-HCV-positive overdose donors accounted for 6% of the US donor pool in 2015–2016.
      • Kling C.E.
      • Perkins J.D.
      • Landis C.S.
      • Limaye A.P.
      • Sibulesky L.
      Utilization of organs from donors according to hepatitis C antibody and nucleic acid testing status: time for change.
      At the same time, the number of chronic HCV transplant recipients decreased, presumably as patients were cured with DAAs.
      • Goldberg D.
      • Ditah I.C.
      • Saeian K.
      • Lalehzari M.
      • Aronsohn A.
      • Gorospe E.C.
      • et al.
      Changes in the prevalence of hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation.
      In addition, HCV NAT testing became widespread during this time, and 0.15% of US donors were found to be anti-HCV-negative NAT-positive in 2015–2016.
      • Kling C.E.
      • Perkins J.D.
      • Landis C.S.
      • Limaye A.P.
      • Sibulesky L.
      Utilization of organs from donors according to hepatitis C antibody and nucleic acid testing status: time for change.
      All of these factors and the growing comfort with DAAs led to the argument for widespread adoption of anti-HCV-positive kidneys in anti-HCV-negative recipients
      • Reese P.P.
      • Abt P.L.
      • Blumberg E.A.
      • Goldberg D.S.
      Transplanting hepatitis C–positive kidneys.
      and the subsequent interest in using HCV-viraemic organs. The first prospective trial of HCV-viraemic kidneys intentionally transplanted into HCV-nonviraemic recipients was reported in 2017,
      • Goldberg D.S.
      • Abt P.L.
      • Blumberg E.A.
      • Van Deerlin V.M.
      • Levine M.
      • Reddy K.R.
      • et al.
      Trial of transplantation of HCV-infected kidneys into uninfected recipients.
      followed by multiple studies on kidney, liver, heart, and lung transplants over the next 3 years.
      • Goldberg D.S.
      • Abt P.L.
      • Blumberg E.A.
      • Van Deerlin V.M.
      • Levine M.
      • Reddy K.R.
      • et al.
      Trial of transplantation of HCV-infected kidneys into uninfected recipients.
      • Abdelbasit A.
      • Hirji A.
      • Halloran K.
      • Weinkauf J.
      • Kapasi A.
      • Lien D.
      • et al.
      Lung transplantation from hepatitis C viremic donors to uninfected recipients.
      • Durand C.M.
      • Bowring M.G.
      • Brown D.M.
      • Chattergoon M.A.
      • Massaccesi G.
      • Bair N.
      • et al.
      Direct-acting antiviral prophylaxis in kidney transplantation from hepatitis C virus-infected donors to noninfected recipients an open-label nonrandomized trial.
      • Kwong A.J.
      • Wall A.
      • Melcher M.
      • Wang U.
      • Ahmed A.
      • Subramanian A.
      • et al.
      Liver transplantation for hepatitis C virus (HCV) non-viremic recipients with HCV viremic donors.
      • Reese P.P.
      • Abt P.L.
      • Blumberg E.A.
      • Van Deerlin V.M.
      • Bloom R.D.
      • Potluri V.S.
      • et al.
      Twelve-month outcomes after transplant of hepatitis C–infected kidneys into uninfected recipients a single-group trial.
      • Schlendorf K.H.
      • Zalawadiya S.
      • Shah A.S.
      • Wigger M.
      • Chung C.Y.
      • Smith S.
      • et al.
      Early outcomes using hepatitis C–positive donors for cardiac transplantation in the era of effective direct-acting anti-viral therapies.
      • Aslam S.
      • Yumul I.
      • Mariski M.
      • Pretorius V.
      • Adler E.
      Outcomes of heart transplantation from hepatitis C virus–positive donors.
      • Bethea E.
      • Gaj K.
      • Gustafson J.L.
      • Axtell A.
      • Lebeis T.
      • Schoenike M.
      • et al.
      Pre-emptive pangenotypic direct acting antiviral therapy in donor HCV-positive to recipient HCV-negative heart transplantation: an open-label study.
      • Gupta G.
      • Yakubu I.
      • Bhati C.S.
      • Zhang Y.
      • Kang L.
      • Patterson J.A.
      • et al.
      Ultra-short duration direct acting antiviral prophylaxis to prevent virus transmission from hepatitis C viremic donors to hepatitis C negative kidney transplant recipients.
      • McLean R.C.
      • Reese P.P.
      • Acker M.
      • Atluri P.
      • Bermudez C.
      • Goldberg L.R.
      • et al.
      Transplanting hepatitis C virus–infected hearts into uninfected recipients: a single-arm trial.
      • Morris K.L.
      • Adlam J.P.
      • Padanilam M.
      • Patel A.
      • Garcia-Cortes R.
      • Chaudhry S.P.
      • et al.
      Hepatitis C donor viremic cardiac transplantation: a practical approach.
      • Schlendorf K.H.
      • Zalawadiya S.
      • Shah A.S.
      • Perri R.
      • Wigger M.
      • Brinkley D.M.
      • et al.
      Expanding heart transplant in the era of direct-acting antiviral therapy for hepatitis C.
      • Woolley A.E.
      • Singh S.K.
      • Goldberg H.J.
      • Mallidi H.R.
      • Givertz M.M.
      • Mehra M.R.
      • et al.
      Heart and lung transplants from HCV infected donors to uninfected recipients.
      • Bethea E.
      • Arvind A.
      • Gustafson J.
      • Andersson K.
      • Pratt D.
      • Bhan I.
      • et al.
      Immediate administration of antiviral therapy after transplantation of hepatitis C-infected livers into uninfected recipients: implications for therapeutic planning.
      • Cypel M.
      • Feld J.J.
      • Galasso M.
      • Pinto Ribeiro R.V.
      • Marks N.
      • Kuczynski M.
      • et al.
      Prevention of viral transmission during lung transplantation with hepatitis C-viraemic donors: an open-label, single-centre, pilot trial.
      • Durand C.M.
      • Barnaba B.
      • Yu S.
      • Brown D.M.
      • Chattergoon M.A.
      • Bair N.
      • et al.
      Four-week direct-acting antiviral prophylaxis for kidney transplantation from hepatitis C-viremic donors to hepatitis C-negative recipients: an open-label nonrandomized study.
      • Feld J.J.
      • Cypel M.
      • Kumar D.
      • Dahari H.
      • Vanin Pinto Riberio R.
      • Marks N.
      • et al.
      Short-course, direct-acting antivirals and ezetimibe to prevent HCV infection in recipients of organs from HCV-infected donors: a phase 3, single-centre, open-label study.
      • Forbes R.C.
      • Concepcion B.P.
      • Clapper D.
      • DuBray B.J.
      • Shawar S.
      • Schaefer H.M.
      • et al.
      The effect of pulsatile pump perfusion on hepatitis C transmission in kidney transplantation: a prospective pilot study.
      • Kapila N.
      • Menon K.V.N.
      • Al-Khalloufi K.
      • Vanatta J.M.
      • Murgas C.
      • Reino D.
      • et al.
      Hepatitis C virus NAT-positive solid organ allografts transplanted into hepatitis C virus–negative recipients: a real-world experience.
      • Reyentovich A.
      • Gidea C.G.
      • Smith D.
      • Lonze B.
      • Kon Z.
      • Fargnoli A.
      • et al.
      Outcomes with treatment with glecaprevir/pibrentasvir following heart transplantation Utilizing hepatitis C viremic donors.
      • Sise M.E.
      • Goldberg D.S.
      • Kort J.J.
      • Schaubel D.E.
      • Alloway R.R.
      • Durand C.M.
      • et al.
      Multicenter study to transplant hepatitis C – infected kidneys ( MYTHIC ): an open-label study of combined glecaprevir and pibrentasvir to treat recipients of transplanted kidneys from deceased donors with Hepatitis C Virus Infect.
      • Smith D.E.
      • Chen S.
      • Fargnoli A.
      • Lewis T.
      • Galloway A.C.
      • Kon Z.N.
      • et al.
      Impact of early initiation of direct-acting antiviral therapy in thoracic organ transplantation from hepatitis C virus positive donors.
      In the DAA era, anti-HCV-positive kidneys were still 3.7× more likely to be discarded than anti-HCV-negative kidneys, though the percentage of anti-HCV-positive kidneys discarded peaked in 2013 at around 55%, and has since decreased to ~35% in 2018, closer to 2× that of anti-HCV negative kidneys.
      • Bowring M.G.
      • Kucirka L.M.
      • Massie A.B.
      • Luo X.
      • Cameron A.
      • Sulkowski M.
      • et al.
      Changes in utilization and discard of hepatitis C–infected donor livers in the recent era.
      ,
      • Hart A.
      • Smith J.M.
      • Skeans M.A.
      • Gustafson S.K.
      • Wilk A.R.
      • Castro S.
      • et al.
      OPTN/SRTR 2018 Annual data report: kidney.
      ,
      • Ariyamuthu V.K.
      • Sandikci B.
      • AbdulRahim N.
      • Hwang C.
      • MacConmara M.P.
      • Parasuraman R.
      • et al.
      Trends in utilization of deceased donor kidneys based on hepatitis C virus status and impact of public health service labeling on discard.
      Similarly, the percentage of anti-HCV-positive livers discarded in the US steadily decreased from over 20% in 2011 to 7.6% in 2018, with comparable discard rates between anti-HCV-positive and anti-HCV-negative livers since 2016 due mainly to the decreased discard rate in anti-HCV-positive nonviraemic donors.
      • Kwong A.
      • Kim W.R.
      • Lake J.R.
      • Smith J.M.
      • Schladt D.P.
      • Skeans M.A.
      • et al.
      OPTN/SRTR 2018 Annual data report: liver.
      ,
      • Cholankeril G.
      • Li A.A.
      • Dennis B.B.
      • Toll A.E.
      • Kim D.
      • Bonham C.A.
      • et al.
      Increasing trends in transplantation of HCV–positive livers into uninfected recipients.
      However, there has been a 35-fold increase in transplantation of HCV-viraemic livers into nonviraemic recipients from 2016 to 2019, greatly expanding the use of HCV-viraemic livers.
      • Cotter T.G.
      • Aronsohn A.
      • Reddy K.G.
      • Charlton M.
      Liver transplantation of HCV-viremic donors into HCV-negative recipients in the USA: increasing frequency with profound geographic variation.
      Similarly, national utilisation rates of anti-HCV-positive viraemic and nonviraemic donor hearts in 2019 was the same as anti-HCV-negative donor hearts.
      • Madan S.
      • Patel S.R.
      • Rahgozar K.
      • Saeed O.
      • Murthy S.
      • Vukelic S.
      • et al.
      Utilization rates and clinical outcomes of hepatitis C positive donor hearts in the contemporary era.
      ,
      • Prakash K.
      • Wainana C.
      • Trageser J.
      • Hahn A.
      • Lay C.
      • Pretorius V.
      • et al.
      Local and regional variability in utilization and allocation of hepatitis C virus–infected hearts for transplantation.
      Lastly, significant regional and centre-specific variation in discard and transplant rates of anti-HCV-positive and viraemic organs has been described, suggesting that more uniform national and international policies may increase utilisation even further.
      • Cotter T.G.
      • Aronsohn A.
      • Reddy K.G.
      • Charlton M.
      Liver transplantation of HCV-viremic donors into HCV-negative recipients in the USA: increasing frequency with profound geographic variation.
      ,
      • Prakash K.
      • Wainana C.
      • Trageser J.
      • Hahn A.
      • Lay C.
      • Pretorius V.
      • et al.
      Local and regional variability in utilization and allocation of hepatitis C virus–infected hearts for transplantation.
      ,
      • Mohan S.
      • Chiles M.C.
      • Patzer R.E.
      • Pastan S.
      • Husain S.A.
      • Carpenter D.
      • et al.
      Factors leading to the discard of deceased donor kidneys in the United States.

      HCV-viraemic donors to nonviraemic recipients

      Kidney

      The advent of safe and highly effective DAA therapies for HCV has enabled the utilisation of organs from HCV-viraemic donors in HCV-nonviraemic recipients.
      The first prospective trial, THINKER in 2017 followed by THINKER-2, included 20 HCV-nonviraemic recipients who all received viraemic kidneys with genotype 1, requiring a rapid pre-transplant donor genotyping strategy
      • Goldberg D.S.
      • Abt P.L.
      • Blumberg E.A.
      • Van Deerlin V.M.
      • Levine M.
      • Reddy K.R.
      • et al.
      Trial of transplantation of HCV-infected kidneys into uninfected recipients.
      ,
      • Reese P.P.
      • Abt P.L.
      • Blumberg E.A.
      • Van Deerlin V.M.
      • Bloom R.D.
      • Potluri V.S.
      • et al.
      Twelve-month outcomes after transplant of hepatitis C–infected kidneys into uninfected recipients a single-group trial.
      (Table 1). All patients had detectable HCV viraemia post-transplant and were subsequently started on elbasvir/grazoprevir (EBR/GZR) for 12 weeks (n = 17) or EBR/GZR/ribavirin (RBV) for 16 weeks if there were NS5A resistance-associated substitutions (RASs) (n = 3). All patients had sustained virological response at 12 weeks post-treatment (SVR12) and renal allograft function at 6 months was better than matched controls, based on the Organ Procurement and Transplantation Network (OPTN) registry. A subsequent trial (EXPANDER) included genotypes 1–3 and a prophylactic treatment regimen. Patients received a single pre-transplant dose of EBR/GZR followed by EBR/GZR × 12 weeks if genotype 1 or unknown (n = 7) or EBR/GZR/sofosbuvir (SOF) for 12 weeks if genotype 2 or 3 (n = 3).
      • Durand C.M.
      • Bowring M.G.
      • Brown D.M.
      • Chattergoon M.A.
      • Massaccesi G.
      • Bair N.
      • et al.
      Direct-acting antiviral prophylaxis in kidney transplantation from hepatitis C virus-infected donors to noninfected recipients an open-label nonrandomized trial.
      All patients achieved SVR12, but only 30% of patients ever had detectable viraemia post-transplant, raising the question of whether patients need a full treatment course. The DAPPeR trial treated patients with a single pre-transplant dose of SOF/velpatasvir (VEL) followed by either 1 or 3 post-transplant doses
      • Gupta G.
      • Yakubu I.
      • Bhati C.S.
      • Zhang Y.
      • Kang L.
      • Patterson J.A.
      • et al.
      Ultra-short duration direct acting antiviral prophylaxis to prevent virus transmission from hepatitis C viremic donors to hepatitis C negative kidney transplant recipients.
      : 17/50 (34%) patients developed detectable viraemia by 14 days post-transplant, but only 6/50 (12%) patients required treatment, as the other 11 had self-limited low-level viraemia. Of these 6 patients, 5 achieved SVR12, though 1 patient required the addition of RBV at week 2 due to resistance and 2 patients relapsed and required re-treatment with second-line DAAs. The 6th patient failed second-line treatment and declined further treatment. Two more recent prospective studies have used glecaprevir/pibrentasvir (G/P) prophylactically for 4 and 8 weeks with 10/10 (100%) and 30/30 (100%), respectively, achieving SVR12.
      • Durand C.M.
      • Barnaba B.
      • Yu S.
      • Brown D.M.
      • Chattergoon M.A.
      • Bair N.
      • et al.
      Four-week direct-acting antiviral prophylaxis for kidney transplantation from hepatitis C-viremic donors to hepatitis C-negative recipients: an open-label nonrandomized study.
      ,
      • Sise M.E.
      • Goldberg D.S.
      • Kort J.J.
      • Schaubel D.E.
      • Alloway R.R.
      • Durand C.M.
      • et al.
      Multicenter study to transplant hepatitis C – infected kidneys ( MYTHIC ): an open-label study of combined glecaprevir and pibrentasvir to treat recipients of transplanted kidneys from deceased donors with Hepatitis C Virus Infect.
      Table 1HCV-viraemic donors in nonviraemic kidney transplant recipients.
      AuthorOrgan(s) transplantedStudy designHCV treatment strategyOutcomesSpecial considerations
      Goldberg et al. 2017
      • Goldberg D.S.
      • Abt P.L.
      • Blumberg E.A.
      • Van Deerlin V.M.
      • Levine M.
      • Reddy K.R.
      • et al.
      Trial of transplantation of HCV-infected kidneys into uninfected recipients.


      THINKER-1
      10 HCV NAT-positive kidneys into NAT-negative recipientsSingle-centre, open-label, single group, pilot trialPost-transplant:
      • -
        HCV NAT starting POD 3
      • -
        If positive, treated with EBR/GZR × 12 weeks or EBR/GZR + RBV × 16 weeks (if NS5A RAS)
      • 10/10 (100%) detectable viraemia post-transplant
      • 10/10 (100%) SVR12
      • 1/10 delayed graft function
      • Median Cr 1.1 mg/dl at 6 months
      • 1/10 proteinuria due to FSGS
      • 2/10 transient elevation in transaminases
      • Rapid genotype assay to select all genotype 1
        • -
          9/10 genotype 1a
      • Median follow-up 6 months
      Durand et al. 2018
      • Durand C.M.
      • Bowring M.G.
      • Brown D.M.
      • Chattergoon M.A.
      • Massaccesi G.
      • Bair N.
      • et al.
      Direct-acting antiviral prophylaxis in kidney transplantation from hepatitis C virus-infected donors to noninfected recipients an open-label nonrandomized trial.


      EXPANDER
      10 HCV NAT-positive kidneys into NAT-negative recipientsSingle-centre, open-label, single group, pilot trialPre-operative:
      • -
        EBR/GZR × 1 dose
      Post-transplant:
      • -
        EBR/GZR × 12 weeks (genotype 1 or unknown)
      • -
        EBR/GZR + SOF × 12 weeks (genotype 2,3)
      • 3/10 (30%) detectable viraemia post-transplant
      • 10/10 (100%) SVR12
      • 5/10 (50%) anti-HCV seroconversion at 6 months
        • -
          Not correlated with donor VL or POD 1 recipient VL
      • 4/10 with delayed graft function
      • Median Cr 1.06 mg/dl at 6 months
      • 0/10 high-grade proteinuria, ACR
      • 1/10 transient elevation in transaminases
      • Donor genotype results by POD 7
        • -
          3/10 genotype 2 or 3
        • -
          SOF started POD 6, 9, and 12 (delayed graft function)
      • Median follow-up 6 months.
      Reese et al. 2018
      • Reese P.P.
      • Abt P.L.
      • Blumberg E.A.
      • Van Deerlin V.M.
      • Bloom R.D.
      • Potluri V.S.
      • et al.
      Twelve-month outcomes after transplant of hepatitis C–infected kidneys into uninfected recipients a single-group trial.


      THINKER-2
      Additional 10 HCV NAT-positive kidneys into NAT-negative recipientsSingle-centre, open-label, single group, pilot trialPost-transplant:
      • -
        HCV NAT starting POD 3
      • -
        If positive, treated with EBR/GZR × 12 weeks or EBR/GZR + RBV × 16 weeks (if NS5A RAS)
      • 20/20 (100%) detectable viraemia post-transplant
      • 20/20 (100%) SVR12
        • -
          3/20 with NS5A RAS
      • 5/20 delayed graft function
      • Renal allograft function better than matched controls from OPTN registry
      • 1/20 proteinuria due to FSGS, improved with ACEi
      • 5/20 transient elevation in transaminases
      • Rapid genotype assay to select all genotype 1
        • -
          17/20 genotype 1a
      • Median follow-up 6 months (THINKER-2) and 12 months (THINKER-1)
      Gupta et al. 2019
      • Gupta G.
      • Yakubu I.
      • Bhati C.S.
      • Zhang Y.
      • Kang L.
      • Patterson J.A.
      • et al.
      Ultra-short duration direct acting antiviral prophylaxis to prevent virus transmission from hepatitis C viremic donors to hepatitis C negative kidney transplant recipients.


      DAPPeR

      REFORM HEPC
      50 HCV NAT-positive kidneys into NAT-negative recipientsSingle-centre, non-randomised trialPre-transplant:
      • -
        SOF/VEL × 1 dose
      Post-transplant:
      • -
        SOF/VEL × 1 (group 1) vs. 3 doses (group 2)
      • -
        HCV NAT testing
      • -
        If positive, treated with EBR/GZR × 12 weeks (group 1, all genotype 1a), SOF/VEL +/- RBV × 12 weeks (group 2A, genotype 2,3), or DAA based on genotype and resistance testing (group 2B)
      • 17/50 (34%) detectable viraemia post-transplant
      • 6/50 (12%) required treatment
        • -
          3/10 (30%) in group 1
        • -
          3/40 (7.5%) in group 2
        • -
          Remaining 11 patients had self-limited low-level viraemia
      • 5/6 with SVR12
        • -
          2/5 required re-treatment with 2nd line DAA
        • -
          6th patient failed 2nd line DAA (unclear adherence, declined further treatment)
      • 6/25 (24%) anti-HCV seroconversion at 6 months
        • -
          Not correlated with post-transplant viraemia
      • 98% patient and graft survival
      • 2/50 ACR (1/6 in patients requiring HCV treatment)
      • 2/50 transient elevation in transaminases (both had negative HCV VL)
      • Donor genotype results POD 7–14 (only sent for 31/50)
        • -
          4/31 indeterminate
        • -
          19/31 genotype 1a
        • -
          2/31 genotype 2
        • -
          6/31 genotype 3
      • Delay of treatment initiation 1–2 months in patients who required second-line DAA for re-treatment (3/6 patients who needed treatment).
      • Median follow-up 8 months
      La Hoz et al. 2019
      • La Hoz R.M.
      • Sandıkçı B.
      • Ariyamuthu V.K.
      • Tanriover B.
      Short-term outcomes of deceased donor renal transplants of HCV uninfected recipients from HCV seropositive nonviremic donors and viremic donors in the era of direct-acting antivirals.
      Anti-HCV-positive (196 NAT-positive, 349 NAT-negative) into NAT-negative recipients
      • -
        Retrospective propensity-matched analysis of OPTN registry 2015–2019
      • -
        Control: 659 anti-HCV-negative NAT-negative donors
      Not reported
      • Less delayed graft function than control (17 vs. 36%, 19 vs. 35%, both p<0.001)
      • Better allograft function at 6 months for HCV NAT-positive donors than control (68 vs. 54, p = 0.004)
      • No difference in graft survival at 1-year (94 vs. 93%, 98 vs. 94%, n.s.)
      • No difference in ACR (2 vs. 4%, 4 vs. 5%, n.s.)
      • HCV NAT and genotype not reported
      • HCV treatments not reported
      • Median follow-up 7.2 months
      Durand et al. 2020
      • Durand C.M.
      • Barnaba B.
      • Yu S.
      • Brown D.M.
      • Chattergoon M.A.
      • Bair N.
      • et al.
      Four-week direct-acting antiviral prophylaxis for kidney transplantation from hepatitis C-viremic donors to hepatitis C-negative recipients: an open-label nonrandomized study.
      10 HCV NAT-positive kidneys into NAT-negative recipientsSingle-centre, prospective, pilot trialPre-transplant:
      • -
        G/P × 1 dose
      Post-transplant:
      • -
        G/P × 4 weeks
      • 5/10 (50%) detectable viraemia post-transplant
      • 10/10 (100%) SVR 12
      • One graft failure due to venous thrombosis
      • No rejection
      • Genotypes 1, 3
        • -
          7/10 genotype 1
        • -
          2/10 genotype 2
        • -
          1/10 indeterminate
      • Median follow-up 12 months
      Forbes et al. 2020
      • Forbes R.C.
      • Concepcion B.P.
      • Clapper D.
      • DuBray B.J.
      • Shawar S.
      • Schaefer H.M.
      • et al.
      The effect of pulsatile pump perfusion on hepatitis C transmission in kidney transplantation: a prospective pilot study.
      12 kidneys from 6 HCV NAT-positive donors into NAT-negative recipientsSingle-centre, prospective, pilot trialPerioperative:
      • -
        6/12 kidneys pumped with perfusate exchange
      • -
        6/12 paired kidneys without intervention
      Post-operative:
      • -
        HCV NAT starting POD 3
      • 12/12 (100%) detectable viraemia post-transplant
      • 6/12 SVR 12 (6 pending)
        • -
          9/12 G/P
        • -
          3/12 LDV/SOF
      • 100% patient survival, 92% graft survival
      • Genotypes 1a/b, 3
        • -
          9/12 genotype 1
        • -
          3/12 genotype 3
      • Median follow-up ~6.2 months
      Kapila et al. 2020
      • Kapila N.
      • Menon K.V.N.
      • Al-Khalloufi K.
      • Vanatta J.M.
      • Murgas C.
      • Reino D.
      • et al.
      Hepatitis C virus NAT-positive solid organ allografts transplanted into hepatitis C virus–negative recipients: a real-world experience.
      64 HCV NAT-positive kidneys into NAT-negative recipientsSingle-centre, prospective cohort studyPost-transplant:
      • -
        HCV NAT POD 3–5
      • -
        If positive, treatment determined by individual outpatient hepatologist based on genotype and insurance approval (33 G/P, 24 SOF/LDV, 1 SOF/VEL)
      • 61/64 (95%) detectable viraemia post-transplant
        • -
          58 of 61 started on DAA's
      • 41/58 with SVR 12 (17 pending)
        • -
          1/58 non-responder due to NS5A resistance, now on SOF/VEL+VOX
      • 98% patient/graft survival
        • -
          1/64 died POD 77 with untreated HCV viraemia, though normal liver chemistries
      • 2/58 fibrosing cholestatic hepatitis at 11 and 14 weeks
      • Both had untreated HCV viraemia and responded well to DAAs
      • Genotypes 1–4
        • -
          42/61 genotype 1
        • -
          6/61 genotype 2
        • -
          8/61 genotype 3
        • -
          3/61 genotype 4
        • -
          2/61 mixed genotypes
      • Median time to DAA initiation: POD 72
      • Median follow-up ~10 months
      Sise et al. 2020
      • Sise M.E.
      • Goldberg D.S.
      • Kort J.J.
      • Schaubel D.E.
      • Alloway R.R.
      • Durand C.M.
      • et al.
      Multicenter study to transplant hepatitis C – infected kidneys ( MYTHIC ): an open-label study of combined glecaprevir and pibrentasvir to treat recipients of transplanted kidneys from deceased donors with Hepatitis C Virus Infect.


      MYTHIC
      30 HCV NAT-positive kidneys into NAT-negative recipientsMulticentre, prospective cohort studyPost-transplant:
      • -
        G/P for 8 weeks starting POD 2–5
      • Median waitlist time from consent to transplant: 6.3 weeks
      • 28/29 (97%) detectable viraemia post-transplant, one not tested
      • 30/30 SVR 12
      • 97% patient/graft survival
        • -
          1 patient died 9 months post-transplant from sepsis
        • -
          7/30 delayed graft function
        • -
          3/7 ACR
        • -
          Median Cr 1.2 at 6 months
      • Genotypes 1,2,4
        • -
          13/15 genotype 1A
        • -
          1/15 genotype 2
        • -
          1/15 genotype 4
      • Median follow-up 9 months
      ACEi, angiotensin-converting enzyme inhibitor; ACR, acute cellular rejection; Anti-HCV, HCV antibody; Cr, creatinine; DAA, direct-acting antiviral; DAPPeR, Ultra-short Direct-acting Antiviral Prophylaxis to Prevent virus transmission from hepatitis C viremic donor to hepatitis C negative Recipients; EBR, elbasvir; EXPANDER, Exploring Renal Transplants Using Hepatitis C Infected Donors for HCV-Negative Recipients; FSGS, focal segmental glomerulosclerosis; G, glecaprevir; GZR, grazoprevir; LDV, ledipasvir; MYTHIC, Multi-center Study to Transplant Hepatitis C-Infected Kidneys; NAT, nucleic acid testing; OPTN, Organ Procurement and Transplantation Network; P, pibrentasvir; POD, post-operative day; RASs, resistance-associated substitutions; RBV, ribavirin; REFORM HEPC, REgistry for the study of ORgan transplants froM HEPatitis C infected donors; SOF, sofosbuvir; SVR12, sustained viral response 12 weeks after therapy completion; THINKER, Transplant Hepatitis C Kidneys into Negative Kidney Recipients; VEL, velpatasvir; VL, viral load; VOX, voxilaprevir.
      The largest prospective real-word experience using HCV-viraemic organs thus far included 77 HCV-nonviraemic recipients who received viraemic organs, including 64 kidneys, followed by post-transplant NAT to determine need for treatment.
      • Kapila N.
      • Menon K.V.N.
      • Al-Khalloufi K.
      • Vanatta J.M.
      • Murgas C.
      • Reino D.
      • et al.
      Hepatitis C virus NAT-positive solid organ allografts transplanted into hepatitis C virus–negative recipients: a real-world experience.
      61/64 (95%) developed HCV viraemia post-transplant with 41 patients having achieved SVR by end of study and only 1 patient not responding to initial therapy due to a NS5A RAS. Patient and graft survival were 98% at a median follow-up of 8 months. Notably, outpatient DAA therapy was initiated at a median 72 days post-transplant, during which time 2 patients developed fibrosing cholestatic hepatitis, at 11 and 14 weeks, though both responded well to DAA therapy. A review of the OPTN registry from 2015 to 2019 compared anti-HCV-positive viraemic (n = 196) and nonviraemic (n = 349) to anti-HCV-negative nonviraemic donors, confirming the excellent short-term outcomes seen in these smaller prospective trials, including better allograft function at 6 months and no difference in 1-year graft survival or frequency of acute cellular rejection (ACR).
      • La Hoz R.M.
      • Sandıkçı B.
      • Ariyamuthu V.K.
      • Tanriover B.
      Short-term outcomes of deceased donor renal transplants of HCV uninfected recipients from HCV seropositive nonviremic donors and viremic donors in the era of direct-acting antivirals.

      Liver

      Two recent studies prospectively followed 80 HCV-nonviraemic recipients who received anti-HCV-positive nonviraemic livers. HCV viraemia was detected post-transplant in 9 recipients (11.5%), and 7 received DAA therapy, of whom 6 achieved SVR12 (2 died from non-HCV-related causes, 1 patient had only completed treatment at time of publication).
      • Bari K.
      • Luckett K.
      • Kaiser T.
      • Diwan T.
      • Cuffy M.
      • Schoech M.R.
      • et al.
      Hepatitis C transmission from seropositive, nonviremic donors to non–hepatitis C liver transplant recipients.
      ,
      • Luckett K.
      • Kaiser T.E.
      • Bari K.
      • Safdar K.
      • Schoech M.R.
      • Apewokin S.
      • et al.
      Use of hepatitis C virus antibody-positive donor livers in hepatitis C nonviremic liver transplant recipients.
      These data and the promising outcomes in kidney transplantation laid the foundation for the use of HCV-viraemic livers in nonviraemic recipients (Table 2). The first prospective study included 10 HCV-nonviraemic recipients who received viraemic livers followed by NAT surveillance and DAA treatment if positive.
      • Kwong A.J.
      • Wall A.
      • Melcher M.
      • Wang U.
      • Ahmed A.
      • Subramanian A.
      • et al.
      Liver transplantation for hepatitis C virus (HCV) non-viremic recipients with HCV viremic donors.
      As in kidney transplants without DAA prophylaxis, 100% of patients had detectable HCV viraemia post-transplant. However, short-term outcomes were excellent with 100% SVR12 and 100% patient and graft survival at median follow-up of 12.7 months. Similarly, 2 other prospective studies included a total of 16 HCV-nonviraemic liver transplant recipients who received viraemic livers with detectable viraemia post-transplant in 94% of recipients. All patients were treated with G/P and 13/16 achieved SVR12 (3 in various stages of treatment at time of publication) with 100% patient and graft survival at median follow-up of 8 to 11 months.
      • Bethea E.
      • Arvind A.
      • Gustafson J.
      • Andersson K.
      • Pratt D.
      • Bhan I.
      • et al.
      Immediate administration of antiviral therapy after transplantation of hepatitis C-infected livers into uninfected recipients: implications for therapeutic planning.
      ,
      • Kapila N.
      • Menon K.V.N.
      • Al-Khalloufi K.
      • Vanatta J.M.
      • Murgas C.
      • Reino D.
      • et al.
      Hepatitis C virus NAT-positive solid organ allografts transplanted into hepatitis C virus–negative recipients: a real-world experience.
      Two recent reviews of the OPTN registry from 2015 to 2020 confirmed that the excellent short-term outcomes achieved by transplanting HCV-viraemic livers into nonviraemic recipients hold true in the real-world setting.
      • Cholankeril G.
      • Li A.A.
      • Dennis B.B.
      • Toll A.E.
      • Kim D.
      • Bonham C.A.
      • et al.
      Increasing trends in transplantation of HCV–positive livers into uninfected recipients.
      ,
      • Cotter T.G.
      • Aronsohn A.
      • Reddy K.G.
      • Charlton M.
      Liver transplantation of HCV-viremic donors into HCV-negative recipients in the USA: increasing frequency with profound geographic variation.
      Table 2HCV-viraemic donors in nonviraemic liver transplant recipients.
      AuthorOrgan(s) transplantedStudy designHCV treatment strategyOutcomesSpecial considerations
      Kwong et al. 2018
      • Kwong A.J.
      • Wall A.
      • Melcher M.
      • Wang U.
      • Ahmed A.
      • Subramanian A.
      • et al.
      Liver transplantation for hepatitis C virus (HCV) non-viremic recipients with HCV viremic donors.
      10 HCV NAT-positive livers into HCV NAT-negative recipientsSingle-centre, prospective cohort studyPost-transplant:
      • -
        HCV NAT by POD 4
      • -
        If positive, treatment determined based on genotype and insurance approval
      • 10/10 (100%) detectable HCV viraemia post-transplant
      • 10/10 (100%) SVR 12
        • -
          4/10 SOF/VEL 3 for 12 weeks, 1 for 24 weeks
        • -
          2/10 SOF/VEL/RBV × 12 weeks
        • -
          2/10 SOF/LDV × 12 weeks
        • -
          1/10 SOF/LDV/RBV × 24 weeks
        • -
          1/10 SOF/DCV/RBV × 24 weeks
      • 100% patient/graft survival
      • 2/10 (20%) ACR, 2/10 (20%) AMR
      • 7/10 HCV NAT-negative recipients with prior HCV treatment
      • Genotypes 1–3
        • -
          3/10 genotype 1
        • -
          3/10 genotype 2
        • -
          4/10 genotype 3
      • Median time to DAA initiation: POD 43
      • Median follow-up 12.7 months
      Cholankeril et al. 2019
      • Cholankeril G.
      • Li A.A.
      • Dennis B.B.
      • Toll A.E.
      • Kim D.
      • Bonham C.A.
      • et al.
      Increasing trends in transplantation of HCV–positive livers into uninfected recipients.
      719 anti-HCV-positive NAT-positive livers transplanted (30 into anti-HCV-negative recipients)
      • -
        Retrospective cohort study of OPTN registry 2015–2017
      • -
        Control: 386 anti-HCV-positive NAT-negative donors and 14,661 anti-HCV-negative donors
      Not reported
      • No difference in 1-year patient survival (92 vs. 92 vs. 92% in HCV NAT-positive, anti-HCV-positive NAT-negative, and anti-HCV-negative)
      • No difference in 1-year graft survival (92 vs. 91 vs. 90% in HCV NAT-positive, anti-HCV-positive NAT-negative, and anti-HCV-negative)
      • HCV transmission rate and genotypes not reported
      • HCV treatment regimens not reported
      • Median follow-up not reported
      Bethea et al. 2020
      • Bethea E.
      • Arvind A.
      • Gustafson J.
      • Andersson K.
      • Pratt D.
      • Bhan I.
      • et al.
      Immediate administration of antiviral therapy after transplantation of hepatitis C-infected livers into uninfected recipients: implications for therapeutic planning.
      14 anti-HCV-positive livers (10 NAT-positive) into anti-HCV-negative recipientsSingle-centre, prospective cohort studyPost-transplant:
      • -
        For NAT-positive donors: G/P × 12 weeks
      • -
        For NAT-negative donors: NAT surveillance and treatment with G/P only if positive
      • NAT-positive donors:
        • -
          9/10 (90%) detectable viraemia post-transplant
        • -
          10/10 (100%) SVR12
        • -
          1/9 (11%) ACR
      • NAT-negative donors:
        • -
          1/4 (25%) detectable viraemia post-transplant, SVR12 pending
      • 100% survival at end of study
      • Included 4 liver-kidney recipients
      • Genotypes 1,2,3
        • -
          8/11 genotype 1
        • -
          1/11 genotype 2
        • -
          2/11 genotype 3
      • G/P started with 5 days post-transplant
      • Median follow-up ~11.5 months
      Cotter et al. 2020
      • Cotter T.G.
      • Aronsohn A.
      • Reddy K.G.
      • Charlton M.
      Liver transplantation of HCV-viremic donors into HCV-negative recipients in the USA: increasing frequency with profound geographic variation.
      NAT-positive livers into NAT-negative recipients
      • -
        Retrospective cohort study of OPTN registry 1/2016–3/2020
      • -
        NAT-negative livers into NAT-negative recipients
      Not reported
      • No difference in graft survival at 2 years (88.5 vs. 87&, p = 0.672)
      • In multi-variate analysis, NAT-positive was not predictive of patient or graft survival
      • HCV transmission rate and genotypes not reported
      • HCV treatment regimens not reported
      • Median follow-up not available
      Kapila et al. 2020
      • Kapila N.
      • Menon K.V.N.
      • Al-Khalloufi K.
      • Vanatta J.M.
      • Murgas C.
      • Reino D.
      • et al.
      Hepatitis C virus NAT-positive solid organ allografts transplanted into hepatitis C virus–negative recipients: a real-world experience.
      6 HCV NAT-positive livers into HCV NAT-negative recipientsSingle-centre, prospective cohort studyPost-transplant:
      • -
        HCV NAT within 3–5 days
      • -
        If positive, treatment determined based on genotype and insurance approval
      • 6/6 (100%) detectable viraemia post-transplant
        • -
          All 6 treated with G/P
      • 3/6 with SVR12 (3 pending)
      • 100% patient/graft survival
      • Included 2 liver-kidney recipients
      • Genotypes 1,3,4
        • -
          4/6 genotype 1
        • -
          1/6 genotype 3
        • -
          1/6 genotype 4
      • Median time to DAA initiation: 51 days from transplant
      • Median follow-up ~8 months
      ACR, acute cellular rejection; AMR, antibody-mediated rejection; Anti-HCV, HCV antibody; DAA, direct-acting antiviral; EBR, elbasvir; G, glecaprevir; GZR, grazoprevir; LDV, ledipasvir; NAT, nucleic acid testing; OPTN, Organ Procurement and Transplantation Network; P, pibrentasvir; POD, post-operative day; RBV, ribavirin; SOF, sofosbuvir; SVR12, sustained viral response 12 weeks after therapy completion; VEL, velpatasvir; VL, viral load; VOX, voxilaprevir.

      Heart

      The first prospective study using HCV-viraemic hearts included 11 nonviraemic recipients who were then followed by NAT post-transplant
      • Schlendorf K.H.
      • Zalawadiya S.
      • Shah A.S.
      • Wigger M.
      • Chung C.Y.
      • Smith S.
      • et al.
      Early outcomes using hepatitis C–positive donors for cardiac transplantation in the era of effective direct-acting anti-viral therapies.
      (Table 3). Nine out of 11 (85%) developed detectable HCV viraemia post-transplant and were started on SOF/ledipasvir (LDV) for 12 weeks (genotype 1) or SOF/VEL for 12–24 weeks (genotype 3), as outpatients, at a median 33 days post-transplant – 100% achieved SVR12. Following this study, several other centres reported their own experiences with similar strategies.
      • Schlendorf K.H.
      • Zalawadiya S.
      • Shah A.S.
      • Wigger M.
      • Chung C.Y.
      • Smith S.
      • et al.
      Early outcomes using hepatitis C–positive donors for cardiac transplantation in the era of effective direct-acting anti-viral therapies.
      ,
      • McLean R.C.
      • Reese P.P.
      • Acker M.
      • Atluri P.
      • Bermudez C.
      • Goldberg L.R.
      • et al.
      Transplanting hepatitis C virus–infected hearts into uninfected recipients: a single-arm trial.
      • Morris K.L.
      • Adlam J.P.
      • Padanilam M.
      • Patel A.
      • Garcia-Cortes R.
      • Chaudhry S.P.
      • et al.
      Hepatitis C donor viremic cardiac transplantation: a practical approach.
      • Schlendorf K.H.
      • Zalawadiya S.
      • Shah A.S.
      • Perri R.
      • Wigger M.
      • Brinkley D.M.
      • et al.
      Expanding heart transplant in the era of direct-acting antiviral therapy for hepatitis C.
      ,
      • Kapila N.
      • Menon K.V.N.
      • Al-Khalloufi K.
      • Vanatta J.M.
      • Murgas C.
      • Reino D.
      • et al.
      Hepatitis C virus NAT-positive solid organ allografts transplanted into hepatitis C virus–negative recipients: a real-world experience.
      ,
      • Reyentovich A.
      • Gidea C.G.
      • Smith D.
      • Lonze B.
      • Kon Z.
      • Fargnoli A.
      • et al.
      Outcomes with treatment with glecaprevir/pibrentasvir following heart transplantation Utilizing hepatitis C viremic donors.
      In total, this included 165 HCV-nonviraemic recipients who received viraemic hearts followed by surveillance NAT and treatment with various DAA regimens if positive. 159/165 (96%) had detectable HCV viraemia post-transplant with SVR12 in 118 patients (4 patients died without viraemia prior to finishing therapy, 37 patients were in various stages of treatment at publication). Reported 1-year survival rates were between 91–95%, with 8–20% ACR, 1.5–10% antibody-mediated rejection, and 0–43% cardiac allograft vasculopathy. No studies reported significant HCV- or DAA-related adverse events. Similarly, several reviews of UNOS data from 2014–2018 reported no difference in primary graft failure, acute rejection, post-transplant need for dialysis, or 1-year survival with HCV-viraemic donors compared to nonviraemic donors.
      • Madan S.
      • Patel S.R.
      • Rahgozar K.
      • Saeed O.
      • Murthy S.
      • Vukelic S.
      • et al.
      Utilization rates and clinical outcomes of hepatitis C positive donor hearts in the contemporary era.
      ,
      • Moayedi Y.
      • Fan C.P.S.
      • Gulamhusein A.F.
      • Manlhiot C.
      • Ross H.J.
      • Teuteberg J.J.
      • et al.
      Current use of hearts from hepatitis C viremic donors.
      ,
      • Kilic A.
      • Hickey G.
      • Mathier M.
      • Sultan I.
      • Gleason T.G.
      • Horn E.
      • et al.
      Outcomes of adult heart transplantation using hepatitis C–positive donors.
      Preliminary data suggests high rates of HCV transmission to recipient when using HCV-viraemic donors, which can be effectively prevented or treated with a variety of different DAA regimens.
      Table 3HCV-viraemic donors in nonviraemic heart transplant recipients.
      AuthorOrgan(s) transplantedStudy designHCV treatment strategyOutcomesSpecial considerations
      Moayedi et al. 2018
      • Moayedi Y.
      • Fan C.P.S.
      • Gulamhusein A.F.
      • Manlhiot C.
      • Ross H.J.
      • Teuteberg J.J.
      • et al.
      Current use of hearts from hepatitis C viremic donors.
      56 HCV NAT-positive donor hearts
      • -
        Retrospective, cohort study of UNOS database from 2014–2017
      • -
        Control: 168 propensity-matched HCV NAT-negative donor hearts
      Not reported
      • Only 64/1306 (5%) of HCV NAT-positive hearts recovered were used for transplant, though this increased from 0% to 12% from 2014 to 2017
      • 88% vs. 89% 1-year survival (n.s.)
      • Recipient NAT not reported
      • Genotypes not reported
      • Median follow-up not reported
      Schlendorf et al. 2018
      • Schlendorf K.H.
      • Zalawadiya S.
      • Shah A.S.
      • Wigger M.
      • Chung C.Y.
      • Smith S.
      • et al.
      Early outcomes using hepatitis C–positive donors for cardiac transplantation in the era of effective direct-acting anti-viral therapies.
      11 HCV NAT-positive hearts into NAT-negative recipientsSingle-centre, prospective cohort studyPost-transplant:
      • -
        HCV NAT testing weekly
      • -
        If positive, treatment initiated in outpatient setting
      • -
        SOF/LDV × 12 weeks (genotype 1)
      • -
        SOF/VEL × 12–24 weeks (genotype 3)
      • 9/11 (85%) detectable viraemia post-transplant
      • 8/9 (89%) SVR12
        • -
          1 died prior due to pulmonary emboli
      • 2/11 with delayed graft function
        • -
          1 complicated by renal dysfunction delaying DAAs for 3 months
      • 6/11 with ACR
        • -
          5/6 HCV-viraemic
      • No significant elevations in liver chemistries
      • 1 recipient with prior HCV treatment (NAT-negative at transplant)
      • Genotypes 1, 3
        • -
          7/9 genotype 1
        • -
          2/9 genotype 3
      • Median time to DAA initiation: POD 33
      • HMG-CoA reductase inhibitors held while on DAAs
      • Minimum 6 months follow-up
      Aslam et al. 2019
      • Aslam S.
      • Yumul I.
      • Mariski M.
      • Pretorius V.
      • Adler E.
      Outcomes of heart transplantation from hepatitis C virus–positive donors.
      21 anti-HCV-positive hearts (19 NAT-positive) into NAT-negative recipientsSingle-centre, retrospective cohort studyPost-transplant:
      • -
        HCV NAT testing day 3, week 1 and 2
      • -
        If positive, treatment started on discharge.
      • -
        Regimen determined by Transplant Infectious Diseases physician and insurance approval
      • 19/19 (100%) detectable viraemia post-transplant for NAT-positive donors
        • -
          0/2 detectable viraemia post-transplant for NAT-positive donors (2/2 anti-HCV-positive- one transient, one sustained)
      • 18/19 SVR12
        • -
          1 patient died without viraemia but before SVR12
        • -
          14/19 (75%) G/P × 12 weeks
        • -
          2/19 (11%) SOF/VEL × 12 weeks
        • -
          2/19 (11%) EBR/GZR × 12 weeks
        • -
          1/19 (5%) SOF/LDV × 12 weeks
      • 100% and 91% 6-month and 1-year survival
        • -
          1 patient died of heart failure POD 217 (undetectable VL, unknown cause of graft failure)
      • 6/19 (32%) elevated LFTs prior to DAA
      • 1/11 AMR, 2/10 CAV at 1-year
      • Includes 3 heart-kidney recipients.
      • Genotypes 1–4
        • -
          11/19 genotype 1
        • -
          4/19 genotype 2
        • -
          4/19 genotype 3
        • -
          1/19 genotype 1/4
      • Median time to DAA initiation from transplant: 31 days (22–40 days)
      • Median follow-up ~12.8 months
      Bethea et al. 2019
      • Bethea E.
      • Gaj K.
      • Gustafson J.L.
      • Axtell A.
      • Lebeis T.
      • Schoenike M.
      • et al.
      Pre-emptive pangenotypic direct acting antiviral therapy in donor HCV-positive to recipient HCV-negative heart transplantation: an open-label study.
      25 anti-HCV-positive hearts (20 NAT-positive) into NAT-negative recipientsSingle-centre, open-label, non-randomised trialPre-transplant:
      • -
        For NAT-positive donors: G/P × 1 dose
      Post-transplant:
      • -
        For NAT-positive donors: G/P × 8 weeks
      • -
        For NAT-negative donors: NAT testing and treatment with G/P only if positive
      • For NAT-positive donors:
        • -
          20/20 (100%) SVR12
      • For NAT-negative donors:
        • -
          0/5 (0%) detectable viraemia post-transplant
      • 100% patient and graft survival
      • Genotypes not available
      • Median follow-up 10.7 months
      Madan et al. 2019
      • Madan S.
      • Patel S.R.
      • Rahgozar K.
      • Saeed O.
      • Murthy S.
      • Vukelic S.
      • et al.
      Utilization rates and clinical outcomes of hepatitis C positive donor hearts in the contemporary era.
      118 HCV NAT-positive and 86 anti-HCV-positive NAT-negative hearts
      • -
        Retrospective, cohort study of UNOS database from 2015–2018
      • -
        Control: Propensity-matched anti-HCV-negative NAT-negative donor hearts
      Not reported
      • No difference in primary graft failure
        • -
          NAT-positive donors: HR 0.7, 0.1–4.8
        • -
          Anti-HCV-positive NAT-negative donors: HR 1.4, 0.3–6.1
      • No difference in mortality
        • -
          NAT-positive donors: HR 0.7, 0.3–1.7
        • -
          Anti-HCV-positive NAT-negative donors: HR 1.4, 0.7–2.8
      • No difference in acute rejection (16% NAT-positive, 12% anti-HCV-positive NAT-negative, 12% anti-HCV-negative NAT-negative)
      • Recipient NAT not reported
      • Genotypes not reported
      • Median follow-up 12.1 months
      McLean et al. 2019
      • McLean R.C.
      • Reese P.P.
      • Acker M.
      • Atluri P.
      • Bermudez C.
      • Goldberg L.R.
      • et al.
      Transplanting hepatitis C virus–infected hearts into uninfected recipients: a single-arm trial.


      USHER
      10 HCV NAT-positive hearts into NAT-negative recipientsSingle-centre, open-label, single group, pilot trialPost-transplant:
      • -
        HCV NAT testing day 3 post-transplant
      • -
        If positive, treated with EBR/GZR × 12 weeks
      • 10/10 (100%) HCV transmission
      • 9/10 (90%) SVR 12
        • -
          1 died prior due to antibody-mediated rejection (NAT negative from POD 7)
      • 1/10 AMR, 2/10 ACR
      • 2/10 with AKI requiring dialysis
      • Rapid genotype assay to select all genotype 1
        • -
          10/10 genotype 1a
      • 6–12-month follow-up
      Morris et al. 2019
      • Morris K.L.
      • Adlam J.P.
      • Padanilam M.
      • Patel A.
      • Garcia-Cortes R.
      • Chaudhry S.P.
      • et al.
      Hepatitis C donor viremic cardiac transplantation: a practical approach.
      25 anti-HCV-positive hearts (23 NAT-positive) into HCV-uninfected recipientsSingle-centre, retrospective cohort studyPost-transplant:
      • -
        HCV NAT testing starting 1-week post-transplant
      • -
        If positive, treated with G/P × 8 weeks unless insurance required alternative
      • 22/23 (96%) and 0/2 (0%) detectable viraemia post-transplant
      • 15/22 with SVR 12 (7 pending)
        • -
          15/22 G/P × 8 weeks
        • -
          5/22 SOF/VEL × 12 weeks
        • -
          2/22 LDV/SOF (1 patient failed but had SVR 12 on SOF/VELF/VOX)
      • 2/25 (8%) >1R rejection
      • 0/10 (0%) CAV at 1 year
      • Genotype 1–3
        • -
          14/22 genotype 1a
        • -
          1/22 genotype 2
        • -
          7/22 genotype 3
      • 11/22 initially denied insurance coverage for DAAs.
      • Median time to DAA initiation from transplant: 74 days (28–169 days)
      • Median follow-up not reported, longest follow-up 13 months
      Schlendorf et al. 2019
      • Schlendorf K.H.
      • Zalawadiya S.
      • Shah A.S.
      • Perri R.
      • Wigger M.
      • Brinkley D.M.
      • et al.
      Expanding heart transplant in the era of direct-acting antiviral therapy for hepatitis C.
      80 anti-HCV-positive (70 NAT-positive) hearts into NAT-negative recipientsSingle-centre, prospective cohort studyPost-transplant:
      • -
        HCV NAT testing weekly
      • -
        If positive, treatment initiated in outpatient setting
      • -
        Regimen determined by hepatologist and insurance approval
      • 67/70 (96%) and 0/10 (0%) detectable viraemia post-transplant
      • 55/67 started on treatment (5 died prior to initiation, 7 not yet started)
        • -
          27/55 SOF/LDV
        • -
          16/55 SOF/VEL
        • -
          12/55 G/P
        • -
          53/55 for 12 weeks, 2/55 for 24 weeks due to persistent viraemia at 4 weeks
      • 37/55 SVR12 (17 pending, 1 died prior to SVR12)
      • 61/67 (91%) 1-year survival
        • -
          5 died due to primary graft failure (median 10 days post-transplant)
        • -
          1 died of PE 112 days post-transplant
      • 11/67 (16%) primary graft failure
      • 10/67 (15%) ACR requiring treatment
      • 1/67 (1.5%) AMR requiring treatment
      • 29/67 (43%) CAV at 1 year
      • Includes 5 heart-kidney and 1 heart-liver recipients
      • Genotypes 1–3
        • -
          40/67 genotype 1a
        • -
          5/67 genotype 1b
        • -
          3/67 genotype 2
        • -
          16/67 genotype 3
      • Median time to DAA initiation from transplant:
        • -
          Outpatient start (n = 52): 55 days (IQR 39–74)
        • -
          Inpatient start (n = 3): 93 days (IQR 43–248)
      • Median follow-up 301 days
      Woolley et al. 2019
      • Woolley A.E.
      • Singh S.K.
      • Goldberg H.J.
      • Mallidi H.R.
      • Givertz M.M.
      • Mehra M.R.
      • et al.
      Heart and lung transplants from HCV infected donors to uninfected recipients.


      DONATE-HCV
      8 HCV NAT-positive hearts into NAT-negative recipients
      • -
        Single-centre, open-label, non-randomised pilot trial
      • -
        Control: 12 NAT-negative hearts into NAT-negative recipients
      Post-transplant:
      • -
        SOF/VEL immediately post-transplant × 4 weeks
      • 8/8 (100%) detectable viraemia post-transplant
      • 7/8 SVR 12 (1 pending)
      • 7/7 (100%) 6-month patient/graft survival
      • Compared to NAT-negative donors:
        • -
          No difference in stage 4/5 CKD or need for dialysis
        • -
          No difference in LFTs
      • 41 donors for heart and lungs with genotypes 1–3
        • -
          24/41 genotype 1a
        • -
          1/41 genotype 1b
        • -
          7/41 genotype 2
        • -
          7/41 genotype 3
        • -
          2/41 indeterminate
      • Median follow-up ~9.5 months
      Feld et al. 2020
      • Feld J.J.
      • Cypel M.
      • Kumar D.
      • Dahari H.
      • Vanin Pinto Riberio R.
      • Marks N.
      • et al.
      Short-course, direct-acting antivirals and ezetimibe to prevent HCV infection in recipients of organs from HCV-infected donors: a phase 3, single-centre, open-label study.
      30 HCV NAT-positive organs (6 heart, 13 lung, 10 kidney, 1 kidney-pancreas) from 18 donors into HCV NAT-negative recipientsSingle-centre, open-label, single group, pilot trialPre-transplant:
      • -
        Ezetimibe + G/P × 1 dose 6–12 hours prior
      Post-transplant:
      • -
        Ezetimibe + G/P × 7 days
      • 21/30 (67%) detectable viraemia post-transplant
      • 30/30 (100%) undetectable HCV VL at 12 weeks post-transplant
      • 1/30 grade 3 elevation in liver chemistries
      • Donor genotypes 1–3
        • -
          9/18 genotype 1
        • -
          2/18 genotype 2
        • -
          5/18 genotype 3
        • -
          2/18 unknown
      • No dose reductions or treatment discontinuations
      • Median follow-up not available
      Kapila et al. 2020
      • Kapila N.
      • Menon K.V.N.
      • Al-Khalloufi K.
      • Vanatta J.M.
      • Murgas C.
      • Reino D.
      • et al.
      Hepatitis C virus NAT-positive solid organ allografts transplanted into hepatitis C virus–negative recipients: a real-world experience.
      7 HCV NAT-positive hearts into NAT-negative recipientsSingle-centre, prospective cohort studyPost-transplant:
      • -
        HCV NAT testing 3–5 days post-transplant
      • -
        If positive, treatment initiated in outpatient setting
      • -
        Regimen determined by hepatologist and insurance approval
      • 6/7 SVR 12 (1 pending)
        • -
          3/7 G/P
        • -
          4/7 SOF/LDV
      • Includes 1 heart-kidney recipient
      • Genotypes 1a, 2
        • -
          6/7 genotype 1
        • -
          1/7 genotype 2
      • Median time to DAA initiation from transplant: 103 days
      • Median follow-up ~52 weeks
      Kilic et al. 2020
      • Kilic A.
      • Hickey G.
      • Mathier M.
      • Sultan I.
      • Gleason T.G.
      • Horn E.
      • et al.
      Outcomes of adult heart transplantation using hepatitis C–positive donors.
      343 anti-HCV-positive hearts (194 NAT-positive) into NAT-negative donors
      • -
        Retrospective, cohort study of UNOS database from 2016–2018
      • -
        Control: 7,546 anti-HCV-negative NAT-negative donor hearts (437 propensity-matched)
      Not reported
      • For anti-HCV-positive vs. negative donors:
        • -
          No difference in 1-year survival (89% vs. 90%)
        • -
          No difference in acute rejection requiring treatment (22% vs. 21%, n.s.)
        • -
          No difference in new-onset post-operative dialysis (15% vs. 11%, n.s.)
      • For NAT-positive vs. NAT-negative donors:
        • -
          No difference in 1-year survival (92% vs. 91%, n.s.), acute rejection, or dialysis
      • 15/343 recipients (4.4%) with prior HCV treatment (NAT-negative at transplant)
      • No recipient NAT testing reported
      • Donor genotypes not reported
      • Median follow-up not reported
      Reyentovich et al. 2020
      • Reyentovich A.
      • Gidea C.G.
      • Smith D.
      • Lonze B.
      • Kon Z.
      • Fargnoli A.
      • et al.
      Outcomes with treatment with glecaprevir/pibrentasvir following heart transplantation Utilizing hepatitis C viremic donors.
      22 HCV NAT-positive hearts into HCV NAT-negative recipients
      • -
        Single-centre, open-label, non-randomised trial
      • -
        Control: 28 NAT-negative (2 anti-HCV-positive) hearts into HCV NAT-negative recipients
      Post-transplant:
      • -
        HCV NAT testing weekly, starting 1-week post-transplant
      • -
        G/P × 8 weeks, starting 1-week post-transplant
      • 22/22 (100%) detectable viraemia post-transplant
      • 22/22 (100%) SVR12
      • No difference in 1-year survival (95% vs. 100%, n.s.)
        • -
          1 death due to necrotising pancreatitis POD 18 (viraemia already cleared)
      • No difference in LFTs at 14- or 60-days post-transplant.
      • No difference in moderate or severe ACR (18% vs. 27%, n.s.)
      • Included 5 combined heart-kidney transplants (2 from HCV NAT-positive donors).
      • HMG-CoA reductase inhibitors dose adjustment while on DAAs
      • 2/22 patients had interruptions in DAAs due to hyperbilirubinemia in setting of shock.
      • Median follow-up 363 days
      ACR, acute cellular rejection; AKI, acute kidney injury; AMR, antibody-mediated rejection; Anti-HCV, HCV antibody; CAV, cardiac allograft vasculopathy; CKD, chronic kidney disease; DAA, direct-acting antiviral; DONATE-HCV, Donors of Hepatitis C NAT Positive Thoracic Allografts for Transplant Evaluation in Non-HCV Recipients; EBR, elbasvir; G, glecaprevir; GZR, grazoprevir; LDV, ledipasvir; NAT, nucleic acid testing; OPTN, Organ Procurement and Transplantation Network; P, pibrentasvir; POD, post-operative day; RBV, ribavirin; SOF, sofosbuvir; SVR12, sustained viral response 12 weeks after therapy completion; UNOS, United Network for Organ Sharing; USHER, USing HEpatitis c positive hearts for negative Recipients; VEL, velpatasvir; VL, viral load; VOX, voxilaprevir.
      As with other HCV-viraemic solid organs, there has been interest in using prophylactic and shortened courses of DAAs to decrease the high HCV transmission rates. The DONATE-HCV trial included 8 HCV-nonviraemic recipients who received viraemic hearts followed immediately by 4 weeks of SOF/VEL,
      • Woolley A.E.
      • Singh S.K.
      • Goldberg H.J.
      • Mallidi H.R.
      • Givertz M.M.
      • Mehra M.R.
      • et al.
      Heart and lung transplants from HCV infected donors to uninfected recipients.
      while another single-centre trial included 20 HCV-nonviraemic recipients who received 1 dose G/P prior to viraemic heart transplant followed by G/P for 8 weeks post-transplant.
      • Bethea E.
      • Gaj K.
      • Gustafson J.L.
      • Axtell A.
      • Lebeis T.
      • Schoenike M.
      • et al.
      Pre-emptive pangenotypic direct acting antiviral therapy in donor HCV-positive to recipient HCV-negative heart transplantation: an open-label study.
      While 100% had detectable HCV viraemia post-transplant, 27/28 (96%) had SVR12 (1 patient without viraemia but not yet SVR12 at time of publication) with 100% 6-month patient and graft survival. Similar to the DAPPeR trial, another trial evaluated the efficacy of a very short DAA course, using 1 dose of ezetimibe and G/P pre-transplant followed by a 7-day course of this combination.
      • Feld J.J.
      • Cypel M.
      • Kumar D.
      • Dahari H.
      • Vanin Pinto Riberio R.
      • Marks N.
      • et al.
      Short-course, direct-acting antivirals and ezetimibe to prevent HCV infection in recipients of organs from HCV-infected donors: a phase 3, single-centre, open-label study.
      The trial included 30 HCV-nonviraemic recipients who received viraemic organs, including 13 lungs, 10 kidneys, 6 hearts, and 1 kidney-pancreas. 21/30 (67%) had detectable HCV viraemia immediately post-transplant; however, 30/30 (100%) had no detectable virus at 12 weeks post-transplant, suggesting that a prophylactic dose followed by 7 days of treatment using a pan-genotypic DAA may be sufficient to prevent chronic HCV infection.

      Lung

      The first report of HCV-viraemicc donors in lung transplantation reviewed 5 cases where HCV-nonviraemic recipients were rapidly deteriorating and accepted viraemic lungs.
      • Abdelbasit A.
      • Hirji A.
      • Halloran K.
      • Weinkauf J.
      • Kapasi A.
      • Lien D.
      • et al.
      Lung transplantation from hepatitis C viremic donors to uninfected recipients.
      All patients had detectable HCV viraemia post-transplant, as well as SVR12 with SOF/LDV or SOF/VEL for 12 weeks. Median time to initiation of therapy was 28 days with no interruptions in therapy or adverse events related to HCV or DAA therapy.
      Interest in strategies to decrease the high HCV transmission rates led to several studies with prophylactic and shortened DAA courses (Table 4). The DONATE-HCV trial also included 36 HCV-nonviraemic recipients who received viraemic lungs followed by SOF/VEL immediately post-transplant for 4 weeks.
      • Woolley A.E.
      • Singh S.K.
      • Goldberg H.J.
      • Mallidi H.R.
      • Givertz M.M.
      • Mehra M.R.
      • et al.
      Heart and lung transplants from HCV infected donors to uninfected recipients.
      34/36 (94%) had detectable viraemia post-transplant and 28/28 had achieved SVR12 at 6 months of follow-up. Another single-centre trial included 16 HCV-nonviraemic recipients who received viraemic lungs followed by G/P for 8 weeks, started within 3 days post-transplant.
      • Smith D.E.
      • Chen S.
      • Fargnoli A.
      • Lewis T.
      • Galloway A.C.
      • Kon Z.N.
      • et al.
      Impact of early initiation of direct-acting antiviral therapy in thoracic organ transplantation from hepatitis C virus positive donors.
      11/16 (69%) patients had detectable viraemia post-transplant with 100% achieving SVR12. Finally, a single-centre trial compared ex vivo lung perfusion with/without ultraviolet C irradiation in 22 HCV-nonviraemic recipients who received viraemic lungs
      • Cypel M.
      • Feld J.J.
      • Galasso M.
      • Pinto Ribeiro R.V.
      • Marks N.
      • Kuczynski M.
      • et al.
      Prevention of viral transmission during lung transplantation with hepatitis C-viraemic donors: an open-label, single-centre, pilot trial.
      : 11/11 (100%) and 9/11 (82%), respectively, had detectable viraemia post-transplant and 18 of these 20 had SVR12 following 12 weeks of SOF/VEL. The other 2 patients relapsed at 8 and 12 weeks after completing treatment, including 1 patient who presented with fibrosing cholestatic hepatitis. Ultimately, both patients achieved SVR12 with SOF/VEL/voxilaprevir/RBV.
      Table 4HCV-viraemic donors in nonviraemic lung transplant recipients.
      AuthorOrgan(s) transplantedStudy designHCV treatment strategyOutcomesSpecial considerations
      Abdelbasit et al. 2018
      • Abdelbasit A.
      • Hirji A.
      • Halloran K.
      • Weinkauf J.
      • Kapasi A.
      • Lien D.
      • et al.
      Lung transplantation from hepatitis C viremic donors to uninfected recipients.
      5 HCV NAT-positive lungs into NAT-negative recipients
      • -
        Retrospective, single-centre, case series
      Post-transplant:
      • -
        HCV NAT testing within first week
      • -
        If positive, treated with SOF/LDV x12 weeks for genotype 1, SOF/VEL × 12 weeks for genotype 2
      • 5/5 (100%) detectable viraemia post-transplant
      • 5/5 (100%) SVR12
      • 100% patient survival at 9–12 months post-transplant
      • No HCV- or DAA-attributed adverse effects
      • Genotypes 1,2
        • -
          4/5 genotype 1
      • 2/5 EVLP, ischemic time 363–663 minutes
      • Median time to DAA initiation: POD 28 (24–94)
      • All PO therapy without interruption in treatment course
      Woolley et al. 2019
      • Woolley A.E.
      • Singh S.K.
      • Goldberg H.J.
      • Mallidi H.R.
      • Givertz M.M.
      • Mehra M.R.
      • et al.
      Heart and lung transplants from HCV infected donors to uninfected recipients.


      DONATE-HCV
      36 HCV NAT-positive lung into NAT-negative recipients
      • -
        Single-centre, open-label, non-randomised pilot trial
      • -
        Control: 44 NAT-negative lungs into NAT-negative recipients
      Post-transplant:
      • -
        SOF/VEL immediately post-transplant × 4 weeks
      • 34/36 (94%) detectable viraemia post-transplant
      • 28/36 SVR 12 (other 8 pending)
      • 28/28 (100%) 6-month patient/graft survival
      • Compared to NAT-negative donors:
        • -
          No difference in stage 4/5 CKD or need for dialysis
        • -
          No difference in liver chemistries
        • -
          Trend to increased ACR in NAT-positive donors (54% vs. 30%)
      • 41 donors for heart and lungs with genotypes 1–3
        • -
          24/41 genotype 1a
        • -
          1/41 genotype 1b
        • -
          7/41 genotype 2
        • -
          7/41 genotype 3
        • -
          2/41 indeterminate
      • Median follow-up ~9.5 months
      Cypel et al. 2020
      • Cypel M.
      • Feld J.J.
      • Galasso M.
      • Pinto Ribeiro R.V.
      • Marks N.
      • Kuczynski M.
      • et al.
      Prevention of viral transmission during lung transplantation with hepatitis C-viraemic donors: an open-label, single-centre, pilot trial.
      22 HCV NAT-positive lungs into NAT-negative recipients
      • -
        Single-centre, open-label, non-randomised trial
      • -
        Control: 187 NAT-negative lungs into NAT-negative recipients
      Intra-operative:
      • -
        11/22 with EVLP
      • -
        11/22 with EVLP+UVC
      Post-transplant:
      • -
        HCV NAT testing daily x1 week, then weekly
      • -
        If positive, treatment initiated when clinically stable and able to swallow pills (not before 2 weeks)
      • -
        SOF/VEL × 12 weeks
      • 20/22 (91%) detectable viraemia post-transplant
        • -
          Both patients without HCV transmission were in EVLP+UVC group, which also had lower HCV VL at day 7 (p = 0.048)
      • 18/20 (90%) SVR12
      • 2/20 HCV relapse at 8 and 12 weeks after treatment completion (both had NS3A and NS5A RAS)
      • 1/2 fibrosing cholestatic hepatitis with relapse
      • 2/2 SVR12 with SOF/VEL/VOX + RBV
      • Compared to NAT-negative donors, no significant difference in:
        • -
          Primary graft dysfunction (14% vs. 6%)
        • -
          Acute rejection (50% vs. 43%)
        • -
          6-month survival (95% vs. 94%)
      • Donor genotypes 1–3
        • -
          14/22 genotype 1a
        • -
          3/22 genotype 2
        • -
          5/22 genotype 3
      • Median time to DAA initiation: POD 21
      • Median follow-up not reported, 19/22 had minimum 6-months
      Feld et al. 2020
      • Feld J.J.
      • Cypel M.
      • Kumar D.
      • Dahari H.
      • Vanin Pinto Riberio R.
      • Marks N.
      • et al.
      Short-course, direct-acting antivirals and ezetimibe to prevent HCV infection in recipients of organs from HCV-infected donors: a phase 3, single-centre, open-label study.
      30 HCV NAT-positive organs (6 heart, 13 lung, 10 kidney, 1 kidney-pancreas) from 18 donors into HCV NAT-negative recipientsSingle-centre, open-label, single group, pilot trialPre-transplant:
      • -
        Ezetimibe + G/P × 1 dose 6–12 hours prior
      Post-transplant:
      • -
        Ezetimibe + G/P × 7 days
      • 21/30 (67%) detectable HCV VL post-transplant
      • 30/30 (100%) undetectable HCV VL at 12 weeks post-transplant
      • 1/30 grade 3 elevation in liver chemistries
      • Donor genotypes 1–3
        • -
          9/18 genotype 1
        • -
          2/18 genotype 2
        • -
          5/18 genotype 3
        • -
          2/18 unknown
      • No dose reductions or treatment discontinuations
      • Median follow-up not available
      Smith et al. 2020
      • Smith D.E.
      • Chen S.
      • Fargnoli A.
      • Lewis T.
      • Galloway A.C.
      • Kon Z.N.
      • et al.
      Impact of early initiation of direct-acting antiviral therapy in thoracic organ transplantation from hepatitis C virus positive donors.
      16 HCV NAT-positive lungs into HCV-NAT-negative recipients
      • -
        Single-centre, open-label, non-randomised trial
      • -
        Control: 26 NAT-negative lungs into HCV NAT-negative recipients
      Post-transplant:
      • -
        G/P × 8 weeks started within 3 days post-transplant
      • 11/16 (69%) detectable viraemia post-transplant
      • 11/11 (100%) SVR12
      • No difference in mortality (6% vs. 4%, n.s.)
      • No difference in liver chemistries at 2 weeks post-transplant.
      • No difference in clinically significant rejection (19% vs. 35%, n.s.).
      • Paper also included 22 heart transplant patients from Reyentovich et al. study.
      • Median follow-up ~5.5 months
      ACR, acute cellular rejection; AMR, antibody-mediated rejection; Anti-HCV, HCV antibody; CKD, chronic kidney disease; DAA, direct-acting antiviral; DONATE-HCV, Donors of Hepatitis C NAT Positive Thoracic Allografts for Transplant Evaluation in Non-HCV Recipients; EBR, elbasvir; EVLP, ex vivo lung perfusion; G, glecaprevir; GZR, grazoprevir; LDV, ledipasvir; NAT, nucleic acid testing; P, pibrentasvir; POD, post-operative day; RASs, resistance-associated substitutions; RBV, ribavirin; SVR12, sustained viral response 12 weeks after therapy completion; SOF, sofosbuvir; UVC, ultraviolet C; VEL, velpatasvir; VL, viral load; VOX, voxilaprevir.

      Special considerations

      While the preliminary data regarding HCV-viraemic organs is promising, there are still many unanswered questions, such as the risks and benefits of this strategy (Table 5) and any special generalisable or organ-specific considerations (Fig. 2).
      Table 5Benefits and risks of transplanting HCV-infected organs into HCV-uninfected recipients.
      BenefitsRisks
      Increases transplant rates and decreases waitlist times
      • -
        Decreased overall waitlist morbidity and mortality, especially in areas with long waitlist times
      HCV transmission and potential for treatment failure leading to:
      • -
        Clinical hepatitis
      • -
        Fibrosing cholestatic hepatitis
      • -
        Rapid evolution to cirrhosis, especially if there are other causes for underlying liver disease (e.g. NAFLD) and HCV treatment is delayed or fails
      • -
        Liver cancer risk in the long-term if cirrhosis develops
      • -
        Extrahepatic manifestations
      • -
        Risk of transmission to personal contacts
      Minimises discarded organs
      • -
        Expands transplanted pool as above
      • -
        Respects donor's wishes
      Treatment approval of DAAs by insurance providers or health agencies
      • -
        Pre-approval feasibility
      • -
        Approval if re-treatment needed
      • -
        Access may be limited in certain countries and patient populations
      Substantial decrease in mortality for specific patient populations:
      • -
        Patients whose MELD does not capture the severity of their liver disease
      • -
        Patients with unresectable HCC and relatively intact liver function
      • -
        Patients deteriorating rapidly
      HCV treatment issues and drug-drug interactions:
      • -
        Inability to deliver drug post-transplant if recipient unable to take oral medication
      • -
        Potential for treatment interruptions and failures
      • -
        Effect on immunosuppression and potential for increased graft rejection
      • -
        Other adverse effects
      Cost-effectiveness
      • -
        DAAs widely available, >90% treatment success rates
      • -
        Cost-effective in both HCV-infected and uninfected kidney recipients due to morbidity and cost associated with haemodialysis
      • -
        Similar high morbidity and healthcare utilisation in patients on liver, heart, and lung transplant waitlists
      Ethical considerations given many unknowns, including:
      • -
        Incidence of treatment postponement, failures, and relapses
      • -
        Effect on acute and/or chronic rejection
      • -
        Long-term patient and graft survival
      DAAs, direct-acting antivirals; HCC, hepatocellular carcinoma; MELD, model for end-stage liver disease; NAFLD, non-alcoholic fatty liver disease.
      Figure thumbnail gr2
      Fig. 2Special considerations for hepatitis C virus infection in solid organ transplantation.
      Anti-HCV, HCV antibody; NAT, nucleic acid testing; DAA, direct-acting antiviral.

      Donor-related

      Currently, anti-HCV-positive and viraemic donors are evaluated using the standard quality measures accepted for each organ. Regarding HCV NAT-positive kidney donors, several of the pilot trials used a cut-off for kidney donor profile index (KDPI), a measure of organ quality, of 85% and age of 55 years.
      • Reese P.P.
      • Abt P.L.
      • Blumberg E.A.
      • Van Deerlin V.M.
      • Bloom R.D.
      • Potluri V.S.
      • et al.
      Twelve-month outcomes after transplant of hepatitis C–infected kidneys into uninfected recipients a single-group trial.
      ,
      • Sise M.E.
      • Goldberg D.S.
      • Kort J.J.
      • Schaubel D.E.
      • Alloway R.R.
      • Durand C.M.
      • et al.
      Multicenter study to transplant hepatitis C – infected kidneys ( MYTHIC ): an open-label study of combined glecaprevir and pibrentasvir to treat recipients of transplanted kidneys from deceased donors with Hepatitis C Virus Infect.
      KDPI includes HCV status based on historical data noting that anti-HCV-positive donor kidneys had worse outcomes, though these studies were performed before widespread DAA therapy. The recent DAPPeR trial removed HCV status and found that the median KDPI decreased from 62 to 37% in their population
      • Gupta G.
      • Yakubu I.
      • Bhati C.S.
      • Zhang Y.
      • Kang L.
      • Patterson J.A.
      • et al.
      Ultra-short duration direct acting antiviral prophylaxis to prevent virus transmission from hepatitis C viremic donors to hepatitis C negative kidney transplant recipients.
      and, further, it has been shown that HCV-viraemic donor kidneys matched to nonviraemic donor kidneys on other measures of KDPI have similar outcomes in the DAA era.
      • Potluri V.S.
      • Goldberg D.S.
      • Mohan S.
      • Bloom R.D.
      • Sawinski D.
      • Abt P.L.
      • et al.
      National trends in utilization and 1-year outcomes with transplantation of HCV-viremic kidneys.
      Similarly, most of the data regarding acceptable degree of fibrosis in donor livers comes from the pre-DAA era; however, there appears to be no difference in post-transplant fibrosis progression rates between grade 0 and grade 1 or 2 fibrosis, nor between steatosis score 0 and >0.
      • Khapra A.P.
      • Agarwal K.
      • Fiel M.I.
      • Kontorinis N.
      • Hossain S.
      • Emre S.
      • et al.
      Impact of donor age on survival and fibrosis progression in patients with hepatitis C undergoing liver transplantation using HCV+ allografts.
      Anti-HCV-positive liver donors ≥50 years old did have increased fibrosis progression and worse graft survival regardless of pre-transplant fibrosis grade, though again this was in the pre-DAA era and does not take into account the potential for improved fibrosis stage with HCV treatment.
      • Levitsky J.
      • Formica R.N.
      • Bloom R.D.
      • Charlton M.
      • Curry M.
      • Friedewald J.
      • et al.
      The American Society of Transplantation Consensus Conference on the use of hepatitis C viremic donors in solid organ transplantation.
      ,
      • Khapra A.P.
      • Agarwal K.
      • Fiel M.I.
      • Kontorinis N.
      • Hossain S.
      • Emre S.
      • et al.
      Impact of donor age on survival and fibrosis progression in patients with hepatitis C undergoing liver transplantation using HCV+ allografts.
      ,
      • Martini S.
      • David E.
      • Tandoi F.
      • Dell Olio D.
      • Salizzoni M.
      • Saracco G.M.
      • et al.
      HCV viremic donors with hepatic bridging fibrosis: are we ready to use their livers in the era of direct-acting antivirals?.
      Thus, it would be reasonable to consider donor livers with a fibrosis grade ≤2 on pre-transplant biopsy as acceptable regardless of donor age.
      It is not clear whether additional clinical factors will impact donor selection and recipient outcomes, including duration of HCV infection, HCV viral load, HCV genotype, and prior HCV treatment. Several of the aforementioned studies excluded organ donors who had previously been treated with DAAs but were still viraemic. Donor HCV genotype clearly impacts treatment regimens and resistance patterns, and it has been shown that people who use injection drugs have higher rates of genotype 1a and 3,
      • Robaeys G.
      • Bielen R.
      • Azar D.G.
      • Razavi H.
      • Nevens F.
      Global genotype distribution of hepatitis C viral infection among people who inject drugs.
      which are associated with more RASs.
      • Robaeys G.
      • Bielen R.
      • Azar D.G.
      • Razavi H.
      • Nevens F.
      Global genotype distribution of hepatitis C viral infection among people who inject drugs.
      However, DAA regimens have been developed that overcome most RASs, and most preliminary studies included multiple genotypes.
      • Puoti M.
      • Foster G.R.
      • Wang S.
      • Mutimer D.
      • Gane E.
      • Moreno C.
      • et al.
      High SVR12 with 8-week and 12-week glecaprevir/pibrentasvir therapy: an integrated analysis of HCV genotype 1–6 patients without cirrhosis.

      Recipient-related

      One of the biggest questions relating to the utilisation of HCV-viraemic organs is recipient selection. In general, this strategy should be considered in patients expected to have long waitlist times and high waitlist mortality. This may include patients with cirrhosis whose MELD scores do not adequately represent their degree of liver dysfunction, patients with hepatocellular carcinoma (HCC) and low MELD, or rapidly deteriorating candidates who may otherwise miss their window of eligibility. Another important consideration when allocating HCV-viraemic organs to non-liver solid organ transplant recipients is what degree of underlying hepatic fibrosis is acceptable given the potential for HCV-induced liver injury. This is especially relevant in a population that is likely to have a high burden of non-alcoholic fatty liver disease, given the high incidence of metabolic co-morbidities in end-stage renal disease and heart failure. Study protocols vary widely in this regard from excluding only those with clinical evidence of cirrhosis to excluding any patient with evidence of any fibrosis on liver biopsy or fibroscan assessment. As such, in clinical practice, a reasonable compromise is a strategy similar to the MYTHIC study, which included measurement of serum biochemical tests and at least a non-invasive assessment of liver fibrosis.
      • Sise M.E.
      • Goldberg D.S.
      • Kort J.J.
      • Schaubel D.E.
      • Alloway R.R.
      • Durand C.M.
      • et al.
      Multicenter study to transplant hepatitis C – infected kidneys ( MYTHIC ): an open-label study of combined glecaprevir and pibrentasvir to treat recipients of transplanted kidneys from deceased donors with Hepatitis C Virus Infect.
      Patients with alanine aminotransferase >2× the upper limit of normal or those with fibroscan score >8 kPa were excluded.
      Another unique consideration is the optimal timing of HCV treatment in HCV-viraemic recipients. A cost-effective analysis suggested that postponing HCV treatment and accepting an HCV-viraemic kidney was preferable to pre-transplant HCV treatment and receiving an HCV-nonviraemic kidney unless the additional wait time for a nonviraemic kidney was less than 161 days.
      • Eckman M.H.
      • Woodle E.S.
      • Thakar C.V.
      • Paterno F.
      • Sherman K.E.
      Transplanting hepatitis C virus–infected versus uninfected kidneys into hepatitis C virus–infected recipients: a cost-effectiveness analysis.
      For patients with decompensated cirrhosis and chronic HCV, the decision to treat their HCV pre- or post-transplant is determined by the degree of liver dysfunction (Fig. 3), as there are some patients who may improve their liver function enough that they may no longer require liver transplantation. This practice is supported by the observation that 6% to 25% of patients are delisted after HCV treatment based on US and European experiences.
      • Perricone G.
      • Duvoux C.
      • Berenguer M.
      • Cortesi P.A.
      • Vinaixa C.
      • Facchetti R.
      • et al.
      Delisting HCV-infected liver transplant candidates who improved after viral eradication: outcome 2 years after delisting.
      ,
      • Bittermann T.
      • Reddy K.R.
      In the era of direct-acting antivirals, liver transplant delisting due to clinical improvement for hepatitis C remains infrequent.
      Factors associated with a decreased likelihood of returning to Child-Pugh class A after HCV treatment include MELD ≥16, Child-Pugh class C (compared to Child-Pugh class B), presence of encephalopathy or ascites, serum albumin <3.5 g/dl, serum alanine aminotransferase <60 U/L, body mass index >25 kg/m2, and liver volume.
      • El-Sherif O.
      • Jiang Z.G.
      • Tapper E.B.
      • Huang K.C.
      • Zhong A.
      • Osinusi A.
      • et al.
      Baseline factors associated with improvements in decompensated cirrhosis after direct-acting antiviral therapy for hepatitis C virus infection.
      • Verna E.C.
      • Morelli G.
      • Terrault N.A.
      • Lok A.S.
      • Lim J.K.
      • Di Bisceglie A.M.
      • et al.
      DAA therapy and long-term hepatic function in advanced/decompensated cirrhosis: real-world experience from HCV-TARGET cohort.
      • Di Maira T.
      • Torregrosa A.
      • Navarro V.
      • Sanchez D.
      • Fornes V.
      • Berenguer M.
      Liver volume as a predictor of functional improvement post-DAA treatment.
      A cost-effective analysis suggests that pre-transplant HCV treatment is cost-effective for patients with MELD ≤20 and without HCC.
      • Cortesi P.A.
      • Belli L.S.
      • Facchetti R.
      • Mazzarelli C.
      • Perricone G.
      • De Nicola S.
      • et al.
      The optimal timing of hepatitis C therapy in liver transplant-eligible patients: cost-effectiveness analysis of new opportunities.
      Given this data, we recommend HCV treatment while on the waitlist for patients with MELD <15 (except those with refractory ascites) and deferring HCV treatment to post-transplant for patients with MELD >25 to increase their chances of transplantation. In between, it is a case-by-case discussion considering overall organ pool, expected waiting time, waitlist mortality, possibility for clinical improvement, and quality of life.
      Potential recipients of HCV-viraemic organs will require a thorough discussion of the pros and cons of this practice, including treating HCV infection prior to or after liver transplantation.
      Figure thumbnail gr3
      Fig. 3Proposed strategy for hepatitis C virus therapy in decompensated cirrhosis.
      ∗Exception is patient with refractory ascites- instead treat post transplant. LT, liver transplant; MELD, model for end-stage liver disease; anti-HCV, HCV antibody; QOL, quality of life.
      Other considerations for HCV-viraemic recipients include genotype competition and prior HCV treatment. While it was important consideration historically, genotype competition is less of an issue now that pan-genotype DAAs are widely available. Further, preliminary data suggests that patients previously treated for HCV have had successful re-treatment of HCV re-infection and can be managed the same as HCV-naïve patients.
      • Kwong A.J.
      • Wall A.
      • Melcher M.
      • Wang U.
      • Ahmed A.
      • Subramanian A.
      • et al.
      Liver transplantation for hepatitis C virus (HCV) non-viremic recipients with HCV viremic donors.
      ,
      • Schlendorf K.H.
      • Zalawadiya S.
      • Shah A.S.
      • Wigger M.
      • Chung C.Y.
      • Smith S.
      • et al.
      Early outcomes using hepatitis C–positive donors for cardiac transplantation in the era of effective direct-acting anti-viral therapies.
      ,
      • Kilic A.
      • Hickey G.
      • Mathier M.
      • Sultan I.
      • Gleason T.G.
      • Horn E.
      • et al.
      Outcomes of adult heart transplantation using hepatitis C–positive donors.
      Our practice is to genotype patients post-transplant and treat accordingly.
      Choosing the patients who stand to benefit the most from this strategy helps decrease the risk-benefit ratio; however, patients still need to be adequately informed of the risks, which include many unknowns at this stage. As much as possible, the consent process should be standardised within and across institutions, while being adaptable in response to new information as research continues.

      HCV treatment logistics

      There are many HCV treatment-specific considerations, including timing of treatment, DAA regimen, duration of therapy, drug-drug interactions, and access to therapy, as this is currently an off-label practice. Prophylactic DAA treatment pre-transplant followed by an abbreviated post-transplant DAA course appears to be as effective as standard DAA courses in preventing chronic HCV infection and could increase cost-effectiveness. However, this strategy has several potential barriers, including (1) payor approval of therapy prior to documented HCV transmission; (2) interruptions in therapy for patients requiring prolonged ventilation, especially heart and lung transplant recipients, as data is still limited on administration of DAAs through nasogastric tube; (3) need for pan-genotype DAA regimens or rapid genotyping and resistance testing; (4) increased number of medications used in the immediate post-transplant period and thus potential for more drug-drug interactions. Several groups have instead advocated for initiating treatment in the outpatient setting after recovery from surgery; however, in the largest, real-world prospective cohort this led to delay in initiation of therapy for a median of 72 days for kidney recipients, 51 days for liver recipients, and 103 days for heart recipients with 2 cases of fibrosing cholestatic hepatitis due to HCV at 11 and 14 weeks post-transplant.
      • Kapila N.
      • Menon K.V.N.
      • Al-Khalloufi K.
      • Vanatta J.M.
      • Murgas C.
      • Reino D.
      • et al.
      Hepatitis C virus NAT-positive solid organ allografts transplanted into hepatitis C virus–negative recipients: a real-world experience.
      Given nearly 100% SVR12 with regimens that are started post-transplant and given for 12 or more weeks, and the high number of patients who required re-treatment with a second-line DAA in the short prophylaxis regimens, our practice is to wait until patients become viraemic post-transplant and to treat for a full 12-week course with regimens based on genotype and resistance testing, recognising that the preliminary data on prophylactic strategies and shorter treatment courses (4–8 weeks with G/P and SOF/VEL) are promising.
      • Bethea E.
      • Gaj K.
      • Gustafson J.L.
      • Axtell A.
      • Lebeis T.
      • Schoenike M.
      • et al.
      Pre-emptive pangenotypic direct acting antiviral therapy in donor HCV-positive to recipient HCV-negative heart transplantation: an open-label study.
      ,
      • Schlendorf K.H.
      • Zalawadiya S.
      • Shah A.S.
      • Perri R.
      • Wigger M.
      • Brinkley D.M.
      • et al.
      Expanding heart transplant in the era of direct-acting antiviral therapy for hepatitis C.
      ,
      • Woolley A.E.
      • Singh S.K.
      • Goldberg H.J.
      • Mallidi H.R.
      • Givertz M.M.
      • Mehra M.R.
      • et al.
      Heart and lung transplants from HCV infected donors to uninfected recipients.
      ,
      • Durand C.M.
      • Barnaba B.
      • Yu S.
      • Brown D.M.
      • Chattergoon M.A.
      • Bair N.
      • et al.
      Four-week direct-acting antiviral prophylaxis for kidney transplantation from hepatitis C-viremic donors to hepatitis C-negative recipients: an open-label nonrandomized study.
      ,
      • Feld J.J.
      • Cypel M.
      • Kumar D.
      • Dahari H.
      • Vanin Pinto Riberio R.
      • Marks N.
      • et al.
      Short-course, direct-acting antivirals and ezetimibe to prevent HCV infection in recipients of organs from HCV-infected donors: a phase 3, single-centre, open-label study.
      ,
      • Reyentovich A.
      • Gidea C.G.
      • Smith D.
      • Lonze B.
      • Kon Z.
      • Fargnoli A.
      • et al.
      Outcomes with treatment with glecaprevir/pibrentasvir following heart transplantation Utilizing hepatitis C viremic donors.
      • Sise M.E.
      • Goldberg D.S.
      • Kort J.J.
      • Schaubel D.E.
      • Alloway R.R.
      • Durand C.M.
      • et al.
      Multicenter study to transplant hepatitis C – infected kidneys ( MYTHIC ): an open-label study of combined glecaprevir and pibrentasvir to treat recipients of transplanted kidneys from deceased donors with Hepatitis C Virus Infect.
      • Smith D.E.
      • Chen S.
      • Fargnoli A.
      • Lewis T.
      • Galloway A.C.
      • Kon Z.N.
      • et al.
      Impact of early initiation of direct-acting antiviral therapy in thoracic organ transplantation from hepatitis C virus positive donors.

      Post-transplant outcomes

      While short-term outcomes appear to be comparable for HCV-viraemic, nonviraemic, and naïve donors, there is limited outcome data past 1 year. It is still unclear whether there are any lasting changes to the immune system from HCV infection and what interaction this may have with immunosuppressive therapy. Similarly, many HCV-nonviraemic recipients transplanted with viraemic organs underwent transplant as part of clinical trials, leading to minimal data on the real-world experience with treatment delays, failure, and relapse. As such, the true incidences of clinically significant hepatitis, fibrosing cholestatic hepatitis, extrahepatic HCV manifestations, and acute or chronic rejection in this population are still unknown.
      More data is needed to determine the most efficacious and cost-effective DAA strategy, the incidence of treatment relapse/failure and complications, and long-term outcomes.

      Cost-effectiveness

      HCV monitoring, DAA therapy, and the management of any HCV-related complications add additional costs to the transplant process; however, 2 recent modelling studies suggested using HCV-viraemic kidneys in nonviraemic recipients is cost-effective and improves health outcomes compared to remaining on the waitlist for an additional 2 years in 1 study or 11 months in the second.
      • Kadatz M.
      • Klarenbach S.
      • Gill J.
      • Gill J.S.
      Cost-effectiveness of using kidneys from hepatitis C nucleic acid test–positive donors for transplantation in hepatitis C–negative recipients.
      ,
      • Eckman M.H.
      • Woodle E.S.
      • Thakar C.V.
      • Alloway R.R.
      • Sherman K.E.
      Cost-effectiveness of using kidneys from HCV-viremic donors for transplantation into HCV-uninfected recipients.
      Data for other solid organ transplantation is limited.

      Conclusion

      Utilisation of anti-HCV-positive viraemic and nonviraemic organs decreases waitlist times by minimising discarded organs and significantly expanding the available donor pool. This practice has the potential to significantly decrease overall waitlist morbidity and mortality, especially in areas with long waitlist times. In the DAA era, this strategy has been shown to be safe and cost-effective in HCV-viraemic recipients, and, more recently, there is a rapidly growing literature that preliminarily suggests this may be true in HCV-nonviraemic recipients as well. However, there is still limited data on non-clinical trial experience with this strategy and a lack of long-term outcome data. Lastly, fundamental to this process is the ability to secure DAA therapy prior to transplant and ensure that patients are fully informed regarding the associated risks, including the potential for HCV treatment failure and its consequences.

      Abbreviations

      ACR, acute cellular rejection; Anti-HCV, HCV antibody; DAA, direct-acting antiviral; EBR, elbasvir; HCC, hepatocellular carcinoma; G, glecaprevir; GZR, grazoprevir; KDPI, kidney donor profile index; LDV, ledipasvir; NAT, nucleic acid testing; OPTN, Organ Procurement and Transplantation Network; RASs, resistance-associated substitutions; RBV, ribavirin; SOF, sofosbuvir; SVR12, sustained virological response at 12 weeks post-treatment; UNOS, United Network for Organ Sharing; VEL, velpatasvir.

      Financial support

      KW is supported by NIH Training Program in Gastrointestinal Sciences T32-DK007066.

      Authors' contributions

      KW and KRR came up with concept and design of review. KW wrote the manuscript and KW/KRR reviewed and edited it.

      Conflict of interest

      KW has no conflicts to disclose. KRR is on advisory boards for Abbvie, Merck, Gilead, Mallinckrodt and receives research grants (paid to the University of Pennsylvania) from Merck, Gilead, Abbvie, BMS, Mallinckrodt, Intercept, Conatus, Exact Sciences, HCV-TARGET, NASH-TARGET, HCC-TARGET.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

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