Download Full GuidanceWith the large disparity between persons in need of organ transplantation and available donor organs, many transplant programs are turning to the use of organs from HCV-viremic donors (Akabane, 2024). In the past, organs from HCV-viremic donors were primarily used in recipients with chronic hepatitis C or discarded. With the advent of safe and effective HCV DAA regimens, however, organs from HCV-viremic donors may be considered for use in recipients without HCV infection. Use of these organs increases the pool of available organs, access to transplantation (Sageshima, 2018), and potentially reduces waitlist time (Bhamidimarri, 2017); (Scalea, 2015) and related mortality (Altshuler, 2022); (Sawinski, 2019); (Shelton, 2018); (Kucirka, 2012).
All organ donors undergo HCV-antibody and HCV nucleic acid testing (NAT). Nonhepatic donors who are HCV antibody positive but HCV RNA negative likely pose a negligible risk of HCV transmission to the recipient, although more data are needed to confirm this. However, among increased-risk donors (as defined by the US Public Health Service [PHS] guidelines) who had a recent HCV exposure, HCV RNA may not yet be detectable and transplant recipients from these donors should be monitored for HCV infection in addition to HBV and HIV per the increased-risk donor testing protocols (Levitsky, 2017); (Seem, 2013b). Transplant recipients who receive a liver from an HCV-antibody–positive/HCV-RNA–negative donor should be monitored more closely after transplantation given the potential risk for HCV transmission (Bari, 2018); (Sobotka, 2021). Donors who are HCV RNA positive (with or without anti-HCV) pose the highest risk for HCV transmission to transplant recipients. Because of the significant risk for HCV infection when transplanting an organ from an HCV-viremic donor into an HCV-uninfected recipient, rigorous informed consent, including discussion of potential secondary risks to caregivers from needlestick exposures (Kim, 2022), and post transplantation HCV-related follow-up processes are recommended.
Recommendations When Considering Use of HCV-Viremic Donor Organs in HCV-Uninfected Recipients |
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| RECOMMENDED | RATING  |
Informed consent should include the following elements:
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I, C |
Transplant programs should have a programmatic strategy to:
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I, C |
Available data indicate increasing acceptance of organs from HCV-viremic donors among HCV-uninfected recipients (Cotter, 2019); (Potluri, 2019); (Bowring, 2018). Although no published data are available regarding the long-term (beyond 1 to 2 years) consequences to HCV-negative recipients transplanted with organs from HCV-viremic donors who are treated post transplant with DAAs, limited short-term data from liver, kidney, heart, and lung transplant programs are encouraging.
Liver Transplantation
Among 10 HCV-negative liver transplant recipients of organs from an HCV-viremic donor,
100% attained SVR12 with 12 weeks to 24 weeks of various DAA regimens (Kwong, 2019). The median time from transplantation to treatment initiation was 43 days (interquartile range 20–59 days). Noteworthy was the high rate of acute cellular or antibody-mediated rejection (30%) during or after DAA therapy in this study. In another study of 14 HCV negative liver transplant recipients from an HCV-viremic donor treated with glecaprevir/pibrentasvir for 12 weeks starting within 5 days of transplant, SVR rates were 100% and only 1 recipient experienced acute rejection (Bethea, 2020). In another single center experience, 61 HCV-negative recipients of a liver allograft from an HCV-viremic donor were compared to 231 HCV-negative recipients of a liver allograft from an HCV negative donor (Bohorquez, 2021a). Of the 61 participants in the study group, 56 received antiviral therapy; treatment was initiated a median of 66.9 days following transplantation. Four study group participants died within 1 year following liver transplantation. One was persistently aviremic and another experienced a complex postoperative course. Of the 51 study participants with complete treatment data, 64% were treated with glecaprevir/pibrentasvir and 36% received sofosbuvir/velpatasvir. All achieved SVR12. One participant required retreatment with sofosbuvir/velpatasvir/voxilaprevir after relapse. There were no significant diAerences between recipients of allografts from HCV-viremic versus HCV-negative donors in terms of other clinical outcomes such as acute cellular rejection, kidney dysfunction, or survival.
A retrospective study of deceased donor liver transplantations in the US from January 2008
through January 2018 demonstrated that 2-year graft survival was similar, regardless of
HCV status concordance or discordance between the allograft donor and recipient (Cotter,
2019). In a single-center retrospective study of 21 HCV-seronegative recipients who
received a liver transplant from an HCV-viremic donor, 95% (20/21) of recipients had
confirmed HCV viremia. One hundred percent of the 15 participants with available data
achieved SVR12 after DAA treatment. There were equivalent rates of posttransplant
complications between the 21 recipients who received a liver from an HCV-viremic donor
when compared to 21 recipients who received a liver from an HCV-antibody-positive, NAT
negative donor (Sobotka, 2021).
In a prospective, multicenter (n=6), single-arm, open-label clinical trial, 13 HCV-negative
liver transplant recipients received an allograft from an HCV-viremic donor. Participants
were treated with 12 weeks of sofosbuvir/velpatasvir; the median time from transplantation
to DAA therapy was 7 days (Terrault, 2020). All liver transplant recipients achieved SVR12.
Serious adverse events possibly related to study participation among the liver recipients
included antibody-mediated rejection, biliary sclerosis, cardiomyopathy, and graft-versus
host disease (which eventually led to the individual’s death). In a prospective multicenter
(n=3) observational study, 20 HCV-negative recipients of a liver transplant from an HCV
viremic donor, all recipients had HCV viremia confirmed within 3 days posttransplant and
100% attained SVR12 after receiving DAA treatment (median 27.5 days posttransplant) (Aqel, 2021). One transplant recipient who was started on DAA treatment on postop day 24
developed end-stage renal disease secondary to HCV-related acute membranous
nephropathy; the individual died 14 months posttransplant due to septic shock from a
presumed infection.
Unlike with other organs, shorter durations of HCV therapy should not be used in recipients
of livers from HCV-viremic donors because of the large reservoir of HCV in the transplanted
organ. Additionally, although prophylactic or pre-emptive therapy has not been as strongly
stressed for recipients of liver grafts from HCV-viremic donors, a case report noted the
development of acute kidney injury (with proteinuria) in the first month post transplant due
to HCV-associated focal proliferative glomerulonephritis. This case report highlights the
potential for HCV-related, extrahepatic manifestations in the early posttransplant setting (Bohorquez, 2021b). The prospective multicenter study noted above (Aqel, 2021) also highlights the importance of considering the initiation of DAA treatment earlier post transplant given that one liver transplant recipient had biopsy-proven acute HCV-related glomerulonephritis on postop day 18, which was 6 days prior to the initiation of DAA therapy. The individual went on to develop end-stage renal disease despite having attained SVR12. The person died due to presumed infectious complications. The possible elevated risk for immunologic complications (eg, rejection) in liver recipients from HCV-viremic donors treated with DAA therapy requires further study but vigilance is appropriate.
Recommendation Regarding Timing of DAA Therapy for HCV-Negative Recipients of a Liver Transplant From an HCV-Viremic Donor |
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| RECOMMENDED | RATING |
| Earlya treatment with a pangenotypic direct-acting antiviral regimen is recommended when the person is clinically stable |
II, B |
| a Early treatment refers to starting within the first 2 weeks after liver trasnplantation but preferably within the first week when the person is clinically stable. | |
Recommended regimens listed by evidence level and alphabetically for:
Treatment of HCV-Uninfected Recipients of a Liver Graft From an HCV Viremic Donor |
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| RECOMMENDED | DURATION | RATING |
| Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg)b | 12 weeks | I, C |
| Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) | 12 weeks | I, C |
a Other considerations in selection of the DAA regimen:
b Dosing is 3 coformulated tablets (glecaprevir [100 mg]/pibrentasvir [40 mg]) taken once daily. Please refer to the prescribing information. |
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Transplantation of Other Organs
In the THINKER trial, 10 HCV-uninfected kidney transplant recipients received an allograft
from a genotype 1 infected HCV-viremic donor and were treated with 12 weeks of elbasvir/grazoprevir; 100% achieved SVR (Goldberg, 2017). In a 1-year follow-up study that
included 10 additional participants (n=20) who received 12 weeks to 16 weeks of
elbasvir/grazoprevir (± ribavirin), all attained SVR12. Kidney function in those who received
a kidney from an HCV-infected donor was comparable to matched controls who received
an allograft from an HCV-uninfected donor (Reese, 2018). A separate open-label trial
similarly demonstrated a 100% SVR12 rate with 12 weeks of elbasvir/grazoprevir (±
sofosbuvir) therapy initiated immediately prior to transplantation in 10 HCV-uninfected
kidney transplant recipients of an allograft from an HCV-viremic donor (Durand, 2018). Notably, organ recipients in this study received the first dose of elbasvir/grazoprevir on call
to the operating room. Of the 10 persons treated, only 3 had detectable HCV viremia
compared to 100% in the THINKER trial, which utilized the same regimen but initiated DAA
therapy on day 3 after transplantation.
In a prospective multicenter (n=7) MYTHIC trial, 30 HCV-negative recipients received a
kidney allograft from an HCV-viremic donor. Early initiation of glecaprevir/pibrentasvir
(target was within 3 days post transplant) for 8 weeks resulted in a 100% SVR12 rate; there
were no significant treatment-related adverse events (Sise, 2020). Three episodes of acute
rejection were noted but all recipients had good graft function at 6 months follow-up. Three
recipients developed transient BK viremia. Four out of 10 of the CMV seronegative
recipients who received a kidney from a CMV seropositive donor developed CMV disease
within the first year post transplant. One-year survival was 93%; 1-year graft function was
excellent (median creatinine 1.17; interquartile range [IQR] 1.02–1.38 mg/dL) (Sise, 2021).
A prospective, multicenter, single-arm, open-label clinical trial evaluated the safety and
eAicacy 12 weeks of sofosbuvir/velpatasvir among 11 HCV-negative kidney transplant
recipients who received a graft from an HCV-viremic donor (Terrault, 2020). The median
time from transplant to initiation of DAA therapy was 16.5 days; all kidney transplant
recipients in this study attained SVR12. No serious adverse events related to study
participation were noted among the kidney recipients. The REHANNA trial evaluated a
shortened 4-week course of glecaprevir/pibrentasvir among HCV-negative kidney
transplant recipients who received a graft from an HCV-viremic donor. The first dose was
administered prior to organ perfusion. All 10 recipients achieved SVR12; there were no
adverse outcomes noted (Durand, 2021). Other studies evaluating HCV discordant kidney
donors and transplant recipients have also demonstrated high SVR12 rates without any
treatment-related toxicities (Binari, 2024) (Franco, 2019); (Friebus-Kardash, 2019). A single-center, retrospective cohort study compared 1-year outcomes among 65 transplant
recipients who received a kidney from an HCV-viremic donor with 59 recipients who
received a kidney from an HCV-negative donor (Molnar, 2021). Allograft biopsy findings and
kidney allograft function during the first year post kidney transplantation were assessed.
There were no statistically significant diAerences between the HCV-positive and HCV
negative cohorts with regards to delayed graft function rates, estimated glomerular
filtration rates (eGFR), and the proportions of recipients with cellular rejection, antibody
mediated rejection, or de novo donor-specific antibodies.
A study of HCV-uninfected recipients who received a heart transplant from an HCV-viremic
donor showed that a 12-week course of elbasvir/grazoprevir initiated a few days after
transplantation (once the recipient became viremic) resulted in SVR12 in 90% (9/10) of the
evaluable recipients (McLean, 2019). In the DONATE HCV trial, 44 HCV-uninfected lung
(n=36) and heart (n=8) transplant recipients of an allograft from an HCV-viremic donor were
treated with sofosbuvir/velpatasvir administered prophylactically or preemptively, starting
within a few hours after transplantation and continued for 4 weeks (compared with the
standard 12-week course). Among the initial 35 recipients with at least 6 months of follow
up after transplantation, 100% achieved SVR and had excellent graft function (Woolley, 2019). There was an increase in the proportion of the HCV-viremic lung cohort who had acute cellular rejection compared with the HCV-uninfected lung cohort, although this finding was not statistically significant. Longer term follow-up is needed to assess for chronic rejection. In a study of 20 HCV-uninfected heart transplant recipients of an allograft from an HCV-viremic donor, participants were treated prophylactically or preemptively with glecaprevir/pibrentasvir beginning just prior to transplantation and continued for 8 weeks. All participants attained SVR12; patient and graft survival were 100% with a median follow-up of 10.7 months (Bethea, 2019). Another clinical trial evaluated 22 HCV-uninfected lung transplant recipients of an allograft from an HCV
viremic donor. The 20 recipients who became viremic after transplantation were treated
with 12 weeks of sofosbuvir/velpatasvir beginning 2 weeks to 6 weeks after transplantation
(median 21 days; IQR 16.76–24.75 days). All lungs from HCV-viremic donors were treated
with ex-vivo lung perfusion ± ultraviolet C perfusate irradiation to reduce HCV RNA
concentration and infectivity, likely contributing to a slower rise in HCV viral load among
recipients. Although all 20 recipients treated with DAAs had undetectable HCV RNA at the
end of treatment, 2 recipients experienced posttreatment relapse. One recipient
experienced severe hepatitis with early signs of fibrosing cholestatic hepatitis on liver
biopsy. Both recipients who experienced a relapse exhibited complex NS3A and NS5A
resistance-associated substitutions (RASs) at the time of relapse. The relapsed recipients
were successfully retreated with 24 weeks of sofosbuvir/velpatasvir/voxilaprevir plus
ribavirin and achieved SVR12 (Cypel, 2019). A retrospective analysis supported utilization
of HCV-viremic lung transplantation, demonstrating a 100% SVR rate with no increased rate
of rejection among the 17 lung transplant recipients (Afshar, 2024).
A study of 22 heart transplants from HCV-viremic donors to HCV-uninfected recipients
evaluated an 8-week course of glecaprevir/pibrentasvir initiated 6 days to 11 days after
transplantation once the viremia developed. Two recipients had DAA interruptions. No
diAerences were noted between the HCV-viremic versus HCV-aviremic donor cohorts in
terms of survival or rejection (Reyentovich, 2020). Another study evaluated 38 thoracic
organ transplants (22 heart, 16 lung) from HCV-viremic donors. Treatment with
glecaprevir/pibrentasvir was initiated at the time of detectable viremia (mean 7 days)
among the heart recipients and within 3 days after transplantation for the lung recipients.
All participants achieved SVR12 (Smith, 2021). DAA treatment interruption occurred in 2
recipients due to hyperbilirubinemia. One recipient resumed treatment within a few days;
the other recipient’s treatment course was shortened to 10 days. Both recipients still
attained SVR12. In the heart transplant recipients, all recipients became viremic within the
first week after transplantation. In contrast, only 11 of the 16 lung transplant recipients developed viremia. Overall, investigators noted reduced HCV transmission, lower viral loads, and more rapid clearance in the lung transplant recipients who received earlier treatment (Smith, 2021). In both these studies, DAA treatment initiation within a few days after transplantation was associated with an occasional need for treatment interruption, although all recipients still achieved SVR12 (Reyentovich, 2020); (Smith, 2021).
A separate study conducted among 50 heart transplant recipients (22 received a heart from
an HCV-viremic donor), an 8-week course of glecaprevir/pibrentasvir was initiated once
viremia developed (mean 7.2 days) (Gidea, 2020). Investigators noted a higher proportion
of acute cellular rejection in the HCV-viremic versus HCV-aviremic donor study groups
(14/22 versus 5/28, respectively) in the first 2 months and at 180 days (17/22 versus 12/28,
respectively). These findings raise concern about a potential association between HCV-viremic donors and transplant rejection.
While these early results are encouraging, the overall number of published cases remains small and treatment approaches notably variable. Known reported risks include DAA treatment failure with emergence of complex RASs and possible severe or rapidly progressive liver disease (fibrosing cholestatic hepatitis) (Cypel, 2020); (Kapila, 2019); (Molnar, 2019). Additionally, ethical and scientific issues remain, including avoidance of selection bias, optimal timing of DAA therapy, and long-term graft and patient outcomes. Due to the limited and heterogeneous experience and lack of longer-term safety data, strong consideration should be given to performing these transplantations with a rigorous informed consent process as recommended by the American Society of Transplantation consensus panel (Levitsky, 2017).
In addition, there have been an increasing number of dual organ transplants performed from HCV-viremic donors for heart-kidney recipients nationally between August 2015 and August 2020. Analyses from the United Network for Organ Sharing registry demonstrated similar 1-year survival between 90 HCV donor seropositive and 896 HCV donor seronegative heart-kidney recipients using unadjusted and adjusted Cox-proportional hazards-regression models including in propensity-score matched cohorts (Madan, 2021); (Diaz-Castrillon, 2022).
Recommendation Regarding Timing of DAA Therapy for HCV-Negative Recipients of a Non-Liver Solid Organ Transplant From an HCV-Viremic Donor |
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| RECOMMENDED | RATING |
| Prophylactica or preemptiveb treatment with a pangenotypic DAA regimen is recommended | II, B |
| a Initiate DAA therapy immediately pretransplant or on day 0 post transplant. No HCV RNA testing of the transplant recipient is required b Initiate DAA therapy on day 0 to day 7 post transplant, as soon as the person is clinically stable. Demonstration of HCV viremia in the transplant recipient is not required |
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Recommended regimensa listed by evidence level and alphabetically for:
Treatment of HCV-Uninfected Recipients of Non-Liver Organs From HCV-Viremic Donors |
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| RECOMMENDED | DURATION | RATING |
| Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg)b | 8 weeks | I, C |
| Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) | 12 weeks | I, C |
a Other considerations in selection of the DAA regimen:
b 8 weeks is recommended for prophylactic/preemptive treatment approaches. However, if treatment initiation is delayed beyond the first week after transplant, treatment should be continued for 12 weeks. Dosing is 3 coformulated tablets (glecaprevir [100 mg]/pibrentasvir [40 mg]) taken once daily. Please refer to the prescribing information. |
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Initiation of DAA therapy for HCV-negative recipients of a non-liver allograft from an HCV-viremic donor can occur prophylactically/preemptively (ie, perioperatively without confirmation of viremia in the recipient) or reactively after documentation of HCV viremia. The goal is to undertake DAA therapy as early as clinically possible to minimize the duration of HCV viremia in the recipient and avoid the development of acute hepatitis and other nonhepatic complications of HCV infection.
Initiating prophylactic/preemptive DAA therapy before viremia occurs may reduce the likelihood of complications, such as fibrosing cholestatic hepatitis, acute HCV-related glomerulonephritis, acute pancreatitis, acute cellular rejection, and allograft vasculopathy (Lopez-Soler, 2023); (Gidea, 2020); (Schlendorf, 2020); (Bethea, 2019); (Cypel, 2020); (Kapila, 2019); (Woolley, 2019); (Molnar, 2019); (Durand, 2018). A prophylactic/preemptive treatment approach may also allow for a shorter duration of DAA therapy in non-liver transplant recipients of organs from HCV-viremic donors (Woolley, 2019). A clinical trial evaluated the use glecaprevir/pibrentasvir combined with ezetimibe 10 mg (as an inhibitor of HCV entry) in 30 recipients of nonhepatic organs (lung, heart, kidney) from HCV-viremic donors. The drugs were administered with 1 dose before and for 7 days after transplantation. With this short therapy, none of the 30 individuals developed chronic HCV infection. It is unknown if infection occurred and was rapidly cleared or if it was prevented entirely (Feld, 2020). Although intriguing, short duration approaches are not currently recommended outside of a clinical trial setting and have only been studied in the context of non-liver transplantation.
While initiating HCV treatment as early as possible post-transplant may be clinically beneficial, barriers to initiating DAA treatment prophylactically/preemptively include the cost of DAA treatment and protracted insurance authorizations. One study compared the clinical and fiscal impact between an institution-subsidized course of initial DAA treatment with an insurance approval process for DAA coverage once HCV viremia was documented in the recipient. The timing of DAA initiation, duration of recipient viremia, and associated costs incurred by the recipient and the institution were assessed in 89 abdominal organ transplant recipients who did not have their DAA treatment subsidized compared to 62 thoracic organ transplant recipients who received DAA treatment that was initially subsidized by the institution. Their analysis showed that by not waiting to initiate DAA treatment for insurance authorization after HCV viremia was documented in the recipient enabled earlier treatment initiation (median 4 days [IQR 2–7 days] versus 10 days [IQR 8–13 days]) and shorter duration of viremia (median 16 days [IQR 12–29 days] versus 36 days [IQR 30–47 days] (Stewart, 2021).
Selection of the DAA therapy for HCV-negative recipients of a non-liver allograft(s) from an HCV-viremic donor should follow the same principles as for those who develop recurrent HCV infection post liver transplantation (see Persons Who Develop Recurrent HCV Infection Post Liver Transplantation). Importantly, since genotyping of HCV-viremic donors is not routinely performed, only pangenotypic regimens should be utilized if a prophylactic/preemptive treatment approach is used. If treatment is delayed until the recipient has quantifiable HCV RNA, the recipient’s genotype can be used to guide DAA treatment selection if a pangenotypic regimen is not used. Selection of regimens that avoid the use of ribavirin (to reduce ribavirin-associated side effects) and that do not require baseline RAS testing are preferred.
Notably, organs from HCV-viremic donors may be used in transplant candidates with current or prior HCV infection (see Persons Who Develop Recurrent HCV Infection Post Liver Transplantation).
Drug-Drug Interactions Between DAAs and Calcineurin Inhibitors
The drug-drug interactions of DAA agents and calcineurin inhibitors are complex and unpredictable without formal studies. A summary of interactions between calcineurin inhibitors and DAAs with recommended dosing is provided in the DAA Interactions With Calcineurin Inhibitors table.
Based on the metabolism of grazoprevir and elbasvir, a 15-fold increase in grazoprevir AUC and a 2-fold increase in elbasvir AUC can be expected with cyclosporine coadministration. Therefore, this combination should be avoided. Since a 40% to 50% increase in tacrolimus level is predicted with coadministration of grazoprevir, no dosing adjustments are anticipated but tacrolimus levels should be monitored. No clinically significant drug-drug interactions have been observed between sofosbuvir-inclusive regimens and tacrolimus.