Hepatitis C viraemic organs in solid organ transplantation

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.^, 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.^, 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.^, Among anti-HCV-positive liver transplant recipients, there was no difference in graft and patient survival with anti-HCV-positive vs. negative donors.^, 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.^{,  ,} 

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. This discard rate remained relatively stable from 2005 to 2014, corresponding to nearly 500 discarded anti-HCV-positive kidneys per year.^, 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.

Concurrent with the development of highly effective and safe DAAs, 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%. In this context, anti-HCV-positive overdose donors accounted for 6% of the US donor pool in 2015–2016. At the same time, the number of chronic HCV transplant recipients decreased, presumably as patients were cured with DAAs. 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. 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 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, followed by multiple studies on kidney, liver, heart, and lung transplants over the next 3 years.^{,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,} 

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.^,, 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.^, 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. Similarly, national utilisation rates of anti-HCV-positive viraemic and nonviraemic donor hearts in 2019 was the same as anti-HCV-negative donor hearts.^, 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.^,,

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^, (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). 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: 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 6^th 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.^,

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. 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).

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).^,

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. 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.^, 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.^,

The first prospective study using HCV-viraemic hearts included 11 nonviraemic recipients who were then followed by NAT post-transplant (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.^{,,  ,  ,,} 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.^,,

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, 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. 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. 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.

The first report of HCV-viraemicc donors in lung transplantation reviewed 5 cases where HCV-nonviraemic recipients were rapidly deteriorating and accepted viraemic lungs. 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. 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. 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: 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.

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.^, 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 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. 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. 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.^,, 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, which are associated with more RASs. However, DAA regimens have been developed that overcome most RASs, and most preliminary studies included multiple genotypes.

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. 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. 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.^, 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.^{,  ,}  A cost-effective analysis suggests that pre-transplant HCV treatment is cost-effective for patients with MELD ≤20 and without HCC. 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.