1.1 Background

Despite increased number of donor liver availability with each year, the uptrend is still not proportional to the increased number of new registrants placed on the waiting list each year.¹ Between 2013 and 2016, an estimated 4.1 million persons living in the United States had a positive HCV antibody and 2.4 million persons had a positive HCV RNA suggestive of chronic HCV infection (1% of all adults).² The majority of those who test positive are undiagnosed and therefore remain untreated.³ Until the introduction of DAA therapies, treatment was not only difficult to tolerate but unlikely to result in a cure. DAA therapies are well tolerated and result in a higher rate of sustained virologic response (SVR) at 90%-95%. Yet, despite the availability of highly effective therapy for chronic HCV, a significant proportion of patients do not receive treatment.⁴ A 2016-2017 pharmacy data analysis found treatment denial rates up to 34.5% for Medicaid and 52.4% for privately insured patients, predominantly on basis on individual fibrosis scores.⁵

The proportion of donors aged 18-34 years has increased noticeably in the past 5-6 years. This trend stems from a dramatic increase in anoxic brain deaths as a result of the opioid epidemic.¹ This has created a potential pool of otherwise healthy organ donors. The majority of the HCV-positive livers are from younger patients and most likely to be of high quality. Despite this, there can still be a significant discard rate of these organs for several reasons including the lack of HCV-positive recipients on the waiting list.⁶ This is now more prominent as the HCV-positive recipient pool is declining in the DAAs era resulting in more patients with HCV cirrhosis achieving SVR leading to an improvement in liver function.⁷

Recurrent hepatitis C post-liver transplantation can safely and effectively be treated with available DAA regimens.^8-10 Achieving SVR in the post-liver transplant setting confers a benefit to the graft and patient survival comparable to hepatitis C negative liver transplant recipients.^{11, 12} Although the current guidelines do not recommend use of HCV-positive donor liver for transplantation of HCV-negative recipients, with the advent of DAA therapies, HCV infection in an allograft liver can be successfully treated. It is important to bridge the gap of organ demand by appropriately utilising and allocating available transplantable livers.

The MELD is the accepted numerical scale method used to prioritise liver organ allocation to patients who are on the transplant waiting list (WL).¹³ A higher MELD score corresponds to a lower 3-month survival and thus a greater need for liver transplantation. It has been validated as a reliable measure to predict disease severity and mortality in the majority of patients with advanced liver disease.¹⁴ However, there is a subgroup of patients with comorbid conditions and/or severe complications of liver disease who also have a high mortality risk that is not accounted for by their low MELD score.¹⁵ Some low MELD patients who have disproportionately high mortality include those with recurrent hepatic encephalopathy, hypoalbuminaemia, recurrent ascites and/or hepatic hydrothorax and recurrent peritonitis. Furthermore, cirrhotic patients with malnutrition and recurrent hospitalisation have a higher rate of being excluded from the WL (‘wait-list drop out’).^16-18 Few of these patients are awarded exception MELD priority points by regional review boards at the request of their transplant physicians. Nonetheless, these patients have been shown to have a high mortality risk.¹⁹ Therefore, expanding the donor pool by inclusion of HCV-positive livers for this subgroup of patients with end-stage liver disease sicker than their calculated MELD scores (ie have a higher mortality/lower survival than the MELD score would suggest) can potentially shorten their time to transplantation.

2.1 Development of clinical programme

A protocol for this clinical programme was developed, reviewed and approved by the members of the liver transplantation team at Einstein Medical Center, Philadelphia. The protocol (#5093) was reviewed by the Institutional Review Board at Einstein Healthcare Network, but a formal IRB review was declined in lieu of it being a clinical programme. A legal and ethics review took place prior to initiation of the programme and approval was obtained to implement it. The team included transplant hepatologists, hepatobiliary transplant surgeons, transplant social workers, transplant coordinators and pharmacist. Potential patients deemed appropriate for enrolment to this clinical programme were presented at the transplant meetings and were vetted by the multidisciplinary team, ensuring that the recipients would meet the key selection criteria. After unanimous agreement on a patient's candidacy for transplantation with an organ from an HCV-infected donor, the transplant physician for the patient discussed the nature, purpose, potential risks, complication, benefits and alternatives to transplantation with the development of HCV infection post-transplant necessitating treatment. The transplant physician also discussed with the patient the possibility of patient's insurance providers’ refusal to pay for DAA therapy, in which case an appeal would be filed by the transplant team. A written informed consent was obtained from the patient for acceptance a liver from HCV-infected donors who are considered HCV positive by both serology and nucleic acid testing (NAT).

At the time of availability of an organ, the standard protocol of informing the patient regarding the organ availability and characteristics including HCV status of the donor was performed. Thus, giving the recipient the option to refuse a liver (and kidney in case of an SLK) from an HCV-infected donor. At the time of organ procurement, donor HCV antibody, HCV NAT and liver biopsy were performed. All recipients under HCV testing by polymerase chain reaction (PCR) on a weekly basis starting post-operative day 7 for the first 4 weeks and subsequently every month until HCV RNA was detected. If HCV RNA PCR remained undetectable for 24 weeks after transplantation, recipients were considered free of HCV infection. Once HCV RNA was detected via PCR, an HCV genotype and HCV RNA NS5A (for genotype 1a) were checked. With confirmation of HCV recurrence in post-transplant recipient, the HCV treatment team comprised of hepatologists, nurse practitioner, pharmacist and social worker initiated a detailed workup including an assessment for co-infections with hepatitis B virus and human immunodeficiency virus (HIV). The pharmacist reviewed any potential drug to drug interactions. The recipient was scheduled for an outpatient HCV specialty clinic visit where education on treatment for HCV was provided and consent for treatment was obtained. The team then submitted the recommended DAA therapy and duration for approval by the patient's individual insurance provider. The individual DAA agent and duration were recommended as per American Association for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA) hepatitis C treatment guidance for post-liver transplant HCV recurrence.

2.2 Recipient selection criteria

Potential transplant candidates were required to meet all our departmental selection criteria. These included: (a) Male or female, 18 years of age or older; (b) Patients who completed a liver transplant evaluation and were accepted by the multidisciplinary liver transplant team as a suitable medical, surgical and psychosocial candidate, and were actively listed and awaiting transplantation; (c) Undetectable HCV RNA PCR test within 3 months of consent, with either no prior history of HCV infection (HCV antibody negative) or possible HCV exposure in the past with no history of active chronic HCV (HCV antibody positive but HCV RNA PCR undetected) or history of chronic HCV infection but treated with SVR in the past; (d) In cases of hepatocellular carcinoma (HCC), patient must have met the standard selection criteria for liver transplant and at least one other factor to justify necessity of HCV-positive organ: age >70 years, suboptimal response to locoregional therapy, outside of Milan criteria but within UCSF criteria, not a candidate for further locoregional therapy and/or clinical decompensation with locoregional therapy; and (e) Were able to demonstrate an understanding of the clinical protocol and were willing to give an informed consent for HCV-seropositive cadaveric donor liver transplantation.

2.3 Recipient exclusion criteria

Any patient not meeting the selection criteria or those with (a) Cognitive impairment (other than controlled hepatic encephalopathy) precluding them from participation in the consent process; (b) Gastrointestinal disorder or any condition which could interfere with absorption of proposed HCV therapy; (c) A history of haemoglobinopathy including sickle cell disease or thalassaemia, as potential contraindication for ribavirin therapy; or (d) Incarcerated patients, were excluded from selection in the clinical programme.

2.4 Donor organ criteria

Donors acceptable for use under this clinical programme included HCV seropositive or HCV positive by virologic testing, such as NAT. The donor organ had to have met other selection criteria including being an acceptable organ for liver transplantation, donor liver biopsy with stage 0 or 1 fibrosis, donor liver with no more than 25% macrosteatosis on biopsy, donor hepatitis B surface antigen (HBsAg) negative and HIV negative.

2.5 Follow-up

In addition to the follow-up of post-liver transplantation clinical visits, the recipient was seen by our departmental HCV treatment team at intermittent intervals to monitor tolerance and effect of therapy until the end of treatment and a visit at 12 weeks after conclusion of therapy to assess SVR.

3.1 Recipient characteristics

The median age of liver transplant recipient was noted to be 60.5 years. The majority of recipients were male (62.5%) and Caucasian (79.2%). The predominant blood group was noted to be O in more than half the recipients (58.3%), followed by a third of recipients with blood group A (37.5%). The aetiology of underlying liver disease in the recipients (Figure 1) was alcohol (29%), non-alcoholic steatohepatitis (NASH, 17%), chronic HCV with prior treatment with SVR (13%), cryptogenic (8%) and miscellaneous, including cases of autoimmune hepatitis, haemochromatosis, alpha-1-antitrypsin deficiency, primary biliary cholangitis, primary sclerosing cholangitis and sarcoidosis (25%). HCC was noted in two cases, one with an underlying diagnosis of alcohol cirrhosis and the other with NASH cirrhosis. Of the five recipients of simultaneous liver kidney transplantation, two recipients received organs from HCV NAT-positive donors. The median MELD score at the time of listing was 21 and median MELD score at the time of transplantation was 27. Table 1 details the characteristics of recipients.

3.2 Donor characteristics

A majority of donors were male (58.3%) with a median age of 34.5 years. All 24 donor organs were as a result of donation after brain death from anoxia, seven of whom were reported to have a history of drug-related overdose. Eighteen (75%) of the donor livers were procured from HCV NAT-positive donors. The median cold ischaemia time was noted to be 6 hours 7 minutes. Table 2 provides details of individual donor characteristics.

3.3 Wait time on liver transplant list

The median wait time period, after a patient listed for liver transplant was consented for HCV organ donor, dropped in comparison to the pre-HCV consent waiting period. The median wait time after implementation of the programme was noted to be 32 days in comparison with 53 days prior to implementation, cutting the post-consent wait by 40%. With the development of the clinical programme and experience with the first 12 patients, HCV donor organ consent was offered to six patients at the onset of their transplant listing. The total median wait time for 24 patients in the clinical programme was 106.5 days. Figure 2 highlights the wait times for individual recipients.

3.4 Post-liver transplant hepatitis C course

All 18 recipients who received HCV NAT-positive organs developed evidence of HCV recurrence, with evidence of HCV viraemia within 1 week of their transplant. None of the six recipients who received HCV-seropositive grafts had any evidence of HCV recurrence, with undetected HCV RNA by PCR up to 12 months post-transplant. Three of the 18 HCV NAT organ recipients had a history of prior chronic HCV infection with confirmed SVR at 12 weeks of treatment completion (SVR12), pre-transplant. Genotype 1a HCV infection was the most common subtype followed by genotype 2 in the donors. All recipients with post-liver transplant HCV infection were successfully approved for DAA therapy with an average wait time from HCV viraemia detection to therapy of 22.1 days. Glecaprevir/Pibrentasvir (GLE/PIB) was used in 61.1% (11 patients) of the treatment regimens. The three recipients with prior history of successfully eradicated HCV pre-transplant were also treated with GLE/PIB. The median duration of treatment with DAA therapy was 12 weeks. No interruption or suspension of HCV treatment regimen was reported in the 18 recipients and all patients had undetected HCV viraemia at the end of treatment with DAA. All 18 patients were successfully treated with eradication of HCV, with confirmed sustained virologic response at 12 weeks post-treatment completion. Table 3 provides details on individual data for HCV course post-transplant.

3.5 Outcomes

As described above, all 18 recipients with recurrence of chronic hepatitis C after receiving livers from HCV NAT-positive donor underwent full course of prescribed DAA therapy with undetected viraemia at end of treatment. This case series had a 100% success rate for treatment and eradication of post-transplant HCV infection, with evidence of SVR12. No mortalities were noted as a direct or indirect result of HCV recurrence post-liver transplant. Two cases of liver enzyme elevation in the setting of HCV recurrence were noted which resolved with initiation of DAA therapy.