Pre- and post-transplant antiviral treatment prevents hepatitis C transmission in all organ recipients, Canadian study finds

Adding a cholesterol-lowering drug to direct-acting antivirals (DAAs) prevented hepatitis C infection in all recipients of organ transplants from donors with hepatitis C, Jordan Feld, Research Director of the Toronto Centre for Liver Disease, reported at the 2019 AASLD Liver Meeting in Boston earlier this week.

The demand for donor organs continues to grow in North America, and the supply of potential organs from donors who die from opioid overdose has also grown substantially over the past decade. Organs from donors who died of opioid overdose now make up around 15% of potential donors in the United States, compared to 1% in 2000.

But up to 30% of potential organ donors who died from overdose were infected with hepatitis C virus (HCV) in 2016, which led many organs from otherwise young and healthy donors to be rejected.

However, multiple small studies have shown that recipients of HCV-infected organs can be successfully treated after transplantation with DAAs.

This study, conducted by researchers at the Toronto Centre for Liver Disease, University Health Network and the University of Toronto in Ontario, Canada, aimed to evaluate pre-emptive DAA therapy combined with ezetimibe, followed by one week of therapy to either prevent or rapidly clear the infection.

The lipid-lowering drug ezetimibe was used in order to block entry of the hepatitis C virus into liver cells. Ezetimibe has been shown to block entry in a mouse study but has not been tested in humans.

“We had done a previous trial treating HCV after transplant. It was generally effective, but there were some challenges,” says lead author Jordan Feld, MD, MPH, R. Phelan Chair in Translational Liver Disease Research at the University of Toronto and Research Director, Toronto Centre for Liver Disease. “There were some drug interactions, and we had two patients relapse after a full course of therapy.  We thought that if we could prevent transmission, we could avoid all of these problems. By adding an entry inhibitor and preloading the liver with DAAs, we thought that treatment could be significantly shortened and our data support that that is indeed the case.”

The study recruited 25 people awaiting lung, liver, kidney, heart or pancreas transplants, under the age of 65 with no evidence of liver disease. Transplants were predominantly of lungs (12) and hearts (8).

Organ recipients received glecaprevir/pibrentasvir (300/120mg) combined with 10mg of ezetimibe six to 12 hours before transplantation, then the same therapy daily for seven days orally or by nasogastric tube as required.

Three recipients had transient detectable HCV RNA after completion of treatment, but 18 recipients achieved a sustained virological response at week 12 (SVR12) and seven recipients had an undetectable HCV RNA at week 6 post-transplant but have not yet completed 12 weeks of post-transplant follow-up.

Transient viraemia was detected in 18 of 25 recipients during treatment, but was quantifiable only in nine patients (in the remainder a signal was detected by the HCV RNA assay but viral load was below the limit of quantification [< 15 IU/ml)). Detectable viraemia was associated with a high viral load or genotype 3 infection in the donor.

Two lung transplant recipients died, one of sepsis and one of a sub-arachnoid haemorrhage. Neither had post-transplant detectable HCV viraemia. One treatment-related serious adverse events was reported but no participant discontinued DAA treatment. One participant experienced a grade 4 ALT elevation and two experienced grade 4 bilirubin elevations.

When compared to a historical control group of patients undergoing heart transplant from HCV-positive donors at Massachusetts General Hospital, who received one dose of glecaprevir/pibrentasvir prior to transplant and eight weeks of post-transplant prophylaxis, the Toronto patients who received ezetimibe had significantly lower transient viraemia (0.72 log IU/ml vs 1.76 log IU/ml, p = 0.01).

Jordan Feld said that it is unclear if ezetimibe reduced HCV entry into liver cells, as detectable viraemia may reflect residual viral replication in the donor organ rather than a new infection in the recipient.

“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” says Dr Feld. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”