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.
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.
The presence of pus-forming bacteria in the body.
small studies have shown that recipients of HCV-infected organs can be
successfully treated after transplantation with DAAs.
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.
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).
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.
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.
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
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.
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.”