Could Combining Direct-Acting Antivirals with a Common Cholesterol Medication Open the Door to More Viable Organs for Transplantation?
New study suggests this combination could prevent or rapidly cure hepatitis C in transplant recipients who receive organs from infected donors
Newswise — BOSTON – Data from a new study presented this week at The Liver Meeting® – held by the American Association for the Study of Liver Diseases – found that combination therapy with direct-acting antivirals (DAAs) and ezetimibe─ a cholesterol medication that has also been shown to block the entry of hepatitis C (or HCV) into the bloodstream of uninfected people ─ given immediately before and seven days after transplantation with an organ from a donor infected with HCV entirely prevented or rapidly cured HCV in the recipient. This short-course treatment strategy reduces costs related to DAAs and allows transplant patients to complete HCV therapy before they are discharged from the hospital, the study’s co-authors concluded.
Many potential organ donors are infected with HCV, which can lead to their organs being rejected for transplantation. 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.
“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.”
HCV-infected organ donors in the study were considered for lung, heart, kidney or kidney-pancreas transplantation. Organ recipients received glecaprevir/pibrentasvir (300/120 mg) combined with 10 mg of ezetimibe six-to-12 hours before transplantation, then the same therapy daily for seven days orally or by nasogastric tube as required. For lung transplantation, ex-vivo lung perfusion ─ a procedure to reduce swelling of the lungs while outside of the donor’s body during transplantation ─ was used for six hours when clinically indicated. Standard cold preservation was used for other organs. HCV RNA was tested daily in the patients for 14 days and then weekly for 10 weeks.
13 HCV-negative recipients have received organs from nine HCV-positive donors, including five lung, five kidney, two heart and one kidney-pancreas. The median age of the recipients was 60; 11 were male and 11 were Caucasian. The median donor HCV RNA level was 5.23 log10IU/mL.
Six recipients (46 percent) had detectable but unquantifiable (<15 IU/mL) HCV RNA on the first post-op day, which was undetectable by the second post-op day in five patients and the fourth post-op day in one patient.
Four recipients (31 percent) developed a quantifiable presence of hepatitis C virus in their blood at any point post-transplantation, with a maximum HCV RNA of 2.96 log10IU/mL. However, HCV RNA declined rapidly and was unquantifiable by the fourth post-op day in all four recipients.
All four patients with quantifiable HCV RNA received either kidney (three) or kidney-pancreas (one) transplants, but no other factors were associated with post-transplantation presence of hepatitis C virus in their blood. No relapses were reported with a median 10 weeks of follow-up.
Additionally, one lung transplantation patient died 10 weeks post-op of sepsis, but never had detectable HCV RNA. No other serious adverse events have been reported by patients in the study, and the medications were well tolerated.
“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.”
Editors Notes: This study is ongoing and new data will be presented at The Liver Meeting®
Dr. Feld will present these findings at AASLD’s press conference in Room 210 at the Hynes Convention Center in Boston on Saturday, Nov. 9 from 4 – 5:30 PM. The study entitled “Transplantation From HCV-Infected Donors to HCV-Uninfected Recipients: Short Course Therapy to Prevent Transmission” will be presented on Sunday, Nov. 10 at 8:30 AM in room 304/306. The corresponding abstract (number 0038) can be found in the journal, HEPATOLOGY.
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Abstract 0038: TRANSPLANTATION FROM HCV-INFECTED DONORS TO HCV- UNINFECTED RECIPIENTS: SHORT COURSE THERAPY TO PREVENT TRANSMISSION
Authors: Dr. Jordan J Feld, MD, MPH, FAASLD1, Dr. Marcelo Cypel2, Dr. Deepali Kumar3, Dr. Kathryn Tinckam 3, Dr. Joseph Kim 3, Dr. Jeffrey Schiff3, Dr. Michael McDonald3, Dr. Mitesh Badiwala3, Dr. Trevor Reichman4, Nikki Marks3, Ilona Bahinskaya3, Nellie Kamkar3, Shaf Keshavjee5, Lianne Singer3 and Atul Humar3, (1)Toronto Centre for Liver Disease, University Health Network, (2)Surgery, Multiorgan Transplant, University of Toronto, (3)Multiorgan Transplant, University of Toronto, (4)Multi Organ Transplant Program, Toronto General Hospital, (5)Multiorgan Transplant, University Health Network
Background: A large proportion of potential organ donors have HCV infection leading their organs to be rejected for transplantation. Multiple small studies have shown that recipients of HCV-infected organs can be successfully treated after transplant with direct- acting antivirals (DAAs). However, prevention of transmission would be preferable to increase recipient acceptance and reduce costs and potential complications. The aim of this study is to evaluate pre-emptive DAA therapy combined with an HCV entry blocker (ezetimibe – EZE) followed by 1 week of therapy to prevent or rapidly clear HCV infection.
Methods: HCV-infected donors were considered for lung, heart, kidney or kidney-pancreas (KP) transplant. Recipients received glecaprevir/pibrentasvir (G/P) 300/120 mg plus EZE 10 mg 6-12h before transplantation and then daily for 7d orally or by NG as required. For lung transplantation, ex-vivo lung perfusion for 6h was used when clinically indicated. Standard cold preservation was used for other organs. HCV RNA was tested daily for 14d and then weekly for 10 wks (Abbott RealTime).
Results: To date, 13 HCV-negative recipients have received transplants from 9 HCV-positive donors: 5 lung, 5 kidney, 2 heart and 1 KP. Median recipient age was 60 (27-76) years, 11 (85%) were male and 11 (85%) were Caucasian. Median donor HCV RNA level was 5.23 log10IU/m L (range 2.24-6.23). Only 4 (31%) recipients developed quantifiable viremia at any point post-transplant with a maximum HCV RNA of 2.96 log10IU/m L. HCV RNA declined rapidly and was unquantifiable by post-op day (POD) 4 in all. Six (46%) other patients had detectable but unquantifiable (<15 IU/m L) HCV RNA on POD1, which was undetectable by POD2 in 5 and POD 4 in 1. All 4 with quantifiable HCV RNA received kidney (3) or KP (1) transplants but no other factors were associated with post- transplant viremia. No relapses have been reported to date with median 10.2 wks follow-up (range 1-12.1). One lung transplant patient died 10 wks post-transplant of sepsis but never had detectable HCV RNA. No other serious adverse events were reported, and medications were well tolerated.
Conclusion: With potent DAA therapy combined with ezetimibe to impair HCV entry given immediately before and for 7 days after transplantation, HCV infection was entirely prevented (9 of 13) or rapidly cured in transplant recipients who received organs from HCV-infected donors. This short-course strategy reduces DAA costs and allows patients to complete HCV therapy prior to discharge
from hospital after transplantation.