Originally published by our sister publication Gastroenterology & Endoscopy News
By Kaitlin Sullivan
A shortened antiviral protocol adding the dyslipidemic agent ezetimibe can prevent infection in solid-organ recipients who receive hepatitis C virus–positive organs, according to new research presented at The Liver Meeting 2023.
The regimen, dubbed the “Toronto Protocol,” uses the current standard-of-care treatment glecaprevir-pibrentasvir (Mavyret, AbbVie) but cuts the course from eight weeks to eight days. It also adds ezetimibe, a cholesterol-lowering drug that has the unique ability to prevent HCV from entering cells (Nat Med 2012;18[2]:281-285). The first dose starts the day before organ transplantation and continues for one week, usually when the patient is still in the hospital recovering from surgery.
This differs starkly from past practices that required a patient to become viremic before starting treatment. Although the newest guidelines advise starting treatment as soon as possible, even before the organ recipient receives a positive HCV test (Clin Infect Dis 2023 May 25. doi:10.1093/cid/ciad319), the Toronto Protocol takes it one step further. To prevent infection from taking hold, it uses a proactive, rather than reactive, approach.
“We shouldn’t wait until people become infected with hepatitis C to begin treating it,” lead researcher Wesam Aleyadeh, MD, told Gastroenterology & Endoscopy News. “We’ve seen a huge rise in overdose deaths from otherwise young and healthy donors, and that’s raised the number of hepatitis C–positive organs available for donations,” noted Dr. Aleyadeh, a research fellow at the Toronto Centre for Liver Disease at Toronto General Hospital. “Waiting,” he said, “would be our second failure as a healthcare system. Our first was not adequately managing hep C in the donors.”
Preventing Infection
Dr. Aleyadeh presented the results of two trials at the meeting (oral presentation 56). The first was an extended follow-up of 30 patients in a previous proof-of-concept study on the protocol. After an average of 211 weeks, the team logged no HCV-related deaths, complications or breakthroughs in patients treated with the Toronto Protocol.
The second trial included 59 patients who had received organ transplants since the hospital adopted the protocol as their standard of care. All the patients received organs from HCV-positive donors and were HCV-negative before transplantation, according to nucleic acid amplification testing.
During follow-up, which occurred at a median of 91 weeks, the researchers found evidence of HCV antibodies in recipients, but according to Dr. Aleyadeh, it’s unclear whether the donor’s antibodies get transplanted into the recipient, or whether the recipient’s own immune system rapidly produces antibodies post-therapy.
In both studies, patients underwent lung, heart, kidney or kidney–pancreas transplants. (Recipients of HCV-positive liver transplants were not eligible for the eight-day treatment, as the liver is the main target of the infection and transplant of an infected organ would require monthslong antiviral therapy, Dr. Aleyadeh explained.) None of the 88 patients treated with the protocol at Toronto General Hospital experienced virologic breakthroughs or HCV-related complications or needed re-treatment. Outcomes related to organ rejection, patient survival and adverse events related to treatment were on par with those documented in patients who underwent the current standard of care.
A New Standard of Care
Other transplant centers also are trying out similar regimens. Massachusetts General Hospital (MGH) has employed a shortened regimen of glecaprevir-pibrentasvir but without ezetimibe (Lancet Gastroenterol Hepatol 2019;4[10]:771-780). While their results also were positive, Dr. Aleyadeh noted that peak recipient HCV RNA was slightly higher in the MGH study (1.76 vs. 0.72 IU/mL; P=0.01). This finding, along with findings that ezetimibe is well tolerated and inexpensive, showed that the drug can be beneficial to include, Dr. Aleyadeh said.
Mayo Clinic, which has adopted a preemptive treatment as its standard of care, expects to publish the results of a clinical trial showing similarly promising results, Bashar Aqel, MD, a transplant hepatologist and the chair of the Mayo Clinic Transplant Center in Phoenix, told Gastroenterology & Endoscopy News.
“There is no gray zone in this. It’s black and white,” he said. “We have proven with experience that this [shortened] treatment is the way to go and should be adopted as a guideline and the standard of care.”
Barriers to Proactive Treatment
However, there are roadblocks, Dr. Aqel said. Adopting a proactive treatment approach as the standard of care across the United States would require more insurance companies to cover the treatment. As of now, “if you need the insurance approval for the treatment, you cannot get approved until after you are infected,” Dr. Aqel said.
With the help of a grant, Mayo Clinic pays for proactive therapy in organ recipients who agree to receive HCV-positive organs, but that isn’t possible for many other facilities, making insurance logistics a significant barrier to treatment.
The same is still true for transplant recipients seeking the current standard treatment, who must be granted prior authorization before treating their HCV infection.
In the long run, proactive treatment can save insurance companies money, Dr. Aqel said. “The cost of one week of treatment is $2,800, compared to $30,000 [for the reactive treatment],” he said. “It also eliminates the anxiety and complications of having an infection in someone who is immunocompromised.”
The proactive treatment also requires transplant centers to plan ahead. A lack of timely access to the drugs needed for the Toronto Protocol was one of the challenges transplant physicians at Toronto General Hospital faced. The drugs are ordered on demand, but transplant centers “need to have them on hand,” Dr. Aqel said. “You should have a one-month supply at any time so the drugs are always available.”
Drs. Aleyadeh and Aqel reported no relevant financial disclosures.