The THINKER trial at Penn Gastroenterology has successfully cured hepatitis C (HCV) infection in kidney-transplant patients who received organs from HCV+ donors.
In an article published in NEJM in 2015, Drs. Reese, Abt, and Blumberg at Penn GI report that the average wait time for a kidney in the US is 5 years [to put this in perspective, the average wait time for a heart in the US is 4 months]. The average mortality for the >100,000 people nationwide currently awaiting a kidney is 4% per year, with a much higher death rate for diabetics and the elderly.
“These grim realities,” the authors report, “have prompted aggressive efforts to procure kidneys that would previously have been considered unacceptable, including kidneys from donors older than 70 years of age, kidneys that have sustained acute injuries, and kidneys with diverse infections.”
Hepatitis C is among the ‘diverse infections’ now garnering attention in the kidney transplant community. Using national registry information, the team identified 6546 HCV+ kidneys from deceased donors over a nine year period at Penn Medicine, of which 2422 (37%) were transplanted. The remaining, discarded, kidneys, the authors conclude, “could have benefited more than 4000 patients during that period and provided more than 12,000 years of graft life by 5 years after transplantation.” The team then proposed that reluctance to use HCV+ kidneys reflected an obsolete paradigm founded in past experiences with post-transplantation HCV complications and issues with interferon therapy. Neither is applicable in the age of direct-acting antivirals.
In a report published in 2016, the same team joined transplant surgeon Matthew H. Levine, MD, PHD, to consider an unexpected and unfortunate source for HCV+ kidneys: the tens of thousands of deaths (>50,000 in 2014) attributable to the ongoing opioid epidemic in the US. Again, evidence of waste emerged in data suggesting that fear of disease transmission was a principal factor in the underuse of organs from donors dying from drug overdose.
HCV infection is common in end-stage renal disease (ESRD) and HCV+ ESRD has been widely studied in the context of kidney transplantation. For the most part, these investigations have involved the safety of transplanting healthy or infected kidneys into HCV+ kidney recipients. The studies generally concur in finding allograft failure and death more likely among HCV+ recipients of HCV+ donors. An evolving consensus holds, however, that these risks are acceptable for HCV+ patients on the waiting list, where mortality and increasing morbidity are a daily presence.
The THINKER Trial
Given this accumulation of knowledge, hepatologist David Goldberg, MD, MSCE, and Peter Reese, MD, MSCE, initiated an open-label pilot study in 2017 at Penn Medicine to further define the safety and efficacy of kidney transplantation from HCV-1 donors into HCV-negative patients, followed by treatment with elbasvir–grazoprevir (Zepatier), a combination DAA approved in 2016.
Called THINKER (Transplanting Hepatitis C Kidneys into Negative Kidney Recipients), the trial included adults undergoing dialysis who had long anticipated waiting times for a kidney transplant. Patients with conditions that substantially elevate the risks of liver disease, allograft failure, or death were excluded. Donors were limited to those who had positive qualitative HCV nucleic acid test results and HCV genotype 1. Per protocol, 10 patients received HCV-infected kidneys.
At three days after surgery, patients were tested for HCV, and all 10 tested positive for the disease. Next, the participants were treated with the standard 12-week course of elbasvir/grazoprevir, a highly effective oral medication prescribed to eradicate HCV. At the conclusion of therapy, all 10 patients were cured of HCV.
Following these early positive results, the research team was granted an extension of their study, which will allow them to transplant and treat an additional 10 patients—20 patients in total.
THINKER was supported by a research grant from the Merck Investigator Initiated Studies Program; Merck supplied the antiviral drugs used in the study.
The Penn Center for Viral Hepatitis
In 2011, the Penn Center for Viral Hepatitis, under the direction of Drs. Rajender Reddy and Kyong-Mi Chang, played a key role in the introduction of the first generation of direct-acting antivirals (DAAs) for the treatment of HCV infection in adults. These drugs allow clinicians to eradicate HCV from infected individuals with every known subtype of the disease, including HCV-1, the most common genotype in the United States. The investigation of newer, safer and more efficacious generations of the DAAs at Penn has now expanded beyond the care of individuals with HCV-associated liver disease to include the treatment of patients receiving kidneys from HCV-infected donors. Moreover, a recently completed clinical trial at Penn examined the application of DAA therapy to the recipients of hearts from HCV+ donors.