The use of direct-acting antiviral (DAA) agents has transformed the kidney transplantation landscape, with virologic cure rates of recipients of kidneys from hepatitis C viremic (HCV+) deceased donors approaching 99 percent. Yet, there are still key scientific questions that require exploration.
Since 2018, the Kidney Transplant Program at Vanderbilt University Medical Center has performed close to 150 transplants from deceased donors who were HCV+. Today, Vanderbilt researchers are co-investigators in two national initiatives to study post-transplant outcomes of HCV+ kidney transplantation for uninfected recipients: the THINKER-NEXT study, funded by the National Institute of Diabetes and Digestive and Kidney Diseases, and the Collaborative for Transplanting Hepatitis C Organs (CO-AUTHOR) consortium.
In a publication in the American Journal of Transplantation, the CO-AUTHOR group reports findings from its first study, which looks at the association of donor HCV infection status and risk of BK polyomavirus viremia after kidney transplantation. A second study will look at the risk of cytomegalovirus infection post-transplant.
“While transplanting HCV-infected kidneys into HCV-naïve recipients is now commonplace, we are still exploring ways to reduce viral transmission, and comparing short- and long-term outcomes,” said Rachel Forbes, M.D., chief of the Division of Kidney and Pancreas Transplantation at Vanderbilt. “It’s important that we’re working together with other nationally-recognized centers to answer some of these questions.”
Unexpected Immunological Complications
Kidney recipients are at risk for developing BK polyomavirus infection or nephropathy, yet there is no demonstrated effective therapy. Guidelines recommend routine surveillance for BK polyomavirus in the first post-transplant year, and when BK polyomavirus is detected, reducing immunosuppression to resolve the infection.
In the CO-AUTHOR study, a retrospective look at kidney transplantation cases across four centers from April 2015 to March 2019, the researchers sought to determine the association between deceased donor HCV infection and risk of BK polyomavirus viremia or nephropathy in HCV-naïve kidney transplant recipients.
The difference between the rates of BK polyomavirus viremia greater than 1000 copies per milliliter among recipients of HCV-viremic and HCV-aviremic kidneys was not statistically significant. However, weighted rates of severe BK polyomavirus viremia (greater than 10,000 copies per milliliter) were higher among recipients of HCV-viremic kidneys and treated as presumptive nephropathy.
“It is possible that HCV infection does not lead to a higher risk of BK polyomavirus viremia but when this infection manifests, the recipient’s immune system is less able to control replication,” wrote the authors.
Research Versus Real World
The timing of DAA initiation may play an important role in the development of potential complications such as BK polyomavirus viremia in recipients of HCV+ kidneys, said Beatrice Concepcion, M.D., medical director of the Vanderbilt Kidney and Pancreas Transplant Program.
“Barriers exist for patients seeking direct-acting antiviral therapy in the real-world setting – outside of a clinical trial,” she said. “These treatment delays may be associated with immunologic and infectious post-transplant complications.”
A Vanderbilt study found that access to DAAs in donor-derived HCV post-transplant is achievable and affordable. However, DAA coverage may be denied by third-party payers and significant added administrative efforts are required for insurance approval, and for obtaining copay assistance.
“Our specialty pharmacy at Vanderbilt works with the insurance companies to obtain coverage for the DAAs,” Concepcion said. “We are usually able to initiate DAA therapy within one month of transplant and at a minimal out-of-pocket cost for the patient. However, it would still be ideal to initiate DAA therapy much sooner.”
Immediate DAA Treatment
The eight-center THINKER-NEXT trial solves the access problem by providing the DAA as part of a prospective study. The trial is being led at Vanderbilt by David Shaffer, M.D., a professor of surgery in the Division of Kidney and Pancreas Transplantation.
In a follow-up to the THINKER trial, THINKER-NEXT will study post-transplant outcomes of recipients who receive HCV+ kidneys. The study will initiate DAA therapy for HCV infection immediately after transplantation, with the DAA provided free of charge.
Concepcion says it’s important to conduct larger studies with longer-term outcomes, and also to compare different approaches to DAA treatment using “granular data.”
“There are a number of studies on this topic, but currently reported outcomes are only up to one year post-transplant. So far, these outcomes have been reassuring with regards to patient and graft survival and cure rates of donor-derived HCV using DAAs.”