Dr Michelle Tran is a first year general nephrology clinical fellow at University of Virginia. Before that, she pursued her Medical Degree at Virginia Commonwealth University (VCU) School of Medicine.

 

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Dr. Sarthak Virmani is a transplant nephrologist and an assistant professor of medicine at University of Virginia. His interests include identifying and removing barriers to patient’s access to transplantation care. Follow him @virmani_sar.

Of the several strategies adopted by the kidney transplant community to expand the donor pool for prospective recipients, the permissive transmission of Hepatitis C viral infections to infection-naïve recipients has perhaps been the most successful of them all.  The effectiveness of direct-acting antiviral agents (DAA) in curing Hepatitis C infections has revolutionized our approach towards organs from donors who had been infected by this virus resulting in a significant impact on lowering wait times, reducing morbidity and mortality on the wait list, and providing a larger number of people who may have otherwise died waiting for a transplant access to a kidney transplant.

A recently published large single-center experience of 211 organ transplants adds to an increasing fund of literature on the use of Hep C Viremic donor kidney transplants. Sutcliffe et al’s review of about 68,000 recipients who were Hepatitis C seronegative, HCV R (-), revealed that kidneys procured from donors with previous Hep C infection were not associated with an increased risk of graft failure at the end of a three-year follow-up period. In fact, they were found to have a lower risk of delayed graft function and a higher estimated glomerular filtration rate (eGFR) at the 1-year mark when compared to HCV negative donors, HCV D (-).

Prior to the routine use of DAA, Interferon was the mainstay treatment for Hepatitis C viremia. The risk of it causing significant immunological risk to the allograft limited its use to those who were yet to receive a kidney transplant. When used, this therapy was found to have limited efficacy and significant adverse effects. In fact, the 2008 KDIGO guidelines recommend inactivating the patients on the transplant waitlist whilst undergoing Interferon therapy. Unfortunately, this was a setup for interrupted therapy, treatment failure, increased resistance and even transplant ineligibility if the patient’s viral infection progressed to fibrosing complications. The use of HCV viremic donors was therefore limited to recipients with active Hep C themselves with a plan for treatment after the transplantation. To further complicate matters, there was limited knowledge on the effect of various induction and maintenance immunosuppressive agents with this approach.

The THINKER Trial first established the successful use of DAA in treatment of Hepatis C after transplantation. Over the past decade, transplant centers and professionals across the country are now increasingly accepting and comfortable with the use of these viremic kidneys. Patients too, are increasingly being made aware of this ‘wait time advantage’ and are more accepting of these viremic kidneys especially when educated about the infection risk, use of DAA, long wait times and the strategy of the transplant centers to monitor and treat these donor-derived infections. Shared decision making remains key in this process of offering viremic organs to patients awaiting transplantation.

With an increasing number of centers rapidly adopting this approach, there is an evolving conversation about the most effective strategy for monitoring and treatment of these recipients. In a recent AJKDBlog Interview, the concern for early rejection with HCV NAT(+) donors at one center was attributed to use of non-lymphocyte depleting agents and was mitigated with the use of the lymphocyte depleting anti-thymocyte globulin instead. In another AJKD Case Report, Steinbrink et al highlighted a case report of 4 cases with treatment failure with the standard protocol of pan-genotypic DAA regimen. Several possible reasons were identified including medication interactions, bariatric surgery, drug resistance and viral dynamics. Reassuringly, all the highlighted cases ultimately achieved cure or sustained virological response with second- or third-line therapy. Since their approval by the FDA, newer and safer DAA are now available with lesser interactions with other medications (Proton Pump Inhibitors) and especially with more commonly used immunosuppressive medications.

Commonly used DAA and their interactions with commonly used immunosuppressive medications. © Tran, Virmani

The appropriate timing to initiate antiviral therapy remains a topic of active discussion. While some centers have better outcomes with starting therapy early and pre-emptively (prior to detection of viremia), a large proportion of centers wait for about 2-4 weeks post transplantation to start therapy. This time lag leads to detection of viremia which in turn helps obtaining insurance authorizations for these expensive drugs to safeguard against interruption of therapy due to cost. A longer delay in therapy should certainly be avoided to minimize the risk of immune activation and allograft dysfunction, partly attributable to the immunomodulatory effects of Hepatitis C and the consequent increased risk of Antibody Mediated Rejection.

Clinical course timeline of all described kidney transplant cases, including time relative to transplant and initial and subsequent antiviral regimen(s), through final sustained virologic response 12 weeks post treatment. © Steinbrink et al.

Nevertheless, if a patient is found to have HCV Viremia pre-transplant and has a long wait time ahead of them, it is recommended that they be promptly treated with DAA to prevent long term complications – both hepatic and non-hepatic, ensuring they remain eligible to undergo kidney transplantation.

Previously, the routine use of these directly acting antiviral drugs was limited due to their prohibitive costs. Several studies have now shown favorable cost analyses of the use of these drugs as compared to progression of Hepatitis C associated Chronic Kidney Disease to End Stage Kidney Disease and need for renal replacement therapies, and in managing long-term allograft dysfunction and other complications if the virus is left untreated. This has been identified by public and private payors alike, bringing the out-of-pocket cost to most patients to a much more affordable amount.

The safety and efficacy of DAA therapy has led to a belief that this hitherto non-utilized waitlist advantage is shrinking but a 2020 study of HCV infected patients in an urban hospital setting found that only about 16% of the estimated 3 million people infected with HCV have received treatment. To be good stewards of population health and healthcare, it is important that each of these patients receive timely DAA with a goal to eradicate this virus with effective treatment. In the meantime, to remain efficient stewards of health, we may use this unfortunate gap in care delivery to benefit our patients waiting on the transplant waitlist.

Despite a paradigm shift in the acceptance of donor organs that are infected by hepatitis C, a lot is yet to be learned – the appropriate timing of therapy, immunosuppressive protocols, screening for co-infections, re-activation of infection in carriers of Hepatitis B, risk of CMV infections, risk of treatment failure, appropriate screening protocol post sustained virological response for the immunosuppressed and long-term graft health outcomes. While we as a transplant community wait on these answers, we should certainly continue to utilize these Hepatitis C infected organs to expand the donor pools in the safest, most efficient ways possible, thereby facilitating access to organ transplantation.

– Post prepared by Michelle Tran and Sarthak Virmani @virmani_sar

To view Steinbrink et al (Open Access), please visit AJKD.org.
Title: Antiviral Treatment Failures After Transplantation of Organs From Donors With Hepatitis C Infection: A Report of 4 Cases
Authors: Julie M. Steinbrink, Shanti Narayanasamy, Cameron R. Wolfe, Eileen Maziarz, Jennifer Byrns, Jennifer J. Kiser, Susanna Naggie
DOI: 10.1053/j.ajkd.2022.12.006