Lessons From the Real World

HCV-Infected Donor Kidney Transplantation as Standard Practice

Christine M. Durand; Michael A. Chattergoon; Niraj M. Desai

Disclosures

American Journal of Transplantation. 2019;19(11):2969-2970. 

Organs from hepatitis C virus–infected (HCV+) deceased donors are a growing resource, primarily due to the unrelenting epidemic of opioid overdose deaths. Direct-acting antivirals (DAAs), which can readily cure HCV, have opened the door to transplanting HCV+ donor organs into HCV-naive recipients.

Since the first two successful pilot trials, THINKER[1] and EXPANDER,[2] HCV D+/R− kidney transplantation has grown substantially, clustered at a few high-utilizing centers.[3] There is debate over whether this innovative practice should be restricted to research, as recommended in an American Society of Transplantation 2017 consensus statement,[4] or whether it should become standard clinical care, given the organ shortage and high waitlist mortality.[5]

In this issue of the Journal, Molnar and colleagues describe their center's experience adopting HCV D+/R− kidney transplantation as standard practice.[6] From March 2018 to December 2018 they performed 53 HCV D+/R− kidney transplants outside of a trial, obtaining DAAs from third-party payers. They report 100% patient survival, 100% graft survival, and 100% HCV cure. This relatively large series provides real-world evidence confirming the efficacy of this strategy reported previously in small clinical trials and observational studies.

Important practical, clinical, and ethical challenges emerge from this real-world experience. Practically speaking, there have been concerns that third-party payers may deny DAAs for HCV D+/R− transplants. In this series, DAAs were started a median of 76 days posttransplant, a significant delay compared to trials where DAAs were initiated pretransplant as prophylaxis[2] or 3 days posttransplant.[1] Treatment delays may have contributed to several clinical complications observed. All patients had high HCV RNA levels (median 5.5 log10 IU/mL), with one patient developing fibrosing cholestatic hepatitis and 19% experiencing aspartate aminotransferases elevations ≥3 times normal. Other notable clinical events included acute rejection (7.5%), donor-specific antibodies (30%), BK viremia (34%), and CMV viremia (60%). One hypothesis to explain these findings is that persistent HCV viremia creates an inflammatory environment leading to immunologic and infectious complications as well as allograft dysfunction (Figure 1). Once HCV viremia was suppressed, Molnar and colleagues observed improvement in estimated glomerular filtration rates (from 61 ± 18 mL/min/1.73 m2 to 67 ± 17 mL/min/1.73 m2). These complications highlight potential benefits of earlier DAA treatment or prophylaxis endorsed by the authors themselves in their discussion.[6]

Figure 1.

Potential impact of treatment timing in HCV D+/R− transplantation. A, Delays in treatment and persistent HCV replication may be associated with immunologic and infectious posttransplant complications such as allograft rejection, BK viremia, CMV viremia, and liver injury. B, DAA prophylaxis or early treatment prevent persistent viremia and avoid downstream complications

A recent in-depth virologic analysis by Barr et al demonstrated that HCV D+/R− kidney and heart transplantation resulted in transmission of a genetically diverse viral population rather than a single founder virus.[7] One theoretical risk of this highly permissive genetic bottleneck is that transmission of resistant viral variants might occur and lead to treatment failure. However, Molnar and colleagues did not observe any treatment failures in their cohort, providing some reassurance that this may be a small risk in practice.[6] Larger studies including other transplant types are needed to fully understand this risk.

What are the barriers to early and universal DAAs in HCV D+/R– transplantation? According to Molnar et al, as providers at their center became more aggressive about prescribing DAAs early, access was obtained at 2–3 weeks posttransplant.[6] Nonetheless, DAAs were initially denied in 20% requiring appeals with approval in all cases. The majority (85%) of recipients had public insurance, which has been associated with increased likelihood of receiving DAAs in kidney and liver recipients;[8] thus it remains to be seen whether this is generalizable. Many states have DAA restrictions according to hepatitis fibrosis stage. Moving forward, it is critical to obtain support from professional societies, practice guidelines committees, as well as third-party payers to ensure access to DAAs in HCV D+/R− transplantation. Ideally, DAAs could be preapproved for prophylaxis or immediate treatment posttransplant given the potential association between viremia and clinical complications.

Another argument for limiting HCV D+/R− transplants to research is to provide greater oversight to the patient education and consent process. Of interest, in this series, transplant candidates were informed and asked to consent to HCV D+ organs by mail. The first provider-patient conversation about this novel practice occurred at the time of organ offer. It is important to understand the decision-making and consent process in this setting, as well as the overall patient experience to ensure that recipients do not feel undue pressure or accept organs with incorrect biases. Molnar and colleagues did not collect data on how many candidates declined to consider HCV D+ organs, nor do we have information on the decision-making experience, the consent process, or quality of life.[6] In THINKER, 55% of candidates declined to consider HCV+ donor organs.[1] Among HCV D+ recipients, quality of life[1] and qualitative studies of the patient experience[9] have been good. Further studies on patient-reported outcomes are needed.

In summary, Molnar and colleagues report their experience with moving HCV D+/R− transplantation from research to the real world. They demonstrate excellent transplant outcomes and HCV cure in all recipients.[6] Their report highlights knowledge gaps regarding optimal timing of treatment and potential harm and indirect effects of HCV replication. From an ethical and practical perspective, further input is welcomed from professional guideline societies, third-party payers, and patients to expand the success of HCV D+/R− transplantation.

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