The widening disparity between patients awaiting transplantation and organs available is well recognized. In 2018 alone, nearly 13 000 people died or were removed from the waiting list for being too sick to transplant.1 Innovative ways to expand the number of usable donors remain a critically important area of research, and in this regard, broader use of hepatitis C (HCV)–infected donors is relevant. Intentional transmission of viral infections via organ transplantation is not a new phenomenon, with donors exposed to hepatitis B, cytomegalovirus, and Epstein-Barr virus routinely used. Intentional transmission of HCV to virus-naive individuals, however, has been mostly avoided because of the nearly universal risk of chronic infection in the recipient and the serious consequences of untreated HCV disease posttransplant. This approach has now changed—driven by, first, the remarkable advances in HCV treatment with safe and highly effective direct-acting antiviral therapies (DAAs) providing nearly 100% cure rates, and second, the marked increase in HCV-viremic (nucleic acid test positive) donors available, due to overdose deaths in association with the opioid crisis. In 2018, drug intoxication was the number 1 cause of death among donors, resulting to 4848 transplanted organs compared with just 851 a decade ago.1
Published experience on the use of HCV-viremic donors in uninfected recipients is growing. In a recent issue study from Brigham and Women’s Hospital in Boston published in the New England Journal of Medicine, Woolley et al2 report on 28 lung and 7 heart recipients of such donors. Immediately after transplant, 95% of recipients were viremic, and HCV treatment using the pangenotypic drug combination of sofosbuvir–velpatasvir was initiated shortly after transplant and given for 4 weeks; all recipients achieved sustained viral clearance assessed 24 weeks after treatment completion (= HCV cure).2 No serious adverse events were reported, although more cases of acute cellular rejection occurred in recipients of HCV viremic compared with HCV-uninfected donors. This study and others highlight the potential advantages of using HCV-viremic donors, including shorter waiting time, being “less sick” at the time of transplant,3 and having access to younger donors, which may offer additional benefits on graft outcomes.4
The approach to HCV treatment in the study by Wooley et al2 warrants comment. First, a pangenotypic regimen was used, obviating the need for genotyping of the donor to determine the best HCV treatment regimen. Pangenotypic combinations offer enhanced simplification of treatment and should be favored in this setting. Second, treatment was started immediately postoperatively, with the median initial HCV RNA level 1800 IU/L (interquartile range, 800–6180), which is 2–4 log10 IU/mL lower than HCV RNA levels when treatment is delayed for days to weeks after transplant.5,6 Early treatment, especially in nonliver transplant recipients, likely allows for shorter duration of therapy due to lower hepatic viral burden. Third, the duration of treatment in the study by Wooley et al2 was 4 weeks, shorter than the approved durations of 8 or 12 weeks, yet rates of HCV eradication were high. Confirmation of the success of this preemptive 4-week treatment approach is essential as this approach may become the standard for non-liver transplants going forward. If treatment is delayed, however, a longer duration of therapy would be wise. Indeed, with the goal of minimizing harm to the recipient, a strategy of overtreating seems prudent rather than pushing to shorten therapy and risk treatment failure.
Use of HCV-viremic donors in liver versus other solid organ transplant recipients requires special attention. The viral burden is higher and the HCV-infected liver graft brings an array of immune cells directed toward controlling HCV replication that may alter immunologic responses to other hepatic insults, such as rejection or cytomegalovirus infection. Several reports, including that from Woolley et al,2 suggest a higher rate of rejection in recipients treated for HCV infection. Whether the activation of innate and adaptive immune responses related to control of acute HCV infection or whether the rapid clearance of viremia from infected hepatocytes alters the immunologic milieu to increase risk of rejection is unknown but acute cellular and antibody-mediated rejection has been reported in the context of HCV DAA therapy in liver transplant recipients with recurrent HCV disease.7 Moreover, some HCV-infected livers may have been damaged by years of prior infection in the donors, thus careful assessment of fibrosis stage is mandatory before implantation. Prior experience using HCV-viremic donors into recipient with chronic HCV infection has shown graft survival to be similar to uninfected donors except when donors are older or have significant fibrosis.8 The HCV-infected liver graft must have sufficient “reserve” to tolerate other liver injuries that may occur posttransplant.
The total published experience of solid organ transplantation using HCV-viremic donors is small. Consequently, infrequent but serious complications may be unrecognized. Of prime interest is the risk of HCV treatment failure and potential consequences. Using approved therapies, the risk of treatment failure is predicted to be <5%.9 Only 1 report of treatment failure has been reported—in a lung transplant recipient in whom complex drug resistance–associated substitutions emerged.5 Fibrosing cholestatic HCV, the most severe form of HCV with the risk of liver failure, has been also described,5 reminding us of how quickly HCV infection can lead to severe liver injury after transplant. There are also well-recognized extrahepatic manifestations of chronic HCV infection, including glomerulonephritis, noninflammatory arthritis, diabetes mellitus, and non-Hodgkin’s B-cell lymphoma. Might a short duration exposure to HCV infection during a period of intense immunosuppression increase the likelihood of these complications? A recent case report of HCV-associated glomerulonephritis in a recipient of an HCV-viremic donor suggests that the answers is “yes.”10 An improved understanding of the immunologic consequences of HCV infection in the recipient, even when infection lasts a few weeks to months in duration, is critical.
Last, but by no means least, is the issue of accessing DAA therapy. In the study by Woolley et al,2 DAA therapy was provided by the hospital. This approach may rather represent an exception than the rule. Most hospital pharmacies do not have DAAs on their formulary because of their high cost and infrequent in-hospital use. Transition from inpatient to outpatient pharmacy plans presents a risk for treatment interruption. Recognition by insurers of this unique circumstance where rapid access to DAAs is necessary would significantly enhance the management of these recipients. However, the bottom line for transplant programs is that if HCV-viremic donors are used, access to antiviral treatment must be guaranteed including the need for retreatment with as many courses as required to achieve HCV cure.
When highly effective DAAs were introduced in 2014, it was clear that we were entering an exciting period of managing HCV infection in transplant recipients. The ensuing years have provided proof that virtually all patients can be cured, regardless of genotype, the presence of cirrhosis, and prior treatment experience. We are now at the point where the previously unimaginable concept of intentionally giving HCV infection to uninfected recipients via organ transplantation is moving to the “routine.” Initial results are encouraging, and the benefits seem to be significant. Yet, with this new donor opportunity comes responsibilities—removal of the disparities related to DAA access, use of treatment algorithms that minimize the risk of treatment failure, careful evaluation and reporting of immunologic complications, and a commitment to long-term follow-up of these patients to capture delayed consequences of HCV infection.
Only if these responsibilities are fully embraced will the optimal use of these HCV-viremic donors be realized.
2. Woolley AE, Singh SK, Goldberg HJ, et al; DONATE HCV Trial TeamHeart and lung transplants from HCV-infected donors to uninfected recipients.N Engl J Med20193801606–1617
3. Bethea E, Gaj K, Gustafson J, et al. Pre-emptive pangenotypic direct acting antiviral therapy in donor HCV-positive to recipient HCV-negative heart transplantation: an open-label study.Lancet Gastroenterol Hepatol20194771–780
4. Reese PP, Abt PL, Blumberg EA, et al. Twelve-month outcomes after transplant of hepatitis C-infected kidneys into uninfected recipients: a single-group trial.Ann Intern Med2018169273–281
5. Feld J, Humar A, Singer L, et al. Lung transplantation from HCV-infected donors to HCV-uninfected recipients.The Liver Meeting, San Francisco2018Abstract 0223
6. McLean RC, Reese PP, Acker M, et al. Transplanting hepatitis C virus-infected hearts into uninfected recipients: a single-arm trial.Am J Transplant2019192533–2542
7. Chan C, Schiano T, Agudelo E, et al. Immune-mediated graft dysfunction in liver transplant recipients with hepatitis C virus treated with direct-acting antiviral therapy.Am J Transplant2018182506–2512
8. Lai JC, O’Leary JG, Trotter JF, et al; Consortium to Study Health Outcomes in HCV Liver Transplant Recipients (CRUSH-C)Risk of advanced fibrosis with grafts from hepatitis C antibody-positive donors: a multicenter cohort study.Liver Transpl201218532–538
9. AASLD/IDSAHCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C.2019Accessed July 1, 2019
10. Wadei HM, Pungpapong S, Cortese C, et al. Transplantation of HCV-infected organs into uninfected recipients: advance with caution.Am J Transplant201919960–961
Innovative ways to expand the number of usable donors remains a critically important area of research and in this regard, broader use of hepatitis C-infected donors is relevant.