The American Society of Transplantation Consensus Conference on the Use of Hepatitis C Viremic Donors in Solid Organ Transplantation

Transcription

1 American Journal of Transplantation 2017; 17: Wiley Periodicals Inc. Meeting Report 2017 The American Society of Transplantation and the American Society of Transplant Surgeons doi: /ajt The American Society of Transplantation Consensus Conference on the Use of Hepatitis C Viremic Donors in Solid Organ Transplantation J. Levitsky 1, *,, R. N. Formica 2,, R. D. Bloom 3, M. Charlton 4, M. Curry 5, J. Friedewald 1, J. Friedman 6, D. Goldberg 3,S.Hall 7, M. Ison 1, T. Kaiser 8, D. Klassen 9, G. Klintmalm 7, J. Kobashigawa 10, A. Liapakis 2, K. O Conner 11, P. Reese 3, D. Stewart 9, N. Terrault 12, N. Theodoropoulos 13, J. Trotter 7, E. Verna 14 and M. Volk 15 1 Northwestern University, Chicago, IL 2 Yale University, New Haven, CT 3 University of Pennsylvania, Philadelphia, PA 4 Intermountain Medical Center, Salt Lake City, UT 5 Beth Israel Deaconess Medical Center, Boston, MA 6 Optum Population Health Solutions, Minneapolis, MN 7 Baylor University Medical Center, Dallas, TX 8 University of Cincinnati, Cincinnati, OH 9 United Network of Organ Sharing, Richmond, VA 10 Cedars Sinai Heart Institute, Los Angeles, CA 11 LifeCenter Norwest, Seattle, WA 12 University of California San Francisco, San Francisco, CA 13 University of Massachusetts, Worcester, MA 14 Columbia University, New York, NY 15 Loma Linda University, San Diego, CA *Corresponding author: Josh Levitsky, j-levitsky@northwestern.edu Both authors contributed equally to the manuscript. The availability of direct-acting antiviral agents for the treatment of hepatitis C virus (HCV) infection has resulted in a profound shift in the approach to the management of this infection. These changes have affected the practice of solid organ transplantation by altering the framework by which patients with endstage organ disease are managed and receive organ transplants. The high level of safety and efficacy of these medications in patients with chronic HCV infection provides the opportunity to explore their use in the setting of transplanting organs from HCV-viremic patients into non HCV-viremic recipients. Because these organs are frequently discarded and typically come from younger donors, this approach has the potential to save lives on the solid organ transplant waitlist. Therefore, an urgent need exists for prospective research protocols that study the risk versus benefit of using organs for hepatitis C infected donors. In response to this rapidly changing practice and the need for scientific study and consensus, the American Society of Transplantation convened a meeting of experts to review current data and develop the framework for the study of using HCV viremic organs in solid organ transplantation. Abbreviations: CDC, Centers for Disease Control and Prevention; ChLIA, chemiluminescence assay; CKD, chronic kidney disease; DAA, direct-acting antiviral agent; EIA, enzyme immunoassay; ESRD, end-stage renal disease; FDA, Food and Drug Administration; G, genotype; HBV, hepatitis B virus; HCV, hepatitis C virus; IRB, institutional review board; IS, immunosuppression; IVDU, injection drug use(rs); LT, liver transplant; MELD, Model for End-Stage Liver Disease; NAT, nucleic acid testing; OPO, Organ Procurement Organization; OPTN, Organ Procurement and Transplantation Network; PCR, polymerase chain reaction; PHS, Public Health Service; PWID, persons who inject drugs; RAS, resistance-associated substitutions; SRTR, Scientific Registry of Transplant Recipients; SVR, sustained virologic response rate; TMA, transcription-mediated amplification; UNOS, United Network for Organ Sharing Received 11 April 2017, revised 12 May 2017 and accepted for publication 18 May 2017 Introduction and Rationale for Consensus Conference The advent of direct-acting antiviral agent (DAA) therapy for hepatitis C virus (HCV) infection has caused a shift in the clinical course and management of this disease, which has, in turn, significantly impacted solid organ transplantation. Patients with HCV infection are being cured at high rates, and there is now evidence that even select patients with advanced HCV-associated liver disease may develop sufficient improvement in liver function to avoid the need for liver transplantation (LT) (1,2). Patients with HCV and end-stage renal disease (ESRD) are now able to be treated and cured before kidney transplantation, which may reduce the risk of advanced liver disease but could alternatively result in longer waiting times due to only limiting acceptance of kidneys from HCV-negative donors. Transplant recipients of all organs can now be safely and successfully treated for HCV, 2790

2 HCV Consensus Conference which may extend patient and graft survival. Given these advancements, it is now possible to entertain the use of organs from HCV-viremic donors into nonviremic recipients. Because of the organ shortage and the fact these organs tend to be from younger and more optimal donors, this practice could result in an increase in transplantations and lives saved for patients with organ failure. Realizing that the science and practice of HCV therapy and the use of organs from HCV-infected donors have been rapidly evolving, the American Society of Transplantation convened a consensus conference of experts in Dallas, Texas, in January 2017 to address these issues in relation to organ transplantation. These individuals (the authors of this manuscript) represented the disciplines of kidney, liver, and thoracic transplantation; transplant infectious disease and pharmacy; organ procurement; government oversight and regulatory agencies; and the insurance industry. The meeting goals were to discuss the potential for use of organs from donors with HCV infection and to provide a framework for further research. This document will summarize the meeting findings and focus on key points agreed on by the consensus group for current and future recommendations. This report has been endorsed by the American Society of Transplantation. Definitions and Interpretations of the Term Hepatitis C Positive Donor HCV infection is identified by serologic tests, such as enzyme immunoassays (EIAs) and chemiluminescence assays (ChLIAs), that detect antibodies within 2 6 months after exposure (3,4), or nucleic acid testing (NAT), which directly measures viral RNA using polymerase chain reaction (PCR) or transcription-mediated amplification (TMA) (Figure 1, Table 1) that are detectable within 5 7 days of exposure (5). Historically, HCV-positive donors were identified based only on serologic testing (i.e. a seropositive donor). However, the development of NAT, which provides a more accurate assessment of transmission risk, has made refining the definition of hepatitis C positive donor necessary. Thus, for the remainder of this report, we put in quotations positive for any clinical data in which there is seropositivity in the setting where there is lack of clarity regarding NAT status. An HCV-seropositive donor who is NAT negative (nonviremic) indicates a spontaneously cleared or successfully treated infection or a false-positive antibody result (6 8). An HCV-seropositive donor who is NAT positive (viremic) indicates active infection and poses a high risk for disease transmission. Similarly, an HCV-seronegative donor who is NAT positive (viremic) generally indicates acute infection (within the past 2 months) and high risk for infection transmission. While there is a small risk of false-positive NAT, the rate in the deceased organ donor screening population is unknown. Unpublished data estimated the false-positive NAT rate in deceased organ donors at < 0.2% in a cohort screened from 2010 through 2013 (N. Theodoropoulos, personal communication), and rates from blood donors have been quoted to be between 0.1% and 0.8% (9,10). The variability may be dependent on the assay used, the laboratory environment, and the experience of the technician. Donors with positive HCV antibody but without viremia have not been documented to transmit HCV. Thus, historical outcomes data of HCV- positive donors must be viewed as limited because they do not specifically differentiate the presence or absence of viremia. The term HCV-viremic donor includes the NAT results and, thus, differentiates the presence of viremia from its absence, allowing for improved communication regarding infection transmission risk. The term HCV-viremic donor should be adopted to replace the term HCV-positive donor. Data on Use of Organs From Hepatitis C Positive Donors OPTN data indicate that 4.1% (6,567/159,552) of all deceased donors between 1995 and 2016 were HCV seropositive (Darren Stewart, personal communication). Transplantation of organs from HCV-seropositive donors to HCV-seronegative recipients has occurred in both abdominal and thoracic settings, although patient outcomes have consistently been inferior compared with transplantations between uninfected donors and recipients (11 13). However, these studies come from the pre-daa era when reported results are for HCV- positive donors without information about viremia status, significantly limiting current applicability of their findings. Thus far, organs from HCV- positive donors have primarily been used in HCV-viremic recipients, although even this practice has not been universally accepted across the different organ transplant disciplines, despite its demonstrated safety. Liver transplantation Studies have shown no difference in patient or graft survival for HCV-infected recipients of organs from HCV positive donors (14 18). Therefore, using a liver is Figure 1: Hepatitis C virus testing in relation to initial exposure. American Journal of Transplantation 2017; 17:

3 Levitsky et al Table 1: Interpreting donor test results HCV antibody HCV NAT Clinical interpretation Concern for transmission + + Active infection (acute Likely or chronic) + No active infection 1 ; cleared or treated No documented transmissions prior infection, or false-positive antibody + Acute infection in the Likely antibody window period or false-positive NAT No HCV infection 1 None HCV, hepatitis C virus; NAT, nuceic acid testing. 1 No infection unless donor had ongoing risk factors for recent HCV acquisition 5 7 days before screening. acceptable if the donor biopsy shows less than stage 2 (no more than periportal fibrosis) (19). Currently, 16.9% of HCV-infected liver recipients receive organs from HCV- positive donors (20). Only half of such donors are viremic, which is lower than the rate of the general population, probably due to careful donor selection (18,21,22). There are few data on HCV-negative liver recipients receiving organs from HCV-viremic donors and, consequently, such transplantations were avoided in the past except in special circumstances. Renal transplantation The overall prevalence of HCV among US ESRD patients is 5 10% (23). Although kidney transplantation is associated with lower mortality than remaining on dialysis for HCV-infected individuals, outcomes for HCV- positive kidney recipients are generally worse than those observed in their HCV-negative counterparts (24 27). In addition, US studies suggest that patients with HCV infection who receive kidneys from HCV- positive donors fare worse than those transplanted with HCV-negative kidneys. However, these data sources lack important donor and recipient clinical information (11). A large observational study from Spain that captured these data demonstrated that there was no difference in 10-year outcomes between recipients with HCV who received kidneys from HCV positive versus those who received kidneys from HCVnegative donors (28). Further, by accepting an organ from an HCV- positive donor, kidney transplant candidates may significantly shorten their waiting time depending on the geographic region (29). Thoracic transplantation The prevalence of HCV in thoracic transplant recipients mirrors that of the general population (~2%) (30 32). A recent analysis of the Scientific Registry of Transplant Recipients (SRTR) reported only 289 HCV- positive lung recipients were transplanted between 1994 and 2011 (33). While early outcomes were poor, survival rates were not significantly different for HCV-infected and uninfected recipients after Despite this, a 2011 survey of lung transplant programs found that <20% would transplant HCV-viremic patients (34). This general avoidance of HCV-infected recipients is also seen in cardiac transplantation, perhaps due to pre-daa data demonstrating inferior outcomes (12). There are few data on the outcomes of HCV-negative recipients receiving thoracic organs from HCV- positive donors. Between 2004 and 2015, only 24 US heart recipients either had HCV or received an organ from an HCV- positive donor, so the patient numbers are insufficient to draw meaningful conclusions. Interestingly, not all such recipients became viremic (35,36). In nonhepatic transplantation, recipients with HCV have demonstrated worse outcomes when receiving from HCV- positive versus HCV-negative donors; in hepatic transplantation, outcomes have been similar. The use of HCV antibody status as opposed to viremia in designating donors as HCV- positive limits the applicability of these prior findings to the current DAA era. Limited data exist on transplantation of HCV- positive donors into negative recipients across all organ transplants. Wait time for an organ is potentially much shorter by accepting an organ from an HCV-infected donor. Projections on the Availability of HCV- Viremic Donors During the next 10 years, HCV-viremic donors are predicted to come from two broad categories: undiagnosed baby boomers (born ) with long-standing chronic HCV (37) and more recently infected younger persons who inject drugs (PWID) (38). While the baby boomers account for a majority of adults with chronic HCV, they are expected to yield fewer viremic organs that are viable for transplantation during the next decade for several reasons. First, this group has been a target for HCV screening and treatment, which will likely yield a larger pool of nonviremic antibody-positive donors. It is estimated that 50% of current viremic individuals have been treated, a rate that will increase in the next decade (39,40). Second, organ viability is expected to be lower among baby boomer donors. After years of chronic HCV infection, the majority will have significant liver fibrosis or comorbidities that will preclude organ donation (41). Finally, a significant proportion will age-out of donation viability within a decade. Since 2000, the rate of deaths from drug overdoses in the United States has increased 137%, including a 200% increase in the rate of opioid deaths. Drug overdose 2792 American Journal of Transplantation 2017; 17:

4 HCV Consensus Conference deaths increased significantly for both sexes, in persons aged years and 55 years, and in those living in the Northeastern, Midwestern, and Southern US regions (42). The prevalence of HCV infection among PWID varies with duration of drug use, needle-sharing practices, and prevalence within the drug-using networks (43). Among rural PWID in Kentucky, the opioid epidemic s unofficial epicenter, 50% were HCV antibody positive with only one-third aware of their diagnosis (44). Due to the growing incidence and high risk of HCV infection, these overdose victims are likely to be a main source of HCV-viremic donors in the next decade. Changes in the donor age distribution have already begun to manifest. Median viremic donor age dropped sharply from 47 in 2012 to 35 in 2016, likely reflecting the shift toward more HCV-infected donors coming from the younger PWID population and fewer from the baby boomers (Figure 2). Analysis of Centers for Disease Control and Prevention (CDC) multicause mortality data in the OPTN-sponsored Deceased Donor Potential Study (DDPS) (45) resulted in an estimated upper bound of potential donors in 2010, compared with 7943 actual donors, and a recent update performed in 2014 came to the same conclusion (UNOS/OPTN, unpublished). Among the estimated potential donors, 11% had drug intoxication as a cause of death and 6.3% were opioid overdose cases. Among actual donors with drug intoxication causing death, 22% were HCV seropositive, suggesting that as many as 860 HCV-seropositive potential donors from drug overdoses (515 from narcotics) may have been available that year. By comparison, organs were actually recovered from only 139 HCV-seropositive donors with drug intoxication deaths in 2014, highlighting that hundreds of additional donation opportunities may have existed. A comparison of serology and NAT results using OPTN data from suggests that one-third of this donation potential is likely to be nonviremic. While overdose deaths may decline, it is likely to take years before a demonstrable downward trend is seen. PWID are anticipated to be the main source of HCVviremic donors in next decade. National data suggest that currently there are ~ additional (unrealized) opportunities for donation among HCV-viremic PWID deaths and the trend line is increasing. Transmission and Treatment Concerns In addition to donors with known viremia, HCV transmission may occur from a donor with or without known HCV risk factors. OPTN policy has always required that all organ donors be screened by serologic tests for HCV. Survey data revealed that between 2008 and 2011, many organ procurement organizations (OPOs) began performing NAT on at least some donors (46,47). In December 2014, OPTN updated the policy requiring that all donors be screened with HCV NAT in addition to serology (48,49). As demonstrated in Figure 1, the eclipse period between viral exposure and positive NAT results is approximately 5 7 days, while the window period to positive serologic results is approximately days (50). Despite improvements in the testing policy, a risk of transmission remains due to the eclipse period. Donors with the highest risk of negative test results in the eclipse period are those infected via injection drug use (PWID): per 10,000 donors with enzyme-linked Figure 2: Median deceased donor age over time, by reported HCV serostatus (D. Stewart, 2017, unpublished, based on OPTN data). American Journal of Transplantation 2017; 17:

5 Levitsky et al immunosorbent assay and 32.4 with NAT (51). Recent CDC data reported that PWID with needle sharing carries about a 1% risk of HCV infection, detected by NAT at a mean of 6.5 days from exposure (52). Figure 3 displays suggested care pathways dependent on donor and recipient HCV status. It should also be mentioned that this eclipse period is relatively similar for HBV and HIV; thus, posttransplantation monitoring for these infections in such increased risk donors is mandatory, despite a rare risk of transmission (53). Patients on the waitlist should be vaccinated against HBV in case these donor organs are offered, and those receiving HBV core positive donors should undergo appropriate monitoring and prophylaxis strategies per center protocol and published guidelines (54). As mentioned, the definition of HCV positivity is important because of the misconception that HCV antibody positive/nat-negative donors could have transmissible HCV RNA (55,56). The prevailing opinion is that residual liver tissue HCV RNA represents degraded viral particles that are unable to replicate and spread disease. This is supported by the observation that there are no cases of documented transmission of HCV via organ transplantation from HCV antibody positive/nat-negative donors, and the safety has previously been shown (57 59). Thus, HCV antibody positive/nat-negative donors are not considered to be at increased risk of transmission absent other risk factors. As a result, based on OPTN policies, posttransplantation recipient testing is required only if the transplant center is concerned about the risk of disease transmission. For instance, a rare scenario could occur in which a donor is being treated with DAA therapy with undetectable virus at the time of donation but has HCV relapse that affects the recipient after transplantation (e.g. transmission). Thus, information on the donor such as this may be important, but ultimately it is up to the center whether and when to test posttransplantation rather than being universally mandated. If posttransplantation testing is performed, NAT is required as serology frequently fails to detect donor-transmitted HCV. In the setting of a non HCV-viremic donor and recipient (D /R ), HCV testing in the posttransplantation period should follow OPTN policy when the donor meets criteria as a Public Health Service (PHS) increased risk donor or when clinically indicated (60). This policy requires programs to develop written protocols for medical follow-up of recipients and their treatment. In the setting of a non HCV-viremic or -viremic donor and a viremic recipient (D /R + ), timing of DAA therapy in the posttransplantation period should follow the policy of the transplant center, according to recent American Association for the Study of Liver Diseases/Infectious Diseases Society of America and transplant guidelines (61,62). The use of HCV-viremic donors for HCV-viremic recipients (D + /R + ) is acceptable in routine clinical practice. Pertinent considerations regarding the donor and recipient virus are genotype and presence of resistance-associated Figure 3: Proposed management strategies based on donor and recipient HCV viremia American Journal of Transplantation 2017; 17:

6 HCV Consensus Conference substitutions (RAS). While genotype (G) 1 is the predominant strain of HCV in the United States, genotype prevalence patterns are likely to change over time with the prevailing genotypes circulating within PWID populations (63,64). In the setting of donor and recipient genotype strain mismatch, both viral strains may exist in the perioperative period. However, over the first few months posttransplantation, one strain will generally predominate (1b > 1a > 2 from limited data), although dual infection is possible depending on the sensitivity of the test performed (65, 66). At the present, it may be undesirable for a patient with chronic kidney disease (creatinine clearance <30 ml/ ml) to convert to G2 or G3, as DAA regimens are more limited in this situation (61,67,68). However, drug development is rapidly advancing, and it is anticipated that all genotypes will be able to be successfully treated in the different transplant populations. RAS refers to genetic viral variants that are less sensitive to DAA therapy than wild-type virus (69). Analysis of naturally occurring RAS in the NS3, NS5A, and NS5B genes in worldwide viral isolates is emerging. Identification of RAS profiles for non-g1/g3 are limited and correlation with data from patients being treated with DAAs is needed to determine the clinical relevance (70). Resistance testing may be important in DAA-na ıve populations before choosing certain regimens and in the setting of prior DAA failure, although the clinical relevance of baseline testing is unclear (61). Current and upcoming pangenotypic DAA regimens will reduce the underserved populations and provide salvage therapy to the sporadic patients who have failed treatment or have RAS (71 76). Planning DAA therapy additionally requires consideration of renal function, drug drug interactions, and organspecific protocols. Noteworthy drug drug interactions, such as protease inhibitors with calcineurin inhibitors, have been highlighted in clinical reviews and interactive databases (77,78) and can be managed with vigilant monitoring, necessary dose modifications, and, in some situations, selection of alternate concomitant medications (e.g. acid-reducing agents). Perioperative or early therapy at time of first positive NAT requires knowledge of genotype only if genotype-specific antiviral therapies are used as prophylaxis. The use of pan-genotypic regimens should obviate the need for HCV genotyping at the time of or after transplantation. If treatment is delayed beyond the early posttransplantation period, protocols that monitor for infection, new-onset diabetes mellitus, glomerulonephritis, and severe cholestatic hepatitis should be put in place (79,80). Severe cholestatic hepatitis is a feared complication occurring in up to 10% of liver and 1.5% of kidney recipients and is associated with high mortality (81, 82). Compassionate-use data for sofosbuvir and other DAA therapy in the setting of severe cholestatic hepatitis have reported high sustained virologic response rates (SVRs) and reversal of liver decompensation (2, 83 89). The highest risk for unexpected HCV transmission is the PWID who donates an organ within the eclipse period. The potential for genotype conversion and presence of RAS should be considered but not contraindicate the use of HCV-viremic donors. Payer Concerns The cost of caring for patients on transplant waitlists is extremely high. For example, the cost of hemodialysis for a patient on the deceased donor waitlist is approximately $250,000 per year and has been increasing 10% per year (Optum Health Analysis, Plosser, July 2015). For status 1A waitlisted heart transplant patients, the average billed charges for left ventricular assist device implants is $732,000, and postimplant charges can range from $30,000 to $580,000 annually (UnitedHealth Group Analysis ). Likewise, treating lung and liver patients awaiting transplant for life-threatening complications in hospitals and intensive care units can be costly. Based on these cost projections of caring for waitlisted patients, shortening waitlist times and lowering maintenance costs should offset the additional costs of DAA therapy. Thus, the potential return on investment for a payer to cover the $50,000 $100,000 cost of DAA therapy to allow the non HCV-viremic recipient to receive an HCV-viremic graft appears to justify the practice. However, there are no published high-quality clinical studies that prove the use of DAAs in this specific scenario leads to acceptable long-term graft and patient survival. Typically, evidence needs to be literature based from welldesigned clinical trials of adequate power with conclusive findings to support payer coverage of medications with indications for use not currently approved by the US Food and Drug Administration. The high cost of caring for waitlisted patients and the savings resulting from more rapid transplantation may financially justify provision of DAA therapy to allow transplantation of HCV-viremic organs into nonviremic recipients. There is a need for well-designed clinical trials of adequate power with conclusive findings to support broad payer coverage of DAA therapies. OPTN Policy The use of organs from HCV-viremic donors has the potential to increase the number of transplantations, American Journal of Transplantation 2017; 17:

7 Levitsky et al which is a strategic goal of the OPTN and UNOS. While OPTN policy mandates the screening of all donors and recipients for HCV using both serology and NAT, there is no OPTN policy restriction on the transplantation of organs from HCV-viremic donors into any recipient, whether HCV positive or negative. Transplant programs must identify and report to UNOS whether individual candidates are willing to accept viremic organs. The use of HCV-viremic organs into nonviremic recipients introduces the potential for outcome risks not accounted for within the SRTR program-specific reports. Donor and recipient HCV status are currently included in SRTR expected outcomes modeling, and the kidney donor profile and risk index include HCV serostatus as a component of risk. However, current SRTR outcomes models do not specifically address risk associated with transplantation of HCV-viremic organs into nonviremic recipients. Although it has been suggested that transplantations occurring in the context of research protocols be excluded from inclusion in SRTR program-specific reports, this approach has not been adopted by the OPTN and raises questions related to the criteria for appropriate research carve-outs and for the oversight of such a process. Finally, if the transplantation of HCVviremic donors into nonviremic recipients is to increase, it is essential that transplant centers develop close working relationships with OPOs to optimize practices and OPOs should consider contracting with transplant infectious disease professionals or other specialists familiar with the diagnosis and treatment of hepatitis C for realtime consultation. No OPTN policies or regulations exist that prevent the transplantation of HCV-viremic organs into non HCVviremic recipients. Risk models and allocation systems need to be updated in light of the difference between a traditional HCV-seropositive organ and an HCV-viremic organ with transmission potential. Ethical and Patient Perspectives of Clinical Trials of HCV-Viremic Donors The mismatch between organ supply and demand results in an ethical mandate to improve organ utilization. This includes broader consideration of HCV- positive organs, which are being currently discarded at relatively high rates (90). This lifesaving mandate means that in appropriate circumstances there is no prima facie contraindication to the intentional transmission of HCV through organ transplantation, provided that attention is paid to safety and informed consent. There are three identifiable settings for which the ethical and patient perspectives must be considered when using HCV-viremic donor organs in transplantation: (1) for a patient never infected with HCV ( HCV naive ), (2) for an HCV-negative patient with a prior HCV infection ( HCV resolved/ cured ), and (3) for an HCV-viremic recipient. HCV-viremic donor for HCV-naive recipient Transplanting organs from HCV-viremic donors into non viremic recipients may allow patients to receive a transplant much sooner and thus reduce death while on the waitlist. In support of this, at the recent 2017 American Transplant Congress, there were two small clinical trials presented (one recently published) demonstrating prevention of HCV transmission using perioperative/ postoperative DAA prophylaxis in nonviremic kidney transplant recipients of HCV-viremic donors (91,92). However, until this practice is clearly shown to be safe and efficacious in larger multiorgan studies, centers performing such transplantations should have institutional review board (IRB)-approved research protocols that have been vetted for safety and adequacy of the informed consent process. There was discussion as to whether such studies should require collaboration with a pharmaceutical company, insurance providers, or another mechanism to insure that HCV treatment can be provided immediately posttransplantation. Given the logistical and financial constraints of such protocols, the group thought that such guarantees should not be a prerequisite, but in studies where providers would depend on insurance approval of therapies after HCV transmission, the discretion would be left to a center s IRB as to whether the risk:benefit profile is acceptable. Patients enrolled in these studies must be counseled that insurance approval is not guaranteed and that HCV therapy may be delayed or denied. Approved protocols should mandate that patients are enrolled before organ offers to allow for a multistep informed consent process that involves the candidate s support system and education regarding HCV complications, treatments, and risks. Important potential risks include hepatic and extrahepatic complications of HCV, treatment failures, graft failure, and sexual transmission of HCV to a partner. Although the available data suggest these risks are minimal, they are still unknown in the setting of intentional HCV transmission. The informed consent process should be framed in the context of the potential benefits of reducing waiting time through earlier transplantation versus the risks of not enrolling, importantly death or health deterioration while on the waitlist. This latter point should be put into light for each patient s clinical status in terms of his or her risk of death. For example, cardiac failure requiring intensive unit management or liver failure with Model for End- Stage Liver Disease (MELD) score >35 portends a low chance of surviving even a few months, whereas survival on dialysis or in patients with a lower MELD score is generally longer; these data can be presented to patients during the informed consent process in 2796 American Journal of Transplantation 2017; 17:

8 HCV Consensus Conference considering the risk and benefit of accepting HCV-viremic organs. HCV-viremic donor for non HCV-viremic resolved patient The ethical principles just referenced would apply to previously treated or self-cleared patients with subtle differences. Patients should be counseled that their response to HCV therapy and the type of treatment may differ from their initial regimen, particularly if a different genotype is transmitted. There are other considerations to payers and the health care system, as total HCV treatment costs would now be increased. HCV-viremic donor for HCV-viremic recipient Ethical concerns in this setting are minimal, as this is already an accepted practice. Patients should be made aware of the impact of donor and recipient HCV genotype mismatch, including potential genotype switching, dual infection with two genotypes, or infection with one predominant genotype. However, pan-genotypic regimens currently or soon available may avert these concerns. It is important to consider the potential impact on response to HCV therapy in these situations, which may become less important as pangenotypic therapy options evolve. Otherwise, there should be no ethical barriers. The efficacy, safety, and tolerability of DAA therapy make transplantation of HCV-viremic donors into HCVnegative recipients feasible to study. The transplantation of organs from HCV-viremic donors into nonviremic recipients should only be conducted under IRB-approved protocols with multistep informed consent processes. Moving Trials Forward Organs from HCV-viremic donors should be used for non viremic recipients in the context of scientific IRBapproved protocols where treatment costs are included and outcomes are transparently and meticulously measured (Table 2). Additionally, the consensus conference members agreed to certain participant selection criteria in an effort to balance medical urgency for transplant with the desire not to bias future use of these organs because of adverse outcomes unrelated to HCV status. First, individuals likely to suffer clinical deterioration while waiting for an organ offer should be considered, as the risk of remaining on the waitlist may outweigh the risk of donor-derived HCV infection (90). Second, because this approach is still experimental, individuals who are at low to moderate risk of posttransplantation complications unrelated to HCV should be considered as a high rate of complications at this early stage might stifle future research initiatives. Organ selection Allografts should be of a quality that minimizes poor outcomes unrelated to HCV. Additionally, donor HCV genotype is usually not known at the time of organ allocation, and currently there is no FDA-approved pangenotypic DAA available for use in individuals with severe renal dysfunction, although these drugs are imminently expected to be available. Thus, it is important in trial design to determine if knowledge of donor genotype is needed before transplantation to determine study candidacy and/or antiviral therapy options, such as type, length of therapy, addition of ribavirin, etc. (93,94). This may depend on the clinical situation, type of organ transplanted, degree of renal dysfunction, and other issues. Pathways to obtain antiviral therapy Difficulty in obtaining approval for DAA may impede the expanded use of HCV-viremic organs. DAAs are normally approved for use in chronic HCV infection but may be restricted to patients with advanced hepatic fibrosis. In contrast, the transplantation of HCV-viremic organs into nonviremic recipients involves treatment for acute, donor-derived infection before the development of liver injury or infection-related comorbidities, raising concerns that coverage may be denied. Additionally, in some states, Medicaid programs have a much higher rate of denying applications for HCV treatment among chronically infected patients compared with other payers (95). While needing further study, the hope is that shorterduration DAA therapy may be possible in preventing transmission, particularly in nonhepatic transplants. This might also be possible in liver recipients with established infection as the majority of virions are removed with removal of the explanted liver (96). The group concluded Table 2: HCV-infected organ clinical trial outcomes Time period Pretransplantation Peritransplantation Posttransplantation Assessment/outcome New or worsening end-stage disease complications New or worsening comorbidities Hospitalizations Death Time to transplantation Donor Complications Graft survival Patient survival Allograft function HCV related (i.e. treatment response, adverse effects) Hepatic (i.e. inflammation, fibrosis, failure) Immunologic (i.e. donor-specific antibodies) Patient reported (i.e. quality of life) American Journal of Transplantation 2017; 17:

9 Levitsky et al that randomized controlled trials where some patients did not receive access to HCV-infected organs would likely generate significant controversy. Therefore, the most feasible approach would be to use observational comparator groups that are matched on characteristics related to the outcome of interest. For instance, when assessing the outcome of time to transplant in kidney transplantation, comparators would be match on the main drivers of waiting time, including blood group, region, sensitization and wait time (or dialysis time, whichever is earlier). Outcomes Outcomes that should be considered in trials involving HCV-viremic organs are time to transplantation and organ quality because the risks of donor-derived HCV infection may be offset by shorter time to transplantation or receiving better organs, deterioration on the waitlist including new or worsening end-stage disease complications, hospitalizations, and death. After transplantation, organ survival, patient survival, and allograft function are important outcomes to document. HCVrelated outcomes should include early response to therapy, SVR, and adverse liver outcomes of hepatic injury, fibrosis, cholestatic hepatitis, and hepatic failure, which should all be rare. There are some data suggesting that rejection and donor-specific antibody formation are increased in the setting of HCV therapy, and these issues require study (97, 98). Trials should also examine patient-reported outcomes to understand how participants perceive donor-derived HCV infection, as well as robustly evaluate the consent process. Finally, overall health care costs related to different approaches need close examination, as ultimately they need to be acceptable for the field to move forward. Clinical trials in the transplantation of HCV-viremic organs into nonviremic recipients pose logistical challenges and require thoughtful study design. Collaborative groups of academic transplant programs should be formed to investigate this topic and perform well-designed trials. Conclusions Deceased donor organs from HCV-viremic individuals represent an underused resource, and protocols to safely use them are needed. The key conclusions of the consensus conference are summarized in Table 3. The group first concluded that it is necessary to clarify the definition of hepatitis C positive organ. Because the risk of disease transmission from HCV antibody positive/natnegative donors is essentially negligible, the group thought that they should not be labeled hepatitis C positive or hepatitis C negative for the purposes of organ Table 3: American Society of Transplantation Consensus Conference hepatitis C conclusions The definition of HCV-positive donor needs to be refined to include NAT results in order to better communicate disease transmission risk. The term HCV-viremic donor should be adopted. The high cost of caring for waitlisted patients and the savings resulting from more rapid transplantation may financially justify provision of DAA to allow transplanting HCV-viremic organs into negative recipients. The transplantation of organs from HCV-viremic donors into HCV-negative recipients should be conducted only under monitored IRB-approved protocols and studies. Rigorous informed consent for all protocols and clinical studies is required. There is a need for well-designed clinical trials of adequate power with conclusive findings to justify payer coverage of DAA medications. There are no policies or regulations that exist to prevent transplantation of HCV-viremic organs into HCV-negative recipients. Risk models and allocation systems need to be updated in light of the difference between a traditional HCV-positive organ and an HCV-viremic organ with transmission potential. DAA, direct-acting antiviral agent; HCV, hepatitis C virus; NAT, nuceic acid testing; IRB, institutional review board. allocation rather, hepatitis C viremic or hepatitis C nonviremic. This definition change would require changes to OPTN/UNOS policies and procedures. The meeting participants thought that the availability of DAA therapy makes expansion of transplanting HCV-viremic organs into nonviremic recipients a possibility. This could result in saving a significant number of lives per year among organ failure patients. However, the group unanimously agreed that more research was needed before making this routine practice. This research should take the form of a prospective registry of patients transplanted with HCV-viremic organs and clinical trials. These clinical trials should a priori define which individuals are most likely to benefit from using these organs, such as those in donor service areas with longer waiting times. Moreover, it was thought that before transplantation, with rare exceptions made for emergency lifesaving transplantations, it was necessary to ensure that the recipient would be guaranteed access to DAA therapy. Due to the increased complexity of decision-making involved as well as with PHS increased risk organs in general, the group thought that OPOs should consider contracting with transplant physicians knowledgeable about DAAs to provide real-time consultation regarding the appropriateness of allocating these organs, for both the OPO and transplant center considerations. It was believed that the cost of this service would likely be offset by an increase in the numbers of organs placed. Finally, the group identified unmet needs. There is a knowledge gap in the general medical community about 2798 American Journal of Transplantation 2017; 17:

10 HCV Consensus Conference which individuals with HCV should be treated before or after transplantation. Similarly, it was thought that increased use of HCV-infected donors requires collaboration with the OPO community, including discussions regarding the willingness of transplant centers to use these organs and common practices for their recovery. There is an urgent need for funding to support welldesigned, IRB-approved research trials to prove the safety of using these organs in uninfected recipients, determine the optimal timing of DAA treatment, and improve the logistics associated with the recovery and allocation. Acknowledgments The authors would like to thank Dr. Melissa Greenwald, director of the Division of Transplantation, Health Resources and Services Administration, for her insight and guidance and Ms. JoAnn Gwynn for her tireless work and dedication to the American Society of Transplantation. Disclosures R.B.: consultant, Abbvie, Advisor, Merck. M.C.: consultant, Gilead Sciences, Bristol-Myers Squibb, and AbbVie; grant support from Gilead Sciences, Mallinkrodt, and Conatus. S.H.: speakers bureau, Novartis, CareDx; consultant: St Jude, Abiomed. R.F.: consultant, Genentech. G.K.: principal investigator for a Novartis Sponsored Research Liver Study. J.L.: advisor and stockholder for Transplant Genomics Incorporated; speaker: Gilead, Salix, Novartis; research grants from Novartis, Abbvie; councilor-at-large for the American Society of Transplantation; councilor for the International Liver Transplantation Society. J.K.: grant support and consultant, Novartis; grant support and speakers bureau, Caredx, Inc.; grant support, advisory board, speakers bureau, Caredx; grant support, Alexion. A.M.L.: financial-advisory board, Gilead; past advisory board, Janssen; primary investigator, Merck Trials; external advisor on project sponsored by Merck grant; Service-Donate Life Connecticut, American Liver Foundation (no payment for these). P.R.: research support to University of Pennsylvania from Merck to support research on transplantation using HCV organs; participation in Merck-organized meetings (including meals) related to transplantation using HCV organs; research support to University of Pennsylvania from CVS Caremark to support research on medication adherence; research support to University of Pennsylvania from Astra-Zeneca/Bristol-Myers Squibb to support research related to renal outcomes for Saxagliptin users; consulting with COHRDATA on epidemiology of medications to control dialysis and phosphorus among dialysis patients; associate editor for the American Journal of Kidney Diseases. N.T.: Gilead, grant support/consultant; Bristol-Myers Squibb, grant support; Biotest, grant support/consultant; Abbvie, grant support; Merck, grant support/consultant; UpToDate, royalty; CCO Hepatitis Educational Material Development; Practice Point Communications Continuing Medical Education; Focus Medical Communications Continuing Medical Education; Annenberg Center for Health Sciences Continuing Medical Education; PRIME Continuing Medical Education; Mylan Pharmaceuticals, consultant. N.T.: research grant funding from Mendez National Institute of Transplantation Foundation (nonprofit), member of OPTN, DTAC committee, member of AST ID COP executive committee. J.T.: Gilead speakers bureau. E.V.: grant support from Salix. M.V.: clinical consultations from Best Doctors. The other remaining authors report no conflicts of interest to disclose as described by the American Journal of Transplantation. References 1. Belli LS, Berenguer M, Cortesi PA, et al. 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