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  • HCV Recurrence

    Dr. Caroline Rochon

    Caroline Rochon, MD, FACS
    Transplant and Hepatobiliary Surgeon
    Hartford Hospital
    Hartford, Connecticut

    Because the treatment of HCV recurrence after liver transplantation, a major cause of graft loss, has shown such disappointing results over the years, transplant programs have tried to attack the recurrence problem with prevention strategies first and desperate therapeutic attempts second. Transplant surgeons anticipate HCV recurrence even before the surgery begins. Several donor factors have been identified with higher potential for HCV recurrence post transplantation and most transplant centers will not accept the same organs for HCV positive recipients that they would for recipients with other indications for transplant.

    Many studies have identified multiple donor factors as being associated with higher/earlier HCV recurrence, the most important being increased donor age and higher percentage of steatosis in the graft. The decision to avoid transplanting HCV recipients with older/fatter grafts varies from center to center. How old is too old and how fat is too fat is a matter of preference, but the practice remains universal: prevent recurrence by judicious graft selection. As a consequence, HCV positive candidates can have a longer wait for transplant or a lower transplant rate than candidates without the disease. Other strategies employed in the post-transplant setting involve avoidance of over immunosuppression or episodes of acute rejection (easier said than done).

    In theory, HCV positive liver transplant recipients can be treated with a pre-emptive approach immediately following transplantation or with a recurrence-based approach when liver damage is diagnosed. The advantages of pre-emptive or early post-transplant treatment are that serum HCV-RNA levels are characteristically low and significant histological graft damage is virtually absent. Although these factors predict a favorable response, this therapeutic approach had traditionally been difficult to manage because of poor tolerability and reduced efficacy of the pegylated interferon/ribavirin combination. Thus, the preferred strategy is usually to delay antiviral treatment until histological evidence of recurrent post-transplant HCV-related chronic hepatitis is established. This evidence is sometimes found on biopsies ordered to investigate clinical abnormalities or on protocol biopsies often done at 1 year post transplantation. The algorithms for care vary greatly between institutions but most centers will treat patients with clinical and histological signs of recurrence and at least Grade 3 or 4 inflammation or stage II fibrosis in the liver graft tissue. In this setting, treatment with a combination of Pegylated Interferon plus ribavirin is associated with an overall sustained virological response (SVR) of about 30% (1).

    The recent introduction of direct-acting antivirals, including drugs that inhibit protease, polymerase and other non-structural proteins, heralds a new era in HCV treatment. In the post-transplant phase, triple therapy, with either telaprevir or boceprevir faces multiple challenges. (2) Post-transplant HCV recipients are often “difficult to treat” patients, either because they were prior non responders or they had a high blood HCV RNA. Still, improved outcomes are expected with the new drugs. Triple therapy with these agents is now being investigated. While the data are still very preliminary, reports show that 70 to 90% of patients are virus free at 12 weeks. (3) Infectious and hematologic complications are frequent and drug levels need to be monitored very carefully due to drug-drug interactions between calcineurin inhibitors and protease inhibitors.

     Therefore, from my perspective, the increased risk of HCV recurrence post-transplant with older, more steatotic donor grafts is offset by the better ability we now have to treat recurrent disease, even if recurrence is still considered an off label indication.

    We also have to wonder, in the era of these new drugs, whether it is wise to wait a full year before protocol biopsies and whether it is worth waiting for stage 2 fibrosis on biopsy to treat. Outcomes may be improved with earlier treatment of HCV recurrence; one might even talk of “recurrence prevention.” As we develop expertise with interferon-free direct acting antiviral therapy, like with sofosbuvir for example, lowering the feared risk of rejection while on treatment, we should all discuss how ethical it is to let the virus damage any graft at all and whether all HCV recipients should be treated preemptively post transplantation. (4) Such approaches seem particularly appropriate if the team decided to forfeit the traditional prevention strategies likes avoidance of older donor grafts. In short, the fight against HCV may be won by breaking the barriers to transplantation, being more liberal with graft acceptance and treating preemptively all grafts before the virus begins to damage the new liver…from my perspective.

    References

    1. Roche B, Samuel D. Hepatitis C virus treatment pre- and post-liver transplantation. Liver Int 2012; 32( suppl 1): 120-128.
    2. Werner CR1, Egetemeyr DP, Lauer UM, Nadalin S, Königsrainer A, Malek NP, Berg CP Telaprevir-based triple therapy in liver transplant patients with hepatitis C virus: a 12-week pilot study providing safety and efficacy data. Liver Transpl. 2012 Dec;18(12):1464-70.
    3. Punpapong S, Murphy JL, Henry TM, Ryland K, Satyanaravana R, Rosser B, Yataco ML, Keaveny A. Preliminary experience using Telaprevir with Peginterferon and Ribavirin for treatment of HCV genotype 1 after liver transplantation. Liver Transpl. 2013 2013 Jul;19(7):690-700.
    4. Charlton M, Gane E, Manns MP, Brown RS Jr, Curry MP, Kwo PY, Fontana RJ, Gilroy R, Teperman L, Muir AJ, McHutchison JG, Symonds WT, Brainard D, Kirby B, Dvory-Sobol H, Denning J, Arterburn S Samuel D, Forns X, Terrault NA. Sofosbuvir and Ribavirin for Treatment of Compensated Recurrent Hepatitis C Virus Infection After Liver Transplantation. Gastroenterology. 2014 Oct 7. [Epub ahead of print]

    Have a different perspective? The ASTS Communications Committee would love to hear it and share it with your fellow members in an upcoming issue of the Chimera. Comment below or send your thoughts to asts@asts.org!
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  • Living Donor Liver Transplantation in the United States: why isn’t it growing?

    Dr. Julie Heimbach

    Julie Heimbach, MD
    Mayo Clinic
    Rochester, Minnesota

    There were 252 cases of living donor liver transplantation (LDLT) performed in the United States in 2013, comprising just 4% of the total liver transplant volume for this year and very similar to the number performed over the past several years.1  By contrast, there were more than 300 LDLTs performed at just one center in Seoul, South Korea, in 2013. There are several centers across Asia which are performing similarly high annual volumes.2,3  Given the critical shortage of available deceased donor liver allografts as well as the increasing waitlist mortality, understanding the reason for the low utilization of LDLT in the United States is an important step toward trying to provide increased access to transplant for patients suffering from the potentially lethal complications of end-stage liver disease.

    Examining why this practice is highly successful in in Asia, while far less prevalent in the United States, may best be done by elucidating differences between these regions and then determining whether these differences are likely to influence the growth of LDLT.  The first and most obvious difference is the availability of deceased donor transplant. While this option is extremely limited in many Asian countries, in the United States the incredible altruism of donor families and individuals who joined donor registries prior to their death, as well as an efficient allocation system, has provided access to LT for more than 130,000 people since 1988 and to nearly 50 percent of the active waitlist in 2013.1 For a variety of reasons, deceased donor organ transplantation has not been nearly as successful in many Asian countries, though important strides forward are being made.2,3  In the United States, the possibility of deceased donor transplant influences both patient and, perhaps more importantly, provider preference.  It may be more difficult for patients to accept the remarkable gift of living donor transplant knowing it comes with the need for their loved one to recover from a major surgery and to incur the risk of serious complications when there is the hope (no matter how unrealistic) of a potential alternative.

    This hope is similar to the core American value that anyone can rise to the top if they just persevere.  Even though there are multiple possibilities for patients waiting for LT—patients can stay the same with ongoing complications such as ascites, encephalopathy, bleeding, and/or recurrent infections, or they can get sicker. If they get sicker, they may get a high enough score to be transplanted, they may get too sick to undergo transplantation, or they may die.  While a patient’s history, etiology of liver disease, and MELD score can sometimes be helpful in predicting these outcomes, there is certainly no crystal ball. Patients know if they chose to undergo LDLT, their donor will undergo a major surgical procedure and will feel unwell for a period of time, and they know that there is a possibility of serious complications. If the patient is willing to just keep waiting and is tough enough, the loved one could be spared this suffering. Hepatologists and surgeons also hold on to this hope for a deceased donor transplant, as we would always prefer to have one patient at risk instead of two. Even though we know the data, we are very good at remembering that one time when our lower MELD patient had an opportunity to get a transplant with an increased risk donor or last minute re-allocation. If there is no access to deceased donor transplantation, then the choice is between continued suffering (and ultimately death) or living donor transplant. This burden of perceived choice can be a heavy one, not only for the donor and recipient but also for the physicians.

    A second difference in the United States is that the relatively small number of LDLTs are spread over a relatively large number of centers. Both the living donor hepatectomy and the transplant are technically demanding procedures, with a well-documented learning curve.4  Beyond the learning curve, however, is the level of assurance for surgeons that comes from doing something over and over and over again. Not only does this impact surgeons, but it also may be easier for hepatologists to recommend and easier for patients to accept when it is perceived as the standard or at least a very common option, rather than the exception. The Asian countries which have adopted this practice so successfully have several large centers with a concentrated experience, built upon a long tradition of very complex and technically demanding hepatobiliary surgery.

    Another barrier to a more widespread adoption of LDLT in the United States is the impact to the donor, which is not only physical and emotional, but also financial. Unlike many other countries, the United States lacks national health care; therefore, if a patient’s ability to remain employed is threatened by the donation process, not only is their livelihood at risk, but also, even more importantly, their health coverage, plus potentially the health coverage for their family.  Concerns about pre-existing conditions and lack of future insurability may have been reduced with the adoption of the Affordable Care Act, though given the complexity of the new system and reports of health care coverage being denied post donation, there is continued uncertainty.5  In addition, the impact of lost wages combined with out of pocket expenses, especially given the long distances many donors need to travel to get to transplant centers, can be quite substantial. The potential impact to the donors’ physical and emotional health is significant and likely quite similar whether donation occurs in the United States or in Asia, although it may be reduced by careful evaluation and robust support systems.

    What is the path forward? Highlighting current waitlist outcomes for LT candidates combined with continued cumulative experience with LDLT gradually being gained by centers across the United States, as well as continued careful reporting of donor and recipient outcomes, will hopefully foster the growth of LDLT in the United States. Advances like laparoscopic assisted mobilization and laparoscopic hepatectomy may also be of benefit in more widespread acceptance. Eliminating the financial disincentives to donation should also be of paramount importance. Reimbursement of living donor expenses, as is currently provided under the National Living Donor Assistance Center, should be expanded to include all donors who request such assistance. Options for ensuring access to health care coverage for all living donors should also be explored, whether this is through individual state exchanges or through other national programs. Finally, during National Donate Life Month, we should designate a special recognition event for living organ donors which would serve the dual purpose of highlighting the heroism of living donors as well as raising awareness for this option…from my perspective.

    References

    1. http://optn.transplant.hrsa.gov/converge/latestData/advancedData.asp
    2. Chen CL, Cheng YF, Yu CY, Ou HY, Tsang LL, et al. Living donor liver transplantation: the Asian perspective. Transplantation. 2014;97 Suppl 8:S3.
    3. Chen CL, Kabiling CS, Concejero AM. Why does living donor liver transplantation flourish in Asia? Nat Rev Gastroenterol Hepatol. 2013;10:746-51.
    4. Olthoff KM, Abecassis MM, Emond JC, Kam I, Merion RM, et al.  Outcomes of adult living donor liver transplantation: comparison of the Adult-to-adult Living Donor Liver Transplantation Cohort Study and the national experience. Liver Transpl. 2011;17(7):789-97.
    5. Rabin RC. The Reward for Donating a Kidney: No Insurance. New York Times June 11, 2012.
    6. Suh SW, Lee KW, Lee JM, Choi Y, Yi NJ, Suh KS.  Clinical outcomes of and patient satisfaction with different incision methods for donor hepatectomy in living donor liver transplantation. Liver Transpl. 2014. [Epub ahead of print]
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  • Accounting for Transplantation in an Accountable Care Organization (ACO)

    Dr. Sander Florman

    Sander S. Florman, MD
    The Charles Miller, MD Professor of Surgery
    Director, Recanati/Miller Transplantation Institute
    Mount Sinai Medical Center

    Accountable Care Organizations (ACOs) are programs designed by the Center for Medicare and Medicaid Innovation (CMMI) under the Affordable Care Act (ACA) to decrease health care costs while improving the quality of care.

    An ACO is composed of a group of providers (e.g., physicians and/or hospitals) that are contracted with Medicare to participate in the Medicare Shared Savings Program. If they can successfully reduce the costs of care for the group of patients they treat while maintaining pre-specified quality targets, they are then eligible to split the savings with Medicare. 

    Patients do not enroll in an ACO; rather, the ACO is held accountable for the patients attributed to them based on which patients they treat. There can be no marketing to patients or cherry picking—patients are assigned to an ACO by Medicare based upon their using one of the ACO physicians for the plurality of their primary health care needs (or using a specialist physician who is a member of the ACO for their health care needs if no primary care physician is identified). While patients cannot opt out of having their costs counted toward an ACO, they can decline to share their claims data with the ACO.

    Once assigned, Centers for Medicare and Medicaid Services (CMS) divides an ACO’s patient list into four cost categories, understanding that these characteristics partially predict utilization and cost: dual eligible (e.g., Medicare and Medicaid) patients, disabled patients, aged non-dual eligible (e.g., average worker who ages into Medicare eligibility after 65 years of age), and End-Stage Renal Disease (ESRD) patients. Each category has a calculated average cost of care based upon a 3-year average cost for similar patients. This is the basis for determining whether spending has been reduced and savings have occurred during the ACO performance year.

    Patients whose cost of care is very high (i.e., > 99th percentile in their assigned category) have their costs truncated at the 99th percentile for their specific patient group. This is intended to protect the ACO from failure due to outlier costs beyond their control. Not surprisingly, the costs for ESRD patients in an ACO will have a higher average annual spend rate as well as a higher truncation point than that for the other groups. 

    There are many benefits to ESRD patients inherent in the robust care coordination provided through an ACO.  In addition to this essential care coordination, the benefits of transplantation are well established, yet there are complex implications for an ACO when their ESRD patients undergo successful transplants.  

    The costs of a transplant raise the expenditures for the ACO. Three months after transplant, however, these patients are reassigned by CMS from the higher-cost ESRD category into one of the three other patient pools with less costly peers. Post-transplant, these ESRD patients are much less expensive to manage due to not needing dialysis. These lower costs are not compared to what the patient would have incurred if not transplanted, but rather to expected costs if they’d never had ESRD at all. This means that the ACO sees less of the long-term cost savings of transplantation.

    With accountability for costs and quality being driven into the health care system by programs such as ACOs, thoughtful consideration needs to be given to ESRD patient populations—especially in medical centers performing transplants—so that encouraging transplantation is central to care and payment models… from my perspective.

     

    Have a different perspective? The ASTS Communications Committee would love to hear it and share it with your fellow members in an upcoming issue of the Chimera. Comment below or send your thoughts to asts@asts.org!
    Go comment!