Retransplantation for HCV—The view through a broken crystal ball

Authors

  • Michael Charlton

    Corresponding author
    1. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
    • Mayo Clinic CH-10, Division of Gastroenterology and Hepatology, 200 First Street SW, Rochester, MN 55902-3129
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    • Telephone: 507-266-7054; FAX: 507-266-1856


  • See Article on Page 434

Liver transplantation is among the very few areas of medicine where the provision of a potentially life-saving treatment is routinely withheld or rationed. In almost every other corner of American healthcare, physicians are limited only by the subjective equations of risk vs. benefit, likelihood of litigation and the presence of insurance coverage. As a profession we can, and do, spend health care dollars like sailors on shore leave. Cost and utility are the Voldemorts of our health care delivery system. We dare not speak their name. Except, that is, unless we are talking about solid organ transplantation. In our field, utility is king, crowned by an ever-present organ shortage. If outcomes for a particular indication are poorer than average, we may stop offering liver transplantation in that setting. This has occurred in recent memory for liver failure secondary to hepatitis B. We even withhold liver transplantation if we perceive that there may be an element of choice in potential recurrence of liver disease that might adversely affect outcomes. We regularly deny access to liver transplantation to patients with less than 6 months of documented sobriety, even though allograft failure due to alcoholic injury is a rarity, for example. In contrast, in the case of liver transplantation for hepatitis C virus (HCV), in which recurrence is inevitable and may lead to allograft failure, transplantation is routinely offered. So long as outcomes, and thus utility, are acceptable, we find room on the list. (Although, based on the large number of patients who undergo liver transplantation with model for end-stage liver disease scores <15, the tipping point at which the risk of dying from the procedure of liver transplantation begins to be less than the risk of dying without liver transplantation,1 a survival advantage is not a universal prerequisite for liver transplantation.) In this milieu, the assertion that liver transplantation for a particular indication is associated with relatively poor outcomes is bound to raise eyebrows and may even send third-party payers reaching for their purse strings. If the assertion is true, we should consider whether it is wise to continue to perform liver transplantation in this setting. If the assertion is false, we need to say so and to state the reasons for our disbelief. Which brings us to the article by Pelletier et al. in this issue of Liver Transplantation.2 Pelletier et al. report the results of a retrospective analysis of a cohort of liver transplant recipients who underwent retransplantation between January 1997 and December 2002, identified in the Scientific Registry of Transplant Recipients (United Network for Organ Sharing [UNOS]) database. The authors used Cox regression analysis to assess the relative effect of HCV on mortality risk after retransplantation. The scale of the study is certainly impressive with 27% (n = 464) of 1,718 liver retransplantations during the study period, “being associated with a diagnosis of HCV infection.” The principal finding was that HCV infection has a “31% higher covariate-adjusted mortality risk” when compared to recipients without HCV infection (hazard ratio, 1.31; 95% confidence interval, 1.11–1.55; P = 0.002). Additional regression analysis revealed that the increase in mortality risk associated with HCV was concentrated between 3 and 24 months post-retransplantation. Younger age predicted a higher mortality for recipients with HCV undergoing retransplantation.

Abbreviations

HCV, hepatitis C virus; UNOS, United Network for Organ Sharing.

At face value, given the poor outcomes associated with retransplantation and Pelletier et al.'s finding of a >30% additional risk associated with HCV infection, we should consider closing the HCV retransplantation shop. Indeed, some centers already do not offer retransplantation for recipients with allograft failure secondary to recurrence of HCV infection. Upon close inspection, however, there may be less to the report by Pelletier et al. than meets the eye. Indications for retransplantation are diverse. Recipients with hepatic artery thrombosis and recipients with hepatitis B virus infection or autoimmune liver disease recurrence, conditions for which we generally have good therapies, are indications for retransplantation that are likely to be quite different physiologically to patients with long-term ischemic type biliary strictures or recurrence of HCV. A recent UNOS database analysis of retransplantation found that patients undergoing retransplantation for recurrence of HCV do significantly less well, in terms of patient and graft survival, than patients undergoing retransplantation whose primary liver disease was hepatitis B virus or autoimmune.3 There was, however, no significant survival difference between retransplant recipients with HCV and any other group. Similarly, a European analysis of retransplantation outcomes (n = 139, including 38 patients with HCV infection) did not find HCV status to be predictive of post-retransplant outcomes.4 Unfortunately, the study by Pelletier et al. does not provide outcome comparisons between retransplant recipients with HCV and specific other liver diseases. But inherent differences between cohorts of recipients undergoing retransplantation may be of relatively less importance than degree of sickness at the time of transplantation. The degree of sickness, as measured by model for end-stage liver disease score, at the time of retransplantation is predictive of patient and graft survival (concordance = 0.78–0.80).3, 5 In another UNOS database analysis of retransplantation by Rosen et al.,6 UNOS status, creatinine, and bilirubin were found to be predictive of post-retransplant survival. The study by Rosen et al.6 is widely perceived as also finding that HCV serostatus is predictive of post-retransplantation survival. What the authors of this study actually found was “although both hepatitis C seropositivity and donor age were significant by univariate and multivariate analyses, neither contributed independently to the estimation of prognosis when added to the final model.” In other words, HCV serostatus could not add to the predictivity of degree of sickness (creatinine, bilirubin, and UNOS status). The central difficulty in interpreting the article by Pelletier et al. is thus not that the conclusions are wrong, but rather that the question is. The question we need to ask is not, “How well do patients undergoing retransplantation for recurrence of HCV do when compared to patients without HCV infection?”, but, “How well do patients with HCV do compared to recipients with other etiologies of disease but who are otherwise similar?” Would an HCV-infected patient with a model for end-stage liver disease score of 34 undergoing retransplantation be likely to do better or worse than someone undergoing retransplantation for ductopenic rejection or recurrence of primary sclerosing cholangitis who also has a model for end-stage liver disease score of 34? So far as we can tell, the answer to that question appears to be a resounding “probably not.” The conventional wisdom is increasingly that retransplantation for recurrence of HCV is of relatively poor utility. When it comes to liver transplantation, however, the journey from conventional wisdom to fallacy can be a short one. The concepts that outcomes are less good in recent years for recipients with HCV infection (probably debunked by 2 multicenter, multinational database studies and a large single center analysis7–9) and an association of mycophenolate mofetil and more severe recurrence of HCV (convincingly refuted by analyses of the UNOS database and a clutch of randomized controlled trials10, 11) are 2 recent examples. Conclusions are always database dependent. When it comes to simple questions, the UNOS dataset is hard to beat. For complex questions concerning the impact of variables on posttransplant outcomes (primary or retransplant) the UNOS dataset is less reliable—too much data are simply missing. For this reason, the results from the study by Pelletier et al. are akin to looking into a crystal ball that has been dropped onto a hard floor. We see something, but the image may be too distorted by our viewing device for the image to be given meaning. We shouldn't plan our future based on what we see.

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