Direct-acting antiviral (DAA) regimens have revolutionized our approach to hepatitis C virus (HCV) management. Guidance from American Association for the Study of Liver Diseases/Infectious Diseases Society of America, European Association for the Study of the Liver, and Asian Pacific Association for the Study of the Liver1-3 now outline simple and highly effective pathways to cure for nearly all patients with HCV. Safety and efficacy of DAA regimens, even among those with decompensated cirrhosis, creates new opportunities for cure in patients who would have been previously ineligible for treatment.4 Although HCV remains a leading indication for liver transplant worldwide, there has been a paucity of data and subsequent guidance for management of liver transplant candidates with HCV. Paradoxically, we have found that simple, effective treatment regimens have spawned perhaps unanticipated complexities of HCV management in liver transplant candidates. These complexities arise because goals of therapy span beyond solely targeting viral eradication but require a comprehensive understanding of the dynamic and sometimes unpredictable nature of liver transplantation (LT) candidacy. Anticipated wait time, risk of hepatocellular carcinoma (HCC) recurrence or progression, physiologic response to cure as well as availability of HCV-positive donors all impact decisions to treat. In this issue of Transplantation, Terrault et al5 define these issues and offer much needed guidance by addressing clinical questions of interest in the International Liver Transplant Society Consensus Statement in Management of Liver Transplantation Candidates.
Data remains sparse and, at times, conflicting regarding the management of HCV in patients with HCC who are awaiting LT. In the single published study evaluating DAA-based treatment outcomes in waitlisted patients with HCV and HCC, duration of time with a negative viral load was found to be a significant predictor of HCV recurrence posttransplant.6 This concept has not yet been validated in newer DAA regimens and minimum duration of an undetectable viral load required before transplant to ensure posttreatment eradication has yet to be defined. Timing matters in HCV treatment pre-LT; however, we are still unsure of how much time we need and how much time we have. In addition, recent controversy regarding a potentially negative impact DAA treatment may play in aggressive cancer recurrence has added another wrinkle in complexity of the decision to treat waitlisted patients with HCC.7,8 Terrault et al5 describe the quality of data that associates a link between HCC recurrence and DAA therapy as low and insufficient to withhold therapy; however, pending further data, they recommend the association should at least be considered. Although the consensus statement recommends HCV treatment in waitlisted patients with HCC, severe limitations of data require this recommendation to be conditional and should be individualized based on patient characteristics and transplant center.
HCV treatment in the setting of waitlisted patients with decompensated cirrhosis is also thoughtfully addressed. Successful HCV treatment may improve survival on the waiting list and may allow for avoidance of OLT altogether.9 These benefits must be balanced with potential unintended negative consequences of treatment. This includes reduced SVR rates in CTP B and C cirrhosis with risk of resistant variant generation as well as negligible clinical benefit achieved after SVR in patients who lack hepatic regenerative capacity. Finally, it may be disadvantageous to treat and create a small improvement in Model for End Stage Liver Disease (MELD)/Child-Turcotte-Pugh (CTP) resulting in a demotion of priority on the waitlist, yet insufficient clinical improvement to avoid LT.4 What remains elusive is a true understanding of the “point of no return,” that is, the degree of liver dysfunction where HCV therapy does not yield any clinical benefit. The consensus statement frames this question based on available metrics, such as MELD, CTP, and transplant center characteristics; however, due to limitations in available data, the strength of these recommendations remain weak. Why is a point of no return so difficult to define? First, HCV treatment in patients with decompensated cirrhosis is only a recently available option, and experience remains limited. Second, the point of no return is simple in theory, but complex in practice. MELD and CTP scores were not designed to answer this question, and we may be using imprecise tools to predict a clinical outcome that relies on regenerative capacity of the liver after viral eradication. Finally, the point of no return is intrinsically related to regional transplant landscape and policy. Waitlist time, DAA availability and allocation schemes will all impact how much benefit HCV treatment will yield. The consensus statement has provided a useful foundation for consideration of this topic, but further study will be necessary to identify more precise, site-specific tools to guide us in this difficult decision to treat.
Finally, the consensus statement supports selective use of anti–HCV-positive grafts in HCV-positive recipients as well as early treatment for all LT patients with HCV.5,10 The efficacy and safety of DAA therapy post-LT has also allowed Terrault and colleagues to boldly offer consideration to use HCV-positive grafts in HCV negative recipients. The Consensus Statement stresses the need for comprehensive informed consent and defines appropriate settings for use such as high medical urgency and severe limitations in organ availability. Although data are limited and firm guidelines for use cannot yet be made, innovative thought leveraging DAA therapy such as this may significantly increase access and optimize use of available organs. However, the concept of knowingly transmitting an infectious disease into an unexposed patient is subject to some degree of moral relativism and thus may not be universally applied even though there is some precedent with infections, such as cytomegalovirus. Nonetheless, routine use of HCV-positive grafts in any recipient underscores the importance of universal access to HCV therapy post-LT.
The new era of DAA therapy has expanded candidacy for HCV treatment to include our sickest patients who are in need of LT. The consensus statement in this issue of Transplantation marks unprecedented progress in HCV therapy and also defines where our understanding is limited. Our tools to determine the optimal timing for therapy seem rudimentary in comparison to the technologically advanced DAAs, and further study to equilibrate the two is crucial. We know how to treat our patients with HCV who are awaiting transplantation, now we just need to know when to treat them.
1. AASLD-IDSA. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. http://www.hcvguidelines.org/
. Accessed February 13, 2017.
2. European Association for Study of Liver. EASL Recommendations on Treatment of Hepatitis C 2015. J Hepatol
3. Omata M, Kanda T, Wei L, et al. APASL consensus statements and recommendation on treatment of hepatitis C. Hepatol Int
4. Curry MP, O’Leary JG, Bzowej N, et al. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med
5. Terrault NA, McCaughan GW, Curry MP, et al. International Liver Transplantation Society Consensus Statement on hepatitis C management in liver transplant candidates. Transplantation
6. Curry MP, Forns X, Chung RT, et al. Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: an open-label study. Gastroenterology
7. Pol S. Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: data from three ANRS cohorts. J Hepatol
8. Reig M, Mariño Z, Perelló C, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol
9. Belli LS, Berenguer M, Cortesi PA, et al. Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: a European study. J Hepatol
10. Northup PG, Argo CK, Nguyen DT, et al. Liver allografts from hepatitis C positive donors can offer good outcomes in hepatitis C positive recipients: a US National Transplant Registry analysis. Transpl Int