ITLS 2014: Liver transplantation – aspiring to excellence: Current challenges and cutting edge developments

Report from the Joint International Congress of ILTS, ELITA and LICAGE 2014.   Recurrence of hepatitis C virus (HCV) infection after transplantation is a major challenge for centres all over the world and continues to take a heavy toll in terms of long-term survival. Registry data from all over the world shows consistently that only malignancies are associated with poorer survival outcomes than HCV as primary indication for liver transplantation. However, Professor Ed Gane from Auckland, New Zealand is holding out hope for the future: in recent years there has been something of a revolution in the treatment of chronic HCV infection with a clear paradigm shift away from treatment with interferons, and early reports seem to suggest that this success can be applied to transplantation as well. Several direct-acting antivirals (DAAs) that are currently in development for the treatment of chronic HCV have been tested in the pre-and post-transplant setting with encouraging results. Open-label studies presented at last year’s International Liver Congress showed that combination therapy with sofosbuvir and ribavirin  was effective and well tolerated for the treatment of compensated [1] and decompensated [2] recurrent HCV infection after liver transplantation. Combination protocols of two or more DAAs have been shown to shorten the duration of HCV infection and increase antiviral efficacy compared with monotherapy. In non-transplant HCV patients, ledipasvir and sofosbuvir combination therapy resulted in high rates of sustained virologic response both in treatment-naïve patients and those who had failed to respond to interferon-based treatment [3-5]; studies are currently in progress in Europe and the United States to document ledipasvir and sofosbuvir in patients undergoing liver transplantation. Other DAA protocols that have demonstrated favourable efficacy and tolerability in transplantation include a combination regimen with protease inhibitor ABT-450 with ritonavir and NS5A inhibitor ombitasvir plus non-nucleoside polymerase inhibitor dasabuvir and ribavirin for post-transplant HCV infection [6], and combined sofosbuvir and ribavirin administered pre-transplant to prevent HCV recurrence [7]. Pre-transplant prophylaxis is a particularly appealing prospect since this could potentially reduce the need for post-transplant monitoring and intervention and improve the cost-effectiveness of liver transplantation for HCV in the longer term.

 

Another challenge for transplantation teams is the occurrence of donor-transmitted infections. Screening for HIV and hepatitis B and C are part of standard donor protocols, but in many cases donor-derived infections come as a complete surprise to the team and may have profound effects on the transplant outcome. Professor Camille Nelson Kotton from Harvard Medical School reviewed some of the less common donor-derived pathogens found in liver transplant patients and reminded the audience of the importance of always expecting the unexpected and being prepared to balance the risk of transplanting against the risk of not transplanting.

 

One notable case in Professor Nelson Kotton’s own centre in Massachusetts was a 54-year-old male who had undergone a liver transplantation for hepatitis B and C infection and hepatocellular carcinoma (HCC), and who developed a fever and mild headache five days after the transplantation. On examination his operation wound was found to be red and angry. The patient deteriorated into progressive sepsis with elevated liver enzymes, renal dysfunction and seizures. A call from another transplant centre where similar symptoms had been noted in a recently transplanted patient led the team at Professor Nelson Kotton’s centre to suspect a donor-transmitted infection. Enquiries soon revealed that the donor, a 49-year-old previously healthy woman who donated organs after brain death due to a stroke, had purchased a hamster shortly before her death, and the infection was caused by a single strain of lymphocytic choriomeningitis virus which was traced to the animal [8].

 

Other factors which may increase the risk of donor infections being transmitted to the recipient include anatomical considerations such as eg open abdomen or biliary issues, perioperative administration of blood products, and the depth and type of immunosuppressive therapy. An illustration of the former was a case where a donor with a gunshot wound to the abdomen transmitted multi-drug resistant Pseudomonas aeruginosa to four recipients who subsequently developed infections and in two cases died [9]. A report published in 2011 estimated that overall, donor-derived disease transmission complicates less than 1% of all transplant procedures but when a transmission occurs, significant morbidity and mortality can result [10]. Registries maintained by the Ad Hoc Disease Transmission Advisory Committee (DTAC) and the United Network for Organ Sharing (UNOS) and the WHO project NOTIFY contain a wealth of data on rare infections that have been transmitted by organ donors, and Professor Nelson Kotton strongly recommended accessing this data as part of the process of weighing potential benefit against risk.

 

 

Cutting-edge developments

The latter part of the symposium provided an update on innovations and cutting-edge research and development to improve conditions for liver transplantation patients and professionals. Professor John Lake from the University of Minnesota reported on a Phase 2B study carried out in Europe and the United States of the ELAD® bioartificial liver system in patients with acute or non-acute alcoholic hepatitis. These patient groups have limited treatment options at their disposal and are usually not available for transplantation. Use of ELAD® resulted in a numerical, statistically non-significant survival benefit and was well tolerated, and the investigators concluded that it warrants further investigation as a potential bridge to recovery and/or transplantation [11]. A pivotal trial is ongoing in patients with severe acute alcoholic hepatitis.

 

Creating organs for transplantation from human stem cells is one of the holy grails of modern science. Results in rodent models are promising; however, upscaling to larger animals is proving a challenge. Professor Eiji Kobayashi from Keio University School of Medicine in Japan is the head of a group that is working on the development of transplantable human organs with the help of pig liver scaffolds. Proof of concept of populating decellularised animal scaffolds with hepatocytes has been shown in rodent models [12]. Pig models have demonstrated successful production and implantation of extracellular matrix scaffolds from kidneys [13] and liver [14], although the methodology has yet to be perfected. Professor Kobayashi stressed that chimeric organ engineering offers realistic prospects of developing human organs with appropriate three-dimensional structures for transplantation in terms of vascular structure and physiological parenchyma. Provided the challenges of xeno-antigenicity and xenozoonosis can be overcome, human-pig chimeric organs could potentially be used to meet the demand for organs and reduce transplantation waiting lists.

 

References

1.         Samuel, D., et al., P1232 SOFOSBUVIR AND RIBAVIRIN FOR THE TREATMENT OF RECURRENT HEPATITIS C INFECTION AFTER LIVER TRANSPLANTATION: RESULTS OF A PROSPECTIVE, MULTICENTER STUDY. Journal of Hepatology. 60(1): p. S499.

2.         Forns, X., et al., O62 SOFOSBUVIR COMPASSIONATE USE PROGRAM FOR PATIENTS WITH SEVERE RECURRENT HEPATITIS C INCLUDING FIBROSING CHOLESTATIC HEPATITIS FOLLOWING LIVER TRANSPLANTATION. Journal of Hepatology. 60(1): p. S26.

3.         Afdhal, N., et al., Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med, 2014. 370(16): p. 1483-93.

4.         Afdhal, N., et al., Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med, 2014. 370(20): p. 1889-98.

5.         Kowdley, K.V., et al., Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med, 2014. 370(20): p. 1879-88.

6.         Kwo, P., et al., O114 RESULTS OF THE PHASE 2 STUDY M12-999: INTERFERON-FREE REGIMEN OF ABT-450/R/ABT-267 + ABT-333 + RIBAVIRIN IN LIVER TRANSPLANT RECIPIENTS WITH RECURRENT HCV GENOTYPE 1 INFECTION. Journal of Hepatology. 60(1): p. S47.

7.         Curry, M., et al., Pretransplant Sofosbuvir and Ribavirin to Prevent Recurrence of HCV Infection after Liver Transplantation. Hepatology, 2013. 58(S1): p. 314A.

8.         Fischer, S.A., et al., Transmission of lymphocytic choriomeningitis virus by organ transplantation. N Engl J Med, 2006. 354(21): p. 2235-49.

9.         Watkins, A.C., et al., The deceased organ donor with an “open abdomen”: proceed with caution. Transpl Infect Dis, 2012. 14(3): p. 311-5.

10.       Ison, M.G. and M.A. Nalesnik, An update on donor-derived disease transmission in organ transplantation. Am J Transplant, 2011. 11(6): p. 1123-30.

11.       Teperman, L., Efficacy and Safety of Human Cell-based Biological Liver Support System (ELAD®) in Subjects with Acute Alcoholic Hepatitis (AAH) or Acute Decompensation of Cirrhosis (Non-AAH). Liver Transplantation, 2012. 18(S1): p. S1-S306.

12.       Uygun, B.E., et al., Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med, 2010. 16(7): p. 814-20.

13.       Orlando, G., et al., Production and implantation of renal extracellular matrix scaffolds from porcine kidneys as a platform for renal bioengineering investigations. Ann Surg, 2012. 256(2): p. 363-70.

14.       Yagi, H., et al., Human-scale whole-organ bioengineering for liver transplantation: a regenerative medicine approach. Cell Transplant, 2013. 22(2): p. 231-42.