LIVER TRANSPLANTATION 20:7–14, 2014

SPECIAL ARTICLE

Meeting Report of the 19th Annual International Congress of the International Liver Transplantation Society (Sydney Convention and Exhibition Centre, Sydney, Australia, June 12-15, 2013) Gabriel C. Oniscu,1 Geraldine Diaz,2 Josh Levitsky3 Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; 2Department of Anesthesia and Critical Care, University of Chicago Medicine, Chicago, IL; and 3Division of Gastroenterology and Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL

1

The International Liver Transplantation Society held its annual meeting from June 12 to 15 in Sydney, Australia. More than 800 registrants attended the congress, which opened with a conference celebrating 50 years of liver transplantation (LT). The program included series of featured symposia, focused topic sessions, and oral and poster presentations. This report is by no means all-inclusive and focuses on specific abstracts on key topics in LT. Similarly to previous reports, this one presents data in the context of the published literature and highlights the current direction of LT. Liver Transpl 20:7-14, C 2013 AASLD. 2014. V Received September 21, 2013; accepted September 24, 2013. The International Liver Transplantation Society (ILTS) held its 19th annual congress in Sydney, Australia. The meeting included several thematic symposia focused on advances in acute liver failure, hepatitis C virus (HCV) in the context of liver transplantation (LT), advances in liver regenerative medicine, the role of LT in alcoholic liver disease, the management of high-risk recipients, ways to improve renal outcomes after LT, and achieving tolerance. A wide range of topics were covered by oral presentations, poster sessions, video, and interactive discussions. In the context of the published literature, this report focuses on several key topics such as viral hepatitis, acute/

chronic liver failure, perioperative management, immunosuppression, rejection, tolerance, renal/metabolic outcomes, liver cancer, expansion of the donor pool, living and split donor LT, other extended criteria donors, and allocation.

VIRAL HEPATITIS AND RECURRENT DISEASE A number of meeting abstracts focused on clinical and biomarker predictors of more rapid HCV recurrence and associated complications. O’Leary et al. (O-46) showed that preformed and de novo

Abbreviations: AFP, alpha-fetoprotein; ALI, acute lung injury; DSA, donor-specific antibody; EVL, everolimus; HBIG, hepatitis B immunoglobulin; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ILTS, International Liver Transplantation Society; LAS, liver allocation system; LDLT, living donor liver transplantation; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; PCAT1, prostate cancer–associated transcription 1; TAC, tacrolimus; TEE, transesophageal echocardiography. Abstracts mentioned in this article (which are cited in the O-# format) can be found in Liver Transplantation 2013;19(suppl 1):S86-S334. The authors have no disclosures to make. Address reprint requests to Gabriel C. Oniscu, M.D., F.R.C.S., Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Little France Crescent, Old Dalkeith Road, Edinburgh EH16 4SA, United Kingdom. E-mail: [email protected] DOI 10.1002/lt.23767 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

C 2013 American Association for the Study of Liver Diseases. V

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donor-specific antibodies (DSAs) increased HCV fibrosis and mortality after LT. This correlated with their recent publication on the impact of DSAs on LT outcomes,1 but now they made specific reference to the higher risk HCV population. A novel cluster of differentiation antibody microarray was shown to help differentiate mild and severe HCV recurrence, with pretransplant cluster of differentiation antibody signatures before transplantation interestingly being the strongest predictors of recurrence (O-115). Tripon et al. (O-48) presented interesting data on factors associated with ascites development early after LT in HCV1 recipients without cirrhosis on early biopsy. A multivariate analysis showed that pretransplant refractory ascites, stage 2 fibrosis 1 year after transplantation, perisinusoidal fibrosis, and cryoglobulinemia were tied to early ascites development, the latter 2 factors suggesting microcirculatory changes leading to portal hypertension. These data support the concept that pressure gradients can increase after LT in the absence of cirrhosis and are predictive of worse complications.2,3 Finally, Song et al. (O-76) identified several variables associated with improved survival after retransplantation for HCV: negative HCV before transplantation, antivirals after LT, the absence of a split graft, a younger age, and a genotype other than 1. Thus, the careful selection of patients for retransplantation can help to prolong patient and graft survival.4,5 Novel data on treatment with triple therapy (pegylated interferon, ribavirin, and a protease inhibitor) for HCV before transplantation and recurrent HCV were presented at the meeting. During the Rising Star Symposium, Saxena et al. (O-6) showed that female sex was a strong predictor of adverse events (eg, anemia) during triple therapy. Later in the meeting, Saxena et al. (O-43) compared the outcomes of triple therapy for pretransplant patients with cirrhosis by the Child class: A versus >A. The sustained virological response rate was better for Child class A patients (55%) versus non-A patients (42%), but the early rapid virological response rate was most predictive of a sustained response. However, tolerability was in general worse with more advanced decompensation, and this finding was similar to the results of other recent studies.6 In both pretransplant patients with cirrhosis and post-LT patients, Vinaixa et al. (O-44) similarly showed worse tolerability and outcomes in comparison with those for a noncirrhotic, nontransplant population. As for hepatitis B, there were 2 studies of successful hepatitis B immunoglobulin (HBIG) withdrawal in conjunction with potent antivirals with minimal or no resistance (O-112 and O-117). No hepatitis B virus recurrence was seen, and this finding was similar to the results of other studies of either no HBIG or HBIG withdrawal in the setting of antiviral therapies with high genetic barriers to resistance.7,8 Another abstract (O-116) showed tremendous cost savings ($28,000 per year) from the cessation of HBIG in favor of tenofovir plus emtricitabine, and it supported this practice and recent data.9

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A few notable presentations focused on long-term recurrent disease and histology. Ravikumar et al. (O-110) showed significantly less recurrent primary sclerosing cholangitis (8% versus 25.8%) in patients undergoing pretransplant/intraoperative colectomy versus patients undergoing post-LT colectomy for inflammatory bowel disease. This supports the notion that the presence of colitis may be the major cofactor for the recurrence of primary sclerosing cholangitis and may be tied to innate immune mechanisms.10 Kim et al. (O-118) reported the results of 200 post-LT protocol biopsies for patients who mainly underwent transplantation for hepatitis B virus cirrhosis and alcohol/fatty liver disease: 25% had steatosis (mostly mild), and only 8% had steatohepatitis. They identified risk factors for steatosis and not surprisingly included a history of alcoholic cirrhosis, body mass index, and obesity. However, long-term follow-up biopsies and clinical data are needed to determine whether steatosis and, in particular, steatohepatitis progress to more advanced fibrosis in the LT population.

IMMUNOSUPPRESSION Much of the ILTS data on immunosuppression in LT recipients focused on everolimus (EVL), a molecular target of rapamycin inhibitor that was recently approved for use in this population. Schlitt et al. (O-8) showed 36 months of data from the PROTECT study, in which LT recipients were randomized at 4 to 8 weeks to EVL with tacrolimus (TAC) elimination or continuation.11 The TAC withdrawal group was shown to have a persistent 9- to 10-mL glomerular filtration rate improvement at 36 months without an increased rate of rejection. This is in contrast to the recently published H2304 study (Everolimus with reduced Tacrolimus), in which the TAC withdrawal group was terminated early because of a higher rate of rejection despite improved renal function.12,13 De Simone et al. (O-135) then presented 24-month data from the H2304 study and compared maintenance TAC with a combination of EVL and reduced (not withdrawn) TAC. The latter group experienced less rejection, and similarly to Schlitt et al.’s study, that group had better renal function than the standard TAC group at 2 years. Although there was more leukopenia, edema, hyperlipidemia, and proteinuria in the EVL group (O78), the discontinuation rates were similar. Mild proteinuria was higher in the first 6 months but was reduced by the end of 24 months and had no obvious clinical significance. Cillo et al. (O-9) showed data from a study in which patients were randomized on day 7 after LT to EVL and reduced TAC (with a plan for TAC weaning on day 30) or standard TAC dosing. Although there was no difference in the primary endpoint (biopsy-proven rejection) at 3 months, those who underwent TAC weaning (40% of the group) had higher rejection rates. Thus, although it is clear that the use of EVL and early TAC minimization can improve renal function without an increased risk of

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rejection, this does not appear to be the case with TAC withdrawal in terms of rejection. Further clinical and biomarker predictors are needed to identify patients who can successfully be withdrawn from TAC and maintained on calcineurin inhibitor–free EVL regimens. Two notable studies reported the impact of different immunosuppressive therapies and HCV fibrosis progression. Saliba et al. (O-47) presented data on the HCV population in the H2304 study and demonstrated a trend toward less fibrosis progression at 24 months in recipients randomized to EVL and reduced TAC versus TAC alone. Although the data are preliminary, other data have supported the finding of less fibrosis development with the use of molecular target of rapamycin inhibitors versus calcineurin inhibitor therapy.14 Levy (O-7) reported on a large randomized study of de novo cyclosporine versus TAC in LT recipients with HCV. Although there was no difference in the development of stage 2 or higher fibrosis, the cyclosporine patients not given corticosteroids had less recurrence at 2 years. This may just reflect the impact of corticosteroids on HCV disease rather than the choice of calcineurin inhibitor therapy.15

IMMUNE COMPLICATIONS AND TOLERANCE Biomarkers correlating with rejection or the risk of rejection were the focus of a number of ILTS abstracts. A group from Baylor (O-81) presented further data on the impact and importance of DSAs in LT recipients. Similarly to recent work,16,17 this group showed that, with or without induction therapy, preformed class I and II antibodies were associated with the development of liver fibrosis, rejection, and death in the LT population. The Baylor group presented another DSA abstract (O-85) and showed that African Americans receiving a race-mismatched graft had an increased risk of graft loss and death that was potentially due to the presence of preformed DSAs. Sood et al. (O-15) presented a novel immune monitoring assay (QuantiFERON Monitor) for liver recipients that may guide weaning from immunosuppression and the avoidance of rejection. Unlike the commercially available ImmuKnow assay (Cylex), this assay assesses both adaptive (CD3) and innate (toll-like receptor) responses, which are becoming increasingly important in the transplant setting.18 One of the highlights of the meeting was a presentation of data from the Enhancing Adherence to Immunosuppression After Liver Transplantation study (O-11). This was a large prospective, longitudinal assessment of nonadherence by self-reporting in liver recipients and included correlations with subsequent outcomes. Nearly one-third of the patients were considered nonadherent because they deviated from the immunosuppression dosing schedule. This was predicted by a lower intention to adhere and a higher barrier to adherence and correlated with the development of rejection over time in comparison with the

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adherent group. However, nonadherence did not have an impact on graft survival, and this may have been due to the tolerogenicity of the liver for handling underimmunosuppression and rejection in comparison with other organs.19 In reference to LT tolerance, a number of exciting, cutting-edge abstracts were delivered at the meeting. One study demonstrated that the failure to wean 20 adult recipients of living donor liver transplantation (LDLT) from immunosuppression was predicted by high adenosine triphosphate levels in the ImmuKnow assay and donor-specific mixed lymphocyte reactions (O-13). During the Rising Star Symposium, Wozniak et al. (O-1) reviewed data from the University of California Los Angeles experience with 17 mostly male patients who either stopped or were weaned from immunosuppression. Although higher levels of regulatory T cells and regulatory B cells on immunophenotyping were present for this group, more than half had abnormal liver biopsies in the long term. Other reports have shown similar graft abnormalities in the long term in presumably tolerant patients, and this raises concerns about whether these patients are truly tolerant or are experiencing low-grade immune activation and injury.20 Finally, Yamashita et al. (O134) presented a novel regulatory T cell infusion protocol for achieving tolerance in 10 LDLT recipients. Using ex vivo expanded, donor-specific regulatory T cells that were re-infused into the recipients postoperatively, they weaned 5 patients from immunosuppression therapy. The infused cells inhibited donor/ recipient (not third-party) mixed lymphocyte reactions. Although the report was preliminary ( 30% had poorer outcomes than patients with a single DSA and a lower panel reactive antibody score. Moon et al. (O-20) presented a comprehensive update of the experience of the Asan Medical Center, where more than 300 LDLT procedures per year were performed over the last few years with a 5-year survival rate in excess of 88%.51 The mortality rate has remained zero, and innovations such as laparoscopic hepatectomy for left lateral segments, dual grafts, and ABO-incompatible transplants are now common practice. Split LT continues to be a significant component of clinical practice,52 and this is reflected by the number of presentations at the meeting. Adam et al. (O-142) presented the outcomes of a 23-year study from the European Liver Transplant Registry. During this period, first split LT was performed 4910 times in

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Europe. Despite higher rates of graft loss and technical complications in comparison with full size LT, the outcomes have improved significantly and are now almost equivalent to those of full size LT.53 Given these improvements, the authors proposed that centers should be incentivized to expand the use of split LT in pediatric and adult recipients. These results were confirmed by a large single-center report from Birmingham, United Kingdom (O-61), where an 82% 10-year survival rate was achieved for pediatric recipients and a 62% 10-year survival rate was achieved for adult recipients. Given these results, Maggi et al. (O-86) suggested that extended right grafts from split LT should not be considered marginal grafts any longer and should be used routinely in all patients.

CONCLUSION The 2013 ILTS meeting in Sydney, Australia was a productive conference with an emphasis on new viral hepatitis treatments, immunosuppression adherence, recipient selection, extended criteria donation, and ways of increasing the donor pool. The meeting also identified new directions in organ preservation and in the optimization of donor graft quality.

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