B. Roche

Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors

BACKGROUND & AIMS Immunotherapy for metastatic cancer may be complicated by the onset of hepatic immune-related adverse events (IRAEs). This study compared hepatic IRAEs associated with anti-PD-1/PD-L1 and anti-CTLA-4 monoclonal antibodies (mAb). METHODS Among 536 patients treated with anti-PD-1/PD-L1 or CTLA-4 immunotherapies, 19 (3.5%) were referred to the liver unit for grade uf0b3 3 hepatitis. Among 16 included patients: 9 received anti-PD-1/PD-L1 while 7 received anti-CTLA-4 mAb, inBACKGROUND & AIMSnImmunotherapy for metastatic cancer can be complicated by the onset of hepatic immune-related adverse events (IRAEs). This study compared hepatic IRAEs associated with anti-programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) monoclonal antibodies (mAbs).nnnMETHODSnAmong 536 patients treated with anti-PD-1/PD-L1 or CTLA-4 immunotherapies, 19 (3.5%) were referred to the liver unit for grade ≥3 hepatitis. Of these patients, nine had received anti-PD-1/PD-L1 and seven had received anti-CTLA-4 mAbs, in monotherapy or in combination with anti-PD-1. Liver investigations were undertaken in these 16 patients, including viral assays, autoimmune tests and liver biopsy, histological review, and immunostaining of liver specimens.nnnRESULTSnIn the 16 patients included in this study, median age was 63 (range 33-84) years, and nine (56%) were female. Time between therapy initiation and hepatitis was five (range, 1-49) weeks and median number of immunotherapy injections was two (range, 1-36). No patients developed hepatic failure. Histology related to anti-CTLA-4 mAbs demonstrated granulomatous hepatitis including fibrin ring granulomas and central vein endotheliitis. Histology related to anti-PD-1/PD-L1 mAbs was characterised by lobular hepatitis. The management of hepatic IRAEs was tailored according to the severity of both the biology and histology of liver injury: six patients improved spontaneously; seven received oral corticosteroids at 0.5-1u202fmg/kg/day; two were maintained on 0.2u202fmg/kg/day corticosteroids; and one patient required pulses and 2.5u202fmg/kg/day of corticosteroids, and the addition of a second immunosuppressive drug. In three patients, immunotherapy was reintroduced without recurrence of liver dysfunction.nnnCONCLUSIONSnAcute hepatitis resulting from immunotherapy for metastatic cancer is rare (3.5%) and, in most cases, not severe. Histological assessment can distinguish between anti-PD-1/PD-L1 and anti-CTLA-4 mAb toxicity. The severity of liver injury is helpful for tailoring patient management, which does not require systematic corticosteroid administration.nnnLAY SUMMARYnImmunotherapy for metastatic cancer can be complicated by immune-related adverse events in the liver. In patients receiving immunotherapy for metastatic cancer who develop immune-mediated hepatitis, liver biopsy is helpful for the diagnosis and evaluation of the severity of liver injury. This study demonstrates the need for patient-oriented management, which could eventually avoid unnecessary systemic corticosteroid treatment.

219 PROSPECTIVE ASSESSMENT OF LIVER FIBROSIS AFTER LIVER TRANSPLANTATION IN HIV/HCV COINFECTED PATIENTS: A USEFUL TOOL ASSESSING SEVERE FIBROSIS ON THE LIVER GRAFT

219 PROSPECTIVE ASSESSMENT OF LIVER FIBROSIS AFTER LIVER TRANSPLANTATION IN HIV/HCV COINFECTED PATIENTS: A USEFUL TOOL ASSESSING SEVERE FIBROSIS ON THE LIVER GRAFT B. Roche, M. Belnard, P. Pham, L. Allain, A.-M. Roque-Afonso, A. Coilly, T.M. Antonini, R. Sobesky, D. Samuel, J.-C. Duclos-Vallee. Centre Hepato-Biliaire, AP-HP – Hopital Paul Brousse, Unit 785, INSERM, Villejuif, Faculte de Medecine, Univ Paris-Sud, Le Kremlin-Bicetre, Laboratoire de Biochimie, AP-HP – Hopital Paul Brousse, Laboratoire Roche, Laboratoire de Virologie, AP-HP – Hopital Paul Brousse, Villejuif, France E-mail: bruno.roche@pbr.aphp.fr

Idiopathic Post Liver-Transplant Hepatitis Remains Obscure with Respect to Its Etiology and Relationship with Immunosuppressiona

Aim: Idiopathic post-liver transplant hepatitis (IPTH) can lead to late graft fibrosis. The treatment for IPTH is not clearly delineated. We aimed to approach its pathophysiology and predictive factors for fibrosis progression (FP). Methods: Patients whose IPTH was diagnosed in 2006 and had undergone at least one subsequent liver biopsy (LB) were included. The index LBs were reviewed and correlated with clinical, laboratory, C4d immunostaining retrospectively performed, and histological data on the most recent LBs. Results: Among the 299 post-transplant LBs, 37 presented IPTH. The index LBs mostly displayed mild fibrosis (65%) and activity (67.5%), and non-significant C4d immunostaining (i.e., weak, focal and/or portal stroma staining, 21.6%). Liver tests were normal in 46% of patients. Virological markers including Hepatitis E were negative. Antinuclear auto-antibodies were present concurrently in four patients and appeared later in two patients, together with features of autoimmune hepatitis (AIH) in one. Isolated AIH features appeared later in one patient. One patient displayed AIH features on the index LB, with negative auto-antibodies and elevated serum IgG. Fibrosis was stable, increased or decreased in 23, 11, and three patients, respectively. FP was less frequent in tacrolimus-treated patients (p = 0.022), more frequent in cyclosporine- (p = 0.035) and MMF-treated patients (p = 0.023), and not influenced by steroid-based treatment or increased overall immunosuppression or steroids. Under multivariate analysis, MMF remained an independent predictor of FP (p = 0.048). Conclusion: The physiopathology of IPTH remained unclear. Increasing steroid doses or overall immunosuppression did not prevent FP. The potential impact of MMF on FP will require prospective studies.

493 RESULTS OF LIVER RETRANSPLANTATION IN A MONOCENTRIC COHORT OF HCV INFECTED PATIENTS

quartile of LDLR mRNA expression in the PI biopsy survived with a significantly (Log-Rank test P < 0.05) better survival than those in the three lowest quartiles. Surviving graft (n = 34, median followup 44.8 months, range 8.6–72.3) had significantly higher LDLR (P < 0.01) and NPC1L1 (P < 0.05) mRNA expression in the PI biopsy and HMGCR (P < 0.05) mRNA expression in the PR biopsy than lost grafts (n = 13, median follow-up 6.0 months, range 0.03–43.7). Conclusions: In the settings of human liver transplantation: 1. hepatic LDLR mRNA is overexpressed immediately after graft reperfusion, suggesting an increased hepatocyte cholesterol uptake from blood; 2. hepatic upregulation of genes involved in cholesterol recruitment and synthesis is inversely related to the severity of IRI and is associated with better graft survival.