Session 4: Whats new in Transplant ID Transplanting the HBV/HCV positive patient Transplant Infectious Disease Conference 2015 Cancun, October 13, 2015 I have financial relationship(s) within the last 12 months relevant to my presentation with: Abbvie, BMS, Gilead, Janssen AND My presentation does not include discussion of off-label or investigational use I do not intend to reference unlabeled/unapproved uses of drugs or products in my presentation. Marina Berenguer, MD La Fe University Hospital and Ciberehd, Valencia, Spain TID 2015 Liver Transplant Spanish Registry: HCV vs Other indications Wilcoxon Test p < 0,001 yrs 70% 59% Cirrhosis HCV Yes (3284) No (4595) Graft survival HCV (3284) no-HCV (4595) 1 m 3 m yrs Memoria del RETH 2008, Sociedad Espaola de Trasplante Heptico Adults/ No HCC / Elective LT / Benefits of antiviral therapy HCV eradication leads to improvements in outcome Berenguer M et al. American Journal of Transplantation 2008; 8: Veldt et al. American Journal of Transplantation 2008; 8: IFN ODYSSEA IFN 6 mo IFN 12 mo IFN/RBV 6 mo IFN/RBV 12 mo PEG-IFN 12 mo PEG-IFN + RBV 12 mo PI + PEG-IFN + RBV 612 mo SOF + PEG-IFN + RBV 3 mo 6379 54 SVR (%) SMV + PEG-IFN + RBV 612 mo 81 90100 IFN-free 824 weeks A revolution in therapy!!!!!! Pre vs post-LT therapy Why should we treat pre-transplant? Prevent HCV recurrence post-liver transplant Prevent death while the patient is on the waiting list Potentially reduce the need for liver transplant Open up access to marginal donors Pre-liver transplantation therapy for HCV Patients treated for >30 days pre-transplant are likely to avoid HCV recurrence post-transplant Curry MP, et al. Gastroenterology 2015;148:1007. *Wilcoxon rank sum test. No recurrence in 24/25 (96%) of patients who maintained HCV RNA TND >30 days No Recurrence (n=30)Recurrence (n=10) >30 days TND Median days TND No recurrence: 90 Recurrence: 5.5 p20 Increasing vasodilatation Worsening liver function >6 Fibrogenesis and neovascularization 100% 95% 90% 80-85% Any antiviral combination (GT, local availability)) SOF/LDV, DCV) SOF ?/LDV, DCV) SVR in patients with decompensated cirrhosis treated with 12 wks SOF/LDV + RBV CTP B & CTP C 1. Flamm SL, et al. AASLD 2014, Abstract #239.; 2. Manns M et al. EASL Abstract G02. SOLAR- 2 Total: CPT B or C: n = 160 (n=78, 12 wks.); GT-1 or -4; GT-1: 90%; CP-B: 65%, CP-C: 35% Safety: D/C due to AEs: 1 (1%) LDV/SOF + RBV 12 weeks CPT >12 excluded SOLAR-1 1 Total: n = 108 (n=53, 12 wks.); GT-1 or -4; GT-1: 97%; CP-B: 55%, CP-C: 45% Safety: D/C due to AEs: 0 (0%) LDV/SOF + RBV 12 weeks CPT >12 excluded SVR12 (% ) PretransplantPostransplant SVR12 (%) SVR in patients with decompensated cirrhosis treated with 12wks SOF+ DCV + RBV CTP A, B & CTP C Poordad F. et al. Oral L08. EASL 2015 SVR 12, % All patients GT 1 50/60 37/45 MELD 8-40* 26/34 11/11 4/55/6 4/4 SVR by Genotype * Only 4 patients with MELD > 20 Real life Cohorts: decompensated cirrhosis a Interim analysis of data from HCV-TARGET, a consortium of more than 50 academic and community medical centers in the U.S., Canada, and Germany HCV TARGET 1a Total n = 277 ; MELD 10; GT-1 n = 199 (72%) 17% MELD 16 Safety: DC due to AE, 8 (5%) SOF + SMVSOF + SMV + RBV SMV+SOFRBV (HCV-TARGET) Foster et al. Oral O002. EASL 2015 Reddy KR, et al. EASL 2015, abstract O007 SOF + DCV or LDV Compassionate Use UK) SOF + DCV or LDV RBV (Compassionate Use UK) N=467; GT1 235, GT 3 189; Mean Meld 12 (6-36), CPB 309, CPC 46 Safety: DC, 42 (9%) LDV/SOF + RBV for patients with decompensated cirrhosis before and after transplantation: changes in MELD & CPT scores (week 4 post vs baseline) 15 *No data of FU in 24 patients Pre/Post-Transplant (CPT B y C, n=136*) n=18 (-17) (-11) (8) Manns M et al, EASL 2015 (abst G02 ) Post-liver transplantation therapy for HCV Numerous and complex DDIs are possible with some DAAs, including with immunosuppressants No dose adjustment is required for TAC or CsA with SOF + RBV, LDV/SOF or SOF + DCV (A2) With OMV/PTV/RTV + DSV: TAC dose must be adjusted (to 0.5 mg once weekly or 0.2 mg every 3 days) CsA dose must be adjusted (to 1/5 of dose given before HCV treatment once daily) Prednisone permitted at 5 mg/day mTOR inhibitors not recommended (A2) EASL Recommendations on Treatment of Hepatitis C J Hepatol 2015;63:199236 The concomitant use of SMV and CsA is not recommended No SMV dose changes are required with TAC and sirolimus, but regular monitoring of their blood concentrations should be performed (A2) Several IFN-free treatment options have now been shown to cure HCV post-liver transplant RegimenPatient characteristicsSVR12 SOF + RBV (24 wks)CTP 7 (A/B); MELD 1770% 2 OMV/PTV/RTV + DSV + RBV (24 wks)F2 only97% 3 LDV/SOF + RBV (12 wks)F396% 4 98% 4 LDV/SOF + RBV (12 wks)CTP A96% 4 CTP B85 4 95% 100% 5 CTP C50 5 60% 4 75% 4,5 SOF + DCV RBV (12-24 wks)F2 F3 F4 (CTP A/B/C) 96% 6 93% 6 98% 6 1. Forns X, et al. Hepatology 2015;61:148594; 2. Charlton M, et al. Gastroenterology 2015;148:10817; 3. Kwo PY et al. N Engl J Med 2014: 371:237582; 4. Charlton M et al. Gastroenterology 2015;149:64959; 5. Manns M, et al. EASL 2015; Oral #GO2; 6. Coilly A, et al. EASL 2015;Oral #G15 Very goood results in the absence of adverse events, even in FCH Lower SVR rates in advanced graft cirrhosis with portal hypertension Clinical improvement associated with viral eradication Before DAAs were available DAA: direct-acting antiviral agent Prevent graft re-infection or rescue from transplantation Prevent infection or reduce risk of disease progression Prevent cirrhosis and graft failure Pre-transplant antiviral therapy Pre-emptive therapies Antiviral therapy for recurrent disease Re-transplant ListedTransplantGraft lossChronic hepatitis Predominant management strategy for HCV patients with PEG-IFN + RBV SVR 40% Very poor tolerability .Where we are now SVR 90% Good tolerability Prevent graft re-infection or rescue from transplantation Prevent infection or reduce risk of disease progression Prevent cirrhosis and graft failure Pre-transplant antiviral therapy Pre-emptive therapies Antiviral therapy for recurrent disease Re-transplant ListedTransplantGraft lossChronic hepatitis SVR 70>90% Good tolerability Point of no-return MELD Purgatory GT 3 RBV-free regimes HBV Prophylaxis in Liver Transplant Recipients: the present 1- Prevention of HBV reinfection is the rule 2- Combination therapy using HBIg plus antiviral agents is standard of practice in most LT programs 1-10 * High efficacy (> 90%) reported with HBIg and lamivudine * Less data available on newer antiviral combinations with HBIg, but unlikely to be inferior 1- Terrault, Roche & Samuel (2005), 2- Han S (2003), 3- Anderson R (2007), 4- Dickson R (2006), 5-Marzano A (2005), 6-Gane (2007), 7-Loomba R (2008), 8-Rao W (2009), 9- Chen J (2010), 10 Kartz LH (2010) HBV Prophylaxis in Liver Transplant Recipients: the Future Individualized Prophylaxis * Antiviral used postLT * Use/dose/duration of HBIg 1- Great heterogeneity in patients awaiting LT * Drug-Resistant HBV * Improved HBV DNA suppression pre-LT with newer antivirals * Viral coinfection (HDV, HIV, HCV) 2- Indefinite combination therapy is expensive * Weight cost and benefit to maximize patient outcomes to lowest possible costs * HBIG: main focus of concern (cost, cumbersome) * New antivirals also expensive 3. Different profile of antiviral drugs---treatment adherence Fundamental concepts for individualized prophylaxis 1. Sustained viral suppression essential Persistence of DNA in intra & extrahepatic sites 2. Different risk of HBV recurrence (non-replicators vs replicators) Strategies to maximize cost-benefit 1- Dose reductions of HBIg 2- Discontinuation of HBIg followed by antiviral therapy 3- Prophylaxis with antiviral therapy without HBIg 4- Discontinuation of HBV prophylaxis 5- HBV vaccination Rates of HBV Recurrence According to First Year HBIg Doses (with LAM) F. Villamil (used with permission) 150, , , ,000 50, ,000 3 log or drug-resistant species? cccDNA in liver tissue? # Recurrent HBV disease 2- What are the clinical implications of HBV recurrence? (potent antivirals era) No cases of FCH in > 10 years Recurrence easily manageable--effective antiviral rescue tx Strict monitoring ----ensure prompt initiation of antiviral tx Individualized prophylaxis against HBV recurrence High Risk HBV DNA 10 4 IU/ml R. mutants Adherence issues HDV (tx options limited) HIV Low Risk Undetectable DNA HBeAg (-) at LT Wild HBV Predicted compliance Low-dose HBIG + NUC long-term combination Selection of NUC based on drug-resistance profile HBIG Minimization strategies Need of HBIg? (mini- short duration?) Strict monitoring