Controversies in Transplantation Eric Adler MD Associate Clinical Professor of Medicine Medical Director Cardiac Transplantation

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1 Controversies in Transplantation 2018 Eric Adler MD Associate Clinical Professor of Medicine Medical Director Cardiac Transplantation

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3 Case 1 45 year old male, Vegetarian, No tob or alcohol. Highly stressful job Presented at outside hospital after family and friends noted he was despondent, fatigued, and vague shoulder pain. Physical Exam Appeared older than stated age 400lbs, BP 140/85 HR 100 Neck veins not veins well visualized. BNP 240, Troponin.3

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9 ISHLT Guidelines For Desensitization Desensitiztion should be considered when likelyhood of finding suitable donor heart is significantly decreased or to decrease chances of rejection post operatively Consider When PRA (Average 35%)

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11 Treatment of Elevated PRA

12 Lindenfeld JA et al, Circ 2004; 110:

13 Induction Therapy

14 Purpose of Induction Therapy Highest risk of rejection occurs early, hence it is useful to use potent immunosuppression at this time. Minimize early calcineurin renal toxicity post operatively Increased risk of Infection Thrombocytopenia Cancers

15 Induction Therapy Thmoglobulin Induction: Basiliximab (Simulect) Basiliximab is a monoclonal antibody selectively targeting interleukin-2 (IL-2) receptor of T-lymphocytes. Indication As above. Currently off-label use only. Dosing 20 mg IV on the day of transplant, followed by a second dose 4 days after transplantation. Infusion over minutes

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18 Donor After Cardiac Death (DCD Donors)

19 One Heart Goes to Three People

20 2 0 Case Report 57 yo male with NICM. H/o bicuspid aortic valve s/p Bioprosthetic AVR (1/2005), CRT Chronic Afib Also history of hepatitis C and prior etoh abuse. Being considered for Harmoni Moved from Guam for evaluation treatment of heart failure

21 Underwent OHT 11/14/16: Hospital D 110, Impella Day

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23 I thank everyone from the bottom of my new heart and liver, said Taitano, father of six children and grandfather of thirteen. I owe the team here everything. After these transplants, it is like nothing was ever wrong with me. I went in one door very sick and came back out a new person. I can breathe again. I can speak again. 2 3

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25 2 5 Hepatitis C Disease Progression Immunocompetent patients: Progression to cirrhosis occurs in small population and takes years Immunosuppressed patients (post liver transplant): Fibrosis and cirrhosis in 20 54% at 5 years and 32 51% at 7 years Data from pre-cure era Berenguer M, et al. J Hepatol May;58(5):

26 2 6 The Directly Acting Antivirals Revolution Year Trade name Generic Genotypes SVR rate 2013 Olysio Simprevir Sovaldi Sofosbuvir (+above) 1, 2, 3, % 2014 Harvoni Ledispasvir/sofosbuvir 1, 4, 5, % 2014 Viekira Pak* Dasabuvir/ombitsavir/paritaprevir/ritonavi r % 2015 Technivie Ombitsavir/paritaprevir/ritonovir % 2015 Daklinza Daclatsavir % 2016 Zepatier* Elbasvir/grazoprevir 1, % 2016 Epclusa Sofosbuvir/velpatasvir 1, 2, 3, 4, 5, % 2017 Vosevi Sofosbuvir/velpatasvir/ voxilaprevir 1, 2, 3, 4, 5, % ** 2017 Mavyret* Glecaprevir/pibrentasvir 1, 2, 3, 4, 5, %

27 Months after Device Implant Intermacs CASD % (93.8%-94.4%) 97.9% (94.4%-99.2%) % (89.1%-90.0%) 97.9% (94.4%-99.2%) % (85.3%-86.3%) 95.3% (90.6%-97.7%) % (80.8%-82.0%) 91.3% (84.7%-95.1%) 27

28 THINKER trial N=10 Kidney transplant: HCV negative recipients, HCV NAT positive donors HCV genotyping during allocation Genotypes 1a or 1b only When HCV NAT was detected in the recipient, Zepatier for 12 weeks SVR in all patients - Excellent allograft function in all patients - No adverse events related to treatment Goldberg DS et al. NEJM 2017; 376:

29 MAGELLAN -2 Non cirrhotic Liver and kidney transplant patients GT 1-6 treated with Mavyret Primary endpoint: SVR12 Inclusion criteria: Stable immunosuppression regimen Prednisone limited to 10 mg/day Cyclosporine limited to 100 mg/day Exclusion criteria: Acute renal failure, coinfection with HBV or HIV, steroid resistant rejection within 3 months of screening, CrCl <30, Plts <70,000 Reau N, et al. MAGELLAN-2. EASL 2017

30 MAGELLAN - 2 N = % of transplant patients achieved SVR12 Non-inferior to historical standard of care G/P was well tolerated One mild liver rejection, unrelated to G/P DDIs Reau N, et al. MAGELLAN-2. EASL 2017

31 Case Report: Epclusa and Heart Transplant Gottlieb RL, et al. J Card Fail. 2017;23(10):

32 3 2 Case Report UCSD Quan%ta%ve HCV RNA HCV Detectable 22 copies Post-Opera%ve Days Start of Treatment End of Treatment YO Male with NICM On Dialysis post LVAD HCV Positive HK Donor Thymo induction Dischrged Post Op Day 46 Developed HCV Genotype 1A with Treated with with elbasvirgrazoprevir for 12 weeks with resolution of viremia within 4 weeks of treatment. HCV RNA remains undetectable after end of therapy

33 The Price of a Cure 3 3

34 3 4 Drug Interactions: Immunosuppressants Immunosuppressant Mavyret Harvoni Epclusa Zepatier Tacrolimus Cyclosporine No clinically significant drug interaction Do not use doses >100 mg/day No clinical significant drug interactions observed No clinical significant drug interactions observed Increases concentrations of tacrolimus Contraindicated -May increase the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition.

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37 Future Directions 3 7

38 Future Directions: Preventing Transmission 3 8

39 3 9 Sulpizio Cardiovascular Center at UC San Diego Health 54 Inpatient Beds Emergency Department San Diego s 1 st Comprehensive Cardiovascular Center Heart / Lung Transplant Ventricular Assist Device / Artificial Heart Pulmonary Endarterectomy (PTE)

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