Current Perspectives on Hepatitis C and Kidney Transplantation Fasika M. Tedla, MD, MSc Associate Professor of Clinical Medicine Medical Director of Transplantation State University of New York Downstate Medical Center 10th Conference on Nephrology and Hypertension Kingston, Jamaica January 20, 2018

Directly Acting Antiviral Therapy Webster et al. Lancet. 2015 Mar 21;385(9973):1124-35.

Epidemiology Actual infections ~ 14x reported Viral Hepatitis – Statistics and Surveillance https://www.cdc.gov/hepatitis/hcv/statisticshcv.htm#section4

Outline Biology of HCV infection Epidemiology and course Virology of HCV Virus-Host interaction Epidemiology and course Dialysis Transplant Evolution of care for HCV+ candidates and recipients

Virology of HCV RNA virus of Flaviviridae family 6 genotypes, with different epidemiology US: 1a and 1b, followed by 2, 3 May influence course of disease and response to treatment – genotype 3 more aggressive Virions associate with lipoprotiens – Lipovirions No small animal host In vivo studies: humans and chimpanzees

Virology of HV Lauer. N Engl J Med 2001; 345:41-52

Viral Entry and Assembly Principles and Practice of Infectious Diseases, 8th ed. 2015

Virus-Host Interactions The anti-viral response Induction of interferons Activation of interferon pathways Inhibit viral replication and protein translation Stimulation of apoptosis Enhancement of recognition and killing of infected cells HCV adaptations Mutations in RNA recognition sites Lysis of mediators of interferon response by NS3 Variations in control of infection by immunity HLA polymorphisms λ-INF 3 polymorphism Viral polymorphisms (e.g in NS5b) Cellular immunity critical to viral clearance Gale. Nature. 2005 Aug 18;436(7053):939-45.

Epidemiology Incidence: 6.4/100,000 US prevalence: 2.7 million (1%)* WHO Global Hepatitis Report. http://apps.who.int/iris/bitstream/10665/255016/1/9789241565455-eng.pdf?ua=1 * Denniston et al. Ann Intern Med. 2014 Mar 4;160(5):293-300

Epidemiology Actual infections ~ 14x reported Viral Hepatitis – Statistics and Surveillance https://www.cdc.gov/hepatitis/hcv/statisticshcv.htm#section4

Epidemiology in ESRD Worldwide prevalence (Japan, Western Europe and USA)1 2.6% - 22.9% US1 Prevalence: 14% Seroconversions: 2.5/100 pt-yrs Waitlist: 6.4%2 Prevalence and seroconversion rates vary from unit to unit Mortality higher in HCV+ dialysis patients3,4,5 Causes of excess mortality4,5 Cardiovascular disease Cirrhosis Hepatocellular carcinoma Fissell et al. Kidney Int. 2004 Jun;65(6):2335-42. Hart et al. Am J Transplant 16[Suppl 2]: 11–46, 2016 Kalantar-Zadeh et al. JASN. 2007;18(5): 1584-1593 Nakayama et al. JASN. 2000; 11: 1896-1902 Fabrizi et al. J Viral Hepat. 2012 Sep;19(9):601-7.

Outcome After Kidney Transplant – Early Period Batty et al. Am J Transplant. 2001;1:179-184 Meier-Kriesche et al. Transplantation. 2001;72(2):241-4.

Outcome After Kidney Transplant Ingsathit et al. Transplantation. 2013 Apr 15;95(7):943-8

Natural History of HCV Infection Lauer. N Engl J Med 2001; 345:41-52

Deciding to Treat – Waitlist Mortality Hart et al. Am J Transplant. 2017 Jan;17 Suppl 1:21-116.

Concerns Before and After Transplant Interferon era High rates of severe complication with pre-Tx Rx Poor response to Rx Glomerular disease in graft Progression of liver disease post-Tx Fibrosing cholestatic hepatitis High rates of rejection with interferon use post-Tx Transmission of another genotype or drug-resistant strains Graft and patient outcomes not favorable HCV+ donor pool diminishing Use of HCV+ donor limited 2/3 of kidneys from HCV+ donors discarded1 Reese et al. N Engl J Med 2015; 373:303-305

Directly Acting Antiviral Therapy Webster et al. Lancet. 2015 Mar 21;385(9973):1124-35.

Epidemiology Actual infections ~ 14x reported Viral Hepatitis – Statistics and Surveillance https://www.cdc.gov/hepatitis/hcv/statisticshcv.htm#section4

Concerns Before and After Transplant Current questions Effectiveness of treatment Side effects of treatment Comparative outcome without treatment Cost of treatment Transmission of another genotype or drug-resistant strains Who and when to treat? With which agent/s?

Diagnosis Infection Hepatic injury Anti-HCV antibody positive AND HCV RNA Or HCV RNA (window period) Hepatic injury Definitive – liver biopsy Others Composite of many lab values Evidence of portal hypertension Elastography (stiffness) Sterling et al. Am J Gastroenterol. 1999; 94:3576-82

Ultrasound Elastography Cirrhosis in Non-CKD1 Sensitivity: 76% Specificity: 85% Affected by congestion and iron overload Cirrhosis in HD2 Sensitivity: 100% Specificity: 96% No validation Few cases of cirrhosis Afdhal et al. Clin Gastroenterol Hepatol. 2015 Apr;13(4):772-9 Liu et al. Clin J Am Soc Nephrol. 2011 May;6(5):1057-65.

Directly Acting Antiviral Therapy Zeuzem. Dtsch Arztebl Int 2017; 114(1-2): 11-21

Treatment - Principles Factors affecting choice Genotype Previous treatment history/drug resistance HBV co-infection Liver function Renal function Drug interactions Insurance coverage Monotherapy with directly acting antivirals leads to failure and resistance Combination of agents with different mechanisms

Timing of Treatment Pre-Tx Post-Tx Pro: Disadvantage: ideal for live donor transplant Less risk of serious drug interaction Reduces risk of liver-related morbidity and mortality Disadvantage: longer wait time for HCV-neg deceased donor Choice of agent limited by renal function Post-Tx Short wait time from HCV-pos donor Drug interactions (not for all) Possibility of acquiring new genotype or strain

Regimens in CKD Ritonavir Elbasvir Ombitasvir Pibrentasvir Grazoprevir Paritaprevir Glecaprevir Dasabuvir Zeuzem. Dtsch Arztebl Int 2017; 114(1-2): 11-21 Roth et al. Lancet 386: 1537–1545, 2015 Pockros et al. Gastroenterology. 2016 Jun;150(7):1590-1598. Gane et al. N Engl J Med 2017; 377:1448-1455

Outcome of Treatment After Kidney Transplant Similar to non-transplant patients Designs Follow up of outcome of HCV+ recipients1 Retrospective reports of treatment after HCV+ to HCV+ transplants2 Pilots of HCV+ to HCV- transplants3 Sawinski et al. Transplantation. 101: 968–973, 2017 Bhamidimarri et al. Transpl Int. 2017 Sep;30(9):865-873 Goldberg et al. N Engl J Med. 376: 2394–2395, 2017

Summary Hepatitis C infection is common in dialysis patients Liver+Kidney transplant better option for patients with advanced cirrhosis Non-invasive markers of cirrhosis not validated in dialysis patients Directly acting antiviral agents offer cure of infection HCV+ to HCV+ transplants reduce wait time HCV+ to HCV- transplants clinically justifiable