1. 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

2. Directly Acting Antiviral Therapy
Webster et al. Lancet Mar 21;385(9973):

3. Epidemiology Actual infections ~ 14x reported
Viral Hepatitis – Statistics and Surveillance

4. 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

5. 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

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

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

8. 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 Aug 18;436(7053):

9. Epidemiology Incidence: 6.4/100,000 US prevalence: 2.7 million (1%)*
WHO Global Hepatitis Report.
* Denniston et al. Ann Intern Med Mar 4;160(5):

10. Epidemiology Actual infections ~ 14x reported
Viral Hepatitis – Statistics and Surveillance

11. Epidemiology in ESRD
Worldwide prevalence (Japan, Western Europe and USA)1
2.6% %
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 Jun;65(6):
Hart et al. Am J Transplant 16[Suppl 2]: 11–46, 2016
Kalantar-Zadeh et al. JASN. 2007;18(5):
Nakayama et al. JASN. 2000; 11:
Fabrizi et al. J Viral Hepat Sep;19(9):601-7.

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

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

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

15. Deciding to Treat – Waitlist Mortality
Hart et al. Am J Transplant Jan;17 Suppl 1:

16. 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:

17. Directly Acting Antiviral Therapy
Webster et al. Lancet Mar 21;385(9973):

18. Epidemiology Actual infections ~ 14x reported
Viral Hepatitis – Statistics and Surveillance

19. 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?

20. 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:

21. 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 Apr;13(4):772-9
Liu et al. Clin J Am Soc Nephrol May;6(5):

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

23. 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

24. 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

25. 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 Jun;150(7):
Gane et al. N Engl J Med 2017; 377:

26. 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 Sep;30(9):
Goldberg et al. N Engl J Med. 376: 2394–2395, 2017

27. 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