Case 1 AND. Treatment of HCV: Pre- vs Post- Transplant. 58 yo male, ESRD/diabetic nephropathy, HD for 3 weeks

Transcription

1 Treatment of HCV: Pre- vs Post- Transplant Roy D. Bloom MD Professor of Medicine University of Pennsylvania Roy D. Bloom MD Professor of Medicine Medical Director, Kidney Transplant Program University of Pennsylvania Perelman School of Medicine, Philadelphia, PA I have financial relationship(s) with: Advisory Board: Abbvie, Merck Consultant: Abbvie AND My presentation does include discussion of off-label or investigational use: DAA in kidney transplant patients Case 1 58 yo male, ESRD/diabetic nephropathy, HD for 3 weeks HCV genotype 1a Liver biopsy: cirrhosis Platelets: 92, albumin 3.3, Bili normal, INR 1.1 Mild portal hypertension, no varices Has incompatible donor, planning on KPD 1

2 Question Would you? 1. Treat HCV pre-live donor transplant 2. Await KPD transplant, treat HCV post-transplant 3. Advise against live donor transplant, wait for a kidney from an HCV-infected deceased donor, treat post-transplant 4. Advise him to go to a competing transplant center Case 2 34 yo male, stage 5 CKD/HIVAN, HIV undetectable on ART, CD4 466; egfr 11, starting HD within weeks HCV genotype 1b Liver biopsy: stage 3 fibrosis Platelets: 141, albumin 3.9, INR 1.1 No portal hypertension No live donors, CPRA 0, blood type B+ (mean wait-time 5 years) Would you? Question 1. Treat HCV now 2. List now, tell his local nephrologist to treat him when he starts dialysis to prevent HD unit transmission 3. List now, transplant with kidney from HCV-infected donor, treat HCV post-transplant 4. List now, wait for kidney from HCV-negative donor, treat HCV post-transplant 2

3 Case 3 53 yo female, HCV genotype 1, mild ascites, 3.2 cm HCC No admissions, in past year Blood type AB Anticipated transplant MELD = 20 bili 2.1, alb 3.5, plt 128, Cr 1.1, MELD = 12 low HCV donor prevalence region Would you? 1. Treat HCV pre-transplant 2. Treat post-transplant Question Road Map Describe the concerns regarding HCV in organ recipients Outcomes MAKE HCV TRANSPLANT Comorbidities OUTCOMES GREAT (AGAIN) Compare treatment of HCV pre- or post transplant: Pros vs Cons Discuss the timing of treatment of HCV post-transplant 3

4 HCV Infection in Organ Transplant Recipients Prevalence Organ (%) Liver 21 Kidney 6.3 Heart 2.1 Lung 1.7 SRTR 2015 Annual Report, Am J Transplant 2017, Kumar et al, Am J Cardiol 2016, Englum et al, J Heart Lung Transplant 2016 P e r c e n t Survival of HCV-Infected Organ Recipients Liver Heart Lung Acute liver failure HCV ALD Chol. disease Malignancy Other/unknown Months post transplant Months post transplant SRTR 2015 Annual Report, Am J Transplant 2017, Kumar et al, Am J Cardiol 2016, Englum et al, J Heart Lung Transplant 2016 Inferior Outcomes in HCV+ Kidney Recipients Mortality Allograft survival Adapted from meta-analyses of observational studies, comparing to HCV- recipients From Baid-Agarwal et al, Am J Transplant

5 Comorbidities Associated with HCV Infection Hepatic Hepatitis Fibrosis Cirrhosis ESLD HCC Extrahepatic Kidney disease Diabetes CVD/metabolic syndrome NODAT Infection PTLD AMR/Transplant GN Glomerular disease Comorbidities Associated with HCV Infection Hepatic Hepatitis Fibrosis Cirrhosis ESLD HCC ESRD patients Mortality (%) CVD 47 Infection 12 Other 14 Liver disease 9 Unknown 18 Bloom et al, Am J Transplant 2005 Road Map Describe the concerns regarding HCV in organ recipients Outcomes Comorbidities Compare treatment of HCV pre- or post-transplant: Pros vs Cons 5

6 Considerations Patient outcomes Optimize access to wait list and transplant Maximize patient and graft survival Virological factors Liver disease histological and clinical status Kidney function Potential drug-drug interactions Regional prevalence of HCV-infected organ donors Treating Pre-transplant: The Pros Mostly curable Decompensated cirrhosis SVR % CKD Stage 4 and 5d Compensated cirrhosis Roth et al, Lancet 2015 Feld et al, J. Hepatol, 2016 Curry et al, NEJM 2015 Treating Pre-transplant: The Pros Mostly curable Slow liver disease progression n=103 listed for OLT; 98% SVR12 1in 3 inactivated AVOID MELD 1 in 5 delisted PURGATORY Sufficiently sick to benefit Low MELD regions Low HCV prevalence Belli et al, J. Hepatol

7 Treating Pre-transplant: The Pros Mostly curable Slow liver disease progression Reduce transplant complications: NODAT Author Organ NODM (%) HCV- HCV+ Baid, 2001 L Khalil, 2004 L 7 15 Bloom, 2002 K Fabrizi, 2005 K OR 3.97 % with NODAT HCV- HCV+/IFN- HCV+/IFN+ Gursoy, Transplant Proc, 2000 Treating Pre-transplant: The Pros Mostly curable Slow liver disease progression Reduce transplant complications: Recurrent disease Glomerular disease Cruzado et al, Am J. Transplantation 2003 Treating Pre-transplant: The Pros Mostly curable Slow liver disease progression Reduce transplant complications: Recurrent disease Avoid post-transplant drug-drug interactions Public health concerns e.g. HD unit transmission 7

8 Why Treat Post-transplant with DAAs HCV viral load, log copies/ml Highly efficacious Not contraindicated (unlike IFN) yrs post-kidney transplant 55% HCV+ donor Weeks after DAA start Am J Transplant, 2015 pt 1 pt 2 pt 3 pt 4 pt 5 pt 6 pt 7 pt 8 pt 9 pt 10 pt 11 pt 12 pt 13 6 yrs post-olt 33% cirrhosis Coilly et al, J. Hepatology 2016 Why Treat Post-transplant with DAAs Highly efficacious Not contraindicated (unlike IFN) Can use kidney from HCV-infected donor Increase organ utilization Shorter waiting time Longer life Lower cost 8

9 Worse Outcomes in HCV-Infected Recipients of HCV+ Kidneys USRDS, , n=36,956 Recipient level data limited Liver disease severity NAT vs serological testing Reasons for use of HCV+ donor Donor level data limited No NAT Clinical information Abbott et al, J Am Soc Nephrol 2003 Worse Outcomes in HCV-Infected Recipients of HCV+ Kidneys Patient survival Graft survival P=0.250 P= HCV+ donors 306 HCV- donors Morales et al, Am J. Transplantation 2010 Shorter Wait Times for Organs From HCV-Infected Donors Bowring et al, Am J Transplant 2017 Flemming et al, Hepatology,

10 Opportunity for Increased Organ Utilization with Procured HCV+ Donors Acceptance of HCV+ kidneys decreases wait time by 395 days Kucirka et al, Am J Transplant, 2010 Reese et al, NEJM, 2015 Timing of DAA Timing of Treatment of HCV+ Transplant Patients: HCV donor Impact on cost * and wait time Anticipated wait time (mos) Dialysis cost^ DAA cost^^ First year transplant cost Total cost until 12 mos posttransplant Pre Neg ,500 80, , ,000 Neg ,000 80, , ,000 Neg >72 630,000 80, , ,000+ Post Pos <12 61,000 80, ,000 <346,200 *Estimates, in USD, from Held et al, Am J Transplant 2016; ^at $121K/year, ^^DAA per course; Modified from Transplant in press, 2017 Road Map Describe concerns regarding HCV in organ recipients Outcomes Comorbidities Compare treatment of HCV pre- or post-transplant: Pros vs Cons Discuss the timing of treatment of HCV post-transplant 10

11 Recipient HCV: Treat Early vs Late Pros Early Prevent complications of HCV? New DM AMR Recurrent disease (GN or liver) Cons Early drug-drug interactions Proportion with NODAT Time to new DM by HCV D/R serostatus +/+ -/+ +/- -/- Years after transplant Abbott et al, J Am Soc Nephrol, 2004 Recipient HCV: Treat Early vs Late Pros Early Prevent complications of HCV? New DM AMR Recurrent disease (GN or liver) Cons Early drug-drug interactions Recipient HCV: Treat Early vs Late Pros Early Prevent complications of HCV? New DM AMR Recurrent disease (GN or liver) Cons Early drug-drug interactions Effect on drug levels Impaired kidney function Sawinski et al, Am J Transplant, 2016; Coilly et al, J. Hepatology

12 Recipient HCV: Treat Early vs Late Pros Early Prevent complications of HCV? New DM AMR Recurrent disease (GN or liver) Cons Early drug-drug interactions Effect on drug levels Impaired kidney function Genotype superinfection Drug Metabolized Renal dosing Sofosbuvir Renal CrCl > 30 ml/min Ledipasvir Hepatic Unknown Grazoprevir Hepatic No restrictions Elbasvir Hepatic No restrictions Daclatasvir Hepatic No restrictions Simeprevir Hepatic CrCl > 30 ml/min Paritaprevir Ombitasvir Dasabuvir Hepatic Hepatic Hepatic No dose adjustment Recipient HCV: Treat Early vs Late Pros Early Prevent complications of HCV? New DM AMR Recurrent disease (GN or liver) Cons Early drug-drug interactions Effect on drug levels Impaired kidney function Genotype superinfection Pros Later Wait until stable Superinfection detected by 3-4 mos Improved kidney function Ventilator issues resolved Drug levels may be less critical Cons Too late to prevent complications Recipient HCV: Treat Early vs Late Who will treat Hepatologists Nephrologists Transplant IDs Emergence of pan-genotypic agents Re-treatment? Pre/Post-transplant Post/Post-transplant Insurance barriers 12

13 Incidence of Denial of DAA Prescription By Insurance Lo Re et al, Clin Gastro Hepatol, 2016 HCV Management: Kidney Candidates Stage 4-6 CKD, HCV RNA+ Hepatologist ID physician Nephrologist Refer to transplant center Potential candidate NO Consider treatment SVR YES On dialysis, or likely KRT need within OPO median wait-time NO HCV+ kidney DAA SVR YES Decompensation/Portal HTN NO DAA SVR HCVkidney YES Advanced liver dx Pre-emptive/LD Short wait-time Pt. preference WAITLIST 1-3 Years Consider for SLK 4-8 Years HCV Management: Liver Candidates Many HCV+ donors Trotter s Treatment Triangle (3T s) few HCV + donors High Child s score NOT TREAT High transplant MELD low Child s score TREAT low transplant MELD 13

14 Summary HCV infection remains a highly prevalent issue in organ transplantation The approach to managing HCV in transplant patients is evolving rapidly in concert with emerging therapies The timing of DAA should be guided by optimizing access to transplant where indicated, and maximizing survival Pre- vs Post-transplant Early vs late post-transplant 14