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HCV treatment focusing on transplant setting in the era of DAA

HCV treatment focusing on transplant setting in the era of DAA. Yonsei University College of Medicine Gangnam Severance Hospital Jung Il Lee. HCV Prevalence. Nguyen LH, Nguyen MH. Aliment Pharmacol Ther 2013;37:921–36.

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HCV treatment focusing on transplant setting in the era of DAA

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  1. HCV treatment focusing on transplant setting in the era of DAA Yonsei University College of Medicine Gangnam Severance Hospital Jung Il Lee

  2. HCV Prevalence Nguyen LH, Nguyen MH. Aliment Pharmacol Ther 2013;37:921–36.

  3. Proportion of liver transplantation for HCV was gradually increased in Korea A total of 5,663 adult liver transplantations (LTs)were performed between 2000 and 2010. HCV-related liver disease was responsible for 277 LTs (4.9%). The annual proportion of LT for HCV fluctuated during the study period, but largely showed a gradually increasing pattern Annual proportion of liver transplantation for hepatitis C virus (HCV) Although <20% of patients transplanted for HCV may have no significant lesions 5 years after LT, most recipients display progressive chronic hepatitis, which is clearly more aggressive than in immunocompetent subjects, and leads to cirrhosis in 10∼50% of recipients at 5 years post-LT. 8 7.4 7 3 6 4 2 1 5 5.6 6.3 5.2 5.2 5.3 Proportion (%) 3.0 3.7 2.9 2.2 1.3 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Year Lee HW, et al. J Korean Soc Transplant. 2012;26:269-76.

  4. HCV and Liver Transplantation • Recurrence of HCV infection post-transplant occurs in nearly all transplanted patients • Post–liver transplantation outcomes are worse for those who undergo transplantation for HCV than other etiologies • Progression to graft cirrhosis and subsequent complications can be rapid and compromises patient and graft survival • Fibrosingcholestatic hepatitis: 2 ~ 8% • Peg-IFN + RBV-based therapy is poorly tolerated in patients with advanced liver disease on transplant waiting lists and also in post-transplant patients with deteriorating liver function

  5. Post-transplant survival rate is lower in HCV+ recipient vs HCV- recipients Factors Leading to Worse Outcome2 100 HCV– 75 HCV+ Patient Survival, % 50 25 0 0 365 730 1095 1460 1825 2190 2555 2920 3285 3650 Days Since Transplant • Based on 2009 OPTN/SRTR Annual Report and deceased donor transplants • Significant differencein unadjusted 3-year and 5-year patient survival between HCV-positive (82%, 75%) and HCV-negative (86%, 81%, P<0.0001) recipients with living donor liver transplants 1. Thuluvath et al. Am J Transplant. 2010 ;10(4 Pt 2):1003; 2. Wertheim et al. Am J Transplant. 2011;11:1773.

  6. Problems concerning treatment In Pre- and Post-transplant setting has been… • Pre-transplantation • Poor tolerance of Peg-IFNregimens • Impaired hepatic metabolism • Renal insufficiency • Post-transplantation • Impact of immunosuppression • Drug–drug interactions • Rejection • Outcome of recurrence: accelerated fibrosis in post-transplant patients with recurrence • Overall SVR rates with Peg-IFN plus RBV are low, ranging between 10 and 40%

  7. Progress in HCV Treatment The great days are coming !! ≒ 90~100 Simeprevir or Sofosbuvir + P/R Boceprevir or Telaprevir + P/R 67~75 Interferon + Ribavirin SVR (%) 2015 2011 2013 54~56 GT1 IFN-free DAA combinations (GT1) 1991 1998 2001 38~43 GT2/3 25~30 2013 Peginterferon/ Ribavirin Standard Interferon 15~20 Sofosbuvir + Ribavirin 8~12 IFN 12~18m IFN/RBV 6~12m PegIFN 6~12m PegIFN/RBV 6~12m PI + PegIFN/RBV 6~12m IFN 6m DAAs

  8. Direct Acting Agents (DAAs) C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B

  9. Sofosbuvir + Ribavirin to Prevent Post-Transplant HCV recurrence Curry MP, et al. Gastroenterology. 2015;148:100-7.

  10. Sofosbuvir + Ribavirin to Prevent Post-Transplant HCV recurrence Virologic Response at Transplant and Post-Transplant 43/46 31/43 31/43 30/43 Data for the 43 patients with HCV RNA <25 IU/mL at time of transplant Curry MP, et al. Gastroenterology. 2015;148:100-7.

  11. Duration of undetectable HCV RNA before transplant predicted lack of recurrence • 64% of pts HCV RNA negative 12 wks post-LT (93% at LT) • Continuous days TND pre-LT only factor predicting HCV recurrence in multivariate analysis • Only 1/24 pts with > 30 days TND experienced recurrence Median days undetectable(P < 0.001) • No recurrence: 95 • Recurrence: 5.5 > 30 days TND (target not detected) No recurrence (n = 28)Recurrence (n = 10) 0 30 60 90 120 150 180 210 240 270 300 330 Days With HCV RNA Continuously TND Prior to Liver Transplant Curry MP, et al. Gastroenterology. 2015;148:100-7.

  12. Sofosbuvir-Ledipasvir+ Ribavirin in Decompensated and Post liver transplant HCV GT 1,4 SOLAR-1 and SOLAR-2 study Week 0 12 24 36 Pre-Transplant CTP B (7–9) CTP C (10–12) LDV/SOF + RBV Post-Transplant Fibrosis (F0–F3) CTP A (5–6) LDV/SOF + RBV SVR12 SVR12 CTP B (7–9) CTP C (10–12) FCH • Broad inclusion criteria: • No hepatocellular carcinoma (HCC) • Total bilirubin ≤ 10 mg/dL, Hemoglobin ≥ 10 g/dL • CrCl ≥ 40 mL/min, Platelets > 30,000/mL • RBV dosing • F0–F3 and CTP A cirrhosis: weight-based (< 75 kg = 1000 mg; ≥ 75 kg = 1200 mg) • CTP B and C cirrhosis: dose escalation, 600–1200 mg/d Charlton M, et al. Gastroenterology2015;149:649-59; Reddy, AASLD, 2014, Oral #8; Manns, EASL, 2015,

  13. Sofosbuvir-Ledipasvir + Ribavirin in Decompensated and Post liver transplant HCV GT 1,4 Charlton M, et al. Gastroenterology2015;149:649-59; Reddy, AASLD, 2014, Oral #8; Manns, EASL, 2015,

  14. Sofosbuvir-Ledipasvir + Ribavirin in Pre-transplant HCV GT 1,4 SOLAR-1 SOLAR-2 SVR12 (%) 26/30 22/26 24/27 24/25 19/22 17/21 20/23 14/20 LDV/SOF + RBV 12 wks LDV/SOF + RBV 24 wks LDV/SOF + RBV 12 wks LDV/SOF + RBV 24 wks CTP B CTP C Comparable efficacy between SOLAR-1 and SOLAR-2 studies The SVR12 analysis included all subjects except those who had undergone transplantation prior to SVR12 at last visit prior to transplantation. Error bars represent 90% confidence intervals. Charlton M, et al. Gastroenterology2015;149:649-59; Reddy, AASLD, 2014, Oral #8; Manns, EASL, 2015,

  15. Sofosbuvir-Ledipasvir + Ribavirin in Post-transplant HCV GT 1,4 SOLAR-1 SOLAR-2 SVR12 (%) 78/81 82/86 79/81 64/65 22/26 21/22 23/26 19/19 3/5 3/4 3/4 1/3 LDV/SOF + RBV 12 wks LDV/SOF + RBV 24 wks LDV/SOF + RBV 12 wks LDV/SOF + RBV 24 wks LDV/SOF + RBV 12 wks LDV/SOF + RBV 24 wks F0-F3 & CTP A CTP B CTP C Comparable efficacy between SOLAR-1 and SOLAR-2 studies The SVR12 analysis included all subjects except those who had undergone transplantation prior to SVR12 at last visit prior to transplantation. Error bars represent 90% confidence intervals. Charlton M, et al. Gastroenterology2015;149:649-59; Reddy, AASLD, 2014, Oral #8; Manns, EASL, 2015,

  16. Sofosbuvir-Ledipasvir + Ribavirin in Decompensated and Post liver transplant HCV GT 1,4 • Treatment-related SAEs were mostly related to RBV treatment • Deaths and AEs that led to D/C of LDV/SOF were not attributed to study treatment LDV/SOF+RBV was safe and well tolerated in decompensated cirrhosis and post-transplantation Charlton M, et al. Gastroenterology2015;149:649-59; Reddy, AASLD, 2014, Oral #8; Manns, EASL, 2015,

  17. ‡ SOLAR-2: LDV/SOF + RBV in Decompensated and Post-Liver Transplant Patients Liver Function Change from Baseline to Follow-Up Week 4 MELD Score Change Change in CTP Class Pre/Post-Transplant (CTP B and C, n=136*) Change in MELD Score n=95 n=18 n=22 no assessment: CTP A, n=3; CTP B, n=12; CTP C, n=12 *Missing FU-4: n=24 Majority of patients showed improvements in MELD and CTP scores (+8) (-11) (-17) Manns, EASL, 2015, GO2

  18. DCV + SOF + RBV in Advanced cirrhosis and Post-Liver Transplant : ALLY-1 Poordad F, et al. Hepatology. 2016 January 11. [Epub ahead of print]

  19. DCV + SOF + RBV in Advanced cirrhosis and Post-Liver Transplant : ALLY-1 ALLY-1: SVR12 Results for Advanced Cirrhosis Cohort by Genotype 50/60 26/34 11/11 4/5 5/6 4/4 0/0 Poordad F, et al. Hepatology. 2016 January 11. [Epub ahead of print]

  20. DCV + SOF + RBV in Advanced cirrhosis and Post-Liver Transplant : ALLY-1 ALLY-1: SVR12 Results for Advanced Cirrhosis Cohort by CTP 50/60 11/12 30/32 9/16 Poordad F, et al. Hepatology. 2016 January 11. [Epub ahead of print]

  21. DCV + SOF + RBV in Advanced cirrhosis and Post-Liver Transplant : ALLY-1 ALLY-1: SVR12 Results for Post-Transplant Cohort by Genotype 50/53 30/31 9/10 0/0 10/11 0/0 1/1 Poordad F, et al. Hepatology. 2016 January 11. [Epub ahead of print]

  22. Guidance for Decompensated Cirrhosis KASL HCV Guidelines 2015 .

  23. Guidance for Recurrent HCV Post Liver Transplant KASL HCV Guidelines 2015 .

  24. Drug-Drug interactions between HCV DAAs and immunosuppresants www.hep-druginteractions.org(University of Liverpool) Tischer S et al. J Hepatol 2014;60:872-84.

  25. Drug-Drug interactions between HCV DAAs and lipid lowering drugs EASL HCV Guidelines 2015 .

  26. Drug-Drug interactions between HCV DAAs and cardiovascular drugs EASL HCV Guidelines 2015 .

  27. Summary and Key Messages • HCV eradication in advanced liver disease • Reduces decompensation • Does not prevent HCC • Prevents HCV recurrence post-transplant • IFN-based therapy is suboptimal in decompensated cirrhosis and post-transplantation • Lower SVR rate • Higher toxicity • Data with new DAAs evolving • Promise for IFN-free therapy pre- and post-transplant • High efficacy and significantly improved tolerability • As choices increase, the factors that are likely to influence treatment choices are • Drug-Drug interactions • Availability/Cost • Previous treatment experience (resistance)

  28. Cure Assessment Testing Treatment Counseling Screening Thank you !

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