Treatment of Hepatitis C Recurrence after Liver Transplantation Maria Carlota Londoño Liver Unit Hospital Clínic Barcelona
Agenda 1. Introduction 2. Treatment options for hepatitis C recurrence after transplantation - Clinical trials - Real life cohorts 3. Unsolved issues
Hepatitis C and Liver Transplantation Patient survival Years after transplantation Prieto et al, Hepatology 1999
Hepatitis C and Liver Transplantation p =.3 Survival RVS (n = 33) vs. NR (n = 56) 2 16 12 8 p =.4 6.7 12. p =.47 5. P=.32 4 3.5 No SVR (n = 26) SVR (n = 11) Follow-up (days) Carrion JA, et al. Gastroenterology 27 Berenguer M et al, Am J Transpl 28
Agenda 1. Introduction 2. Treatment options for hepatitis C recurrence after transplantation - Clinical trials - Real life cohorts 3. Unsolved issues
Sofosbuvir + RBV 4 LT recipients (>6mo) 1 1% 1% 33 were G1 16 cirrhotics DC due to AE =2 Relapse 9 patients Percentage (%) 8 6 4 2 77% 7% W4 EOT SVR4 SVR12 Charlton et al, Gastroenterology 215
Ombitasvir/Paritaprevir/r + Dasabuvir + RBV Mild-Moderate fibrosis (F-F2) n=34 G1a 85% HCV-RNA undetectable (%) 1 1 1 96 96 Anemia 17% 8 Rejection 6 Renal Impairement 4 Early Discontinuation 3% 2 SAEs 6% Deaths w4 EOT SVR4 SVR12 CNI adjustment (Tac.5mg/w and CyA 1/5 of previous dose) Kwo P, NEJM 214
Ledipasvir/Sofosbuvir + RBV W W 12 W 24 W 48 W 72 n=112 SOF/LDV+ RBV SVR12 SOF/LDV + RBV n=111 SVR12 Randomized trial (1:1), Genotype 1 or 4, naïve or treatment experienced F-F3, Child A, B, C Reddy et al, AASLD 214
Ledipasvir/Sofosbuvir + RBV 1 96 98 96 96 8 6 85 83 6 67 12 weeks 4 24 weeks 2 53/55 55/56 25/26 24/25 22/26 15/18 3/5 2/3 F-F3 Child A Child B Child C Reddy et al, AASLD214
Sofosbuvir + Simeprevir ± RBV p=.5 p=.4 p=ns 1 9 93 91 96 92 123 LT recipients 8 81 71 15 with SVR12 data 3% F3-F4 82% treatmentexperienced 12% PI failure SVR12% 6 4 2 All G1a G1b Global F-F2 F3-F4 Pungpapong et al, Hepatology 215
Sofosbuvir + Simeprevir ± RBV 143 LT recipients, >6% with cirrhosis, >2% with MELD>1, including PI failures 1 8 9 82 91 89 9 86 94 92 77 83 95 6 SVR4 (%) 4 2 RBV No RBV No Yes Yes No <1 1 1a 1b 61 /68 9/11 52/57 33/37 26/31 32/37 29/31 11/12 1/13 3/36 18/19 Overall SMV+SOF±RBV Previous treatment Cirrhosis MELD Genotype Brown et al, AASLD 214
Sofosbuvir + Daclatasvir ± RBV CULPIT cohort, 23 patients with FCH 1 8 1 1 93 1 1 1 88 88 SVR12% 6 4 38 35 2 8 15 8 15 8 15 8 13 8 11 W4 W12 W24 SVR4 SVR12 SOF+RBV SOF+DCV Leroy et al, AASLD 214
Simeprevir + Daclatasvir ± RBV RNA undetectable (%) 1 8 6 4 2 46 25 63 86 75 94 93 1 1 88 87 81 4 7 13 28 3 12 1 16 24 28 9 12 W2 W4 W12 EOT PTW12 15 16 26 28 11 11 14 16 2 23 7 7 13 16 All SMV+SOF SMV+DCV Londoño, AASLD 214
Agenda 1. Introduction 2. Treatment options for hepatitis C recurrence after transplantation - Clinical trials - Real life cohorts 3. Unsolved issues
Treatment After Liver Transplant: Unsolved Issues Which is the right time to start antiviral therapy? Is preemptive therapy a good option? Is there a point where we might be able to eradicate HCV but not to revert liver cirrhosis (liver function, portal hypertension)? Which one is the best regimen?
Treatment After Liver Transplant: Unsolved Issues Which is the right time to start antiviral therapy? Severe acute hepatitis/early recurrence (<12 months from liver transplant with typical biochemical and histological findings) n=52 Post transplant compensated and decompensated cirrhosis (liver biopsy (F4) or clinical decompensation) n=52 Early term due to AE n=7 Liver transplant n=12 Death n=13 SOF Compassionate Use Program SOF + RBV ± PEG n=14 Forns, et al. Hepatology 215
Treatment After Liver Transplant: Unsolved Issues Which is the right time to start antiviral therapy? Patients HCV RNA < LLOQ (%) 1 8 6 4 2 82 59 76/93 54/92 SVR(%) 1 8 6 4 2 73 43 EOT SVR Early Late Forns, et al. Hepatology 215
Treatment After Liver Transplant: Unsolved Issues Which is the right time to start antiviral therapy? 1 8 69 6 45 4 28 28 2 17 14 Early Late Improved Stable Worsened Forns, et al. Hepatology 215
Treatment After Liver Transplant: Unsolved Issues Is pre-emptive therapy a good option? Type of Advantages therapy Pre-emptive 1. It may prevent the infection of the graft 2. It may prevent the development of liver fibrosis Disadvantages 1. Difficult administration (renal function, potential for DDI, ability to take oral medications) 2. No data on safety and efficacy with DAAs. Mariño, Londoño & Forns. Current Opinion in Organ Transplant, accepted
Treatment After Liver Transplant: Unsolved Issues Is there a no-return point? CTP A Patients (n=48) CTP B Patients (n=41) 4 2-2 -4-6 12 Wk (n=23) 24 Wk (n=25) 12 Wk (n=21) 24 Wk (n=2) n=9 n=4 4 2-2 -4 n=4 n=1-8 (-11) -6-8 Reddy, AASLD, 214,
Treatment After Liver Transplant: Unsolved Issues Which one is the best regimen? - The degree of liver dysfunction - Renal function - Drug-drug interactions
Treatment After Liver Transplant: Unsolved Issues Which one is the best regimen? DRUG METABOLISM/ ELIMINATION CIRRHOSIS CTP-A CTP-B CTP-C RENAL FAILURE Sofosbuvir Kidney yes yes yes No if CrCl < 3 ml/min Simeprevir Liver yes yes no yes Paritaprevir/r Liver yes yes no yes Ledipasvir Liver yes yes yes yes Ombitasvir Liver yes yes yes yes Daclatasvir Liver yes yes yes yes Dasabuvir Liver yes yes yes yes
Treatment After Liver Transplant: Unsolved Issues Which one is the best regimen? Drug-drug interactions? Cyclosporine Tacrolimus Healthy volunteers Dose adjustment Healthy volunteers Dose adjustment Sofosbuvir No change Not necessary No change Not necessary Simeprevir SMV 19% Under investigation 17% Not necessary Daclatasvir No change Not necessary No change Not necessary Ledipasvir No change Not necessary No change Not necessary Paritaprevir/r 5.8 fold 5 fold 58 fold 1 fold Gambato et al, J Hepatol 214
Conclusions After liver transplantation, antiviral therapy administered in patients with mild fibrosis stages achieves higher response rates as compared to patients with cirrhosis and decompensation. The election of antiviral regimen should be based on patients characteristics (liver function, immunosuppression, renal function). The use of pre-emptive therapy needs further investigation. It is currently unknown if there is a no-return point in which antiviral therapy should not be administered.