Treatment of Hepatitis C Recurrence after Liver Transplantation. Maria Carlota Londoño Liver Unit Hospital Clínic Barcelona

Transcription

1 Treatment of Hepatitis C Recurrence after Liver Transplantation Maria Carlota Londoño Liver Unit Hospital Clínic Barcelona

2 Agenda 1. Introduction 2. Treatment options for hepatitis C recurrence after transplantation - Clinical trials - Real life cohorts 3. Unsolved issues

3 Hepatitis C and Liver Transplantation Patient survival Years after transplantation Prieto et al, Hepatology 1999

4 Hepatitis C and Liver Transplantation p =.3 Survival RVS (n = 33) vs. NR (n = 56) p = p = P= No SVR (n = 26) SVR (n = 11) Follow-up (days) Carrion JA, et al. Gastroenterology 27 Berenguer M et al, Am J Transpl 28

5 Agenda 1. Introduction 2. Treatment options for hepatitis C recurrence after transplantation - Clinical trials - Real life cohorts 3. Unsolved issues

6 Sofosbuvir + RBV 4 LT recipients (>6mo) 1 1% 1% 33 were G1 16 cirrhotics DC due to AE =2 Relapse 9 patients Percentage (%) % 7% W4 EOT SVR4 SVR12 Charlton et al, Gastroenterology 215

7 Ombitasvir/Paritaprevir/r + Dasabuvir + RBV Mild-Moderate fibrosis (F-F2) n=34 G1a 85% HCV-RNA undetectable (%) 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

8 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

9 Ledipasvir/Sofosbuvir + RBV 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

10 Sofosbuvir + Simeprevir ± RBV p=.5 p=.4 p=ns LT recipients with SVR12 data 3% F3-F4 82% treatmentexperienced 12% PI failure SVR12% All G1a G1b Global F-F2 F3-F4 Pungpapong et al, Hepatology 215

11 Sofosbuvir + Simeprevir ± RBV 143 LT recipients, >6% with cirrhosis, >2% with MELD>1, including PI failures 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

12 Sofosbuvir + Daclatasvir ± RBV CULPIT cohort, 23 patients with FCH SVR12% W4 W12 W24 SVR4 SVR12 SOF+RBV SOF+DCV Leroy et al, AASLD 214

13 Simeprevir + Daclatasvir ± RBV RNA undetectable (%) W2 W4 W12 EOT PTW All SMV+SOF SMV+DCV Londoño, AASLD 214

14 Agenda 1. Introduction 2. Treatment options for hepatitis C recurrence after transplantation - Clinical trials - Real life cohorts 3. Unsolved issues

15 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?

16 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

17 Treatment After Liver Transplant: Unsolved Issues Which is the right time to start antiviral therapy? Patients HCV RNA < LLOQ (%) /93 54/92 SVR(%) EOT SVR Early Late Forns, et al. Hepatology 215

18 Treatment After Liver Transplant: Unsolved Issues Which is the right time to start antiviral therapy? Early Late Improved Stable Worsened Forns, et al. Hepatology 215

19 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

20 Treatment After Liver Transplant: Unsolved Issues Is there a no-return point? CTP A Patients (n=48) CTP B Patients (n=41) Wk (n=23) 24 Wk (n=25) 12 Wk (n=21) 24 Wk (n=2) n=9 n= n=4 n=1-8 (-11) -6-8 Reddy, AASLD, 214,

21 Treatment After Liver Transplant: Unsolved Issues Which one is the best regimen? - The degree of liver dysfunction - Renal function - Drug-drug interactions

22 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

23 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

24 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.