DAA-based treatment in cirrhotic and post-transplanted patients. Audrey Coilly, MD Hôpital Paul Brousse, Villejuif, France

Transcription

1 DAA-based treatment in cirrhotic and post-transplanted patients Audrey Coilly, MD Hôpital Paul Brousse, Villejuif, France

2 Cirrhosis and transplantation 2 populations with similar issues Hepatic impairment Poor efficacy and safety of PEG-IFN regimen Rapid fibrosis progression in HIV-HCV co-infected patients leading to poor outcome

3 Agenda Cirrhotic patients Compensated decompensated Patients in the liver transplantation setting Pre-transplant Post-transplant

4 Agenda Cirrhotic patients Compensated decompensated Patients in the liver transplantation setting Pre-transplant Post-transplant

5 Where do we come from? In cirrhotic patients, data on literature show that patient could achieve a sustained virological response from: 10 to 44% genotypes 1 /4 33 to 72% genotypes 2/3 SVR rate in cirrhotic and co-infected patients 100% 80% 60% 66% 40% 20% 0% 30% 18% 21% G1 G2-3 Vezali E et al. Clin Ther 2010; 32:

6 Where do we come from? Cirrhosis Compensated Decompensated Genotype 1 Other genotypes No treatment Peg- IFN+RBV+BOCE/TELA Peg-IFN+RBV

7 1rst generation PI Some lessons Very few data on HIV-HCV co-infected and cirrhotic patients French multicenter cohort (n=511) Treatment-experienced, G1, cirrhotic patients BOC ou TELA +PR 48 weeks 65% 30% Dual therapy Triple therapy SVR rate Hezode C. Gastroenterology. 2014

8 1rst generation PI Some lessons Very few data on HIV-HCV co-infected and cirrhotic patients French multicenter cohort (n=511) Treatment-experienced, G1, cirrhotic patients BOC ou TELA +PR 48 weeks Hezode C. Gastroenterology. 2014

9 Where are we? Efficacy improves Compensated cirrhosis G1 Naive G1 Tt Exp weeks 24 weeks 12 weeks 24 weeks

10 Where are we? Efficacy improves Compensated cirrhosis naive Tt exp naive SOF+RBV 12 SOF+RBV 12 SOF+RBV 16 SOF+DAC 24 SOF+DAC+RBV 24 G2 G3 G2 and G3

11 Where are we? Safety improves Good tolerance profile AE linked to Peg-IFN and/or RBV use No hepatic decompensation Drugs Sofosbuvir Simeprevir Daclatasvir Side effects Headache Fatigue Follow the kidney function Mild to moderate rash Indirect hyperbilirubinemia Asthenia Nausea

12 Where we are? Liver function improves too! 50 patients with a decompensated cirrhosis treated with SOFO+RBV: 24 weeks on-treatment results Child-Pugh A and B, PHT gradient > 6 mmhg, varices SOF + RBV (n = 25) Ascites Observation (n = 25) Hepatic Encephalopathy SOF + RBV (n = 25) Observation (n = 25) baseline week week Afdhal N, Etats-Unis, EASL 2014, Abs. O68 actualisé

13 Where shall we go? G1 Naive G1a G1b ,2 92,

14 Where shall we go? G1 Tt Exp G1a G1b , , , Relapse or NR Relapse Partial R Nul R relapse Partial R Nul R Nul R

15 What will be taken into account? Hepatic impairment Mild Moderate Severe Avoid Simeprevir Child C? Sofosbuvir Ledipasvir Pas d ajustement ABT-450/r Child C Ombitasvir Dasabuvir Child C? Asunaprevi r Pharmacokinetic changes according to liver function Child B/C Daclatasvir

16 To sum-up Cirrhosis Compensated Decompensated Genotype 1-4 Genotype 2-3 Genotype 1-4 Genotype 2-3 SOF+DACLA±RBV SOF+SIME±RBV SOF+LEDI±RBV Quad therapy ABT (G1) SOF+RBV SOF+DACLA (G3) SOF+DACLA±RBV SOF+SIME±RBV (Child B) SOF+LEDI±RBV SOF+RBV SOF+DACLA (G3)

17 To sum-up Cirrhosis Compensated Decompensated Genotype 1-4 Genotype 2-3 Genotype 1-4 Genotype 2-3 SOF+DACLA±RBV SOF+SIME±RBV SOF+LEDI±RBV Quad therapy ABT (G1) SOF+RBV SOF+DACLA (G3) SOF+DACLA±RBV SOF+SIME±RBV (Child B) SOF+LEDI±RBV SOF+RBV SOF+DACLA (G3) Optimal duration? RBV use?

18 Agenda Cirrhotic patients Compensated decompensated Patients in the liver transplantation setting Pre-transplant Post-transplant

19 Hepatitis C and liver transplantation Analysis of 55,714 transplants in Europe 1 2% 20% of cirrhosis at 5 years post-lt 2 with a high rate of decompensation 1% 4% 4% 8% 9% 39% n=39 33% 40% Virus-related Viral and alcoholic Secondary biliary Primary biliary Alcoholic Autoimmune Unknown Others 1. ELTR 2. Berenguer M. Hepatology. 2000

20 Transplant patients with HCV RNA positive have the worst prognosis Mono-infected patients HIV-HCV co-infected patients p=0.04 HCV- 5 yrs: 58% HCV+ 11,791 LT from 1992 to LT from 1999 to Forman LM. Gastroenterology. 2002; 2. Duclos-Vallée. AASLD.2011

21 Two strategies to avoid recurrence Pre-transplant Liver transplantation Post-transplant

22 Two strategies to avoid recurrence Pre-transplant Liver transplantation Post-transplant

23 Where are we? SOF + RBV (N=61) Male, n (%) 49 (80) Median age, y (range) 59 (46 73) BMI < 30 kg/m 2, n (%) 43 (70) Genotype, % 1a/1b/2/3a/4 39/34/13/12/2 IL28B non-cc allele, n (%) 47/60 (78) CTP score, n (%) 5/6/7/8 43/30/23/5 Median MELD score, (range) 8 (6 14) Prior HCV treatment, n (%) 46 (75) Curry MP, et al. APASL Oral #201

24 Where are we? Virological responses No recurrence (n=29) Recurrence (n=10) % of patients who had >30 days TND did not have HCV recurrence 43/46 29/42 Transplant ptvr 12 Curry MP, et al. APASL Oral # Days

25 Two strategies to avoid recurrence Pre-transplant Liver transplantation Post-transplant

26 Poor results of PR therapy in HIV-HCV co-infected patients after LT Samuel D. J Hepatol. 2008

27 First generation protease inhibitors A transition 63% 81 Burton SVR 12 47% 81 Coilly Coilly A. J Hepatol. 2014, actualized; Burton J. J Hepatol 2014 % Coilly (n=81) Burton (n=81) Anemia Leukopenia 54 NA Thrombopenia 38 NA RBV reduction EPO RBC transfusion GCSF Elthrombopag 6 4 BPAR 12 2 Kidney Failure 7 38 Infection Death 7 9

28 Where are we? LT 6 months CPT 7 MELD 17 Samuel D, EASL 2014, P1232 SOF + RBV (N=40) Male, n (%) 31 (78) Median age, y (range) 59 (49 75) Genotype, %: 1a / 1b / 2 /3 / 4 55/28/0/15/3 Metavir-equivalent fibrosis stage, % F0 F2/F3/F4 38/23/40 Prior HCV treatment, % 88 Immunosuppressants (%): tacrolimus/ mycophenolate mofetil/prednisone/ciclosporin/azathioprine 70/35/ 28/25/5

29 Where are we? Both efficacy and tolerability improve Week 4 EOT SVR4 SVR12 SVR24 Good tolerance profile: no death, no rejection, no graft loss No drug-drug interaction with CNI Samuel D, EASL 2014, P1232

30 Where are we? Improvement of graft function Severe recurrence (cirrhosis, FCH ou severe acute hepatitis <1 one year posttransplant) SOFO+RBV±PEG-IFN, 24 to 48 weeks MELD median: 15 79% Patients (%) /104 22/104 Improved Stabilized 22/104 Worsened or died Forns X et al. EASL 2014, O62

31 Drug-drug interactions with CNI Dose reduction Tacrolimus Ciclosporine Boceprevir 5 2 Telaprevir 35 4 Simeprevir No adjustement No adjustement Sofosbuvir No adjustement No adjustement Daclatasvir No adjustement No adjustement ABT-450/r >10 5

32 To sum-up HCV recurrence Genotype 1-4 Genotype 3 Genotype 2 CNI dose adjestement SOFO+RBV SOFO+SIME±RBV SOFO+DACLA±RBV CNI dose adjustement G1 ABT-450/r + Ombistavir + Dasabuvir + RBV SOFO+DACLA±RBV SOFO+RBV SOFO+LEDI±RBV* SIME+DACLA±RBV* * On-going studies

33 To sum-up HCV recurrence Genotype 1-4 Genotype 3 Genotype 2 CNI dose adjestement SOFO+RBV SOFO+SIME±RBV SOFO+DACLA±RBV SOFO+LEDI±RBV* SIME+DACLA±RBV* * On-going studies CNI dose adjustement G1 ABT-450/r + Ombistavir + Dasabuvir + RBV SOFO+DACLA±RBV Optimal timing? SOFO+RBV Optimal duration? RBV use?

34 Clinical case Female patient, 54 years, HIV-HCV coinfection, G4, naive With a FCH at 2 months post-lt 25 LT SOFO+DACLA+RBV 20 HCV RNA (log IU/mL) Bilirubin level (mg/dl) Ascites disappearance Severe cytopenia during treatment 5 0 Before LT Day 0 Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 Month 7 Month 8 Month 9 Personal data

35 Key messages Current IFN-based regimen have a low efficacy profile and a poor safety profile in patients on the awaiting list and after liver transplantation to treat HIV-HCV infection Preliminary data on IFN-free regimens are very encouraging as they do not only improve efficacy and safety results but they also dramatically facilitate the management of HCV treatment in LT setting Although data are lacking, I am convinced that HIV-HCV coinfected patients will be no exception In the next future, we will be able to cure almost all the patients in this setting, with the ultimate goal of not transplanting patients in this indication anymore

36 Acknowledgments Centre Hépato-Biliaire Virologues S Haïm-Boukobza AM Roque-Afonso D Samuel JC Duclos-Vallée F Saliba G Pelletier T Antonini F Artru M Boudon E De Martin P Ichai B Roche R Sobesky Anatomopathologistes M Sebagh C Guettier