Recurrent HCV after a Pre-LTx Course of SOF/DAC: Didier Samuel, Teresa Antonini Centre Hépato-Biliaire, Inserm Paris Sud Research Unit 1193 Hôpital Paul Brousse, Villejuif, France 3 rd Optimize Workshop, Using DAAs in Patients with Cirrhosis and Liver Recipients, Wien
Case presentation: M. D, 56 y History of HCV: Transfusional contamination Genotype 1a IL-28B polymorphism CT Peg IFN/RBV 2005 Non responder
Case presentation Liver function: Albumin: 37 g/l Total Bilirubin: 22 μmol/l Prothrombin: 75%, INR 1.2 Creatinine: 80 μmol/l Platelet count: 120x10 9 /L Mild ascites No hepatic encephalopathy
Case presentation Liver function: Albumin: 37 g/l Total Bilirubin: 22 μmol/l Prothrombin: 75%, INR 1.2 Creatinine: 80 μmol/l Platelet count: 120x10 9 /L Mild ascites No hepatic encephalopathy Child-Pugh Score A 6 MELD 9
Case presentation Hepatocellular carcinoma: 1 Nodule 3 cm, segm VI-VII Successfully treated by microwave ablation in 2012
Strategy?
Strategy? Anti HCV therapy?
Strategy? Anti HCV therapy? Liver Transplantation
Strategy? Anti HCV therapy? Before Liver Transplantation After Liver Transplantation
Impact of SVR: Risk of death HCV HCV/F4 HCV/HIV 0-10 Meta-analysis 15 studies N= 34 563 patients Réduction of death % -20-30 -40-50 -60-70 -80-71 -62-73 -75-73 -90-84 Univariate Multivariate Hill AM, AASLD 2015
Impact of SVR: Risk of HCC 20 18 16 14 HCV n = 12 496 Follow-up 6,1 y HCV/F4 n = 4 987 Follow-up 6,6 y 13,9 Co-infected HCV/HIV n = 2 085 Follow-up 4,7 y Meta-analysis 15 studies N= 34 563 patients % pts after 5 y 12 10 8 6 9,3 5,3 10 4 2,9 2 0,9 0 HCV HCV/F4 HCV/HIV SVR Non SVR Hill AM, AASLD 2015
Impact of SVR: Risk of LT 20 18 HCV n = 108 Follow-up 4,2 y HCV/F4 n = 1 046 Follow-up 7,7 y VIH VHC n = 2 039 Follow-up 4,9 y Meta-analysis 15 studies N= 34 563 patients Patients after 5 y (%) 16 14 12 10 8 6 4 2 0 0 HCV 2,2 SVR 7,3 0,2 HCV/F4 Non SVR 2,7 0,6 HIV/HCV Hill AM, AASLD 2015
Sofosbuvir/Ledipasvir/RBV in Decompensated Cirrhotics 12 Improvement (n = 33) Stability (n = 10) Worsening (n = 4) Child- Pugh Score 11 10 9 8 7 6 5 (n = 2) (n = 3) (n = 5) Flamm SL et al, AASLD, 2014
Forman, Gastroenterology 2002 High risk of recurrence HCV recurrence is universal Natural history of HCV is accelerated compared to non-transplant setting 30% of patients develop cirrhosis at 5 years post-lt
What Type of Treatment ( France 2012)?
2 nd Treatment Peg IFN/RBV/Tela Peg α2a: 180 μg/w RBV: 1000 mg/d (15mg/Kg) Telaprevir: 750 mg/tid
2 nd Treatment Peg IFN/RBV/Tela Peg α2a: 180 μg/w RBV: 1000 mg/d (15mg/Kg) Telaprevir: 750 mg/tid 8 log 7 6 5 4 3 log 2 1 0 W4 W8 W12
2 nd treatment Peg IFN/RBV/Tela Peg α2a: 180 μg/w RBV: 1000 mg/d (15mg/Kg) Telaprevir: 750 mg/tid 8 7 6 5 4 3 2 1 log STOP log 0 W4 W8 W12
2 nd Treatment Peg IFN/RBV/Tela Peg α2a: 180 μg/w RBV: 1000 mg/d (15mg/Kg) Telaprevir: 750 mg/tid 8 7 6 5 4 3 2 1 log STOP Mutation R155K 0 W4 W8 W12
2 nd Treatment Peg IFN/RBV/Tela Peg α2a: 180 μg/w RBV: 1000 mg/d (15mg/Kg) Telaprevir: 750 mg/tid
Case presentation Deteriorating Liver function : Albumin: 24 g/l Total Bilirubin: 27 μmol/l Prothrombin: 58%, INR 1.56 Creatinine: 100 μmol/l Mild ascites No hepatic encephalopathy Child-Pugh Score B7 MELD 14 REFERRED FOR OLT
3rd Treatment before LT? Peg IFN/RBV Peg IFN/RBV/Tela? 2005 Non responder 2012 Non responder R155K
3rd Treatment before LT? SOF/RBV? SOF/SIM? SOF/DCV? SOF/LDV? Omb- ABT450/r Dasa+RBV?
3rd treatment before LT? SOF/ RBV? Osinusi A et al. Jama 2013
3rd treatment before LT? SOF/ RBV? SOF/ SIM? SOF/ DCV? SOF/ LDV? Omb- ABT450/r Dasa+ RBV?
SOF/ SIM? 3rd Treatment before LT? www.hcvforum.org
3rd treatment before LT? SOF/ RBV? SOF/ SIM? SOF/ DCV? SOF/ LDV? Omb- ABT450/r Dasa+ RBV?
SOF/DCV SVR12% Sukowski M et al.nejm 2014
3rd Treatment before LT? SOF/ RBV? SOF/ SIM? SOF/ DCV? SOF/ LDV? Omb- ABT450/r Dasa+ RBV?
3rd treatment before LT? SOF/ RBV? SOF/ SIM? SOF/ DCV? SOF/ LDV? Omb- ABT450/r Dasa+ RBV? NOT AVAILABLE AT THAT TIME IN FRANCE
3rd Treatment before LT? Peg IFN/RBV 2005 Non responder Peg IFN/RBV/Tela 2012 Non responder R155K SOF/ DCV
3 rd Treatment Sofosbuvir Daclatasvir SOF= 400mg/d DCV= 60mg/d
3 rd Treatment Sofosbuvir Daclatasvir SOF= 400mg/d DCV= 60mg/d STOP
3 rd Treatment Sofosbuvir Daclatasvir SOF= 400mg/d DCV= 60mg/d STOP Mutation 31M,58P
3 rd treatment Sofosbuvir Daclatasvir Mutation 31M,58P http://www.genafor.org
3 rd treatment Sofosbuvir Daclatasvir Mutation 31M,58P
SOF/ RBV? Finally.. SOF/S IM? SOF/ DCV? Omb- ABT450/r Dasa+ RBV? SOF/LD V?
SOF/ RBV? Finally.. SOF/S IM? SOF/ DCV? Omb- ABT450/r Dasa+ RBV? SOF/LD V?
SOF/ RBV? Finally.. SOF/S IM? Omb- ABT450/r Dasa+ RBV? Virological Resistance SOF/ DCV? SOF/LD V?
SOF/ RBV? Finally.. SOF/S IM? Omb- ABT450/r Dasa+ RBV? Virological Resistance SOF/ DCV? SOF/LD V? Virological Resistance
And Now?
Resistant variants Potent antiviral therapy eliminates sensitive variants Resistant variants can expand
Resistant variants Persistance of resistant virus Potent antiviral therapy eliminates sensitive variants Return to pre-treatment status
Finally.. - HCV population and clonal amino acid analyses in patient treated by PI, suggest that PI resistant population may return to pre-treatment levels over time For telaprevir, 60-89% of patients no longer had detectable resistant variants after a median FU of 10,6 months for G1a Sullivan et al, CID 2013
DISCUSSION -This patient developed NS5A resistance in addition to PI s resistance. -No clear identified Strategy - Retreat before LT? Whith what drug? - Treat after LT? - Add IFN to decrease resistance? - Add RBV? - Assess mutation before retreatment?