Stick or twist management options in hepatitis C Dr. Chris Durojaiye & Dr. Matthijs Backx SpR Microbiology and Infectious Diseases University Hospital of Wales, Cardiff
Patient history 63 year old female Von Willebrand disease HCV genotype 1 diagnosed 1993 Acquired through pooled blood product Interferon treatment 1994 stopped due to side effects Interferon + ribavirin treatment 1997 responder relapser Cirrhosis 2010 Varices 2011 Asthma, hypertension, IBS, obesity, psoriasis
Patient history Patient previously very anxious about treatment with pegylated interferon and ribavirin Phase III trials of protease inhibitors boceprevir and telaprevir published in NEJM 2011 Blood results (in 2012) FBC Hb 11.7, WBC 4.5, Plt 132 U&E Na 140, K 2.9, Ur 3.9, Cr 74 LFTs Alb 26, Alp 221, ALT 35, Bili 24 Compensated cirrhosis (Child-Pugh B, MELD 8) REALIZE study team. Telaprevir for Retreatment of HCV infection. N Engl J Med 2011; 364: 2417-28 RESPOND-2. Boceprevir for Previously Treated Chronic HCV Genotype 1. N Engl J Med 2011; 364: 1207-17
The trials Telaprevir 12 weeks +/- pegylated interferon and ribavirin lead-in REALIZE study team. Telaprevir for Retreatment of HCV infection. N Engl J Med 2011; 364: 2417-28
Question 1 What would you recommend? A No treatment B Treatment with pegylated interferon and ribavirin C Treatment with pegylated interferon and ribavirin and Boceprevir D - Treatment with pegylated interferon and ribavirin and Telaprevir
Treatment Cirrhotics are at high risk of:- Decompensation (3.5-3.8% annually) Hepatocellular carcinoma (2.8-2.9% annually) Liver related death (2.4-3.0% annually) SVR reduces these risks Bruno et al. Predicting Mortality Risk in Patients with compensated HCVinduced cirrhosis: A long-term prospective study. Am J Gastroenterol 2009; 104:1147-58
Patient history Patient reviewed by the Liver and Hepatobiliary Unit Birmingham Compensated cirrhosis Likely excellent response to protease inhibitors Suggest telaprevir shorter exposure Treatment may result in decompensation and in most extreme circumstance death After weighing up benefits and risks patient opts for treatment
Question 2 Would you lead-in with pegylated interferon and ribavirin before commencing telaprevir? A No B Yes primarily to assess tolerability C Yes primarily to assess compliance D Telaprevir is not licensed for lead in and so you can t lead in with this product
Lead-in Lowering HCV RNA theoretically reduces the risk of resistance to protease inhibitor Lack of interferon responsiveness related to lower SVR rates Addition of protease inhibitor to poor responders still leads to significantly improved SVR rates Test of commitment and resolve Foster GR et al. Subanalyses of the Telaprevir lead-in arm in the REALIZE study. Presented at EASL 2011
Patient history Decision was made to treat without lead-in Previously tolerated interferon and ribavirin therapy Previously had a good response to interferon therapy Treatment would have been continued regardless of lead-in response
Patient history Patient developed nausea and vomiting week 1 Decision made to stop therapy after week 2 due to side effects and blood parameters Pre treatment Week 1 Week 2 Hb 11.7 11.2 9.2 Plt 132 61 52 Bili 24 65 143 Cr 74 132 136 Alb 26 24 25 VL 58,000 96
The real world Exclusion criteria telaprevir REALIZE trial Subject has history of decompensated liver disease: history of ascites, hepatic encephalopathy, or bleeding esophageal varices, and/or any of the following screening laboratory results: International Normalized Ratio (INR) of 1.5; Serum albumin < 3.3 g/dl; Serum total bilirubin > 1.8 times ULN, unless isolated and for subjects with Gilbert s syndrome. Subject has screening laboratory values of the following variables that do not meet the acceptable values defined below: Absolute neutrophil count 1,200/mm3 Platelet count 90,000/mm3 Hemoglobin 12 g/dl for females 13 g/dl for males REALIZE study team. Telaprevir for Retreatment of HCV infection. N Engl J Med 2011; 364: 2417-28
The real world CUPIC cohort CUPIC cohort. Journal of Hepatology 2013; 59: 434-441
SVR12 (%) The real world CUPIC cohort CUPIC cohort. Journal of Hepatology 2013; 59: 434-441 100 80 Telaprevir + P/R Boceprevir + P/R 60 53 51 40 40 41 32 40 29 20 n/n = 0 118/ 295 79/ 190 61/ 116 43/ 85 43/ 135 32/ 80 8/ 11 28 1/9 Overall Relapsers Partial Response Null Response Previous Response to P/R Fontaine H, et al. EASL 2013. Abstract 60. Reproduced with permission.
The real world 12% (REALIZE) 13% (REALIZE) CUPIC cohort. Journal of Hepatology 2013; 59: 434-441
Risk stratification Platelet count (10 9 /L) Complications / death (n (%)) Albumin (g/l) Complications/ death (n (%)) 50 3 (25%) 32 9 (32%) 51-80 8 (16%) 33-34 8 (27%) 81-100 8 (16%) 35-36 3 (9%) 101-120 7 (11%) 37-38 2 (4%) 121-150 4 (4%) 39-40 3 (4%) >150 2 (1%) >40 5 (2%) CUPIC cohort. J of Hep 2013; 59: 434-441 FACTORS Platelet count >100,000/mm 3 Platelet count <100,000/mm 3 Albumin 35 g/l 3.4% (10/298) 4.3% (3/69) Albumin <35 g/l 7.1% (2/28) 44.1% (15/34)
Question 3 What would you have offered this patient? A No treatment B treatment with pegylated interferon and ribavirin C treatment with pegylated interferon and ribavirin and Boceprevir D - treatment with pegylated interferon and ribavirin and Telaprevir
The future HPA. Hepatitis C in the UK: 2012 Report
The future NS5B nucleotide analogue polymerase inhibitor Class Drug Genotype Development Sofosbuvir (GS-7977) Pangenotypic Phase III NS3A protease inhibitor Faldaprevir (BI 201335) GT 1, 4, 5, 6 Phase III NS3A protease inhibitor Simeprevir (TMC435) GT 1, 2, 4, 5, 6 Phase III