Εξελίξεις στη θεραπεία της CHC Θεμιστοκλής Γ. Βασιλειάδης Επίκουρος Καθηγητής Παθολογίας Γ Παθολογική Κλινική ΑΠΘ Νοσοκομείο «Γ Παπαγεωργίου»
CHC AASLD-IDSA 2015
Recommendation for treatment
SVR: Sustained Virological Response
SVR Associated With Reduced 5-Yr Risk of Death and HCC in All Populations SVR on IFN-based therapy was associated with substantial benefit vs no SVR 62% to 84% reduction in all-cause mortality, 90% reduction in liver transplantation, 68% to 79% reduction in HCC 5-Yr Risk of All-Cause Death by SVR SVR No SVR 5-Yr Risk of HCC by SVR Pts Dead After 5 Yrs (%) 25 20 15 10 5 0 4.5 10.5 General 3.6 11.3 1.3 10.0 Cirrhotic Pts HIV- Coinfected Pts Pts With HCC After 5 Yrs (%) 25 20 15 10 5 0 2.9 9.3 General 5.3 13.9 0.9 10.0 Cirrhotic Pts HIV- Coinfected Pts Hill AM, et al. AASLD 2014. Abstract 44.
Ποιούς θεραπεύουμε
TREATMENT naïve CHC patients
The Good News 100 PegIFN DAAs 2011 2014 90+ 80 60 40 Standard IFN 1991 RBV 1998 34 42 2001 39 55 70+ 20 16 6 0 IFN 6 mos IFN 12 mos IFN/RBV 6 mos IFN/RBV 12 mos PegIFN 12 mos PegIFN/ RBV 12 mos PegIFN/ RBV/ DAA DAA + RBV ± PegIFN
HEPATITIS C VIRUS Genome 5 C E1 E2/NS 1 NS2 NS3 NS4A NS4B NS5A NS5B 3 Internal Ribosomal Entry Site RNA Binding Site Envelope Glycoproteins Signal peptide Serine protease/ helicase RNA dependent RNA polymerase STRUCTURAL PROTEINS NONSTRUCTURAL PROTEINS
HCV Life Cycle and DAA Targets NS5A inhibitors Block replication complex formation, assembly Receptor binding and endocytosis Transport and release Fusion and uncoating Translation and polyprotein processing (+) RNA LD ER lumen LD Virion assembly NS3/4 protease inhibitors ER lumen Membranous web LD NS5B polymerase RNA replication inhibitors Nucleoside/nucleotide RNA replication Nonnucleoside
How to Use Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir
Recommended Regimen Design According to Patient Population Duration and inclusion of ribavirin vary according to patient population GT1 subtype, presence of cirrhosis If subtype is unknown or is mixed, use as described for GT1a HIV coinfection: use regimen and duration as described for HCV monoinfection Population Regimen Duration GT1a, TN or TE, noncirrhotic OMV/PTV/RTV + DSV + RBV 12 wks GT1a, TN or TE, cirrhotic OMV/PTV/RTV + DSV + RBV 24 wks* GT1b, TN or TE, noncirrhotic OMV/PTV/RTV + DSV 12 wks GT1b, TN or TE, cirrhotic OMV/PTV/RTV + DSV + RBV 12 wks GT1, post-olt (Metavir 2) OMV/PTV/RTV + DSV + RBV 24 wks *12-wk course may be considered for some patients based on previous treatment history. Ombitasvir/paritaprevir/ritonavir and dasabuvir [package insert].
12 Wks of OMV/PTV/RTV + DSV + RBV in Noncirrhotic GT1a Pts SVR12 (%) 100 80 60 40 20 n/n = 0 Naive 96 97 308/ 322 97/ 100 SAPPHIRE-I PEARL-IV Experienced 96 95 100 166/ 173 83/ 87 36/ 36 SAPPHIRE-II 94 47/ 50 All Null responders Partial responders Relapsers Outcome for Subjects Without SVR12, % SAPPHIRE-I PEARL-IV SAPPHIRE-II Virologic failure < 1 1 0 Relapse 2 1 3 Other 2 1 1 Ombitasvir/paritaprevir/ritonavir and dasabuvir [package insert].
12 Wks of OMV/PTV/RTV + DSV Without RBV in Noncirrhotic GT1b Pts 100 80 Naive 100 Experienced 100 100 100 100 All Null responders Partial responders SVR12 (%) 60 40 Relapsers 20 n/n = 0 209/ 209 PEARL-III 91/ 91 32/ 32 26/ 26 PEARL-II Ombitasvir/paritaprevir/ritonavir and dasabuvir [package insert]. 33/ 33
TURQUOISE II: 12 vs 24 Wks of OMV/PTV/RTV + DSV + RBV in Cirrhotics Genotype 1a 12 wks 24 wks Genotype 1b 100 80 100 100 100 92 93 93 80 93 89 95 100 100 100 100 100 100 100 99 100 86 SVR12 (%) 60 40 20 n/n = 0 59/ 64 52/ 56 14/ 15 13/ 13 11/ 11 10/ 10 40/ 50 39/ 42 124/ 140 Naive Relapse Partial Null Overall Treatment Experienced 115/ 121 22/ 22 18/ 18 25/ 25 20/ 20 6/ 7 3/ 3 14/ 14 10/ 10 67/ 68 51/ 51 Naive Relapse Partial Null Overall Treatment Experienced Poordad F, et al. EASL 2014. Abstract O163. Poordad F, et al. N Engl J Med. 2014;370:1973-1982. Ombitasvir/paritaprevir/ritonavir and dasabuvir [package insert].
All-Oral Regimens for Other Populations Population Regimen Duration GT2 SOF + RBV [1] 12 wks GT3 SOF + RBV [1] 24 wks GT1/2/3/4 HCC pre-olt SOF + RBV [1] 48 wks* GT1, post-olt (Metavir 2) OMV/PTV/RTV + DSV + RBV [2] 24 wks GT1/4 decompensated cirrhosis (CTP B or C) SOF/LDV + RBV [3] 12 wks GT2/3 decompensated cirrhosis (CTP B or C) SOF + RBV [3] Up to 48 wks *Up to 48 wks or until transplantation, whichever occurs first. Not FDA approved but recommended in AASLD/IDSA guidance. 24 wks of SOF/LDV if anemia or RBV intolerance; 24 wks of SOF/LDV + RBV (600 mg/day with increasing dose if tolerated) if prior SOF failure. Refer to www.hcvguidelines.org for further information on how to use these therapies 1. Sofosbuvir [package insert]. 2. Ombitasvir/paritaprevir/ritonavir plus dasabuvir [package insert]. 3. AASLD/IDSA HCV Guidelines. Accessed January 5, 2015.
Επιστημονική Επιτροπή Ιογενούς Ηπατίτιδας- ΚΕΕΛΠΝΟ
Το κόστος των νεότερων φαρμάκων SOVALDI: 12600 Euro/Bt OLYSIO : 7500 Euro/Bt DACLATASVIR: 8000 Euro/Bt HARVONI(sofosbuvir+ledipasvir): 17131 Euro/Bt