Massimo Puoti SC Malattie Infettive AO Ospedale Niguarda Cà Granda, Milano Eradicazione da HCV e nuove prospettive: Prospetive Terapeutiche future
DAA classes and subclasses Drug Class Subclass Potency Resistance barrier Protease inhibitors - previr 1 st Generation first wave i.e. Telaprevir/Boceprevir 1 st Generation 2 nd wave i.e. Simeprevir/Asunaprevir Paritaprevir/r Medium- Low Medium Low Low 2 nd Generation Grazoprevir (in vivo) ABT 493 (in vitro) High High NS5a inhibitor..asvir 1 st Generation Daclatasvir, Ledipasvir Ombitasvir, High Medium- High Ppolymerase inhibitors..buvir NN 2 nd Generation Velpatasvir Elbasvir (in vivo) ABT530 (in vitro) Dasabuvir Beclobuvir High Low- Medium High Nucleos/tides 2 nd Generation : Sofosbuvir High High Low 2
ABT-530 & ABT-493 in vitro activity against HCV Genotype NS5A & NS3 Resistanceassociated Variants in vitro Ng T et al AASLD 2014
DAA classes and subclasses Drug Class Subclass Potency Resistance barrier Protease inhibitors - previr 1 st Generation first wave i.e. Telaprevir/Boceprevir 1 st Generation 2 nd wave i.e. Simeprevir/Asunaprevir Paritaprevir/r Medium- Low Medium Low Low 2 nd Generation Grazoprevir (in vivo) ABT 493 (in vitro) High High NS5a inhibitor..asvir 1 st Generation Daclatasvir, Ledipasvir Ombitasvir, High Medium- High Ppolymerase inhibitors..buvir NN 2 nd Generation Velpatasvir Elbasvir (in vivo) ABT530 (in vitro) Dasabuvir Beclobuvir High Low- Medium High Nucleos/tides 2 nd Generation : Sofosbuvir High High Low 8
CONSEQUENCES OF HCV VARIABILITY AT POPULATION LEVEL: HCV GENOTYPES
HCV protein variability 47% amino acid of HCV PROTEASE NS3 are conserved among All HCVgenotypes Amino acid variability: 0% <1% 1-5% 5-10% 10-25% >25% 46.1% amino acid of HCV NS5A are conserved among All HCV-genotypes 54.8% amino acid of HCV POLYMERASE NS5B are conserved among All HCV-genotypes Amino acid variability: 0% <1% 1-5% 5-10% 10-25% >25% Cento et al., PLoS ONE 2012 Love et al., J Vir 2009 Di Maio et al., submitted 2013
DAA classes and subclasses: antiviral potency and resistance barrier according to HCV genotype Drug Class Subclass 1 b 1a 2 3 4 Protease inhibitors NS5a Inhibitor NN Polymerase Inhibitors Nucleos/tides Polymerase inhibitors 1 st Generation first wave i.e. Telaprevir/Boceprevir 1 st Generation 2 nd wave i.e. Simeprevir Paritaprevir/r Asunaprevir 2nd Generation Grazoprevir ABT 493 1 st Generation Ledipasvir Ombitasvir Elbasvir Daclatasvir Dasabuvir 2 nd Generation : Sofosbuvir High Moderate Low Very low
In Vitro activity of upcoming NS5A inhibitors
In Vitro activity of upcoming NS3/NS4 inhibitors
DAA classes and subclasses: antiviral potency and resistance barrier according to HCV genotype Drug Class Subclass 1 b 1a 2 3 4 Protease inhibitors NS5a Inhibitor NN Polymerase Inhibitors Nucleos/tides Polymerase inhibitors 1 st Generation first wave i.e. Telaprevir/Boceprevir 1 st Generation 2 nd wave i.e. Simeprevir Paritaprevir/r Asunaprevir 2nd Generation Grazoprevir ABT 493 1 st Generation Ledipasvir Ombitasvir Elbasvir Daclatasvir 2 nd Generation Velpatasvir ABT 530 Dasabuvir 2 nd Generation : Sofosbuvir High Moderate Low Very low
Pitfalls of current anti HCV Tx HCV G1 & 4: need for Ribavirin or prolonged treatment duration in cirrhotics Only one Sofosbuvir free treatment HCV G2: Need for Ribavirin or PEG IFN + RBV (Indication not reported in Daclatasvir SPC) Low response in cirrhotics No sofosbuvir free treatment HCV G3 Need for Ribavirin or PEG IFN + RBV in cirrhotics Low response rate in cirrhotics PEGIFN RBV failures All Genotypes: Need for treatment tailoring according to HCV genotype/subtype, disease stage & previous treatment history No data on treatment of NS5A failure
Strategies of DAA based HCV eradication Sofosbuvir based pangenotypic Sofosbuvir (high resistance barrier) + RBV Sofosbuvir (high resistance barrier) + 1 DAA + RBV Sofosbuvir free HCV G1 &4 3 (2) DAAs low resistance barrier Sofosbuvir based pangenotypic Sofosbuvir + 1/2 DAA Pangenotypic Sofosbuvir free pangenotypic 2 DAA pangenotypic Still challenging Phase IV Adjusted for HCV Genotype. Fine tuning by RBV & Tx duration In PR failures & Cirrhosis Smoother Phase II-III One pill (injection?) for all
Everson G EASL 2015
ASTRAL studies : Sofosbuvir + Velpatasvir FDC in HCV G1, 4, 5, 6 stratified according to liver disease stage 323/ 328 116/ 116 34/ 35 41/ 41 Gilead sciences Inc: http://www.businesswire.com/news/home/20150921005402/en/
ASTRAL studies : Sofosbuvir + Velpatasvir FDC in HCV G 2 & 3 stratified according to liver disease stage 237/ 238 264/ 277 Gilead sciences Inc: http://www.businesswire.com/news/home/20150921005402/en/
SOFOSBUVIR + VELPATASVIR IN DECOMPENSATED ( CHILD B) CIRRHOSIS Gilead sciences Inc: http://www.businesswire.com/news/home/20150921005402/en/
ASTRAL STUDIES VIROLOGICAL FAILURES WITH RELAPSE STRATIFIED ACCORDING TO GENOTYPES & SAFETY 1015/1035 SVR (98%) 20 failures: 7 lost to follow up 1 reinfection 12 Virological relapse: 2 HCV G1 10 HCV G3 In CH or compensated cirrhosis adverse events similar to placebo 2/1035 stopped treatment for adverse events In 257 pts with decompensated cirrhosis pts 46 had 1 or more SAE (18%) and 9 died (3.5%) in relationship with liver disease Gilead sciences Inc: http://www.businesswire.com/news/home/20150921005402/en/
SOFOSBUVIR/Velpatasvir FDC 1 Single Tablet Regimen (STR) x 12 w for HCV G 1,2,4,5,6 with Chronic Hepatitis (CH) or Compensated Cirrhosis (CC) 1 STR x 12 w + RBV 1000/1200 for HCV G 1,2,4,5,6 with Decompensated Cirrhosis (DC: Child Pugh class B score > 7) HCV G3 CH & CC 1 STR x 12 w or 1 STR x 12 w + RBV? DC 1 STR + R x 12 w or 1 STR + R x 24 w i?
GRAZOPREVIR + ELBASVIR IN NAÏVE PTS WITH HCV G1,4,or 6 Zeuzem S et al. EASL 2015
EFFICACY OF AN 8-WEEK REGIMEN OF GRAZOPREVIR PLUS ELBASVIR WITH AND WITHOUT RIBAVIRIN IN TREATMENT-NAIVE, NONCIRRHOTIC HCV GENOTYPE 1B INFECTION Vierling JM et al EASL 2015
EFFICACY AND SAFETY OF GRAZOPREVIR/ELBASVIR +/- RBV FOR 12 OR 16 WEEKS IN PATIENTS WITH HCV G1, G4 OR G6 INFECTION WHO PREVIOUSLY FAILED PEGINTERFERON/RBV: C-EDGE TREATMENT-EXPERIENCED Kwo P et al EASL 2015
GRAZOPREVIR + ELBASVIR IN HCV G1 CP B CIRRHOSIS Jacobson I et al. EASL 2015
C-SURFER: GRAZOPREVIR PLUS ELBASVIR IN TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS WITH HEPATITIS C VIRUS GENOTYPE 1 INFECTION AND CHRONIC KIDNEY DISEASE Roth D et al. EASL 2015
EFFICACY OF 12 OR 18 WEEKS OF GRAZOPREVIR PLUS ELBASVIR WITH RIBAVIRIN IN TREATMENT-NAIVE, NONCIRROHTIC HCV GENOTYPE 3 INFECTED PATIENTS Gane E et al EASL 2015
Poordad et al EASL 2015
Poordad et al EASL 2015
Poordad et al EASL 2015
Simeprevir plus daclatasvir and sofosbuvir in treatment-naïve and treatment-experienced patients with chronic hepatitis C virus genotype 1 or 4 infection and decompensated liver disease: interim results from the Phase II IMPACT study Lawitz E et al EASL 2015
New perspectives HCV G1 & 4: No need for Ribavirin or prolonged treatment duration in compensated cirrhotics More Sofosbuvir free treatment HCV G2: No Need for Ribavirin or PEG IFN + RBV (Indication not reported in Daclatasvir SPC) HIGHER response in cirrhotics One sofosbuvir free treatment HCV G3 No Need for Ribavirin or PEG IFN + RBV in cirrhotics? Higher response rates also with triple therapy All Genotypes: Need for treatment tailoring only according to Decompensated status No data on treatment of NS5A failure
Van der Reee et al EASL 2015