Advances in Hepatitis C Virus Therapeutics HBV HIV HCV. Advances in HCV Therapeutics. Greg Dore. Viral Hepatitis Clinical Research Program

Transcription

1 Advances in Hepatitis C Virus Therapeutics Greg Dore Viral Hepatitis Clinical Research Program National Centre in HIV Epidemiology and Clinical Research Hepatitis C notifications: Estimates of BBV prevalence in Australia HBV 9, 16, , HCV HIV 12, Source: NCHECR Annual Surveillance Report 24 Estimates of people with hepatitis C by disease stage Estimates of people with HCV-related cirrhosis: Year CIrrhosis Stage 2/3 fibrosis Stage /1 firbosis Exposed HCV, virus cleared Dore et al J Clin Virol 23 Dore et al J Clin Virol 23 1

2 Sustained Virological Response IFN-α2b+RBV 48 weeks PEG-IFN weeks IFN-α2b weeks IFN-α2b weeks 8-12 PEG-IFN+RBV weeks PEG-IFN α2b+rbv 8/8/8 adherence 72 IFN action The dsrna-dependent Protein Kinase (PKR) Pathway ATP PKR ADP PKR-Pi elf2α+atp elf2α-pi+adp 3ATP Viral dsrna ACTIVATES 2Pi SIGNAL TRANSDUCTION IFN INDUCES 2-5A Synthetases pppa2 p5 A2 p5 A (2-5A) ACTIVATES 2-5A Dependent RNase (RNase L) The Mx Pathway Mx Proteins GTP GDP+ PI ssrna -UpN3 p/ 1 years INHIBITION OF PROTEIN SYNTHESIS AND TRANSCRIPTIONAL CONTROL RNA CLEAVAGE TRANSCRIPTION INHIBITION, OTHER Rationale for Pegylation PEG-IFN serum concentrations Pegylation = binding of ethylene oxide polymers to drug molecule Decreases clearance prolonged half life / sustained blood levels Decreases proteolysis and immunogenicity Less frequent dosing PEG-IFN α-2b 1.5mcg/kg SC weekly IFN α 3 MIU 3x weekly Mean Concentration (pg/ml) Hours PEG-IFN α-2a 18 µg SC weekly Hours Glue P et al. Clin Pharmacol Ther. 2 Zeuzem et al. Sem Liver Disease 23 Sustained virological response (PEG-IFN-α2a/RBV) PEG-IFN 2a + placebo IFN + RBV PEG-IFN 2a + RBV Fried et al NEJM 22 2

3 SVR for HCV genotype 1 SVR for HCV genotype 2, PEG-IFN 2a + placebo IFN + RBV PEG-IFN 2a + RBV PEG-IFN 2a + placebo IFN + RBV PEG-IFN 2a + RBV Fried et al NEJM 22 Fried et al NEJM 22 HCV genotype distribution PEG-IFNα2a/RBV 24 vs 48 wks and high vs low RBV dose (Genotype 1) 1a,1b,2b 1a,1b,3a 1a,3a 1b,2b,3a 1, a,1b 3a 1b,2a 2a 1b 1b,6a 7,8,9 3a,6a 1a,1b,3a weeks - RBV 8 24 wks - RBV wks - RBV 8 48 wks - RBV 1-12 Hadziyannis et al AIM 24 PEG-IFNα2a/RBV 24 vs 48 wks and high vs low RBV dose (Genotype 2/3) Factors associated with poorer SVR weeks - RBV 8 24 wks - RBV wks - RBV 8 48 wks - RBV 1-12 Hadziyannis et al AIM 24 HCV genotype 1 HCV viral load (genotype 1) Severe fibrosis cirrhosis High body weight Age > 4 years African American ethnicity HIV coinfection < 8 adherence (RBV > PEG-IFN) 3

4 ETR and SVR among current IDUs and MMT clients ETR SVR Backmund et al (n=5) Sylvestre et al (n=66) Schaefer et al (n=21) Mausss et al (n=5) Matthews et al (n=12) Treatment efficacy in difficult to treat groups MMT (n=21) Psychatric (n=16) Former IDU (n=21) Control (n=23) 2 1 SVR Schaefer et al 23 Impact of HCV treatment on liver disease burden Estimates of people with chronic HCV infection Access to Australian government funded HCV treatment requires: >= 18 years liver biopsy consistent with chronic HCV infection at least fibrosis (F) 1 with moderate inflammation or F2 compensated liver disease naïve to HCV treatment Current levels of HCV treatment in Australia are low ~1,5-2,/year HCV treatment scenarios assessed: 2, 1,/year Total N living with HCV infection

5 Estimates of people with cirrhosis Estimates of people with liver failure N individuals with cirrhosis N individuals with liver failure QALYs lost Estimates of total QALYs lost Therapeutic strategies currently under investigation (I) High dose PEG-IFN induction for genotype 1 (CHARIOT) Longer duration of PEG/RBV (72 wks) for genotype 1 Shorter duration of PEG/RBV (16 wks) for genotype 2/3 Therapeutic strategies currently under investigation (II) Use of RBV pro-drug (Viramidine) G-CSF and EPO supplementation Prophylactic anti-depressant therapy High individualized RBV dosing Long-term low dose PEG-IFN in non-responders (HALT-C) 5

6 HCV Genome 3 UTR 5 UTR structural non- structural Translation processing IRES internal ribosomal entry site E1 C E2 P7 NS2 NS3 NS4A NS4B NS5A NS5B core replication NS3 cofactor cysproteinase envelope metalloprotease replication? RdRp glycoproteins serine protease RNA helicase HCV Replication HCV enzymes are targets for new therapies C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B (+) RNA NS3-5 (-) RNA Translation processing P7 NS2 C E1 E2 NS3-5 (+) RNA Golgi Endoplasmic Reticulum Nucleus NS3 Protease domain NS3 Helicase domain NS3 Bifunctional protease / helicase Challenges in drug development Therapies in development High variation in HCV genome High mutational capacity - resistance On market Phase III Phase II Phase I Viramidine Other IFNs Gamma IFN IMPDH inhibitors IL 1 & IL 12 Others Histamine Hcl Antisense Ribozymes Lack of small animal model Lack of understanding of HCV pathogenesis IFN & PEG-IFN Ribavirin Thymosin Lack of conventional tissue culture system for in vitro studies NS5B RNA-dependent RNA polymerase Histamine HCl E2 Vaccine Polymerase inhibitors Levovirin Levovirin Apoptosis inhibitors Protease inhibitors HCV immunotherapy Preclinical Research HCV vaccines Many others including Antisense Antifibrotics Immune stimulants Gene therapy 6

7 Protease Inhibitor BILN 261 NS3/4A protease inhibitor First small molecule agent to demonstrate HCV antiviral activity Active in inhibiting HCV RNA replicons in cultured cells Phase I clinical trial (genotype 1) 2mg bd for 2 days 2-3 log reduction in HCV RNA within 48 hours Further toxicology (animals) at higher doses demonstrated cardiac toxicity?? Resistance Strategies for increased access to HCV treatment Increasing awareness of improved treatment response Broadened base of practitioners involved in HCV care Multidisciplinary clinics Enhanced clinical trial infrastructure Research on most appropriate treatment delivery models Removal of liver biopsy requirement Advocacy 7