Research Gaps in Viral Hepatitis Prof. Jean-Michel Pawlotsky, MD, PhD National Reference Center for Viral Hepatitis B, C and delta Department of Virology & INSERM U955 Henri Mondor Hospital University of Paris-Est Créteil, France
Research never ends
Research Gaps in Viral Hepatitis Epidemiology Virology Virus-host interactions Pathophysiology of liver and extrahepatic diseases Antiviral therapy
Research Gaps in Viral Hepatitis Epidemiology Virology Virus-host interactions Pathophysiology of liver and extrahepatic diseases Antiviral therapy
Hepatitis C
Remaining Issues in HCV Theapy Access to care, care cascade Genotype 3 Patients with decompensated liver disease Patients with advanced chronic kidney disease HCV resistance and DAA treatment failures
Genotype 3 patients, the most difficult-to-cure?
SVR12 rate (%) Sofosbuvir + Velpatasvir ASTRAL-3 Phase III, TN and TE (26%), Gt 3, 30% cirrhosis, 12 weeks 100 90 98% 93% 91% 89% 80 70 60 50 40 30 20 10 N=163 N=43 N=34 N=37 0 No cirrhosis Cirrhosis No cirrhosis Cirrhosis Treatment-naïve Treatment-experienced (Foster et al., N Engl J Med 2015;373:2608-17)
HCV RNA level HCV Kinetics by Genotype IFN-free, DAA-based regimens LLD Gen 2 Gen 3 Gen 1a Gen 1b
Ideal timing for treatment of patients with decompensated cirrhosis and an indication for liver transplantation?
Ideal Timing for HCV Treatment Prior to Liver Transplantation (Chhatwal et al., Hepatology 2017;65:777-88)
Ideal Timing for HCV Treatment Prior to Liver Transplantation (Chhatwal et al., Hepatology 2017;65:777-88)
HCV resistance and treatment failures?
Baseline and Post-Treatment Sequence in Patients who Failed SOF/VEL/VOX (Réau et al., AASLD 2016)
Retreatment with Glecaprevir + Pibrentasvir MAGELLAN-I- Phase II, Prior DAA failure 2 virologic failures Prior DAAs Response NS3 RASs NS5A RASs Baseline Failure Baseline Failure OBV/PTV/r + DSV + RBV Breakthrough Y56H D168A/T V36M Y56H D168A M28V Q30R H58C M28G Q30R H58C DCV; TVR + PR Relapse None A156V L31M H58D Q30R L31M H58D (Ng et al., AASLD 2016)
French National Observatory for HCV Resistance Full-length HCV RNA sequence analysis by shotgun metagenomics (S. Fourati, C Rodriguez, et al., unpublished data)
French National Observatory for HCV Resistance Full-length HCV RNA sequence analysis by shotgun metagenomics Patient who failed to achieve SVR after 12 weeks of SOF + DCV Full-length HCV RNA sequence at baseline 31 93 Full-length HCV RNA sequence at treatment relapse 52 63 98 147 386 113 168 31 93 442 447 (S. Fourati, C Rodriguez, et al., unpublished data)
French National Observatory for HCV Resistance Phenotypic resistance assays: transient transfection Transfection WT Huh7.5 Assessment of replicon replication (4h, 24h, 48h, 72h, 96h) Mutant site-directed mutagenesis on NS3, NS5A and/or NS5B In vitro transcription Huh7.5 with increasing DAA concentrations (S. Fourati, S. Chevaliez, J.M. Pawlotsky, National Reference Center for Viral Hepatitis B, C and D)
French National Observatory for HCV Resistance Phenotypic resistance assays: stable transfection WT Linearized DNA RNA Transfection Selection pressure (G418) Adapted cell line stably expressing the replicon Mutant site-directed mutagenesis on NS3, NS5A and/or NS5B In vitro transcription Huh7.5 cells GT 1a replicon Anti-NS5A IF Several weeks Increasing DAA concentrations Assessment of replicon replication in the presence of DAAs (S. Fourati, S. Chevaliez, J.M. Pawlotsky, National Reference Center for Viral Hepatitis B, C and D)
French National Observatory for HCV Resistance Phenotypic resistance assays NS5A RAS profile Patient Genotype Treatment Baseline Failure A 1b SOF/DCV R30S/L31M L28I/R30S*/L31M B 1b SOF/LDV None R30N/L31M/Y93H *Amino acid substitution conferring NS5A inhibitor resistance in GT4 replicons (Fourati et al., unpublished data)
Global HCV Prevalence
Hepatitis B
Treatment of the immunotolerant patient (HBeAg-positive chronic HBV infection)?
New Nomenclature for Chronic HBV States HBeAg-positive HBeAg-negative Chronic infection Chronic hepatitis Chronic infection Chronic hepatitis HBsAg High High/intermediate Low Intermediate HBeAg + + - - HBV DNA >10 7 IU/mL 10 4-10 7 IU/mL <2000 IU/mL* >2000 IU/mL ALT Normal Elevated Normal Persistently or intermittently elevated Liver disease None/minimal Moderate/severe None Moderate/severe Old terminology Immune tolerant Immune reactive HBeAg-positive *can be between 2000 and 20,000 without signs of chronic hepatitis Inactive carrier HBeAg-negative chronic hepatitis (EASL CPGs: Management of HBV infection 2017)
Reasons to Consider Earlier Treatment of CHB to Prevent HCC Need for long-term follow-up and risk of missing the time when therapy is indicated No proof that delaying therapy does not impact on the prevention of HCC No proof that HBV infection is harmless until active liver disease is readily apparent Based on numerous models, clonal hepatocyte repopulation is a major risk factor for HCC and therefore may be important in the etiology of HBV- associated HCC, even in early stages of infection, before the appearance of signs of liver disease (Zoulim & Mason, Gut 2012;61:333-6)
Evidence for Hepatocyte Damage during the Immunotolerant Phase Liver histology not strictly normal in immunotolerant patients Immune pressure on the virus is present, detectable, and has an impact on HBV diversity ALT values at the high end of normal and low virus titers (<10 8 IU/mL) both point to accumulating hepatocyte damage (Zoulim & Mason, Gut 2012;61:333-6)
Stopping NUC treatment?
Stopping Adefovir at Year 4-5 in HBeAg-Negative Patients (Hadziyannis et al., Gastroenterology 2012;143:629-36)
NA Discontinuations Should be Can be May be After confirmed HBsAg loss, with or without anti-hbs seroconversion In noncirrhotic HBeAg-positive CHB patients who achieve stable HBeAg seroconversion and undetectable HBV DNA and who complete at least 12 months of consolidation therapy (close post-na monitoring is warranted) In selected HBeAg-negative patients who have achieved long-term ( 3 years) virological suppression under NA(s) (close post-na monitoring is warranted) (EASL CPGs: Management of HBV infection 2017)
Rates of Virological Response Off Therapy after NA Discontinuation (Systematic Review) *Majority of patients from East Asia (Papatheodoridis et al., Hepatology 2016;63:1481-92)
New HBV drugs: towards an HBV cure?
HBV Lifecycle Targets (Testoni et al., Liver Int 2017;37(suppl. 1):33-9)
HBV Lifecycle Targets Target Approach Compound(s) HBV entry through NTCP rcdna conversion to cccdna Myristoylated pre-s peptide Cyclophilin inhibitors Disubstituted sulfonamide Myrcludex B CsA, alisporivir CCC-0975 CCC0346 cccdna damage and destruction Cytokines upregulating APOBEC3A/B DNA cleavage enzymes IFN-a Lymphotoxin-b receptor agonist IFN-g TNF-a Pending cccdna functional silencing Epigenome modifiers Pending HBV mrnas sirnas ARC-520 (ArrowHead) ARB-1467 (Arbutus) ALN-HBV (Alnylam) Pre-genomic RNA packaging HBc allosteric modulators (CpAMs) BAY41-4109 (Bayer) NVR 3-778 (Novira) GLS-4 (HEC Pharm) JNJ-56136379 (Janssen) HBV polymerase RNAse H inhibitors Pending Virion assembly and secretion Monoclonal antibodies Nucleic acid polymers Pending Rep2139 (Replicor) (Testoni et al., Liver Int 2017;37(suppl. 1):33-9)
HBV Immune Targets (Testoni et al., Liver Int 2017;37(suppl. 1):33-9)
HBV Immune Targets Target Approach Compound(s) Innate immune responses Adaptive immune response TLR agonists Pattern recognition receptor (PRR) agonists Cellular inhibitors of apoptosis proteins (ciap) T cell engineering Checkpoint inhibitors Inhibitors of CD39/CD73 Therapeutic vaccines TLR7 agonists (GS-9620, Gilead) Pending Birinapant (Tetralogic) Adoptive transfer of autologous cells Transient delivery of TCR-encoding RNAs Retargeting of immune effector cells Anti-PD1/PD-L1 Pending Recombinant HBV proteins Boosting HBV-specific CD8 T cells (Testoni et al., Liver Int 2017;37(suppl. 1):33-9)
And now, what am I gonna do?
Log HCV RNA Alisporivir (DEBIO-025) Phase Ib 9 8 7 Log 10 copies/ml 6 5 4 3 2 1 Treatment Genotype 1 Genotype 3 Genotype 4 0 5 15 25 35 45 Time (Days) (Flisiak et al., Hepatology 2008;47:817-26)
Fragment-Based Drug Design Fragment Library 1 Binding Fragment Hit 2 Linking Hit compound (Ahmed-Belkacem et al., Nat Commun 2016;7:12777)
Fragment Screening (X-Ray Crystallography) (Ahmed-Belkacem et al., Nat Commun 2016;7:12777)
Linking Strategy Hit compound F428 (Ahmed-Belkacem et al., Nat Commun 2016;7:12777)
Compound Optimization F759 CsA F428 F680 F684 F712 F716 F759 Cyp A IC 50 (µm) 0.01 13.1 0.55 0.37 3.3 0.79 0.1 Cyp D IC 50 (µm) ND 6.2 1.1 0.64 3.1 0.67 0.21 Cyp B IC 50 (µm) ND 6.1 0.76 0.65 ND ND 0.08 (Ahmed-Belkacem et al., Nat Commun 2016;7:12777)
Broad-Spectrum Antiviral Effectiveness of SMCypIs Viral family Virus Common compound Maximal fold VL reduction Most potent compound Maximal fold VL reduction Hepatitis C virus F759 83 F759 83 Zika virus F759 2 F833 471 Flaviviridae Dengue virus F759 26 pending pending Yellow fever virus F759 5 pending pending Coronaviridae West Nile virus F759 2 pending pending Japanese encephalitis virus F759 2 pending pending Human coronavirus 229E F759 3 F833 509 Human coronavirus OC43 F759 6 F832 142 MERS coronavirus F759 1 F833 50% inhibition of infection* Paramyxoviridae Respiratory syncytial virus F759 6 F836 442 Togaviridae Chikungunya virus F759 4 pending pending (Ahmed-Belkacem et al., Nat Commun 2016;7:12777; Unpublished data)
Inhibition of the Cytopathic Effect of Human Coronavirus (HCoV) 229E Huh7 cells DMSO F759 20 um (Ahmed-Belkacem et al., Nat Commun 2016;7:12777)
Follow me on Twitter @JMPawlotsky