BCC4: Pierre Janin on 4 Newer Agents for Hepatitis C
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BCC4: Pierre Janin on 4 Newer Agents for Hepatitis C

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Janin speaks on the dawn of a revolution for treating Hepatitis C. This was recorded at Bedside Critical Care Conference 4. Full postings can be found at www.intensivecarenetwork.com

Janin speaks on the dawn of a revolution for treating Hepatitis C. This was recorded at Bedside Critical Care Conference 4. Full postings can be found at www.intensivecarenetwork.com

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  • 1. Dawn of a revolution P. Janin RNSH – ICU 26.09.2013
  • 2.  1965 - Blumberg & Alter  1973 – Feinstone, Kapikian & Purcell The hepatitis puzzle was still incomplete
  • 3. …. ….
  • 4.  Part of Flaviviridae family of viruses  Associated with both human and animal disease  3 genera: pestiviruses (cattle, pigs), flaviviruses (dengue, yellow fever), hepaciviruses (HCV)  In hepacivirus family  6 major clades  >100 different subtypes  Countless quasispecies: mult. seen in each infected individual
  • 5. Study of Infection, Replication and Release Difficult:  Lack of reliable culture system  Does not integrate into host genome  Low number of circulating virions
  • 6. Structural genes Non-structural genes
  • 7. Pathogenesis Prevention Therapy
  • 8.  Complex, dynamic distributions of non-identical but related mutant RNA genomes  Encompasses a master genome (dominant) and a multitude of minor genomes
  • 9. Escapes host immune surveillance ? Establishes persistent infection ?
  • 10. Exposure (Acute Phase) Resolved Chronic CirrhosisStable Liver Decompensation Hepatocellular Carcinoma 5%-25% over 20-30 years 15-45% 55-85% 5%/yr decompensation 2-8%/yr HCC 75-95% Primary Point of Intervention  Acute Hepatitis C  Generally benign:  No jaundice (80%). Usually asymptomatic.  Can be severe, but liver failure rare  15-40% will usually resolve.
  • 11.  Only real threat of acute Hepatitis C is its ability to reach chronic stages undetected and untreated.
  • 12. 90% 5-10% 80-90% 70-85% 2% (coinfection) 90% (superinfection)  Infants  Adults Normal liver Chronic hepatitis Cirrhosis
  • 13.  3.2 million persons chronically infected (average age 55 years, perhaps 40% have cirrhosis)  8000-10.000 deaths each year (US)  Majority unaware of infection: not clinically ill (only 25-30% have been diagnosed, only 11% have been treated)
  • 14.  221.000 people with chronic hepatitis C  Leading reason for liver transplant  Deaths have surpassed HIV HIV HCV
  • 15. Indirect Serological assays Direct Virological assays Commercial HCV Assays Antibody assays EIA-III RIBA-III HCV RNA detection - Qualitative - Quantitative Molecular HCV genotyping There is a seronegative window in which HCV RNA is the only marker that permits the diagnosis of primary HCV infection and the identification of potentially infectious patients that would be missed by conventional antibody testing
  • 16.  Genetic heterogeneity  High rate of viral persistence  Lack of solid immunity  Poor definition of protection correlates  Technical limitations in the study of HCV
  • 17.  Viral eradication  SVR = cure  Arrest progression of necrosis/fibrosis  Reduce progression of fibrosis/cirrhosis  Prevent decompensation  Prevent HCC Primary objectives Secondary objectives SVR: Sustained Virological Response
  • 18.  SVR is defined as absence of HCV RNA in the serum at the end of treatment and 6 months later  Patients who achieve an SVR may be deemed clinically cured of chronic HCV
  • 19. ~1990’s mid-90’s ~2000-01
  • 20. Peginterferon alfa-2a (40KD) Ribavirin SC injection, once weekly By mouth, twice daily  Direct inhibition of HCV RNA- dependent RNA polymerase ? RNA mutagenesis ?  Depletion of intracellular GTP pools via IMPDH inhibition ?  T-cell enhancement  OAS: activates antiviral RNAses  PKR: inactivates viral ptn translation  ADA: edits viral RNA
  • 21. 30-40% 80%
  • 22. RVR RapidVirologic Response HCV RNA negative at 4 weeks (< 50 IU/mL) EVR EarlyVirologic Response HCV RNA negative or > 2 log10 drop at week 12. cEVR (complete) or pEVR (partial) SVR Sustained Virologic Response HCV RNA negative 24 weeks after end of treatment Relapse HCV RNA negative at end of treatment but HCV RNA positive after treatment stopped
  • 23.  Previously, treatment recommendation was based on the HCV genotype  The early kinetics of HCV viremia (week 4) are emerging as the most reliable predictive marker of response  Quantification of HCV viremia is essential for tailoring the treatment schedule: Response Guided Therapy
  • 24.  Favorable  Genotype 2 and 3  HCV RNA < 400,000 IU/ml  Mild fibrosis (F0-F2)  Age < 40  IL28B CC  Adherence  RVR and cEVR  Unfavorable  Genotype 1  HCV RNA > 400,000 IU/ml  Advanced fibrosis (F3-F4)  Age > 40  Steatosis, Insulin Resistance, high BMI  IL28B CT or TT  Dose reduction > 60%  Non-adherence
  • 25. Side effects  Flu-like symptoms  Weight loss  Depression  Neutropenia  Concentration/memory disturbance  Insomnia  Thrombocytopenia
  • 26. Side effects  Haemolytic anaemia  Significant teratogenicity  Rash  Fatigue  Itching  Sinusitis
  • 27. Log(10)HCVRNAIU/ml Days 8 6 4 2 14 Telaprevir 100 Peginterferon + Ribavirin Telaprevir + Peg/RBV
  • 28.  Are added to (do not replace) original therapy.  Indications:  treatment of chronic Hep C (genotype 1).  with compensated liver disease, including cirrhosis.  previously untreated or who have failed previous interferon and ribavirin therapy.
  • 29. Telaprevir (GT1) (ADVANCE & REALIZE trials) Boceprevir (GT1) (SPRINT2 & RESPOND2) %SVR
  • 30. Mono infected  GT 2,3: pegIFN + RBV x 24wk  GT 4: x 48wk  GT 1: pegIFN + RBV + DAA  Variable duration based on response (24, 36, or 48 wk)
  • 31. Telaprevir Time point HCV RNA Action Week 4 or 12 > 1000 IU/mL Stop T/P/R Week 24 Detectable Stop P/R Boceprevir Time point HCV RNA Action Week 8 or 12 > 100 IU/mL Stop B/P/R Week 24 Detectable Stop P/R
  • 32. Telaprevir DAA/P/R P/R Pruritis 45-50% 28% Nausea 40-43% 31% Rash 56% 34% Anemia 37-39% 19% Diarrhea 28-32% 17% Anorectal discomfort 11% 3% Boceprevir Anemia 50% 30% Dysgeusia 35-43% 16% Neutropenia 25% 19% Nausea 46% 42%
  • 33.  Wave 1 (2011-2014): add-on Rx  1st generation PIs + SOC: naïve and experienced  Wave 2 (2014-2016): the better mousetrap  Substitution of 2nd generation PIs (better barrier to resistance, tolerance), Nucs (better PK, tolerability)  Substitution of better tolerated IFNs  4 drug regimens for P/R/PI failures (quad therapy)  Wave 3 (2015-2020): the holy grail  Oral cocktails of DAAs, host cofactor inhibitors, RBV  IFN-free regimen!
  • 34.  Improved efficacy ?
  • 35.  NEUTRINO study (Phase III registration trial)  AE in >20%
  • 36.  Strong barrier to resistance !
  • 37.  For GT 1  No anemia and no grade 3-4 AE
  • 38.  For GT 2 and 3
  • 39.  DCV (PI) + SOF (Nuc-PoI) in Boceprevir/PR failures.
  • 40.  Genotype 1:  PEG / RBV + Simeprevir (2nd gen PI)  PEG / RBV + Sofosbuvir (PoI)  Genotype 2, 3:  RBV + Sofosbuvir  Off label combination of available DAA classes  Simeprevir + Sofosbuvir + RBV for GT1
  • 41.  Emerging DAA therapy against 3 major viral proteins will provide solutions for most patients with HCV.  Strong potency  Nonoverlapping resistance profile  Enough genotypic / subgenotypic range  High barriers compounds desirable for simplified regimens. Can be matched by combinations of DAA classes.  Novel host targets increasingly identified, including many involved in Lipid metabolism. Inherently high barrier to resistance.
  • 42.  Thank you. Printed material and product information available here !!