UPDATE ON NEW HEPATITIS C MEDICINES

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1 UPDATE ON NEW HEPATITIS C MEDICINES Diana Sylvestre, MD 2014 AASLD/IDSA Guidelines: Gt 1 Treatment naïve Interferon eligible: sofosuvir + ribavirin + PEG-IFN x 12 weeks Interferon ineligible: sofosbuvir + simeprevir +/- riba x 12 weeks Treatment experienced Interferon eligible: sofosuvir + ribavirin + PEG-IFN x 12 weeks Interferon ineligible: sofosbuvir + simeprevir +/- riba x 12 weeks 1

2 Interferon OVERVIEW A few quick points about HCV Designing treatment regimens HCV studies The future 2

3 HCV Exposure = Infection ~25% of those exposed to HCV clear the virus spontaneously It is NOT in remission, it is gone The antibody to HCV will persist and the screening test will thus remain positive The diagnosis of chronic HCV is made on the basis of viral tests: PCR or Genotype The Viral Load Doesn t Really Matter It indicates current infection, that s about it High/Low viral loads do not correlate with more/less liver damage Repeat the viral load during/after treatment or during acute exposure In other words: STOP RECHECKING THE VIRAL LOAD 3

4 Genotype is an Important Test Represents polymorphisms in the 5 UT region 1-6 with some subtypes No correlation with extent of liver damage Determines treatment options and expected outcomes New Tests You May Not Be Familiar With IL-28B Genotype Involved in the immune response to interferon CC: more likely to spontaneously remit and respond to IFN CT and TT: less likely NS3 Genotype Mutations may be involved in protease inhibitor resistance Q80K confers resistance to simeprevir Gt 1a requires only a single nucleotide mutation HepaScore Blood test that predicts extent of liver fibrosis <0.55 is considered negative Immune thrombocytopenia shoots it through the roof 4

5 YES, THERE IS A CURE DESIGNING TREATMENT REGIMENS 5

6 Principles to Consider 1-10 billion virions daily No proofreading Resistance to monotherapy in < 1 week >2 DAAs necessary, or combine with interferon or ribavirin HCV Genome 6

7 HCV Genome HCV Genome Serine Protease Phosphoprotein RNA Polymerase 7

8 HCV Genome Serine Protease Protease Inhibitors HCV Genome Serine Protease Protease Inhibitors 1 st Gen: Telaprevir and Boceprevir 2 nd Gen: Simeprevir (Asunaprevir) 8

9 HCV Genome Serine Protease Protease Inhibitors 1 st Gen: Telaprevir and Boceprevir 2 nd Gen: Simeprevir (Asunaprevir) HCV Genome RNA Polymerase Polymerase Inhibitors 9

10 HCV Genome RNA Polymerase Polymerase Inhibitors Nucleoside/tide: High barrier to resistance Effective across genotypes NonNucleoside/tide: Lower barrier to resistance Genotype specific HCV Genome RNA Polymerase Polymerase Inhibitors Nucleotide Pol Inh: Sofosbuvir NonNucleoside Pol Inh: (Dasabuvir) 10

11 HCV Genome RNA Polymerase Polymerase Inhibitors Nucleotide Pol Inh: Sofosbuvir NonNucleoside Pol Inh: (Dasabuvir) HCV Genome Phosphoprotein NS5a Inhibitors 11

12 HCV Genome Phosphoprotein NS5a Inhibitors (Ledipasvir) (Ombitasvir) (Daclatasvir) HCV Genome Phosphoprotein NS5a Inhibitors (Ledipasvir) (Ombitasvir) (Daclatasvir) 12

13 Designing Your Treatment Regimen Protease Inhibitor s NS5a Inhibitors Polymerase Inhibitors -previr -asvir -buvir You can mix and match!!! Don t forget interferon and ribavirin!!! THE DATA 13

14 HCV / HIV patients should perhaps not be thought of as a special population in HCV but instead as a group at risk for drug drug interactions with some HCV regimens. Treatment for HCV / HIV patients should be strongly considered given the increased risk of fibrosis progression and complications of cirrhosis among this group. The Rapid Evolution of Treatment Strategies for Hepatitis C Andrew J. Muir, MD, MHS STUDY 1 14

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16 Sofosbuvir ART Interactions But: Atazanavir elevated total bili (Grade 3 or 4) in 30/32 (94%) of those receiving sofosbuvir 16

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20 STUDY 2 20

21 HCV Genome Ledipasvir + Sofosbuvir 21

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26 STUDY 3 26

27 HCV Genome MK MK /- Ribavirin 27

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30 OTHER STUDY RESULTS HCV Monoinfection 30

31 Abbvie ABT-450/r + Ombitasvir + Dasabuvir With or without ribavirin 31

32 BMS Asunaprevir + Daclatasvir With or without ribavirin 32

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34 COSMOS Simeprevir + Sofosbuvir With or without ribavirin Simeprevir ART Interactions 34

35 COSMOS Conclusions Current DAA s Sofosbuvir, simeprevir, boceprevir, telaprevir Agents soon to be approved Ledipasvir, ABT-450/r, ombitasvir, daclatasvir, dasabuvir, others There ARE no special populations The issue in HIV/HCV coinfection will be drug-drug interactions 35

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