Interferon free hepatitis C treatment. Cynthia Solomon, RN, BS, ACNP-BS Hepatology Nurse Practitioner

Transcription

1 Interferon free hepatitis C treatment Cynthia Solomon, RN, BS, ACNP-BS Hepatology Nurse Practitioner

2 DISCLAIMER I have no potentially biasing relationships of a personal, financial or professional nature in relation to this educational activity. I do not own stock or act as a consult for any of the medications discussed in today s lecture. Off label use of any product will not be discussed.

3 Objecives Identify key aspects of Hepatitis C virology Describe pharmacological advances in Hepatitis C treatment Identify the classes of medication used in Hepatitis C treatment Distinguish differences in Hepatitis C regimens

4 HCV prevalence: Million (High estimate) Gower E, et al AASLD, Abtr. 1488

5 Hepatitis C: Background Between 4-5 Million Americans with Hepatitis C 4% of Veterans infected with HCV vs. 1.3% of US adult population 10% of Vietnam Veterans 3-times more prevalent than HIV Significant proportion not yet diagnosed

6 Sequelae of HCV Chronic HCV infection is a leading cause of liver disease [1] 10% to 20% of patients will develop cirrhosis over yrs 1% to 5% of patients with HCV cirrhosis will develop HCC 25% of the ~ 500,000 new HCC cases identified globally each yr are attributable to HCV [2] HCV-related complications estimated to increase ~ 2-fold within the next 10 yrs [3] Other diseases/manifestations associated with HCV infection [4] Mixed cryoglobulinemia vasculitis, lymphoproliferative disorders, diabetes, renal disease, rheumatoid arthritis like polyarthritis, sicca syndrome, depression, cognitive impairment 1. Lavanchy D. Clin Microbiol Infect. 2011;17: Montalto G, et al. Ann N Y Acad Sci. 2002;963: Milliman, Inc. Consequences of HCV: costs of a baby boomer epidemic, Jacobson IM, et al. Clin Gastroenterol Hepatol. 2010;8:

7 Viral Transmission: Patient Teaching Pearls HCV is transmitted through blood to blood contact Sharing needles, syringes, or other equipment to inject drugs Needle stick injuries in health care settings Direct blood exposure Being born to a mother who has Hepatitis C 4 in every 100 births to Hepatitis C infected moms Rarely Transmitted by: Contact with personal items such as razors, nail clippers, or toothbrushes Having sexual contact with a person infected with the Hepatitis C

8 HCV Life Cycle Binding & Entry Trafficking Translation & Replication (not shown above) Assembly Secretion & Cell-to-Cell Transmission Barreiro P, et al. Clin Infec Dis. 2013;56(4):560.

9 Hepatitis C Medications Peginterferon Ribavirin Protease inhibitors (NS3 and NS4A) NS5A and NS5B inhibitor Non-nucleotide and nucleotide inhibitors

10 Historical treatments Interferon based treatments peginterferon Ribavirin Telaprevir Boceprevir

11 Peginterferon Weeks Self injections Many negative Side Effects

12 Ribavirin Pharmacology Category Antihepaciviral, Nucleoside Mechanism of action Inhibits replication of RNA and DNA viruses Prevents viral protein synthesis Half-life ~298 hours at steady state Peaks at 2-3 hours Metabolism Hepatic and intracellular Excretion Urine 61%, feces 12% Side Effects Nausea Weight loss Anemia Pancytopenia Fatigue Hair loss Teratrogenic Category X

13 New Generation of Hepatitis C Treatment Interferon free Reduced ribavirin use Increased tolerability Decreased treatment duration Increased rate of cure

14 FDA Approved DAAs Drug Brand Name Approval Year Genotype Boceprevir Victrelis Telapravir Incivek Simeprevir Olysio Sofosbuvir Solvaldi Sofosbuvir/ledipasvir Harvoni Paritaprevir/ritonavir/ Ombitasvir + dasabuvir Viekira &4 Paritaprevir/ritonavir/Ombitasvir Technivie Daclatasvir Daklinza Grazoprevir + Elbasvir 2015? 1

15 Comparison of DAAs PI: 1st Generation PI: 2nd Generation NS5A Inhibitors NS5B Nucleoside Inhibitor NS5B Nonnucleoside Inhibitor Drug Boceprevir Telaprevir Simeprevir Paritaprevir Grazoprevir Ledipasvir Ombitasvir Daclatasvir Elbasvir Sofosbuvir Dasabuvir Efficacy Resistance Pangenotypic Efficacy ADR Drug Interactions

16 Nomenclature of HCV antivirals -previr (NS3-, Protease-Inhibitor) Telaprevir (Vertex), Boceprevir (Merck), Simeprevir (J&J), Asunaprevir (BMS), Paritaprevir (AbbVie), Grazoprevir (MK- 5172), Sovaprevir (ACH ), ACH asvir (NS5A inhibitor) Daclatasvir (BMS), Ledipasvir (Gilead), Ombitasvir (AbbVie), Elbasvir (MK-8742), Samatasvir (MK-1894 acquired with Idenix), ACH-2684, IDX719 -buvir (NS5B inhibitor, Polymerase-inhibitor) Sofosbuvir ([uridine nuc] Gilead), Dasabuvir ([nnuc]abbvie), Beclabuvir (BMS ), MK-IDX21439, MK-IDX21459 on hold; ACH-3422 ([uridine nuc] Achilion), AL-335 AL-516 ([nuc], Alios bought by J&J) ALS- 2200/Vx-135 ([uridine nuc], Vertex, stopped)

17 Protease Cleaves the HCV Polyprotein Cleavage E1 E2 P7 NS2 NS3/4A Protease NS4B NS5A C NS5B Kwong A, et al. Beyond interferon and ribavirin: Antiviral therapies for hepatitis C virus. Drug Discovery Today: Therapeutic Strategies. 2006;3:

18 NS Protein Replication Enzymes NS3 & NS4A Protease enzymes & form NS3/4A complex Post-translational processing of NS proteins NS4B Organize replication complex & rearrangements NS5A Binds RNA required for replication & assembly NS5B Polymerase, catalyzes HCV genome amplification Barreiro P, et al. Clin Infec Dis. 2013;56(4):560.

19 First Generation NS3/4A PIs Agents Telaprevir (TVR) Boceprevir (BOC) FDA Approved 5/2011 Use Genotype 1 only No longer recommended Shah N, et al. Expert Opin Investig Drugs. 2013;22(9):1107.

20 Second Generation NS3/4A PIs Agents Simeprevir Paritaprevir Faldaprevir, asunaprevir, vaniprevir Danoprevir, GS-9451, MK-5172 Mechanism of Action Reversible non-covalent inhibitors of NS3/4A Dosing Asunaprevir, vaniprevir: twice daily All others studied as once daily. Shah N, et al. Expert Opin Investig Drugs. 2013;22(9):1107. Flisiak R, et al. Expert Opin Emerg Drugs Oct 8. [Epub ahead of print].

21 NS3/4A PI Gt DDI Potential AE Profile NS3/4A PIs Overview Simeprevir 1,2, 4-6 CYP3A, OATP hyperbilirubinemia, fatigue Faldaprevir 1,4-6 CYP3A, 2C9 rash, jaundice, photosensitivity Asunaprevir 1 CYP2D6, OATP headache, diarrhea, weakness Vaniprevir 1 No data vomiting Danoprevir 1,4 CYP3A anemia, neutropenia, rash ABT450/rtv 1 CYP3A, OATP hyperbilirubinemia, fatigue, pain GS No data rash MK No data hyperbilirubinemia, increase LFTs PI, protease inhibitor; Gt, genotype; DDI, drug-drug interaction; AE, adverse effects.

22 NS3/4A PIs Clinical Trial Experience NS3/4A PI Regimen Duration SVR BOC PegIFN/RBV wks(rgt) 50-69% TVR PegIFN/RBV wks(rgt) 50-72% Simeprevir PegIFN/RBV Sofosbuvir RBV wks (RGT) 12 or 24 wks 75-80% 90% Faldaprevir PegIFN/RBV Deleobuvir + RBV wks (RGT) wks 87% 52-69% Asunaprevir PegIFN/RBV Daclatasvir Daclatasvir + BMS RGT, response guided therapy. 48 wks 24 wks wks 80-90% 76% 88-94%

23 NS3/4A Clinical Trial Experience NS3/4A PI Regimen Duration SVR Vaniprevir PegIFN/RBV wks 68% Danoprevir PegIFN/RBV wks(rgt) 68-76% ABT450/rtv ABT333 + RBV ABT333 + RBV + ABT267 GS9451 Ledipasvir + PegIFN/RBV Ledipasvir + PegIFN/RBV 12 wks wks 6-12 wks (RGT) wks (RGT) 47-95% % 79-98% % MK5172 PegIFN/RBV wks(rgt) 86-92% RGT, response guided therapy; rtv, ritonavir.

24 Simeprevir (SMV) FDA Approved 11/2013 NS3/4A Macrocyclic Protease Inhibitor (PI) Blocks NS3-NS5 post-translational processing Viral replication components not generated Macrocyclic non-covalent inhibitor Improved affinity & selectivity for HCV target Resistance Different profile compared to BOC and TVR Exception: R155K Not recommended for DAA treated patients Tanwar S, et al. Expert Opin Investig Drugs. 2012;21(8):1193.

25 Simeprevir Pharmacokinetics Absorption Oral bioavailability ~44% (food effect?) Elimination Half-life ~40 hours (once daily dosing) Metabolism Hepatic via CYP 3A4 and CYP 1A2 Substrate and mild inhibitor of both enzymes Safe in moderate hepatic impairment (Childs B) Inhibits bilirubin transporters (OATP1B1 & MRP2) Mild and transient increases in bilirubin Tanwar S, et al. Expert Opin Investig Drugs. 2012;21(8):1193.

26 Drug-Drug Interactions CYP 3A4 Metabolism Ritonavir (strong CYP3A4 inhibitor) Caused significantly increased SMV levels Rifampicin (strong CYP 3A4 inducer) Caused significanlty decreased SMV levels Methadone (CYP 3A4 substrate) No effect on methadone concentrations Escitalopram (CYP 3A4 substrate) No clinically significant escitalopram changes Tanwar S, et al. Expert Opin Investig Drugs. 2012;21(8):1193.

27 Drug-Drug Interactions CYP 1A2 No specific studies available for review SMV may increase CYP 1A2 substrate levels Clozapine, mirtazapine, olanzapine Cyclobenzaprine, tizanidine CYP 1A2 inhibitors may increase SMV levels Ciprofloxacin, fluvoxamine, ketoconazole Tanwar S, et al. Expert Opin Investig Drugs. 2012;21(8):1193.

28 Paritaprevir FDA Approved 12/2014 Inhibits HCV NS3/4A protease Interferes with HCV coded polyprotein cleavage necessary for viral replication. Used in combination with ombitasvir, dasabuvir, and ritonavir

29 Grazoprevir NS3/4A protease inhibitor high potency in vitro against HCV GT 1, GT2, GT4, GT5, and GT6 less active against GT3 substantial activity against resistanceassociated variants (RAVs) commonly detected after failed therapy with firstgeneration protease inhibitors Used with Elbasvir Zeuzem, S. et al. Ann Intern Med. 2015;163(1):1-13

30 Membrane Bound Proteins

31 NS5A Inhibitors Ledipasvir Ombitasvir Daclatasvir Elbasvir

32 NS5A Inhibitor Overview NS5A DDI Potential AE Profile ABT-267 No data Headache, nausea, fatigue Daclatas vir Ledipasv ir Minimal Minimal Headache, diarrhea, nausea Anemia, depression, coagulation increased DDI, drug-drug interaction; AE, adverse effect.

33 NS5A Inhibitors Agents ABT-267, daclatasvir, ledipasvir Mechanism of Action Block formation of essential replication components Intermediate barrier to resistance Genotype activity: Daclatasvir, ledipasvir: Genotype 1 only ABT-267: Multiple but focus genotype 1 Dosing All dosed once daily Shah N, et al. Expert Opin Investig Drugs. 2013;22(9):1107. Flisiak R, et al. Expert Opin Emerg Drugs Oct 8. [Epub ahead of print].

34 Ledipasvir Pharmacokinetics Absorption Peak: 4-6 hours Distribution 99% protein binding-wide distribution Metabolism P-gp, BCRP Excretion Feces >95%; Urine <1.5% Half-life 50 hours Harvoni PI 2014

35 German P, Mathias A, Yang JC, et al. The PK of Ledipasvir, an HCV Specific NS5A Inhibitor in HCV Uninfected Subjects with Moderate and Severe Hepatic Impairment. Hepatology 2013;58:432A Ledipasvir: Hepatic Impairment 10 Class B subjects; ledipasvir 30 mg x 12 days 10 Class C subjects; ledipasvir 90 mg x 1 day Matched to healthy controls Exposure was similar in subjects with liver cirrhosis and healthy controls Authors concluded that no dose adjustment is required for patients with severe liver impairment

36 Ombitasvir Inhibits HCV NS5A Interferes with viral RNA replication and virion assembly Used in combination with paritaprevir, dasabuvir, and ritonavir

37 Daclatasvir FDA Approved 7/2015 Binds to the N-terminus within NS5A Inhibits viral RNA replication and virion assembly. Tablets contain lactose Need to ask about tolerance Used in combination with sofosbuvir Treatment of HCV Genotype 3 Ally-1: Cirrhosis or post-transplant (GT1 or 3) Ally-2 HIV/HCV co-infection (GT1-6)

38 Daclatasvir 99% protein binding Metabolism CYP3A4, P-glycoprotein Half-Life hours; Peak 2 hours Excretion Feces 88%; urine 6.6%

39 NS5B Nucleos(t)ide Inhibitors Agents Sofosbuvir Dasabuvir Mechanism of Action Chain termination due to incomplete translation High barrier to resistance Active against all/most genotypes Shah N, et al. Expert Opin Investig Drugs. 2013;22(9):1107. Flisiak R, et al. Expert Opin Emerg Drugs Oct 8. [Epub ahead of print].

40 Sofosbuvir Pharmacology NS5B Polymerase Nucelotide Analogue Blocks RNA elongation by NS5B polymerase Incorporated into nascent HCV RNA Chain termination during replication Activity against all HCV genotypes Polymerase site highly conserved Pharmacokinetics (PK) Doses are given by mouth only once a day Minimal to no PK drug interactions noted Barreiro P, et al. Clin Infec Dis. 2013;56(4):560.

41 Sofosbuvir: Hepatic Impairment Studied in HCV patients Cirrhosis had no effect No dose adjustment for mild-severe impairment SOF 400 mg x 7 days in HCV subjects GS Child- Pugh Class B Child- Pugh Class C C max AUC Sofosbuvir C max AUC Sofosbuvir PI 2014

42 Sofosbuvir: Renal Impairment Fold Change of PK of SOF 400 mg x 1 dose Mild Renal impairment (GFR: 50-80) Moderate Renal impairment (GFR: 30-50) Severe Renal impairme nt (GFR: < 30) ESRD (SOF administere d 1 hour before Dialysis) ESRD (SOF administere d 1 hour after Dialysis) GS (inactive metabolite) C max AUC SOF C max AUC Sofosbuvir PI 2014

43 Renal Dosing Recommendations Sofosbuvir Ledipasvir Use in caution in ESRD and Dialysis Accumulation of inactive metabolite Dialysis removes 18% of SOF dose prior to dialysis, and significant amounts of GS Likely safe Feces > 98% unchanged Dialysis unlikely to have an effect (high Vd, and protein binding)

44 Special Populations: Summary No CYP450 hepatic metabolism No dose adjustment in hepatic impairment No dose adjustment if CrCl >30 ml/min No impact of HCV patient characteristics on exposure BMI, age, sex, race, or cirrhosis Pregnancy Category B Harvoni PI 2014

45 Dasabuvir Non-Nucleoside Inhibitor of NS5B Inhibits HCV RNA-dependent RNA polymerase (encoded by the NS5B gene) which is also necessary for viral replication. Twice daily dosing Used in combination with ombitasvir, paritaprevir and ritonavir

46 Ritonavir Pharmacological category Protease inhibitor, antiretroviral Boosting agent-increased serum paritaprevir 98-99% Protein binding Metabolism CYP1A2, CYP2B6, CYP2D6, CYP3A4, P-glycoprotein Half-Life 3-5hours; peak 2 hours (fasting) 4hours (non-fasting) Excretion Feces ~ 86%; urine ~11%

47 Direct Acting Antivirals (DAA s) The right combination

48 Ledipasvir 90 mg/sofosbuvir 400 mg Brand name: Harvoni Tablets: Orange diamond shape GSI on one side and 7985 on the other side Each bottle contains 28 tablets Store at room temperature below 86 F Dispense in amber vial Disintegrated in water, juice, or milk Harvoni PI 2014

49 LED/SOF: FDA Indications Patient Population: GT 1 Tx Naïve without cirrhosis (Pre-tx HCV VL < 6 million IU/mL) Tx Naïve with/without cirrhosis Tx Experienced without cirrhosis* Tx Experienced with cirrhosis* Tx Duration 8 weeks 12 weeks 12 weeks 24 weeks * Tx experienced includes failed tx with past DAA + PEG INF + RBV Harvoni PI 2014

50 Daclatasvir -used with Sofosbuvir Brand name: Daklinza Tablets: Light green pentagons BMS on one side and 215 on the other side Each box contains 28 tablets No special storage instructions Shelf life: 30 months Contains lactose Daklinza PI 2015

51 Renal Dosing Recommendations Est CrCL Daclatasvir Sofosbuvir Ledipasvir CrCl > 30 No adjustment CrCl < 30 Safe Not studied Not studied ESRD Clinical Considerations Daclatasvir Safe Feces > 88% Dialysis unlikely to have an effect (high Vd, and protein binding) Sofosbuvir Use in caution in ESRD and Dialysis Accumulation of inactive metabolite Dialysis removes 18% of SOF dose prior to dialysis, and significant amounts of GS

52 Daclatasvir: FDA Indications use in combination with Sofosbuvir Patient Population Treatment Tx Duration GT 3: Tx naïve or experienced +/- Cirrhosis DCV + SOF 12 wks DCV = Daclatasvir; SOF = Sofosbuvir; RBV = Ribavirin; PEG = Peg-Interferon Daklinza PI 2015

53 Administration: Patient Counseling Take whole tablet Chewing or crushing leads to unpleasant taste Take on a regular dosing schedule with or without food Counsel about Lactose Store at room temperature Missed dose can be taken up to 20 hours late The patient should resume the regular dosing schedule on the next day Daklinza PI 2015

54 3D Regimen Mechanism of Action

55 Viekira Pak: FDA Indications Patient Population Treatment Duration GT 1a without cirrhosis 3D + Ribavirin GT 1a with cirrhosis 3D + Ribavirin GT 1b without cirrhosis 3D GT 1b with cirrhosis 3D + Ribavirin Post Liver transplant (Class A, mild fibrosis) 3D + Ribavirin 12 weeks 24 weeks 12 weeks 12 weeks 24 weeks HCV/HIV-1: follow the above recommendations If unknown GT or mixed, then use GT 1a recommendations Viekira Pak PI 2014

56 Summary: Key GT1 Studies in Special Populations 3D + RBV x 12 wks could be considered in cirrhotics in GT1a Tx Naïve Prior Relapse or Partial Response to PEG + RBV HCV/HIV Co-infection: 3D not preferred regimen Drug interactions, should be on HAART Not recommended: efavirenz, darunavir, lopinavir, rilpivirine Post-Liver Transplant: 3D not preferred regimen High SVR12 rates in minimal fibrotic pts, but significant drug interactions

57 Summa Antimicrobial Agent Chemotherapy 2012 Coburn ChemMedChem 2013 Harper ACS Med Chem Lett

58 Summary: Merck Not yet FDA approved 58 Grazoprevir (NS3; 100 mg) / elbasvir (NS5A; 50 mg) One pill, once a day, for 12 weeks, without ribavirin GT1, 4, 5, 6 16 weeks, possibly with ribavirin, for TE cirrhotics Effective in renal failure/dialysis (without RBV) Effective in HIV/HCV (no EFV, no boosted PI) GT1a: baseline RAV to NS5A (>5-fold resistance) reduces SVR Baseline testing for RAV to NS5A for GT1a (but not GT1b)?? 8-weeks may be sufficient if combined with NS5B NRT (SOF or Merck)

59 Barrier to Resistance: HCV genome NS5A NS3/4A NS5B NS2 NS4B Protease Inhibitors Inhibition of Nucleoside or RNA replication Non-nucleosides assembly RNA polymerase inhibition

60 HCV Resistance Genetic Barrier or Threshold Number of amino acid substitutions needed for a viral variant to acquire full resistance Higher the number = higher barrier Viral Fitness Ability of the mutant HCV to replicate Mutants with low fitness unlikely clinically significant due to impaired replication ability Pawlotsky JM. Hepatology. 2011;53:1742.

61 Patterns of RAVs Target RAV NS3 inhibitor NS5A inhibitor NS5B nuc NS5B non-nuc Peg-IFN RBV V36M NS3 T54A R155K A156T D168V NS5A L31V Y93H S282T C316Y NS5B M414T R422K M423T P495S Note: not a comprehensive list of all known HCV DAA RAVs. Susceptible Resistant Adapted from HCV DrAG ResisSS 2012 v.1. Available at hivforum.org/projects/hcv-drugdevelopment-advisory group/hcv-drug-resistance-slide-set. Accessed September 30, 2014.

62 Retreatment Strategies: First Generation DAA Failure Regimen 1 1st Gen NS3/4A Boceprevir Or Telaprevir PegINF Regimen 2 2 nd Gen NS3/4A Paritaprevi r NS5A Ombitasvir NS5B Non-Nuc Dasabuvir Regimen 3 NS5A Ledipasvi r or Daclatas vir NS5B Nuc Sofosbuvir Regimen 4 2 nd Gen NS3/4A Simeprevir NS5B Nuc Sofosbuvir Ribavirin Ribavirin Ribavirin Ribavirin

63 Retreatment Strategies: First Generation DAA Failure Regimen 1 1st Gen NS3/4A Boceprevir Or Telaprevir PegIN F Ribavirin Regimen 2 2 nd Gen NS3/4A Paritaprevi r NS5A Ombitasv NS5B ir Non- Nuc Dasabuv ir Ribavirin Regimen 3 NS5A Ledipasvi r or Daclatas vir NS5B Nuc Sofosbuvir Ribavirin Regimen 4 2 nd Gen NS3/4A Simeprevir NS5B Nuc Sofosbuvir Ribavirin

64 Retreatment Strategies: Failed Sofosbuvir + RBV Regimen 1 NS5B Nuc Sofosbuvir Ribavirin Regimen 2 2 nd Gen NS3/4A Paritaprevi r NS5A Ombitasv NS5B ir Non- Nuc Dasabuv ir Ribavirin Regimen 3 NS5A Ledipasvi r or Daclatas vir NS5B Nuc Sofosbuvir Ribavirin Regimen 4 2 nd Gen NS3/4A Simeprevir NS5B Nuc Sofosbuvir Ribavirin

65 Retreatment Strategies: Viekira, or Harvoni Failure Regimen 1 2 nd Gen NS3/4A Paritaprevi r NS5A Ombitasv NS5B ir Non- Nuc Dasabu vir Ribavirin Regimen 2 NS5A Ledipasvi r or Daclatas vir NS5B Nuc Sofosbuvir Ribavirin Regimen 3 2 nd Gen NS3/4A Simeprevir NS5B Nuc Sofosbuvir Ribavirin Regimen 4 2 nd Gen NS3/4A Grazoprevi r NS5A Elbasvir Ribavirin

66 Resources Clinical Care Options American Association for the Study of Liver Diseases VA National Hepatitis C Program or vaww.hepatitis.va.gov CDC: Viral Hepatitis