Associate Professor Catherine Stedman

Transcription

1 Associate Professor Catherine Stedman Gastroenterologist Clinical Pharmacologist Christchurch Hospital University of Otago, Christchurch 7:00-7:55 AbbVie Breakfast Session Hepatitis C - How to Find and Treat

2 Hepatitis C: How to find and treat patients in primary care Catherine Stedman Associate Professor of Medicine, University of Otago, Christchurch Gastroenterology Department, Christchurch Hospital

3 Disclaimer The views and opinions expressed in the following presentations are those of the presenter and do not necessarily reflect those of AbbVie Limited. AbbVie Limited does not endorse the use of unregistered products or products outside of their registered indications. Please refer to the Product Information or Data Sheet for licensed instructions. AbbVie Limited, Wellington. Aug NZ-MAVI

4 Disclosures I have been a member of Advisory Boards for AbbVie, Gilead Sciences, Janssen, and MSD. The opinions expressed are my own. 4

5 What is Hepatitis C?

6 What is hepatitis C? Hepatitis C is a blood-borne virus that infects the liver and causes inflammation. Infection with Hepatitis C virus is often undiagnosed, and acute infections clear spontaneously in 25% of patients. Chronic infection can damage the liver, and progress to fibrosis, cirrhosis, liver failure, hepatocellular carcinoma, and death. In most patients, the virus also has effects beyond the liver, causing cardiovascular, renal, metabolic, neurological, and immune disorders. 1 CDC. Hepatitis C Questions and Answers for the Public. Available at Accessed July Cacoub P, et al. Ther Adv Infect Dis 2016; Feb; 3(1):

7 Systemic disease associated with Chronic Hepatitis C Type 2 diabetes and insulin resistance Skin Rashes Cryoglobulinaemia Porphyna cutanea tarda Lichen Planus Psoriasis Dry eyes and mouth Lymphoma Fatigue, depression, cognitive impairment Cardiovascular disorders (stroke, ischemic heart disease) Chronic kidney disease (glomerulonephritis, proteinuria) Arthralgias, myalgias, inflammatory polyarthritis, fibromylagia In most patients with chronic HCV, the virus also causes negative effects beyond the liver, including cardiovascular, renal, metabolic, neurological, and immune diseases Cacoub P, et al. Ther Adv Infect Dis 2016; Feb; 3(1): Garcovich S, et al. World J Hepatol Nov 28; 7(27):

8 Complications of Cirrhosis Portal hypertension Hepatic insufficiency Varices Hepatic encephalopathy (HE) Ascites Jaundice Hepatocellular carcinoma (HCC) Hepatorenal syndrome (HRS) Spontaneous bacterial peritonitis (SBP) Complications 10 20% of cirrhosis patients will progress to cirrhosis which is associated with significant morbidity and mortality Healthline. Cirrhosis and Hepatitis C: Their Connection, Prognosis, and More. Available at Accessed July

9 Hepatitis C: from Virus Discovery to Plans for Elimination in 30 years 1" 2" Pan-genotypic era " 4" non-a, non-b hepatitis 1989: Identification of HCV Early era of DAA s 2016: The WHO Global Health Sector DAA established revolution the goal of HCV elimination as a major public heath target by 2030 The IFN era 9

10 WHO has set ambitious global targets to control viral hepatitis by 2030 Percentage 90% reduction in new cases of Hep C 80% eligible people receive Hep C treatment 65% reduction in deaths from Hep C In May 2016, NZ was one of 194 countries who adopted the World Health Organization s Global Hepatitis Strategy New cases of chronic hepatitis B and C Treatment-eligible people with chronic hepatitis B and C Hepatitis B and C deaths WHO: World Health Organization WHO global health sector strategy on viral hepatitis. Available at: (accessed April 2017) 10

11 Hepatitis C in New Zealand

12 Chronic hepatitis C in New Zealand 50,000 people are estimated to have chronic hepatitis C infection in New Zealand. Approximately 50% of these have been diagnosed new infections per year (estimate) Median age of diagnosis is 47y and duration of infection is >25y NZ HCV genotype distribution Hepatitis C can be categorized into 6 major genotypes: GT1,2,3,4,5 & 6 GT1a GT1b GT3a GT 2a & 2c GT4 GT6 Gane E, et al. NZ Med J 2014;127(1407): Cacoub P, et al. Ther Adv Infect Dis 2016 Feb; 3(1):3-14. El-Kamary S, et al. Clin Infect Dis Jul 15; 53(2): Ministry of Health. Hepatitis C

13 Risk Factors for Hepatitis C Infection in New Zealand In NZ, the majority of people with chronic HCV were infected via injecting drug use. Most were years old between 1970 and Blood transfusion in NZ before screening began in Transmission may have occurred more recently in other countries (e.g. South East Asia, India, the Middle East, or Eastern Europe). Infection can occur via tattoos or body piercings, due to unsterile equipment or unsafe practices. Any blood-blood contact (including sporting, sexual, violent, or occupational activities). Prison inmates have relatively high rates of infection with HCV. Mother to child transmission during birth (5% risk), and transmission also occasionally occurs within households. All children of women with chronic HCV should be tested once they are at least a year old. Gane E, et al. NZ Med J 2014;127(1407): Hepatitis Foundation of NZ. Report; Nov

14 Finding patients with HCV We need a national screening programme for hepatitis C We must identify and enable all NZ people infected with hepatitis C the opportunity for a curative treatment * *2 nd NZ Hepatitis C Summit

15 Practicalities of finding HCV in primary care Screening test: HCV antibody Confirmatory test: HCV viral load Genotyping is unlikely to be necessary with new drugs (except treatment failures) There is a trend away from targeted testing as discrimination means many people are not being diagnosed All people should be able to request a hepatitis C test without disclosing specific risk factors Just test once. Avoid repeat testing (unless a new/ongoing risk factor) 15

16 Additional testing once HCV diagnosed CBC- (platelets) LFTs & INR Hep B screening if not done (HBsAg and anti-hbc) Assess liver for fibrosis before treatment: Fibroscan within 3 years If Fibroscan <10.5KPa and platelets/inr/albumin normal treat in primary care If a FibroScan is unsuccessful: Calculate APRI (AST to platelet ratio, APRI free online calculator) If APRI <1.0 treat in primary care Refer to secondary care if: - abnormal bilirubin/platelets/inr/albumin/fibroscan 10.5 or APRI 1 Free online APRI calculator at /albuminast= aspartate aminotransferase 16

17 MAVIRET glecaprevir/pibrentasvir

18 Direct Acting Antivirals (DAAs) are HCV Enzyme Inhibitors NS5A protein HCV replication & virion assembly Ledipasvir, ombitasvir, Daclatasvir, Elbasvir Pibrentasvir, Velpatasvir asvir NS3/4A protease HCV protein processing Boceprevir, Telaprevir, Simeprevir Paritaprevir, Grazoprevir Glecaprevir, Voxilaprevir previr Sofosbuvir Nuc NS5B polymerase HCV replication Dasbuvir Non-nuc buvir Dore G, et al. Clin Infect Dis Jun 15;60(12): doi: /cid/civ

19 Introduction to Maviret Glecaprevir/pibrentasvir approval was based on clinical trial data in over 2,300 patients including placebo and active-controlled studies Glecaprevir/pibrentasvir is a fixed-dose combination of glecaprevir, an HCV NS3/4A protease inhibitor, and pibrentasvir, an HCV NS5A inhibitor Maviret is indicated for the treatment of adult patients with chronic HCV GT 1, 2, 3, 4, 5 or 6 infection without cirrhosis and with compensated cirrhosis (Child-Pugh A) GT=genotype. HCV=hepatitis C virus. NS=non-structural protein. MAVIRET Data Sheet. Available at 19

20 Formulation & Packaging Co-formulated, film-coated tablet of glecaprevir (100mg) and pibrentasvir (40mg) Recommended oral dose is 3 tablets taken once daily with food Tablets should be taken whole and not chewed, crushed or broken Daily dose is packaged into foil blister sheets, each containing 3 tablets MAVIRET Data Sheet. Available at 20

21 Treatment Duration for Treatment-naïve Patients Recommended treatment duration for treatment-naïve patients Patient populations Recommended Treatment Duration No cirrhosis Dosage and durations are applicable to patients with: HCV/HIV-1 coinfection Any stage of renal impairment including patients receiving dialysis Compensated cirrhosis GT 1,2,3,4,5 or 6 8 weeks 12 weeks Treatment in Primary care: treat all suitable treatment-naive people with HCV (any genotype) who are non-cirrhotic with 8 weeks of Maviret GT=genotype. HCV=hepatitis C virus. HIV=human immunodeficiency virus. MAVIRET Data Sheet. Available at 21

22 Efficacy Treatment-naive* Non-cirrhotic Patients with HCV GT 1 6 MAVIRET for 8 Weeks (ITT) * Based on pooled data. Data included non-cirrhotic, treatment-experienced patients to peginf, RBV, and/or sofosbuvir with GT1, 2, 4, 5 & 6. GT3 patients included in this analysis were treatment-naïve only. MAVIRET Data Sheet. Available at Puoti M et al. J Hepatol 2018; doi: /j.hep

23 Efficacy Integrated Subgroup Analysis of Treatment-naive Non-cirrhotic Patients with HCV GT weeks of MAVIRET treatment High SVR12 was achieved irrespective of baseline patient and viral characteristics APRI=aspartate aminotransferase to platelet ratio. BMI=body mass index. GT=genotype. HCV=hepatitis C virus. HIV=human immunodeficiency virus. mitt=modified ITT (excludes patients with non virologic failure). OST=opioid substitution therapy. pegifn=peginterferon. PPI=proton pump inhibitor. RBV=ribavirin. RNA=ribonucleic acid. SVR=sustained virologic response. SVR12=HCV RNA below the lower limit of detection at 12 weeks post end-of-treatment. TE=treatment experienced. MAVIRET Data Sheet. Available at Puoti M et al. J Hepatol 2018; doi: /j.hep Brown A et al. Hepatology 2017; 66(Suppl 1):114A 115A (Oral presentation, 198). 23

24 Treatment Duration for Treatment-experienced Patients Recommended duration for treatment-experienced patients Patient Population Recommended treatment duration No cirrhosis Compensated Cirrhosis NS5A inhibitor naïve* GT 1,2,4-6 8 weeks 12 weeks NS5A inhibitor experienced GT 1,2,4-6 GT3 any experience * experienced with PR, SOF + PR, SOF + R, SMV + SOF, SMV + PR, TVR + PR or BOC + PR. PR = Pegylated interferon + ribavirin; SOF = Sofosbuvir; R = Ribavirin; SMV = Simeprevir; TVR = Telaprevir; BOC = Boceprevir. 16 Weeks Dosage and durations are applicable to patients with: HCV/HIV-1 co-infection Any stage of renal impairment including patients receiving dialysis BOC=boceprevir. DCV=daclatasvir. GT=genotype. LDV=ledipasvir. NS3=non-structural protein 3. NS4A=non-structural protein 4A. NS5A=non-structural protein 5A. pegifn=peginterferon. PR=peginterferon/ribavirin. RBV=ribavirin. SMV=simeprevir. SOF=sofosbuvir. TVR=telaprevir. VEL=velpatasvir. MAVIRET Data Sheet. Available at 24

25 Treatment Duration for Treatment-experienced Patients Recommended duration for treatment-experienced patients Patient Population Dosage and durations are applicable to patients with: HCV/HIV-1 co-infection Any stage of renal impairment including patients receiving dialysis Recommended treatment duration No cirrhosis Compensated Cirrhosis NS5A inhibitor naïve* GT 1,2,4-6 8 weeks 12 weeks NS5A inhibitor experienced GT 1,2,4-6 GT3 any experience * experienced with PR, SOF + PR, SOF + R, SMV + SOF, SMV + PR, TVR + PR or BOC + PR. PR = Pegylated interferon + ribavirin; SOF = Sofosbuvir; R = Ribavirin; SMV = Simeprevir; TVR = Telaprevir; BOC = Boceprevir. Refer to secondary care if patients are HCV- Treatment-experienced 16 Weeks BOC=boceprevir. DCV=daclatasvir. GT=genotype. LDV=ledipasvir. NS3=non-structural protein 3. NS4A=non-structural protein 4A. NS5A=non-structural protein 5A. pegifn=peginterferon. PR=peginterferon/ribavirin. RBV=ribavirin. SMV=simeprevir. SOF=sofosbuvir. TVR=telaprevir. VEL=velpatasvir. MAVIRET Data Sheet. Available at 25

26 Safety & Tolerability Adverse events observed in >5% of approximately 2,300 patients who received 8, 12 or 16 weeks of MAVIRET in Phase 2 and 3 clinical studies The rate of adverse events in patients receiving MAVIRET (8, 12 or 16 weeks) was similar to those who received placebo The proportion of patients treated with MAVIRET who permanently discontinued treatment due to adverse events was 0.1% The type and severity of adverse events in patients with cirrhosis were overall comparable to those seen in patients without cirrhosis MAVIRET Data Sheet. Available at 26

27 Integrated Safety Analysis Comparison of 8, 12, or 16 weeks of MAVIRET treatment in patients with HCV GT 1 6 infection, without cirrhosis or with compensated cirrhosis*, across eight Phase 2 or 3 clinical trials AE=adverse event. ALT=alanine aminotransferase. AST=aspartate aminotransferase. DAA=directacting antiviral. DC=discontinuation. GGT= gamma glutamyl transferase. GT=genotype. HCV=hepatitis C virus. PI=protease inhibitor. PRS=interferon, peginterferon +_ ribavirin, or sofosbuvir + ribavirin +_ peginterferon. SAE=serious adverse event. ULN=upper limit of normal. MAVIRET Data Sheet. Available at Dufour J et al. J Hepatol 2017;66(Suppl):S721. (poster presentation FRI

28 Special Populations Primary care: Patients with renal impairment: No dose adjustment of MAVIRET is required in patients with any degree of renal impairment, including patients on dialysis. Check for drug interactions Elderly patients: No dose adjustment of MAVIRET is required Secondary Care: Patients with cirrhosis Child-Pugh A: No dose adjustment of MAVIRET is but treatment duration may be extended MAVIRET is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh C). Paediatric population: No data are available MAVIRET Data Sheet. Available at 28

29 Pregnancy & Breastfeeding Pregnancy There are no or limited data from the use of glecaprevir or pibrentasvir in pregnant women. Animal studies with glecaprevir or pibrentasvir do not indicate direct harmful effects on reproductive toxicity. Maternal toxicity in the rabbit precluded evaluation of glecaprevir at clinical exposures. As a precautionary measure, MAVIRET use is not recommended in pregnancy. Breastfeeding It is unknown whether glecaprevir or pibrentasvir are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of glecaprevir and pibrentasvir in milk, and a risk to newborns or infants cannot be excluded. Therefore, a decision must be made whether to discontinue breastfeeding or to discontinue/abstain from MAVIRET therapy, taking into account the benefits of breastfeeding for the child and the benefit of therapy for the woman. MAVIRET Data Sheet. Available at 29

30 Pregnancy & Breastfeeding Pregnancy There are no or limited data from the use of glecaprevir or pibrentasvir in pregnant women. Animal studies with glecaprevir or pibrentasvir do not indicate direct harmful effects on reproductive toxicity. Maternal toxicity in the rabbit precluded evaluation of glecaprevir at clinical exposures. As a precautionary measure, MAVIRET use is not recommended in pregnancy. Insufficient data for safety so generally avoid use in Breastfeeding pregnancy/breastfeeding It is unknown whether glecaprevir or pibrentasvir are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of glecaprevir and pibrentasvir in milk, and a risk to newborns or infants cannot be excluded. Therefore, a decision must be made whether to discontinue breastfeeding or to discontinue/abstain from MAVIRET therapy, taking into account the benefits of breastfeeding for the child and the benefit of therapy for the woman. MAVIRET Data Sheet. Available at 30

31 Drug Interactions Direct-acting antivirals interact with drug metabolising enzymes or transporters. MAVIRET undergoes hepatic metabolism. All patients with hepatitis C should undergo a careful medicines review before treatment: Ask about other medications or supplements including recreational drugs and complementary/alternative medicines or supplements. Many drug interactions are not clinically relevant, or can be managed by monitoring and /or dose adjustment. Others are contraindicated, and should be stopped or switched to alternatives. There is no dose adjustment for MAVIRET itself. 31

32 Drug-Drug Interactions* Glecaprevir and pibrentasvir are substrates of P-gp and/or BCRP transporters. Glecaprevir is a substrate of OATP1B1/3 transporters. Co-administration of MAVIRET with medicinal products that inhibit hepatic P-gp, BCRP, or OATP1B1/3 may increase the plasma concentrations of glecaprevir and/or pibrentasvir. Co-administration of MAVIRET with medicinal products that induce P-gp/CYP3A may decrease plasma concentrations of glecaprevir and pibrentasvir. *This is not an exhaustive list please refer to the full MAVIRET data sheet & The University of Liverpool Hep Drug Interactions Contraindicated Atazanavir Rifampicin Not Recommended Dabigatran Carbamazepine St John s Wort Darunavir Efavirenz Lopinavir/ritonavir Atrovastatin Lovastatin Simvastatin Ciclosporin >100mg Ethinyloestradiol MAVIRET Data Sheet. Available at 32

33 Drug-Drug Interactions* Glecaprevir and pibrentasvir are substrates of P-gp and/or BCRP transporters. Glecaprevir is a substrate of OATP1B1/3 transporters. Co-administration of MAVIRET with medicinal products that inhibit hepatic P-gp, BCRP, or OATP1B1/3 may increase the plasma concentrations of glecaprevir and/or pibrentasvir. Co-administration of MAVIRET with medicinal products that induce P-gp/CYP3A may decrease plasma concentrations of glecaprevir and pibrentasvir. *This is not an exhaustive list please refer to the full MAVIRET data sheet & The University of Liverpool Hep Drug Interactions Contraindicated Atazanavir Rifampicin Not Recommended Dabigatran Carbamazepine St John s Wort Darunavir Efavirenz Lopinavir/ritonavir Atrovastatin Lovastatin Simvastatin Ciclosporin >100mg Ethinyloestradiol MAVIRET Data Sheet. Available at 33

34 Drug-Drug Interactions* Glecaprevir and pibrentasvir are substrates of P-gp and/or BCRP transporters. Glecaprevir is a substrate of OATP1B1/3 transporters. Co-administration of MAVIRET with medicinal products that inhibit hepatic P-gp, BCRP, or OATP1B1/3 may increase the plasma concentrations of glecaprevir and/or pibrentasvir. Co-administration of MAVIRET with medicinal products that induce P-gp/CYP3A may decrease plasma concentrations of glecaprevir and pibrentasvir. *This is not an exhaustive list please refer to the full MAVIRET data sheet & The University of Liverpool Hep Drug Interactions Contraindicated Atazanavir Rifampicin Not Recommended Dabigatran Carbamazepine St John s Wort Darunavir Efavirenz Lopinavir/ritonavir Atorvastatin Lovastatin Simvastatin Ciclosporin >100mg Ethinyloestradiol MAVIRET Data Sheet. Available at 34

35 Drug-Drug Interactions* Glecaprevir and pibrentasvir are substrates of P-gp and/or BCRP transporters. Glecaprevir is a substrate of OATP1B1/3 transporters. Co-administration of MAVIRET with medicinal products that inhibit hepatic P-gp, BCRP, or OATP1B1/3 may increase the plasma concentrations of glecaprevir and/or pibrentasvir. Co-administration of MAVIRET with medicinal products that induce P-gp/CYP3A may decrease plasma concentrations of glecaprevir and pibrentasvir. *This is not an exhaustive list please refer to the full MAVIRET data sheet & The University of Liverpool Hep Drug Interactions Contraindicated Atazanavir Rifampicin Not Recommended Dabigatran Carbamazepine St John s Wort Darunavir Efavirenz Lopinavir/ritonavir Atrovastatin Lovastatin Simvastatin Ciclosporin >100mg Ethinyloestradiol MAVIRET Data Sheet. Available at 35

36 Maviret has no expected drug interaction with OST or the Majority of Illicit Drugs This is not an exhaustive list. Please visit hep-druginteractions.org to check all drug drug interactions for HCV treatments. MAVIRET Data Sheet available at University of Liverpool. HEP drug interactions. Available at: hep-druginteractions.org. Accessed: 18 May

37 Where to Find Information on Interactions 1. Medsafe-approved Data Sheet: Please first refer to the New Zealand label for all contraindicated medications, drug interactions, and precautions 2. University of Liverpool website: Searchable by alphabetical list of drugs (A-Z), by drug class, or by trade name. A mobile app is also available 3. AbbVie Medical Information: , medinfoanz@abbvie.com AbbVie can answer questions based on data on file built up through the clinical development programme and post-marketing experience 4. NZ Formulary: nzformulary.org 37

38 Summary New Zealand has a goal of achieving hepatitis C elimination by 2030 To achieve this we must substantially increase new diagnosis rates and offer everyone infected with hepatitis C curative treatment Liver fibrosis assessment (usually Fibroscan) should be done prior to treatment New treatments are pangenotypic and the majority of non-cirrhotic treatmentnaïve patients can be treated and cured* in primary care with an 8 week treatment regimen (Maviret) All treatment-experienced patients or those with cirrhosis should still be referred to secondary care Gastro hepatology nurse specialists are very happy to be contacted for advice or support *Cure defined as HCV RNA below the lower limit of detection at 12 weeks post end-of-treatment (SVR12). 38

39 Spare slides 39