Curing Hepatitis C 1/30/2018 OBJECTIVES HCV DEFINED. Anne Lord Bailey, PharmD, BCPS Clinical Pharmacy Specialist February 22, 2018

Transcription

1 Curing Hepatitis C Anne Lord Bailey, PharmD, BCPS Clinical Pharmacy Specialist February 22, 2018 OBJECTIVES Review pathophysiology of Hepatitis C (HCV) Evaluate prevalence of HCV Consider updated treatment options and recommendations Discuss pertinent drug-drug interactions HCV DEFINED Enveloped single-stranded RNA virus Humans are the only natural host Begins as an acute infection 75-85% progress to chronic infection 1

2 PREVALENCE 170 million cases worldwide 3.5 million currently infected in the US Enrolled in healthcare ~1.8% of the general population ~5.4% of the veteran population Leading indication for liver transplant 30% associated with HCV 18% associated with alcoholic liver disease GLOBAL BURDEN OF DISEASE DUE TO HCV USA BURDEN OF DISEASE DUE TO HCV Release.html 2

3 MANY REMAIN UNDIAGNOSED PREVALENCE 850 cases reported in cases reported in 2015 CDC estimation: 34,000 actual cases in AT RISK POPULATIONS Born between 1945 and 1965 IV drug users/abusers and IN cocaine abuse History of blood product receipt prior to July 1992 Solid organ transplant recipients Receipt of factor concentrates prior to 1987 MSM Body tattoos HIV patients Healthcare workers Children of HCV+ mothers Chronic hemodialysis patients 3

4 AWARENESS & TRANSMISSION 60-70% of new infections are asymptomatic HCV RNA detectable in 1-3 weeks post-exposure Seroconversion to Anti-HCV occurs in 8-9 weeks and is detectable in 97% at 6 months Transmission Most commonly with large, percutaneous exposure Can be occupational, perinatal, sexual ROLE OF HEALTHCARE PROVIDERS Overcome diagnostic obstacles Misconceptions about causes of liver disease Stigmas of at risk populations Lack of symptoms Overcome treatment obstacles Misconceptions about treatment options Misconceptions about side effects and duration ROLE OF HEALTHCARE PROVIDERS Offer support to those who are HCV(+) Prevent transmission Decrease or eliminate alcohol use Weight management HepA vaccine: if no antibodies present HepB vaccine: if pre-existing antibodies and risk factors 4

5 CASCADE OF CARE Linkage to care Confirmatory testing Staging disease Initiating therapy Adhering to therapy despite ADRs Follow-up assessments and support PROGRESSION OF HCV Acute HCV can last up to 6 months 15-25% will clear virus with no treatment 75-85% will develop chronic infection Most common cause of liver-related death and liver transplant 12,000 deaths annually from HCV related disease HCV > HIV for infection as a cause of death POTENTIAL COMPLICATIONS Hepatic Encephalopathy Cognitive, fine-motor, emotional Ascites Spontaneous bacterial peritonitis Hepatorenal syndrome Portal Hypertension Variceal bleeding 5

6 CONFIRMATORY TESTING Confirmation: Recombinant Immunoassay Confirmation: HCV RNA Polymerase Chain Reaction Interpretation NEGATIVE NEGATIVE No infection * POSITIVE POSITIVE Infected POSITIVE NEGATIVE Past exposure * May be false negative if within 8-9 weeks of exposure QUESTIONS? ABNORMAL ALT/AST/ALK PHOS ALK Phos: Likely cholestatic ALT/AST <6 months = Acute >6 months = Chronic AST/ALT: >15 xuln = marked <15 = mild-to-mod Acute on chronic hepatocellular injury Chronic hepatocellular injury 6

7 STAGING THE DISEASE Fibrosis Direct result of inflammation in the liver Contributors: chronic alcoholism, HIV/HepB coinfection, diabetes, obesity, immunosuppression Major complication of HCV and associated morbidity and mortality Eradication may reverse fibrosis SVR might reverse cirrhosis STAGING THE DISEASE Non-invasive markers APRI = [(AST/AST ULN)/PLT] x 100 > 0.7 correlates with moderate fibrosis > 1.0 correlates with severe/advanced fibrosis Fib-4 = [Age (yrs) x AST (U/L)]/[PLT x ALT -2 ] <1.45 correlates with no significant fibrosis >3.25 correlates with significant fibrosis necessitates further workup STAGING THE DISEASE Non-invasive markers (cont): elastography Invasive markers: biopsy 7

8 TARGETING TREATMENT Urgent to treat: Advanced fibrosis (Metavir F3) Compensated cirrhosis (Metavir F4) Liver transplant patients* Renal transplant patients* Severe extra-hepatic HCV * In concert with transplant provider(s) TARGETING TREATMENT Important to treat: Women wishing to become pregnant Long-term hemodialysis patients MSM with high-risk sexual practices IV drug users/abusers Incarcerated persons WHY TREAT? 8

9 TREATMENT GOALS Sustained viral response (SVR) Halt or slow progression of fibrosis Prevent cirrhosis and/or HCC Ultimately, decrease risk of liver-related death PREDICTED LIVER DISEASE COMPLICATIONS THE C WORD HCC has more than tripled since 1980 Increased by ~3% every year since Predictions 42,220 new HCC cases diagnosed 30,200 will die of HCC 9

10 THE C WORD Cancer death rates in the United States continue to drop for all cancers combined as well as for most cancer types, finds a new government report that examined data between 2003 and While overall positive, the report findings also emphasize the large number of new cancer cases that can be prevented and examines the troubling rise of liver cancer Death rates due to liver cancer have increased the most compared with all cancer sites, and liver cancer incidence rates have also increased sharply. American Institute for Cancer, March QUESTIONS? 10

11 MEMBRANE-BOUND PROTEINS THE PATH TO A CURE Cell-culture systems: viral life cycle, virus host interactions, and pathogenesis Subgenomic selectable replicons Viral nonstructural proteins (NS3 5) responsible for genome replication Replicons permitted efficient screening, and testing of DAAs Faster & cheaper than animal model studies Scheel TKH. Nat Med 2013;19: Bartenschlager R. Nat Rev Drug Disc THE PATH TO A CURE HCV Viral genome Positive-stranded RNA virus No DNA intermediate No latent forms Requires continuous replication Viral Genotypes Image: AbbVie CDC Choo QL. Science. 1989;244:

12 % Sustained Virologic Response 1/30/2018 THE PATH TO A CURE Lessons learned from HIV drug development Highly error-prone RNA polymerase Monotherapy leads to resistance Combination therapy with Interferon alfa and Ribavirin Combine second generation DDAs to apply HIV combination-therapy principle Agents from two or more classes with nonoverlapping resistance profiles Provide rapid and potent suppression Prevent emergence of resistant variants 100 TREATMENT INF IFN+RBV PEG-IFN+RBV PEG-INF+DAA RBV+DAA DAA+DAA Treatment Duration in weeks INF=interferon alpha; PEG-Interferon=Pegalated Interferon alpha; RBV=Ribavirin; DAA=Direct Acting Antiviral 12

13 Log HCV RNA (IU/mL) 1/30/2018 TREATMENT End of Treatment Null Response Partial Response Virologic Breakthrough Relapse SVR (sustained response) Weeks RVR (rapid response) HOW DOES THE MEDICATION WORK? Direct Acting Antivirals Drug FDA APPROVALS Brand Name Approval Year Genotype Boceprevir Victrelis Telapravir Incivek Simeprevir Olysio Sofosbuvir Sovaldi

14 FDA APPROVALS Drug Brand Name Approval Year Genotype Sofosbuvir/ledipasvir Harvoni Paritaprevir/ritonavir/ Ombitasvir + dasabuvir Viekira Paritaprevir/ritonavir/Ombitasvir Technivie Daclatasvir Daklinza Grazoprevir/Elbasvir Zepatier , 4 Sofosbuvir/velpatasvir Epclusa * Sofosbuvir/velpatasvir/voxilaprevi r/ Vosevi Glecaprevir/Pibrentasvir Mavyret BARRIER TO RESISTANCE: DAA DRUG CLASSES NS3/4A Boceprevir NS3/4A Telaprevir Simeprevir Boceprevir Paritaprevir Telaprevir Grazoprevir Simeprevir Voxilaprevir Paritaprevir Glecaprevir NS5A Ledipasvir Daclatasvir Ombitasvir Elbasvir Velpatasvir NS5B Pibrentasvir Nucleoside NS5B Sofosbuvir Nucleoside Non-Nucleoside Sofosbuvir Dasabuvir Non-Nucleoside Dasabuvir 14

15 QUESTIONS? TREATMENT Genotype Genotype 1 = ~75% of Americans Genotype 2 and 3 = ~20-25% Genotype 4-6 = < 5% Presence of cirrhosis Compensated Decompensated Treatment history Resistance TREATMENT Mostly 1 tablet, once daily Mostly of therapy Greater than 90% cure (SVR12) rate Drug interactions Adverse drug reactions Past medical history Renal impairment Cardiovascular risk 15

16 GENOTYPE 1, TREATMENT NAÏVE, NON-CIRRHOTIC Duratio n Special Considerations Elbasvir/Grazoprevir If GT1a, complete RAP testing; add RBV and treat x 16 weeks if present Glecaprevir/Pibrentasvi r 8 weeks Ledipasvir/Sofosbuvir 8 weeks if VL < 6 million, non-african American, and mono-infected Elbasvir/Grazoprevir (Zepatier) Glecaprevir/Pibrentasvi r GENOTYPE 1, TREATMENT NAÏVE, CHILD PUGH A CIRRHOTIC Duratio n Special Considerations If GT1a, complete RAP testing; add weight-based RBV and treat x 16 weeks if present Ledipasvir/Sofosbuvir Consider adding RBV Ledipasvir/Sofosbuvir + low-dose RBV Ledipasvir/Sofosbuvir + low-dose RBV GENOTYPE 1, TREATMENT NAÏVE, CHILD PUGH B OR C CIRRHOTIC Duratio n Special Considerations RBV 600mg/day; increase by 200mg/day as tolerated up to weightbased dosing; OR 24 weeks WITHOUT RBV 24 weeks RBV 600mg/day; increase by 200mg/day as tolerated up to weightbased dosing; OR 24 weeks WITHOUT RBV 24 weeks 16

17 GENOTYPE 1, TREATMENT EXPERIENCED (PEGIFN/RBV), NON-CIRRHOTIC OR CHILD PUGH A CIRRHOTIC Duratio n Special Considerations Elbasvir/Grazoprevir Add weight-based RBV if NS3a/4 failure If GT1a, complete RAP testing; add weight-based RBV and treat x 16 weeks if present Glecaprevir/Pibrentasvir 8 weeks if cirrhotic or if Simeprevir + Sofosbuvir failure Ledipasvir/Sofosbuvir Add weight-based RBV if cirrhotic Voxilaprevir/velpatasvir/ Sofosbuvir GENOTYPE 1, TREATMENT EXPERIENCED (PEGIFN/RBV), CHILD PUGH B-C CIRRHOTIC Ledipasvir/Sofosbuvir + low-dose RBV Ledipasvir/Sofosbuvir + low-dose RBV Duratio n Special Considerations RBV 600mg/day; increase by 200mg/day as tolerated up to weightbased dosing 24 weeks RBV 600mg/day; increase by 200mg/day as tolerated up to weightbased dosing 24 weeks GENOTYPE 1, TREATMENT EXPERIENCED (NS5A), NON-CIRRHOTIC OR CHILD PUGH A CIRRHOTIC Glecaprevir/Pibrentasvir Voxilaprevir/velpatasvir/Sofosbuv ir Duration 16 weeks GENOTYPE 1, TREATMENT EXPERIENCED (NS5A), CHILD PUGH B-C CIRRHOTIC + low-dose RBV **not FDA-approved Duratio n Special Considerations 24 weeks RBV 600mg/day; increase by 200mg/day as tolerated up to weight-based dosing 17

18 GENOTYPE 2, TREATMENT NAIVE, NON-CIRRHOTIC OR CHILD PUGH A CIRRHOTIC Duration Special Considerations Glecaprevir/Pibrentas vir Velpatasvir/Sofosbuvi r 8 weeks if cirrhotic Duration Special Considerations + low-dose RBV GENOTYPE 2, TREATMENT NAIVE, CHILD PUGH B-C CIRRHOTIC RBV 600mg/day; increase by 200mg/day as tolerated up to weight-based dosing 24 weeks GENOTYPE 2, TREATMENT NAÏVE OR SOFOSBUVIR/RBV EXPERIENCED, NON-CIRRHOTIC OR CHILD PUGH A CIRRHOTIC Duration Special Considerations Glecaprevir/Pibrentas vir Velpatasvir/Sofosbuvi r 8 weeks if cirrhotic GENOTYPE 2, TREATMENT NAÏVE OR SOFOSBUVIR/RBV EXPERIENCED, Duration Special Considerations + low-dose RBV CHILD PUGH B-C CIRRHOTIC RBV 600mg/day; increase by 200mg/day as tolerated up to weight-based dosing 24 weeks GENOTYPE 2, NS5A EXPERIENCED, NON-CIRRHOTIC OR CHILD PUGH A CIRRHOTIC Voxilaprevir/Velpatasvir/ Sofosbuvir Duratio n Special Considerations Duration Special Considerations + low-dose RBV RBV 600mg/day; increase by 200mg/day as tolerated up to weight-based dosing 24 weeks If NS5a-naive + low-dose RBV *not FDA-approved GENOTYPE 2, NS5A EXPERIENCED, CHILD PUGH B-C CIRRHOTIC 24 weeks If NS5a-experienced 18

19 GENOTYPE 3, TREATMENT NAÏVE, NON-CIRRHOTIC Glecaprevir/Pibrentasvir Duration 8 weeks GENOTYPE 3, TREATMENT NAÏVE, CHILD PUGH A CIRRHOTIC Duration Special Considerations Glecaprevir/Pibrentasvir Test for Y93H; Add weight-based RBV if present GENOTYPE 3, TREATMENT NAIVE, CHILD PUGH B-C CIRRHOTIC + low-dose RBV Ledipasvir/Sofosbuvir Duratio n Special Considerations RBV 600mg/day; increase by 200mg/day as tolerated up to weightbased dosing 24 weeks 24 weeks GENOTYPE 3, TREATMENT EXPERIENCED, NON-CIRRHOTIC OR CHILD PUGH A CIRRHOTIC Glecaprevir/Pibrentasvir Voxilaprevir/ Duration 16 weeks 19

20 GENOTYPE 3, NS5A EXPERIENCED, NON-CIRRHOTIC OR CHILD PUGH A CIRRHOTIC Duration Special Considerations Voxilaprevir/Velpatasvir/Sof osbuvir Consider adding weight-based RBV if cirrhotic; no data to support GENOTYPE 3, NS5A EXPERIENCED, CHILD PUGH B-C CIRRHOTIC Duration Special Considerations + low-dose RBV RBV 600mg/day; increase by 200mg/day as tolerated up to weight-based dosing 24 weeks If NS5a-naive + low-dose RBV *not FDA-approved 24 weeks If NS5a-experienced GENOTYPE 4, TREATMENT NAÏVE, NON-CIRRHOTIC OR CHILD PUGH A CIRRHOTIC Duration Special Considerations Elbasvir/Grazoprevir Glecaprevir/Pibrentasvir 8 weeks if cirrhotic Ledipasvir/Sofosbuvir Ledipasvir/Sofosbuvir + low-dose RBV Ledipasvir/Sofosbuvir + low-dose RBV GENOTYPE 4, TREATMENT NAÏVE, CHILD PUGH B-C CIRRHOTIC Duratio n Special Considerations RBV 600mg/day; increase by 200mg/day as tolerated up to weightbased dosing 24 weeks RBV 600mg/day; increase by 200mg/day as tolerated up to weightbased dosing 24 weeks 20

21 GENOTYPE 4, SOFSOBUVIR-EXPERIENCED/NS5A-NAIVE, NON-CIRRHOTIC OR CHILD PUGH A CIRRHOTIC Elbasvir/Grazoprevir + weight-based RBV Durati on 16 weeks Special Considerations *PegIFN/RBV-experienced Glecaprevir/Pibrentasvir 8 weeks if cirrhotic 12 weeks GENOTYPE 4, NS5A EXPERIENCED, NON-CIRRHOTIC OR CHILD PUGH A CIRRHOTIC Voxilaprevir/ Duration GENOTYPE 4, NS5A EXPERIENCED, CHILD PUGH B-C CIRRHOTIC Duration Special Considerations + low-dose RBV RBV 600mg/day; increase by 200mg/day as tolerated up to weight-based dosing 24 weeks If NS5a-naive + low-dose RBV *not FDA-approved 24 weeks If NS5a-experienced GENOTYPE 5-6, TREATMENT NAÏVE OR PEGIFN/RBV EXPERIENCED, NON-CIRRHOTIC OR CHILD PUGH A CIRRHOTIC Duration Special Considerations Glecaprevir/Pibrentasvir 8 weeks if cirrhotic Ledipasvir/Sofosbuvir GENOTYPE 5-6, NS5A-EXPERIENCED, NON-CIRRHOTIC OR CHILD PUGH A CIRRHOTIC Voxilaprevir/Velpatasvir/Sofosbuv ir Duration 21

22 MUST KNOW TREATMENT CONSIDERATIONS 4 week supply of medication per package May store in original bottle, amber pharmacy vial, or pill box Exception: prepackaged dosing* Keep at room temperature below 86 F Avoid storing in the bathroom MUST KNOW TREATMENT CONSIDERATIONS Take whole tablet Follow instructions of medicine label Missed dose can be taken later in the day Resume regular dosing schedule on the next day Drug interactions including over-the-counter products Acid reducing agents, herbals MUST KNOW TREATMENT CONSIDERATIONS NO Sofosbuvir-containing regimens if CrCL < 30 ml/min Elbasvir/Grazoprevir and glecaprevir/pibrentasvir both have indications for CKD patients NO Elbasvir/Grazoprevir, glecaprevir/pibrentasvir, voxilaprevir/velpatasvir/sofosbuvir in decompensated cirrhosis 22

23 MUST KNOW TREATMENT CONSIDERATIONS RAP testing GT1a if considering elbasvir/grazoprevir Add weight-based RBV and extend to 16 weeks if Y93, M28, Q30, L31 are present GT1 if treatment experienced and considering ledipasvir/sofosbuvir GT3 if considering velpatasvir/sofosbuvir Add weight-based RBV and treat for if Y93H present MUST KNOW TREATMENT CONSIDERATIONS Avoiding HBV reactivation Pre-treatment workup to include HBV serologies: HBV Surface antigen HBV Surface antibody HBV Core If positive, test HBV DNA VL Continue monitoring as warranted throughout treatment Vaccinate as appropriate MUST KNOW TREATMENT CONSIDERATIONS Ribavirin: up to 3 capsules twice daily Birth defects Category X Birth control 2 forms throughout therapy Continue for at least 6 months following therapy 23

24 MUST KNOW TREATMENT CONSIDERATIONS Anemia Low Discontinuation rate Mean Hgb reduction of 2.4 g/dl First 2 weeks Return to baseline 4 weeks post treatment CNS, GI, dermatologic MUST KNOW DRUG-DRUG INTERACTIONS NO Sofosbuvir-containing regimens with amiodarone NO concomitant use of strong inducers (e.g. rifampin, phenytoin, carbamazepine) CAUTION with ledipasvir/sofosbuvir, velpatasvir/sofosbuvir, and voxilaprevir/velpatasvir/sofosbuvir and acidreducers QUESTIONS? 24

25 Non-HCV Drug TUMS (aluminum and magnesium hydroxide) Elbasvir/Gr azoprevir Glecaprevir/ Pibrentasvir Ledipasvir/ Sofosbuvir? Separate by 4 hours Digoxin Use caution and monitor; may increase dig levels Use caution and monitor; may increase dig levels Velpatasvir/ Sofosbuvir Separate by 4 hours Use caution and monitor; may increase dig levels Voxilaprevir/ve lpatasvir/sofos buvir Separate by 4 hours Use caution and monitor; may increase dig levels Amiodarone?? X X X Dabigatran? May increase dabigatran levels?? May increase dabigatran levels Non-HCV Drug Carbamazepine, phenytoin, phenobarbitol, oxcarbazepine Elbasvir/Gr azoprevir Glecaprevir/ Pibrentasvir Ledipasvir/ Sofosbuvir Velpatasvir/ Sofosbuvir Voxilaprevir/v elpatasvir/sofo sbuvir X X X X X Lamotrigine???? Ketoconazole X?? Gemfibrozil?? X Rifampin X X X X X Amlodipine, Nifedipine, et al Budesonide, prednisone, methylprednisone??????? Non-HCV Drug H2 Antagonists Elbasvir/Gra zoprevir Glecaprevir/ Pibrentasvir Ledipasvir/Sof osbuvir Do not exceed famotidine 40mg BID equivalent; given 12 hours part Velpatasvir/So fosbuvir Do not exceed famotidine 40mg BID equivalent; given 12 hours part Voxilaprevir/v elpatasvir/sofo sbuvir Do not exceed famotidine 40mg BID equivalent; given 12 hours part St John s Wort X X X X X Atorvastatin < 20mg X?? Lowest dose Simvastatin X?? Pravastatin X X X X X Rosuvastatin < 10mg < 10mg X < 10mg X Cyclosporine X Okay if < 1000mg daily dose X Tacrolimus Monitor 25

26 Non-HCV Drug Buprenorphine, naloxone Elbasvir/Gr azoprevir Glecaprevir/ Pibrentasvir Ledipasvir/So fosbuvir Velpatasvir/ Sofosbuvir Voxilaprevir/v elpatasvir/sofo sbuvir??? Methadone Omeprazole (PPIs) Do not exceed omeprazole 20mg once daily equivalent; administer simultaneously Do not exceed omeprazole 20mg once daily equivalent; give 4 hours BEFORE omeprazole, with food Do not exceed omeprazole 20mg once daily equivalent; administer simultaneously QUESTIONS? POT OF GOLD Interferon and Ribavirin free 4 weeks of treatment One pill once daily No drug interactions Low ADRs Pangenotypic High barrier to resistance Limited lab follow up Affordable & Available?? 26

27 HOW DOES THE CLINIC WORK? Screening Appointme nt Labs Start Medicati on Pick up medication 2 week Follow up 4 week Follow up Pick up medication 12 week Follow up After END of Treatment 8 week Follow up Pick up medication 12 week Follow up: END of Treatment HOW DOES THE CLINIC WORK? Get blood work (at least 2 hours before) Have you missed any doses Tell us about all of the medicines you take including over-the-counter medicines Report recent illness or planned procedures Report adverse drug reactions Follow appointments last about 15 minutes Pick up medication at pharmacy window Check you bag before leaving pharmacy QUESTIONS? 27