Managing New Treatments for Hepatitis C in Primary Care Christina Connel, PharmD, BCPS, AAHIVP Objectives 2 Review HCV disease burden Identify risk factors and recommended testing for HCV Describe who should be treated Describe monitoring before and during and after treatment Review direct acting HCV therapy options 1
HCV in the US Estimated 2.7 to 3.9 million people in the US 3 In 2014 Acute cases of acute HCV: 2,194 Estimated actual new cases: 30, 500 No. of deaths from HCV: 19,659 Liver disease was the 12 th leading cause of death Centers for Disease Control and Prevention (CDC, 2016) 4 75-80 % 20-25% 1-4% risk/year Natural History of Hepatitis C. http://www.hepatitisc.uw.edu/go/evaluation-staging-monitoring/natural-history/core-concept/all. Assessed 8 April 2017 2
5 HCV treatment cascade Yehia BR, Schranz AJ, Umscheid CA, Lo Re V III (2014) The Treatment Cascade for Chronic Hepatitis C Virus Infection in the United States: A Systematic Review and Meta-Analysis. PLOS ONE 9(7): e101554 6 Guidelines can be found at http://www.hcvguidelines.org/full-report/introduction 3
Risk factors 7 Injection-drug use (ever) Intranasal illicit drug use Percutaneous/parenteral exposures in an unregulated setting Long-term hemodialysis (ever) Healthcare workers after exposures to HCVinfected blood Children born to HCVinfected women Prior recipients of transfusions or organ transplants Persons who were ever incarcerated AASLD-IDSA HCV Guidance. HCV testing and linkage to care. Recommendations for testing and linkage to care. Date accessed here August 10, 2016 Screening 8 One time testing Patients born between 1945 and 1965 Patients with risk factors of HCV infection Patients behaviors or exposures associated with increased risk Annual testing IV drug users HIV-seropositive MSM Periodic testing should be offered to other persons with ongoing risk factors for exposure to HCV. AASLD-IDSA HCV Guidance. HCV testing and linkage to care. Recommendations for testing and linkage to care. Date accessed August 10, 2016 4
CDC testing sequence Patients exposed in the last 6 months should receive follow up antibody testing or HCV RNA testing 9 Patients suspected to have had exposures in the last 6months or questions concerning the handling of the test specimen should have an RNA repeated AASLD-IDSA HCV Guidance. HCV testing and linkage to care. CDC Recommended Testing Sequence for Identifying Current HIV Infection. Date accessed January 16, 2017 Preventing Transmission 10 Avoid sharing toothbrushes/dental equipment or shaving equipment. Stop IVDU Avoid sharing/reusing needles Dispose of needles in a puncture-proof container Do not donate blood Avoid sexual transmission by using barrier protection in those Co-infection with HIV multiple sex partners Clean visible blood on household surfaces with bleach-water AASLD-IDSA HCV Guidance. HCV testing and linkage to care. Measures to prevent transmission of HCV. Date accessed January 16, 2017 5
Treatment: Who? Why? When? 11 All patients should be treated except those with short life expectancies Goal of treatment is cure Reduces mortality and liver related disease Patient considerations Understanding Willingness to adhere/follow up Access to medication AASLD-IDSA HCV Guideance. HCV testing and linkage to care. When and in whom to initiate HCV therapy. Date accessed August 10, 2016 Pre-treatment Assessment Labs: Genotype/subtype Quantitative HCV RNA (HCV viral load) HBV status Resistance associated variants, when applicable 12 AASLD-IDSA HCV Guidance. Monitoring patients who are starting Hepatitis C treatment, re on treatment, or have completed therapy. Date accessed August 25, 2016 6
13 Child Pugh Score 1 2 3 Encephalopathy None Grade 1-2 (or precipitant induced) Ascites None Mild/Moderate (diuretic-responsive) Grade 3-4 (or chronic) Severe (diuretic refractory) Bilirubin (mg/dl) <2 2-3 >3 Albumin (g/dl) >3.5 2.8-3.5 <2.8 PT or INR <4 <1.7 4-6 1.7-2.3 Bedosa P etal. Histologic and non invasive Estimates of Liver Fibrosis. Clinical Liver Disease. 2015; 6:5-8 Natural History of Hepatitis C. http://www.hepatitisc.uw.edu/go/evaluation-staging-monitoring/natural-history/core-concept/all. Assessed 8 April 2017 >6 >2.3 Pre-treatment labs 14 Within 12 weeks of starting treatment CBC and INR Hepatic function (ALT/AST; total and direct bilirubin, alkaline phosphatase) Renal function TSH (if interferon is used) AASLD-IDSA HCV Guidance. Monitoring patients who are starting Hepatitis C treatment, re on treatment, or have completed therapy. Date accessed August 25, 2016 7
Monitoring during treatment 15 Clinic visits or telephone contact as needed ensure medication adherence monitor for adverse events drug-drug interactions with newly prescribed medications. At week 4 of treatment CBC Renal and hepatic function HCV viral load Repeat 12 weeks after the end of treatment for SVR AASLD-IDSA HCV Guideance. Monitoring patients who are starting Hepatitis C treatment, re on treatment, or have completed therapy. Date accessed August 25, 2016 Where we have come from. 16 Strader DB, Seeff LB. A Brief History of the Treatment of Viral Hepatitis C. Clinical Liver Disease. 2012;1(1):6-11. doi:10.1002/cld.a 8
Available HCV medications 17 Brand Generic Mechanism Olysio Simeprevir* NS3/4A Sovaldi Sofosbuvir* NS5B Harvoni Ledipasvir/sofosbuvir NS5A + NS5B Viekera Pak Viekera XR ombitasvir/paritaprevir/ritonavir and dasabuvir (PrOD) NS5A + NS3/4A + CYP3A + NS5B Technivie ombitasvir/paritaprevir/ritonavir NS3/4A + NS5A + CYP3A (PrO) Daklinza Daclatasvir* NS5A Zepatier Elbasvir/grazoprevir NS5A + NS3/4A Epclusa Sofosbuvir/velpatasvir NS5B + NS5A *must be used with an additional DAA 18 Treatment for Genotype 1a (naïve) Drug Duration Duration for compensated cirrhosis Simeprevir + sofosbuvir X 12 weeks X 24 weeks +/- ribavirin (alternative) Ledipasvir/sofosbuvir X 12 weeks X 12 weeks ombitasvir/paritaprevir/rito navir and dasabuvir (PrOD) + wt based ribavirin X 12 weeks X 24 weeks (alternative) Daclatasvir + sofosbuvir X 12 weeks X 24 weeks + ribavirin (alternative) Elbasvir/grazoprevir X 12 weeks* X 12 weeks* Sofosbuvir/velpatasvir X 12 weeks X 12 weeks * In whom no NS5A RAVs are detected AASLD-IDSA HCV Guidance. HCV testing and linkage to care. Initial Treatment of HCV Infection. Date accessed August 10, 2016 9
19 Treatment for Genotype 1b (naïve) Drug Duration Duration for compensated cirrhosis Simeprevir + sofosbuvir X 12 weeks X 24 weeks +/- ribavirin (alternative) Ledipasvir/sofosbuvir X 12 weeks X 12 weeks ombitasvir/paritaprevir/rito navir and dasabuvir (PrOD) X 12 weeks X 24 weeks Daclatasvir + sofosbuvir X 12 weeks X 24 weeks +/- ribavirin (alternative) Elbasvir/grazoprevir X 12 weeks X 12 weeks Sofosbuvir/velpatasvir X 12 weeks X 12 weeks AASLD-IDSA HCV Guideance. HCV testing and linkage to care. Initial Treatment of HCV Infection. Date accessed here August 10, 2016 Treatment for Genotype 2 (naïve) 20 Drug Duration Duration for compensated cirrhosis Sofosbuvir/velpatasvir X 12 weeks X 12 weeks Daclatasvir + sofosbuvir X 12 weeks (alternative) X16-24 weeks (alternative) Treatment for Genotype 3 (naïve) Drug Duration Duration for compensated cirrhosis Sofosbuvir/velpatasvir X 12 weeks X 12 weeks Daclatasvir + sofosbuvir X 12 weeks 24 weeks AASLD-IDSA HCV Guidance. HCV testing and linkage to care. Initial Treatment of HCV Infection. Date accessed here August 10, 2016 10
Treatment for Genotype 4 (naïve) 21 Drug Duration Duration for compensated cirrhosis Ledipasvir/sofosbuvir X 12 weeks X 12 weeks ombitasvir/paritaprevir/ ritonavir (PrO) + wt based ribavirin Elbasvir/grazoprevir Sofosbuvir/velpatasvir X 12 weeks X 12 weeks X 12 weeks X 12 weeks X 12 weeks X 12 weeks Treatment for Genotype 5/6 (naïve) Drug Duration with or without compensated cirrhosis Ledipasvir/sofosbuvir X 12 weeks Sofosbuvir/velpatasvir X 12 weeks AASLD-IDSA HCV Guideance. HCV testing and linkage to care. Initial Treatment of HCV Infection. Date accessed here August 10, 2016 Simeprevir + Sofosbuvir 22 Genotypes 1 a and b without cirrhosis Consider baseline polymorphism testing in cirrhotic patients Not recommended for those with Child-Pugh B or C Amiodarone AASLD-IDSA HCV Guideance. HCV testing and linkage to care. Initial Treatment of HCV Infection. Date accessed here August 10, 2016 Olysio [package insert] Titusvill, NJ. Janssen Therapeutics. 2016 11
Simeprevir + Sofosbuvir 23 Administration Not coformulated Once daily with food Common ADRs Fatigue (16%), headache (17%), dizziness (3%), rash including photosensitivity (12%) Sulfa allergy? AASLD-IDSA HCV Guideance. HCV testing and linkage to care. Initial Treatment of HCV Infection. Date accessed here August 10, 2016 Olysio [package insert] Titusvill, NJ. Janssen Therapeutics. 2016 Ledipasvir/sofosbuvir 24 Genotype 1, 4, 5, 6 With or without compensated cirrhosis Can we shorten to 8 weeks of therapy? Drug interactions Amiodarone Acid reducing agents Harvoni [package insert] Foster City, CA. Gildead Sciences Inc. 2016 Lexicomp Online. 29 Aug 2016 12
25 Ledipasvir/sofosbuvir Administration Coformulated Daily with or without food Common ADRs: >10% :headache, fatigue, weakness 5-10%Irritability, insomnia, dizziness, nausea, diarrhea, myalgia Harvoni [package insert] Foster City, CA. Gildead Sciences Inc. 2016 Lexicomp Online. 29 Aug 2016 velpatasvir/sofosbuvir 26 Pan genotypic (1, 2, 3, 4, 5, 6) With or without compensated cirrhosis Common ADRs: >10%: Headache, fatigue 5-10%: Irritability, insomnia, nausea, weakness Drug interactions: Amiodarone Acid reducing agents Epclusa [package insert] Foster City, CA. Gildead Sciences Inc. 2016 Lexicomp Online. 29 Aug 2016 13
ombitasvir/paritaprevir/ritonavir and dasabuvir (PrOD) Available as an extended release product 27 Genotype 1 with or without cirrhosis + ribavirin in 1a patients ADRs (w/o ribavirin): (5-10%) nausea, pruritus and insomnia Drug interactions: multiple contains ritonavir Viekira XR [package insert] North Chicago, IL. AbbVie Inc. 2016 Viekira Pak [package insert] North Chicago, IL. AbbVie Inc. 2016 Lexicomp Online. 29 Aug 2016 ombitasvir/paritaprevir/ritonavir and dasabuvir (PrOD) Contraindicated in patients with Child Pugh class B or C 28 Increase risk of liver injury or progression to decompensated cirrhosis Usually within the first 4 weeks; associated with increase bilirubin and liver enzyme levels D/C Estrogen containing medications prior to use Viekira XR [package insert] North Chicago, IL. AbbVie Inc. 2016 Viekira Pak [package insert] North Chicago, IL. AbbVie Inc. 2016 Lexicomp Online. 29 Aug 2016 14
ombitasvir/paritaprevir/ritonavir (PrO) Genotype 4 with or without cirrhosis + ribavirin ADRs (without ribavirin): (>10%) weakness, fatigue, nausea 29 Drug interactions: multiple contains ritonavir Contraindicated in patients with Child Pugh class B or C Same warnings as with PrOD Technivie [package insert] North Chicago, IL. AbbVie Inc. 2016 Daclatasvir + sofosbuvir 30 Genotype 1 & 3 without cirrhosis Consider NS5A testing in cirrhotic patients ADRs: >10%: Headache, fatigue. 5-10%: Nausea, diarrhea Daklinza [package insert] Princeton, NJ. Brostol-Myers Squibb Company. 2016 15
Daclatasvir + sofosbuvir 31 Daclatasvir dosing: 60mg daily Strong CYP3A inhibitors: 30mg daily Moderate CYP3A inducers: 90mg daily Strong CYP3A inducers: contraindicated Amiodarone Daklinza [package insert] Princeton, NJ. Brostol-Myers Squibb Company. 2016 Elbasvir/grazoprevir Genotype 1 & 4 with or without compensated cirrhosis 32 Requires baseline NS5A resistance testing Safe in patients with renal impairment Including those on HD Contraindicated in patients with Child Pugh class B or C Avoid use with moderate/strong CYP3A inducers ADRs: (>10%) Fatigue, headache, nausea Zepatier [package insert]whitehouse Station, NJ. Merck&Co, INC. 2016 16
Ribavirin 33 Weight based dosing Hemolytic Anemia Decrease dose if Hgb <10g/dL Discontinue if HgB<8.5g/dL Pregnancy Category X ADRs: GI effects, hematologic abnormalities, pruritus, rash, AASLD-IDSA. Monitoring patients who are starting Hepatitis C treatment, re on treatment, or have completed therapy. Date accessed August 25, 2016 Lexicomp Online. 29 Aug 2016 Copegus [package insert] South Sanfancisco, CA. Genentech USA, INC. 2011 When to stop treatment Safety A 10-fold increase in ALT at week 4 Any increase less than 10- fold at week 4 and accompanied with symptoms Asymptomatic less than 10- fold elevated at week 4 should be repeated at week 6 and week 8. Consideration discontinuation Efficacy Week 4 HCV RNA is detectable repeat viral load testing is at week 6. If viral load has increased by greater than 10-fold then discontinuation is recommended. The significance of positive a viral load that does not increase by 10-fold is unknown. 34 AASLD-IDSA. Monitoring patients who are starting Hepatitis C treatment, re on treatment, or have completed therapy. Date accessed August 25, 2016 17
Drug Interaction Resources 35 www.hep-druginteractions.org Monitoring after Treatment 36 For patients without advanced fibrosis (Metavir stage F0-F2: follow up as if never infected For patients with advanced fibrosis (Metavir stage F3-F4): Ultra sound every 6 months to screen for HCC Ongoing HCV monitoring is only recommended if patient has on going risk or otherwise explained hepatic dysfunction HCV RNA should be obtained rather than anti-hcv serology AASLD-IDSA. Monitoring patients who are starting Hepatitis C treatment, re on treatment, or have completed therapy. Date accessed 7 April 2017 18
Summary 37 The largest drop in the treatment cascade is in diagnosis An estimated 50% of patients don t know they have HCV Treating HCV can decrease liver related mortality Treatment is now with direct acting agents Shorter duration Better tolerability HCV treatment is an every changing area of medicine Managing New Treatments for Hepatitis C in Primary Care Christina Connel, PharmD, BCPS, AAHIVP 19