9/2/21 OBJECTIVES Project ECHO HCV Collaborative HCV in 21: New Therapies and New Opportunities Paulina Deming, PharmD Assistant Director Hepatitis C Programs, ECHO Institute Associate Professor College of Pharmacy University of New Mexico Health Sciences Center Albuquerque, NM August 15, 21 Presentation prepared by: Date prepared: For pharmacists: 1. Describe the clinical and economic burden associated with hepatitis C virus (HCV) infection 2. Describe new therapeutic options for the treatment of chronic HCV 3. Use national algorithms and guidelines to guide treatment strategies for patients with HCV infection 4. Discuss challenges to HCV treatment in New Mexico For technicians: 1. Identify risk factors for chronic HCV infections 2. Recognize new HCV therapies 3. Describe health systems challenges which can affect outcomes of HCV therapy 4. Identify challenges to HCV treatment Hepatitis C is a Global Health Problem Estimated 1 million persons with HCV infection worldwide Hepatitis C Genotypes 6 major genotypes (1 6), most with subtypes Genotype 1 GT 1b different than GT 1a GT 2 easier to treat than GT 3 Prevalence of infection > 1% 2.5%-1% 1%-2.5% NA GT 3 associated with higher mortality, steatohepatitis World Health Organization 28 (http://www.who.int/ith/es/index.html) Alter MJ et al. N Engl J Med 1999; 341:556 62 Risk Factors for HCV Infection Hepatitis C: Progression of Disease Persons born between 1945 1965 Normal Liver Time 2 25 years 25 3 years Received blood transfusion or organ donation prior to 1992 Current or former injection drug users Chronic hemodialysis patients Any known blood exposure to HCV positive blood Persons with HIV Children born to HCV infected mother HCV Infection Chronic Hepatitis Cirrhosis HCC ESLD Death 1
9/2/21 HCV is Not Just a Liver Disease Common Symptoms of HCV in Absence of Cirrhosis Fatigue Impaired cognitive function (brain fog) Migratory arthralgia or myalgia Depression Extrahepatic Manifestations of Chronic HCV Renal Disease Lymphomas Neuropathy Dermatologic Manifestations Diabetes Neurological Impairments Changes in HCV Therapy Goals of HCV Therapy Differences in Therapy Cure Defined as sustained virologic response (SVR) Improvements in liver function Improvements in fibrosis, reversal of cirrhosis? Improvements in extrahepatic manifestations of HCV Interferon Based Injectable Long duration of treatment High side effect profile Multiple laboratory abnormalities Low cure rates Direct Acting Antivirals Oral Short durations Minimal side effects Minimal laboratory abnormalities High cure rates The Evolution of Highly Effective Treatment HCV Direct Acting Antivirals (DAAs) 1 8 Standard IFN 6 1998 1991 4 2 6 34 PegIFN 21 42 55 BOC and TPV 211 + 213 SOF SMV 89+ 8+ 214 LDV/ SOF PrOD >9 >9 2 DCV+ EBR/ SOF GZR >9 >9 SOF/ VEL >9 21 SOF/ VEL/ GLE/ VOX PIB >9 >9 Target NS3/4A: Protease Inhibitors ( previr) Boceprevir Telaprevir Simeprevir Paritaprevir Grazoprevir Glecaprevir Voxilaprevir NS5A: Replication Complex Inhibitors ( asvir) Ledipasvir Ombitasvir Daclatasvir Elbasvir Velpatavir Pibrentasvir NS5B: Polymerase Inhibitors ( buvir) Nucleotide: Sofosbuvir Non nucleoside: Dasabuvir IFN 6 mos IFN mos IFN/ 6 mos IFN/ mos PegIFN mos PegIFN/ / BOC or TPV 6- mos PegIFN/ PegIFN/ LDV/ / / SOF SMV SOF 8-24-48-24 PrOD + -24 SOF + DCV EBR/ GZR - SOF/ SOF/ GLE/ VEL VEL/ PIB VOX 8-2
9/2/21 Side Effect Profile of DAAs Laboratory Abnormalities Overall very well tolerated Most commonly reported side effects: Headache Fatigue Nausea Diarrhea (reported with voxilaprevir) Overall not common Most common laboratory abnormalities: ALT elevations Concomitant use of ethinyl estradiol with PrOD or glecaprevir/pibrentasvir Elbasvir/grazoprevir Bilirubin elevations Many DAAs inhibit bilirubin transporters Anemia with concomitant use of ribavirin Ribavirin causes hemolytic anemia Main Drug Interaction Concerns for DAAs Case Study: Managing Interactions New DAAs overall have low potential for causing drug drug interactions Amiodarone with sofosbuvir and other DAA: Serious symptomatic bradycardia Potential for other drugs to lower DAA concentrations: Strong CYP3A inducers: carbamazepine, oxcarbazepine, phenobarbital, phenytoin Strong intestinal P glycoprotein inducers: rifabutin, rifampin, rifapentine St. John s wort Statins: Interactions vary by DAA and statin Acid suppressive therapy: Ledipasvir and velpatasvir solubility decreases with increases in ph Requires acidity for absorption 48 yo female admitted to hospital with orders including PPI drip Patient s home medications include ledipasvir/sofosbuvir Use of HCV DAAs in Renal Insufficiency and Cirrhosis Ledipasvir/ sofosbuvir Elbasvir/gra zoprevir Sofosbuvir/ velpatasvir Sofosbuvir/ velpatasvir/ voxilaprevir Glecaprevir/ pibrentasvir Use in renal impairment or endstage renal disease? > 3 ml/min Safe to use in all levels of renal impairment including dialysis > 3 ml/min > 3 ml/min Safe to use in all levels of renal impairment including dialysis www.hep druginteractions.org Also available as an app: hepichart Use in cirrhosis? Childs Class A, B or C Child Class A Childs Class A, B or C Child Class A Child Class A 3
9/2/21 Ledipavir/Sofosbuvir ION Phase 3 Program (ION 1, ION 2, ION 3) Efficacy Summary Harvoni [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2. Combination of NS5B polymerase inhibitor (Sofosbuvir); NS5A inhibitor (ledipasvir) Administration One tablet once daily with food or without food Requires acidic environment for absorption Indicated for GT 1 and 4 SVR (%) 1 8 6 4 2 LDV/SOF LDV/SOF+ 99 9 98 99 94 93 95 94 96 99 99 211/ 214 211/ 21 2/ 21 8 Weeks Weeks Weeks 24 Weeks Weeks 24 Weeks ION 1 GT 1 treatment naïve including cirrhotics ION 3 GT 1 treatment naïve non cirrhotic ION 2 GT 1 treatment experienced including cirrhotics and PI failures Afdhal N, et al. N Engl J Med 214; 214 Apr [Epub ahead of print] Kowdley K, et al. N Engl J Med 214; 214 Apr 11 [Epub ahead of print] Afdhal N, et al. N Engl J Med 214; 214 Apr [Epub ahead of print] 215/ 21 9% (1886/1952) overall SVR rate Error bars represent 95% confidence intervals. 22/ 215 21/ 2 26/ 2 / 19 1/ 111 18/ 19 11/ 111 Elbasvir/ Grazoprevir (EBR/GZR) Laboratory Abnormalities and Adverse Effects Fixed dose combination tablet 5 mg elbasvir (NS5A replication complex inhibitor) 1 mg grazoprevir (NS3/4A protease inhibitor) Dosing: 1 tablet per day with or without food Approved Feb. 2 Indicated for HCV genotypes 1 and 4 Patients with GT 1a require pre treatment resistance testing If present, must add ribavirin and extend treatment duration to weeks Increased risk of ALT elevations 5x ULN in 1% of patients 2% in women, Asian race, or patients aged 65 years or older Occurred at treatment week 8 or later Mostly asymptomatic Resolved with ongoing or completed therapy Monitor LFTs every 4 weeks or as clinically indicated Adverse effects: Fatigue, headache, and nausea Elbasvir Grazoprevir in Treatment Naïve HCV GT 1, 4 or 6 C EDGE TN: Results C EDGE TN: SVR Results by Genotype 299/3 144/15 9/131 18/18 8/1 Sofosbuvir/Velpatasvir Fixed dose combination of sofosbuvir (NS5B inhibitor) and velpatasvir (NS5A inhibitor) Approved June 28, 2 for chronic HCV genotypes 1, 2, 3, 4, 5, or 6 Treatment naïve Treatment experienced (Peg IFN/ with or without PI) Primary efficacy analysis included all patients who received 1 dose of drug. Epclusa [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2. Source: Zeuzem S, et al. Ann Intern Med. 215;3:1-13. Slide courtesy of HCV Online; H. Nina Kim MD, MSc and David Spach MD 4
9/2/21 ASTRAL-1: SOF/VEL STR for Weeks in GT 1, 2, 4, 5, 6 HCV-Infected Patients SVR by Cirrhosis Status or Treatment History Sofosbuvir/Velpatasvir/Voxilaprevir SVR (%) 1 8 6 4 2 99 99 99 99 99 618/624 496/51 /1 418/423 Total Non-Cirrhotic Cirrhotic Treatment- Naïve 2/21 Treatment- Experienced Combination of NS5B polymerase inhibitor (Sofosbuvir); NS5A inhibitor (Velapatasvir); NS3/4A protease inhibitor (Voxilaprevir) Administration One tablet once daily with food Approved July 18, 21 Vosevi [package insert]. Foster City, CA: Gilead Sciences, Inc.; 21. Error bars represent 95% confidence intervals. Feld, AASLD, 215, LB-2. Feld JJ, et al. N Engl J Med. 215. DOI: 1.156/NEJMoa1561 25 Indications: DAA Treatment Experienced Patients Patients with genotype 1, 2, 3, 4, 5, or 6 who were previously treated with an NS5A inhibitor Patients with genotype 1a or 3 infection previously treated without an NS5A inhibitor No advantage of using sofosbuvir/velpatasvir/voxilaprevir over sofosbuvir/velpatasvir for retreatment of patients with GT 1b, 2, 4, 5, or 6 POLARIS 1: SOF/VEL/VOX for Weeks in NS5A Inhibitor Experienced HCV GT 1 6 SVR Results Overall and by Cirrhosis Status SVR, % 1 8 6 4 2 96 99 6 relapses 1 on treatment failure** 2 withdrew consent 1 LTFU 253/263 1 withdrew consent 1 LTFU Overall* No Cirrhosis Cirrhosis 93 14/142 113/1 6 relapses 1 on treatment failure** 1 withdrew consent * p <.1 for superiority compared with prespecified 85% performance goal for SOF/VEL/VOX ** Exposure was consistent with non adherence Bourliere M, AASLD 2, Oral 194 POLARIS 1: SOF/VEL/VOX for Weeks in NS5A Inhibitor Experienced HCV GT 1 6 SVR by Genotype and Cirrhosis Status SVR, % 1 8 6 4 2 99 98 9 1 1 1 1 93 96 94 1 93 86 14* 113 142 1 No Cirrhosis 9 99 49 51 66 68 31 33 Overall GT 1 GT 1a GT 1b GT 2 GT 3 GT 4/5/6 *1/1 patient with GT unknown achieved SVR; 4/4 patients with GT 1 other (cirrhosis, n=2; no cirrhosis, n=2) achieved SVR; Includes only GT 4 patients. 29 29 5 5 Cirrhosis 22 22 52 56 15 15 14 SVR, % POLARIS-4: SOF/VEL/VOX or SOF/VEL for Weeks in Non-NS5A Inhibitor DAA- Experienced HCV GT 1 4 1 8 6 4 2 1 3 3 SOF/VEL/VOX Weeks Overall SVR 9% No Cirrhosis 94 92 1 1 1 96 94 1 1 1 SVR by Genotype and Cirrhosis Status 13 11 11 18 18 GT 1a GT 1b GT 2 GT 3 GT 4 13 13 22 23 29 31 1 8 6 4 2 Cirrhosis SOF/VEL Weeks Overall SVR 9% 93 93 1 94 1 81 95 26 28 13 14 15 1 GT 1a GT 1b GT 2 GT 3 GT 4 21 22 23 3 Data on file, Gilead Sciences 29 Data on file, Gilead Sciences 3 5
9/2/21 Adverse Reactions and Laboratory Abnormalities Glecaprevir/Pibrentasvir Adverse reactions: Headache Fatigue Diarrhea Nausea Laboratory abnormalities: increases in total bilirubin Voxilaprevir can inhibit bilirubin transporters Combination of Glecaprevir an NS3/4A protease inhibitor Pibrentasvir an NS5A inhibitor Dosage and administration: 3 tablets once daily with food Approved Aug. 3, 21 Indications and Duration of Therapy Glecaprevir Pibrentasvir for 8 or weeks in Non Cirrhotic GT 1 ENDURANCE 1: Baseline Characteristics HCV Genotype Prior Treatment Experience Without Cirrhosis With Compensated Cirrhosis 1,2,3,4,5,6 Naïve 8 weeks weeks 1,2,4,5,6 Pegylated interferon, ribavirin and/or sofosbuvir 8 weeks weeks 3 Pegylated interferon, ribavirin and/or sofosbuvir weeks weeks 1 NS3/4A (NS5A naïve) weeks weeks NS5A (NS3/4A naïve) weeks weeks Patients (%) with SVR 1 8 6 4 2 99.1 99. 1 1 ITT-PS GLE-PIB x 8 Weeks GLE-PIB x Weeks 332/335 331/332 331/331 332/332 ITT-PS-PP ITT-PS population: ITT excluding patients with HIV coinfection or treatment experience with sofosbuvir ITT-PS-per protocol (PP) population: ITT-PS excluding patients with premature discontinuation of study drug, virologic failure before Week 8, and missing SVR data Source: Zeuzem S, et al. AASLD 2.Abstract 253. Patients with SVR (%) Glecaprevir Pibrentasvir in Treatment Naïve Non Cirrhotic GT 3 ENDURANCE 3 Study: Results 1 ION-3: SVR by Treatment Duration and Regimen (ITT Analysis) 8 6 4 2 95 9 95 222/233 GLE-PIB SOF + DCV GLE-PIB -Week Regimens GLE-PIB = glecaprevir-pibrentasvir; SOF = sofosbuvir; DCV = daclatasvir ITT = Intent-to-treat Source: Foster G, et al. EASL 21. Abstract GS-. 111/115 149/15 8-Week Regimen Patients with SVR (%) Glecaprevir Pibrentasvir in Genotype 1 6 with Renal Disease EXPEDITION 4: Results 1 8 6 4 2 Source: Gane E, et. al, AASLD 2. Abstract 935. SVR by Type of Analysis 98 1 1 discontinuation 1 lost to follow-up /14 / ITT mitt ITT, intent-to-treat analysis; mitt, modified intent-to-treat analysis 6
9/2/21 Adverse Reactions and Laboratory Abnormalities Adverse reactions reported: Headache, fatigue, nausea, diarrhea Rates similar to placebo Laboratory abnormalities: Serum bilirubin abnormalities in approximately 3% of patients Glecaprevir/pibrentasvir can affect bilirubin transporters Joint guidelines of the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) Updated frequently check online for most current version of guidelines Available at: http://www.hcvguidelines.org/ New Mexico has the highest prevalence of HCV in the US Milliman 213: Health Care Reform and Hepatitis C: Convergence of Risk and Opportunity (analysis of NHANES, MarketScan 21, Medicare 5% Sample, and Medicaid Contributor data. Does not include prison population). HCV in New Mexico.4% 1.3% Slide courtesy Dr. David Scrase Centennial Treatment Criteria Expanded Effective Sept 15, 21 All members over age 1, all HCV genotypes, with F level or greater of fibrosis Case Study: Systems Challenges to Effective Therapy Patient on HCV therapy At 4 5 weeks of therapy, questions regarding use and dosing of ribavirin were identified and pharmacist did not authorize refill of therapy to complete HCV course until these issues were clarified
9/2/21 Conclusions Remaining Challenges in HCV Therapy Chronic HCV infections pose a high healthcare burden DAA therapies are highly effective with SVR rates >9% New therapies available for patients with all genotypes, renal insufficiency, and prior DAA failure Regimens are well tolerated, have limited drug interactions, and few laboratory abnormalities Need for increased screening to identify patients and link to treatment HCV treatment in patients with decompensated cirrhosis Screening and identifying patients with chronic HCV Treatment interruptions Concerns for HCV resistance Access to HCV therapy Resources Project ECHO HCV Collaborative AASLD/IDSA HCV Treatment Guidelines: Available at: http://www.hcvguidelines.org HCV Drug Interactions (University of Liverpool): Available at: http://www.hep druginteractions.org Educational material, clinical calculators, HCV therapy summaries (University of Washington) Available at: http://www.hepatitisc.uw.edu End of Presentation Questions? 8