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Current Treatment of Chronic Hepatitis C

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LUIS S. MARSANO, MD, FACG, FAASLD, AGAF, FASGE Professor of Medicine Jewish Hospital Distinguished Chair in Hepatology Division of Gastroenterology, Hepatology and Nutrition University of Louisville and Louisville VAMC October 2020 No conflict of interest to report. Several of the treatment protocols described are not within FDA label but they are inside the “Practice Guidelines Recommendations” from the AASLD and IDSA. Combinations Type of Antiviral Non-Nuc Nuc NS3 NS5A RBV NS5B NS5B “previr” “asvir” “buvir” “buvir” Simeprevir + sofosbuvir Ledipasvir/sofosbuvir FDC (HARVONI) Paritaprevir/r/Ombitasvir FDC (TECHNIVIE or PrO) + Dasabuvir (VIEKIRA Pak and XR or RBV only for 1a PrOD or 3D) or F3-4 Sofosbuvir + ribavirin Daclatasvir + sofosbuvir Grazoprevir + Elbasvir (ZEPATIER) Velpatasvir + Sofosbuvir (EPCLUSA) Sofosbuvir + Velpatasvir + Voxilaprevir (Vosevi®) Glecaprevir + Pibrentasvir (Mavyret) Regimen-SpecificSimplified Recommendations HCV Treatment for Use for of RAS TestingTreatment in Clinical-Naïve Practice Patients Without Cirrhosis ELIGIBLE FOR SIMPLIFIED HCV TREATMENT NOT ELIGIBLE FOR SIMPLIFIED HCV TREATMENT Patients with chronic hepatitis C who do not have cirrhosis and have not previously received Hepatitis C treatment Patients who have any of the following characteristics: • Prior hepatitis C treatment • Cirrhosis • Prior liver transplant PRETREATMENT ASSESSMENT • HIV or HBsAg positive Cirrhosis Assessment Pretreatment Lab Testing • Known or Suspected Hepatocellular Carcinoma • Biopsy not required Within 6 months • Currently pregnant • Cutoffs suggesting cirrhosis • CBC • FIB-4 >3.25 • Hepatic function panel • APRI >2.0 • eGFR • Platelets <150,000/mm3 • FibroScan >12.5 kPa Prior to starting antiviral therapy • Quantitative HCV RNA (HCV viral Medication Reconciliation load) RECOMMENDED REGIMENS • Current Rx and OTC • HIV antigen/antibody test • HBsAg SOF/VEL for a duration of GLE/PIB to be taken with DDI Assessment 12 weeks food for a duration of 8 Before initiating Tx weeks Education • Serum pregnancy testing and counseling • Tx administration, adherence, avoidance of about pregnancy risks of HCV alcohol, and reinfection APRI, aspartate aminotransferase (AST) to platelet ratio index; CBC, complete blood count; medication should be offered to women DDI, drug–drug interaction; FIB-4, Fibrosis-4; GLE, glecaprevir; OTC, over-the-counter; of childbearing age. PIB, pibrentasvir; RNA, ribonucleic acid. AASLD/IDSA HCV Guidance, updated August 27, 2020 Available at: https://www.hcvguidelines.org/sites/default/files/full-guidance-pdf/AASLD-IDSA_HCV-Guidance_TxN-Simplified-Treatment_a.pdf Regimen-SpecificSimplified Recommendations HCV Treatment for Usefor of RAS TestingTreatment in- NaïveClinical Patients Practice With Compensated Cirrhosis ELIGIBLE FOR SIMPLIFIED HCV TREATMENT NOT ELIGIBLE FOR SIMPLIFIED HCV TREATMENT Patients with chronic hepatitis C who do not have cirrhosis and have not previously received Hepatitis C treatment Patients who have any of the following characteristics: • Prior hepatitis C treatment • Current or Prior Cirrhosis Decompensation (Child-Pugh >/= 7) • ESRD with GFR < 30 mL/min/m2 PRETREATMENT ASSESSMENT • Prior liver transplant • HIV or HBsAg positive Cirrhosis Assessment Pretreatment Lab Testing • Known or Suspected Hepatocellular Carcinoma • Prior Biopsy showing Cirrhosis, or Within 6 months • Cutoffs suggesting cirrhosis (Biopsy not • CBC • Currently pregnant required) • Hepatic function panel • FIB-4 >3.25 • eGFR • APRI >2.0 • Platelets <150,000/mm3 Prior to starting antiviral therapy • FibroScan >12.5 kPa • Quantitative HCV RNA (HCV viral load) RECOMMENDED REGIMENS Medication Reconciliation • HIV antigen/antibody test • Current Rx and OTC • HBsAg SOF/VEL in Genotypes 1, 2, GLE/PIB to be taken with Drug-Drug Interaction Assessment 4, 5, 6, or in 3 without Y93H food for a duration of 8 Before initiating Tx for a duration of 12 weeks • Serum pregnancy testing and counseling NS5A RAS, Education about pregnancy risks of HCV medication weeks • Tx administration, adherence, avoidance of should be offered to women of alcohol, and reinfection childbearing age. APRI, aspartate aminotransferase (AST) to platelet ratio index; CBC, complete blood count; DDI, drug–drug interaction; FIB-4, Fibrosis-4; GLE, glecaprevir; OTC, over-the-counter; PIB, pibrentasvir; RNA, ribonucleic acid. AASLD/IDSA HCV Guidance, updated August 27, 2020 Available at: https://www.hcvguidelines.org/sites/default/files/full-guidance-pdf/AASLD-IDSA_HCV-Guidance_TxN-Simplified-Treatment_a.pdf Simplified HCV Treatment for Treatment-Naïve Patients ON-TREATMENT MONITORING • Inform patients taking diabetes medication of the potential • No laboratory monitoring is required for other patients. for symptomatic hypoglycemia. Monitoring for • An in-person or telehealth visit may be scheduled, if hypoglycemia is recommended. needed, for patient support, assessment of symptoms, • Inform patients taking warfarin of the potential for changes and/or new medications. in their anticoagulation status. Monitoring INR for subtherapeutic anticoagulation is recommended. POST-TREATMENT ASSESSMENT FOLLOW-UP AFTER SVR FOLLOW-UP FOR PATIENTS WHO DO NOT ACHIEVE SVR • In patients with cirrhosis, may order blood • No liver-related follow-up is tests to monitor for decompensation. recommended for noncirrhotic • Assessment for disease progression every • Monitoring patients taking diabetes patients who achieve SVR; 6 to 12 months with a hepatic function medication • Cirrhotic patients should have U/S +/- panel, CBC, and international normalized • Monitoring INR for patients taking warfarin AFP every 6 months, and ratio (INR) is recommended. • Assessment of quantitative HCV RNA and surveillance with EGD for varices as • Cirrhotic patients should have U/S +/- AFP hepatic function 12 weeks after completion per AASLD. every 6 months, and surveillance with EGD of therapy • Patients with ongoing risk for HCV for varices as per AASLD. • Assessment for other causes of liver disease infection (eg, intravenous drug use or • Patients in whom initial HCV treatment fails is recommended for patients with elevated MSM engaging in unprotected sex) to achieve cure (SVR) can be retreated, transaminase levels after achieving SVR should be counseled about risk often successfully. Consult the reduction and tested for HCV RNA AASLD/IDSA guidance annually and whenever they develop 8 elevated ALT, AST, or bilirubin. ALT, alanine aminotransferase; CBC, compete blood count; INR, international normalized ratio; MSM, men who have sex with men; SVR, sustained virologic response. AASLD/IDSA HCV Guidance, updated August 27, 2020 Available at: https://www.hcvguidelines.org/sites/default/files/full-guidance-pdf/AASLD-IDSA_HCV-Guidance_TxN-Simplified-Treatment_a.pdf HCV: Genotype 1A and 1B Treatment Naïve or PEG-IFN/RBV Relapser, Non-cirrhotic Regimen Weeks Study SVR12 Sofosbuvir + Ledipasvir (HCV RNA <6 M IU/mL) 8 ION-3 119/123 (97%) (HCV RNA >6 M IU/mL) 12 206/216 (95%) Elbasvir/Grazoprevir (1b) 12 C-EDGE 133/135 (99%) (-) for NS5A RAVs (1a) 129/131 (99%) Glecaprevir + Pibrentasvir 8 Endurance 333/336 (99%) Sofosbuvir+ Velpatasvir 12 ASTRAL-1 251/257 (98)% NOT HEAD TO HEAD TRIALS AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed 10/17/17 HCV: Genotype 2 and 3 Treatment Naïve or PEG-IFN/RBV Relapser, Non-cirrhotic Regimen Geno-type Weeks Study SVR12 Velpatasvir + Sofosbuvir 2 12 ASTRAL-1 99% Glecaprevir + Pibrentasvir 2 8 SURVEYOR-II 99% Velpatasvir + Sofosbuvir 3 12 ASTRAL-3 98% Glecaprevir + Pibrentasvir 3 8 Endurance 3 95% NOT HEAD TO HEAD TRIALS AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed 10/17/17 HCV: Genotype 4 Treatment Naïve or PEG-IFN/RBV Relapser , Non-cirrhotic Regimen Weeks Study SVR12 Velpatasvir + Sofosbuvir 12 ASTRAL-1 100% Sofosbuvir + Ledipasvir 12 Synergy 95% Elbasvir + Grazoprevir 12 C-Edge 97% Glecaprevir + Pibrentasvir 8 Endurance 4 99% NOT HEAD TO HEAD TRIALS AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed 10/17/17 HCV: Genotype 5 and 6 Treatment Naïve or PEG-IFN/RBV Relapser, Non-cirrhotic Geno- Weeks Study SVR12 Regimen type Velpatasvir + Sofosbuvir 5 12 ASTRAL-1 96% Sofosbuvir + Ledipasvir 5 12 95% Glecaprevir + Pibrentasvir 5 8 Endurance 4 100% Velpatasvir + Sofosbuvir 6 12 ASTRAL-1 100% Sofosbuvir + Ledipasvir 6 12 Synergy 100% Glecaprevir + Pibrentasvir 6 8 Endurance 4 100% NOT HEAD TO HEAD TRIALS AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Updated 08/27/2020 HCV: Genotype 1a & 1b Compensated Cirrhosis Treatment-Naïve or PEG-IFN/RBV Relapser Genotype 1a & 1b Patients With Compensated Cirrhosis RECOMMENDED DURATION RATING SVR12 Daily fixed-dose combination of Elbasvir (50 mg)/ Grazoprevir (100 mg) for patients with genotype 1b, 97% 12 weeks I, A or with 1a without baseline NS5A RASsb for Elbasvir Daily fixed-dose combination of Ledipasvir (90 12 weeks I, A mg)/sofosbuvir (400 mg) 97% Daily fixed-dose combination of Sofosbuvir (400 99% 12 weeks I, A mg)/Velpatasvir (100 mg) Daily fixed-dose combination of Glecaprevir (300 99% c 8 weeks I, B mg)/ Pibrentasvir (120 mg) NOT HEAD TO HEAD TRIALS AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Updated 08/27/2020 HCV: Genotype 2 Compensated
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  • A Phase II, Open-Label Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK

    A Phase II, Open-Label Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK

    Official Protocol Title: A Phase II, Open-Label Clinical Trial to Study the Efficacy and Safety of the CombinationRegimen of MK-3682 + MK-8408 in Subjects with Chronic HCV Genotype 1, 2, 3, 4, 5 or 6 Infection NCT number: NCT02759315 Document Date: 26-Oct-2017 Product: MK-3682 1 Protocol/Amendment No.: 035-04 THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., WHITEHOUSE STATION, NJ, U.S.A. SPONSOR: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (hereafter referred to as the Sponsor or Merck) One Merck Drive P.O. Box 100 Whitehouse Station, New Jersey, 08889-0100, U.S.A. Protocol-specific Sponsor Contact information can be found in the Investigator Trial File Binder (or equivalent). TITLE: A Phase II, Open-Label Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK-3682 + MK-8408 in Subjects with Chronic HCV Genotype 1, 2, 3, 4, 5 or 6 Infection IND NUMBER: 123,749 EudraCT NUMBER: Not Applicable MK-3682-035-04 Final Protocol 26-Oct-2017 04S4N9 Confidential Product: MK-3682 2 Protocol/Amendment No.: 035-04 TABLE OF CONTENTS SUMMARY OF CHANGES................................................................................................ 10 1.0 TRIAL SUMMARY.................................................................................................. 12 2.0 TRIAL DESIGN........................................................................................................ 13