Treatment of HCV Genotype 3 in Patients with Cirrhosis

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Project ECHO - UNM HIV TeleECHO Clinic Treatment of HCV Genotype 3 in Patients with Cirrhosis September 14, 2021 Professor, Division of Infectious Diseases University of New Mexico Health Sciences Center Senior Associate Director Project ECHO Karla Thornton, MD, MPH Version_ MM YYYY 1 Conflict of Interest Disclosure Statement Speaker has nothing to disclose. This presentation was reviewed by UNMHSC and SCAETC faculty to ensure it meets Continuing Education guidelines. This project is supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS). Under grant number U1OHA33225 (South Central AIDS Education and Training Center). It was awarded to the University of New Mexico. No percentage of this project was financed with non-governmental sources. This information or content and conclusions are those of the authors and should not be construed as the official position or policy of, nor should any endorsements be inferred by HRSA, HHS, or the U.S. Government. 2 Learning Objectives Recognize the difference between HCV genotype 3 and other genotypes Identify appropriate treatment options for patients with HCV genotype 3 and cirrhosis https://www.hcvguidelines.org/ 3 HCV Genotype 3 (GT3) In U.S., prevalence of GT3 approximately 10% GT3 infection more common in younger patients (4% in patients born before 1946 - 18% in those born after 1976) Higher proportion of GT3 among people who inject drugs (PWID) Faster rates of fibrosis progression Increased risk of cirrhosis Higher prevalence of severe steatosis Higher incidence of hepatocellular carcinoma https://www.hepatitisc.uw.edu/go/treatment-infection/treatment-genotype-... Abstract Data show that viral genotype 1 may increase the risk of cirrhosis and hepatocellular carcinoma (HCC) compared to genotype 2 in patients with chronic hepatitis C virus (HCV) infection. However, the effect of HCV genotype 3 on cirrhosis and HCC risk is uncertain. We identified patients with active HCV infection, confirmed by positive polymerase chain reaction (PCR) and a known HCV genotype, from the VA HCV Clinical Case Registry between 2000 and 2009. We examined the effect of HCV genotype on the risk of cirrhosis and HCC in a Cox proportional hazards model adjusting for patients' age, period of service (World War I/II, Vietnam era, post-Vietnam era), race, gender, human immunodeficiency virus (HIV) infection, alcohol use, diabetes, body mass index, and antiviral treatment receipt. Of the 110,484 patients with active HCV viremia, 88,348 (79.9%) had genotype 1, 13,077 (11.8%) genotype 2, 8,337 (7.5%) genotype 3, and 1,082 (0.9%) patients had genotype 4 infection. Despite being younger, patients with genotype 3 had a higher risk of developing cirrhosis (unadjusted hazard ratio [HR] = 1.40, 95% confidence interval [CI] = 1.32-1.50) and HCC (unadjusted HR = 1.66, 95% CI = 1.48-1.85) than HCV genotype 1 patients. After adjustment for prespecified demographic, clinical, and antiviral treatment factors, the risk of cirrhosis and HCC was 31% (adjusted HR = 1.31, 95% CI = 1.22-1.39) and 80% (adjusted HR = 1.80, 95% CI = 1.61-2.03) higher in patients with genotype 3 compared to genotype 1 infected patients. Conclusion: HCV genotype 3 is associated with a significantly increased risk of developing cirrhosis and HCC compared to HCV genotype 1. This association is independent of patients' age, diabetes, body mass index, or antiviral treatment 4 HCV GT3 Treatment In direct-acting antiviral (DAA) era, GT3 relatively difficult to cure compared with other genotypes in patients with cirrhosis For treatment-nave adults with compensated cirrhosis, two regimens recommended: glecaprevir-pibrentasvirfor 8 weeks (in persons without HIV) sofosbuvir-velpatasvirfor 12 weeks If considering sofosbuvir-velpatasvir: Baseline NS5A genotype 3 resistance testing required Ribavirinshould be addedif the Y93H resistance-associated substitution (RAS) is detected https://www.hepatitisc.uw.edu/go/treatment-infection/treatment-genotype-... AASLD/IDSA HCV Guidelines:Treatment Naive Genotype 3 With Compensated Cirrhosis https://www.hcvguidelines.org/treatment-naive/gt3/compensated-cirrhosis Rating System Used to Rate Level of Evidence and Strength of Recommendation https://www.hcvguidelines.org/contents/methods/table-2 Glecaprevir-Pibrentasvir in HCV GT 3, +/- Cirrhosis SURVEYOR-II (Part 3) Phase 3 Treatment-Nave and Treatment-Experienced Source: Wyles D, et al. Hepatology. 2018;67:514-23. Source: Wyles D, et al. Hepatology. 2018;67:514-23. Glecaprevir-Pibrentasvir in HCV GT 3, with Cirrhosis and Prior TreatmentSURVEYOR-II (Part 3): Study Design Drug Dosing: Glecaprevir-pibrentasvir (100/40 mg) fixed dose combination; three pills once daily 0 20 Week 8 Week 0 28 12 16 24 GLE-PIB(n = 40) SVR12 GLE-PIB(n = 22) SVR12 GLE-PIB(n = 22) SVR12 GLE-PIB(n = 47) SVR12 GT 3, Treatment-Naive With cirrhosis GT3, Treatment-Experienced Without cirrhosis GT 3, Treatment-Experienced Without cirrhosis GT 3, Treatment-Experienced With cirrhosis 9 Source: Wyles D, et al. Hepatology. 2018;67:514-23. Glecaprevir-Pibrentasvir in HCV GT 3, with Cirrhosis and Prior TreatmentSURVEYOR-II (Part 3): Results 39/40 20/22 45/47 21/22 Abbreviations: TN = Treatment Nave; TE = Treatment Experienced Glecaprevir-Pibrentasvir in GT 1-6 and Compensated CirrhosisEXPEDITION-8 Phase 3 Treatment-Nave and Treatment-Experienced Source: Brown RS, et al. J Hepatol. 2020;72:441-8. Cirrhosis Source: Brown RS, et al. J Hepatol. 2020;72:441-8. Glecaprevir-Pibrentasvir in GT 1-6 & Compensated CirrhosisEXPEDITION-8: Treatment Protocol *Drug Dosing: Glecaprevir-pibrentasvir (100/40 mg) fixed-dose combination; 3 pills once daily *Glecaprevir-Pibrentasvir (n = 343) GT 1-6 Compensated Cirrhosis 0 Week 12 8 4 32 24 20 SVR12 HCV RNA Source: Brown RS, et al. J Hepatol. 2020;72:441-8. Glecaprevir-Pibrentasvir in GT 1-6 & Compensated CirrhosisEXPEDITION-8: Method to Determine Cirrhosis Eligibility Method Used to Determine Cirrhosis Eligibility Patients (%) (n = 343) Histology (Metavir F4 or equivalent 32 (9.3) Fibroscan 14.6 kPa (no histology data available) 285 (83.1) FibroTest 0.75 and APRI >2 (no histology or FibroScan data available) 26 (7.6) Glecaprevir-Pibrentasvir in GT 1-6 & Compensated CirrhosisEXPEDITION-8: Results (Intent-to-Treat) Source: Brown RS, et al. J Hepatol. 2020;72:441-8. Sustained Virologic Response Rates (SVR): ITT Analysis 325/343 226/231 26/26 60/63 1/1 9/9 13/13 Sofosbuvir-Velpatasvir in Genotype 3ASTRAL-3* Phase 3 Treatment Nave & Experienced Source: Foster GR, et al. N Engl J Med. 2015;373:2608-17. *Published in tandem with ASTRAL-2 Trial Source: Foster GR, et al. N Engl J Med. 2015;373:2608-17. Sofosbuvir-Velpatasvir in HCV Genotype 3ASTRAL-3: Study Design SOF-VEL SVR12 Treatment-nave or Treatment-experienced GT 3 (n = 552) n = 277 SOF + RBV SVR12 n = 275 *Randomization stratified by treatment experience and cirrhosis status. Week 0 12 36 24 Abbreviations: SOF-VEL = sofosbuvir-velpatasvir; RBV = ribavirin Drug DosingSofosbuvir-velpatasvir (400/100 mg): fixed-dose combination; one pill once dailySofosbuvir: 400 mg once dailyRibavirin (weight-based and divided bid): 1000 mg/day if <75 kg or 1200 mg/day if 75 kg 16 Sofosbuvir-Velpatasvir in HCV Genotype 3ASTRAL-3: Results SVR12 Results by Treatment Experience and Cirrhosis Status Source: Foster GR, et al. N Engl J Med. 2015;373:2608-17. 160/163 40/43 31/34 33/37 141/156 33/45 22/31 22/38 Treatment Nave Treatment-Experienced Source: Foster GR, et al. N Engl J Med. 2015;373:2608-17. Sofosbuvir-Velpatasvir in HCV Genotype 3ASTRAL-3: Resistance *SVR12 in 84% (21/25) of patients with Y93H 225/231 38/43* (n = 231) (n = 43) Baseline Resistance-Associated Variants (RAVs) Response to Treatment (SVR12) 18 Summary Infection with HCV GT 3 is an independent risk factor for cirrhosis, hepatocellular carcinoma (HCC) and liver related death Patients with GT3 and cirrhosis are the most difficult to cure The two preferred regimens from AASLD/IDSA for GT3 patient with cirrhosis are: glecaprevir-pibrentasvirfor 8 weeks (in persons without HIV) sofosbuvir-velpatasvirfor 12 weeks (in persons without a baseline Y93H RAS) https://www.hcvguidelines.org/treatment-naive/gt3/compensated-cirrhosis 19 References Gordon SC, et al; CHeCS investigators. Race, Age, and Geography Impact Hepatitis C Genotype Distribution in the United States. J Clin Gastroenterol. 2019 Jan;53(1):40-50 McMahon BJ, et al. Infection With Hepatitis C Virus Genotype 3 Is an Independent Risk Factor for End-Stage Liver Disease, Hepatocellular Carcinoma, and Liver-Related Death. Clin Gastroenterol Hepatol. 2017 Mar;15(3):431-437. Kanwal F, et al.. HCV genotype 3 is associated with an increased risk of cirrhosis and hepatocellular cancer in a national sample of U.S. Veterans with HCV. Hepatology. 2014 Jul;60(1):98-105. doi: 10.1002/hep.27095. Epub 2014 May 27. Bochud PY; Swiss Hepatitis C Cohort Study Group. Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C. J Hepatol. 2009 Oct;51(4):655-66. 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