Updates in Hepatitis C Management Hayley Blackburn, Pharm.D., - PowerPoint PPT Presentation

Updates in Hepatitis C Management Hayley Blackburn, Pharm.D., BCACP Montana Pharmacy Association Winter CE

Disclosures  I have no relevant financial or nonfinancial interests related to this presentation

Learning Objectives 1. Explain the most recent developments in direct-acting antiviral (DAA) therapy for the treatment of chronic hepatitis C. 2. Describe the trends toward non-specialist treatment of chronic hepatitis C.

Pre-Assessment Questions 1. True/false: New direct-acting antiviral combinations are highly effective against all hepatitis C genotypes. 2. True/false: Current data suggests that HCV treatment provided by a specialist is superior to treatment provided by a non-specialist provider for the majority of those with chronic HCV infection.

2011- Telaprevir and boceprevir approved 1975 - "Non-A/Non-B" Hepatitis 2013 - Sofosbuvir found and simeprevir 1981 - First Effective Hepatitis A approved Vaccine, Merck develops hepatitis B 1960 - Hepatitis B vaccine 2014 - Harvoni approved discovered by FDA 1989 - Hepatitis C Virus 1969 - First Hepatitis B vaccine Identified 2016 - Zepatier and invented Epclusa approved by 1991 - IFN-alpha is approved for 1973 - Hepatitis A FDA hepatitis C treatment discovered 2017 – Mavyret and Vosevi approved 1945 2021 1945 1952 1959 1966 1973 1980 1987 1994 2001 2008 2015 "Baby Boomers" Testing of the blood supply begins Today Vietnam War HIV/AIDS epidemic begins 2001 - FDA approves Peginterferon alfa-2b 1998 - FDA approves Interferon + Ribavirin for HCV treatment The History of Hepatitis

Hepatitis C Epidemiology  Approximately 70 million people living with chronic hepatitis C worldwide  50% of total infections are found in 7 countries:  China  Pakistan  India  Egypt  Russia  United States  Nigeria Polaris Observatory HCV Collaborators. Lancet Gastroenterol Hepatol. 2017;2:161-176.

Hepatitis C Epidemiology: Reported Cases of Acute HCV in United States Based on these data, CDC 3,500 3,000 estimates that 2,500 Number of cases more than 2,000 1,500 41,000 1,000 Americans were 500 newly infected 0 with hepatitis C in 2016 alone Year Source: Division of Viral Hepatitis. Statistics and Surveillance

Incidence of Acute HCV By Age Group: CDC Surveillance Data 2001-2016 population 3 0-19 yrs Reported cases/100,000 2.5 20-29 yrs 2 30-39 yrs 1.5 40-49 yrs 1 0.5 0 Year Source: CDC, National Notifiable Diseases Surveillance System (NNDSS)

Opioid Epidemic and HCV Transmission: Reported Acute HCV Infection 2006 to 2012 Suryaprasad AG, et al. Clin Infect Dis. 2014;59:1411-1419.

Incidence of Acute HCV By Age Group: Reported cases/100,000 population CDC Surveillance Data 2001-2016 American Indian/Alaska 3.5 Native Asian/Pacific Islander 3 Black, Non-Hispanic 2.5 2 White, Non-Hispanic 1.5 1 0.5 0 Year Source: CDC, National Notifiable Diseases Surveillance System (NNDSS)

CDC HCV Surveillance Data: Montana  1026 new cases of confirmed past or present chronic HCV reported in 2016 Reported Cases of Acute HCV (*Rate per 100,000) 2013 2014 2015 2016 No. Rate* No. Rate* No. Rate* No. Rate* Montana 16 1.6 13 1.3 15 1.5 20 1.9 US Total 2138 0.7 2194 0.7 2436 0.8 2967 1.0

DHHS National Viral Hepatitis Action Plan  2020 DHHS goal: Increase the percentage of persons aware of their hepatitis C virus infection to 66%  25% reduction in mortality  CDC, DHHS, and National Academies of Sciences, Engineering, and Medicine have set a strategy to eliminate viral hepatitis in the US by 2030 DHHS. National Viral Hepatitis Action Plan 2017-2020.

HCV Screening Recommendations Population CDC AASLD USPSTF NIH Born in the US between 1945-1965 X X X X Any injection of illicit drugs (IVDU/PWID) X X X X Received blood transfusion or organ transplant X X X X before 1992 Chronic hemodialysis X X X X Evidence of liver disease X X X HIV infection X X X HCW after exposure X X X Received an unregulated tattoo X Children born to HCV+ women X X X Incarceration X X Intranasal drug use (cocaine) X X

Progression of Hepatitis C 15-25% No chronic disease

Progression of Hepatitis C Compensated Fibrosis 15% No chronic 5% per disease year Decompensated cirrhosis: Jaundice, ascites, variceal hemorrhage, and/or hepatic encephalopathy

Progression of Hepatitis C  Higher risk of disease progression:  HCV acquired after age 40  Male gender  Coinfection with HIV/HBV  Alcohol use  Lower risk:  Female gender  Acquired at a younger age Source: Wiley TE, McCarthy M, Breidi L, McCarthy M, Layden TJ. Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology. 1998;28:805-9.

Forecasted Deaths Associated with Chronic HCV  Projected 1.76 million people with chronic HCV will develop cirrhosis over the next 50 years  Predicted to peak at 2030 :  1 million with cirrhosis  131,000 with ESLD  3200 HCV-related transplants per year  BUT these numbers are assuming no widespread treatment of chronic HCV Source: Rein DB, et al. Dig Liver Dis. 2011 ;43:66-72.

Treatment Goals: The “SVR”  SVR12 = undetectable HCV RNA at 12 weeks after the end of treatment  SVR12 is the most indicative of cure  Patients will also be tested at 24 and/or 48 weeks after treatment to assess  Less than 1% will go on to relapse at 24 or 48 weeks post-treatment if undetectable at 12 weeks

Treatment Goals: The “SVR” Delayed response Viral relapse Source: Hepatitis C Online – University of Washington

Sustained Virologic Response: Effects on Morbidity and Mortality  SVR is associated with significant reductions in liver-related complications and death, as well as a number of other extrahepatic benefits Source: van der Meer AJ, et al. JAMA. 2012;308:2584-2593.

Benefits of SVR: Beyond the Liver  Extrahepatic benefits 1,2 :  Decreased all-cause mortality  Improved quality of life  Improved control of diabetes/insulin resistance  Improved neurocognition  Improved HCV-related liver transplant outcomes  2018 observational VA study 3 : HCV treatment associated with a significant reduction in CVD events  Veterans treated with either PEG-IFN + RBV (n=4436) or DAA (n=12,667)  7.2% incidence of CVD events in treatment group vs 13.8% in control group (p<0.0001) 1. Smith-Palmer J, et al. BMC Infect Dis. 2015;15:19. 2. Negro F, et al. Gastroenterology. 2015;149:1345-1360. 3. Butt AA, et al. Gastroenterology. 2018;49:729-738.

Benefits of SVR: Beyond the Liver Societal benefits:  Cost-effective, potentially cost-saving  2017 systematic review: 71% of analyses found second-generation DAAs to be cost- saving at a discounted price of $60K  Public health – increase cure rates mean reduced transmission rates  BUT does not protect against reinfection

Hepatitis C Treatment: The Era of Direct-Acting Antivirals

History of HCV Treatment: Interferon+Ribavirin Duration of treatment: 24-72 weeks ~up to 50% overall early discontinuation rate ~40% discontinued due to intolerance • • ~10% discontinued early due to lack of efficacy Of those that finished “Sustained treatment, Virologic Response” only 40-50% “Rapid “Early achieved SVR Virologic Virologic Response” Response” (NO LONGER USED)

Peg-IFN/RBV/DAA: IFN/RBV: 70-90% cure 2011- Telaprevir and boceprevir approved 1/1/2011 34-42% 2013 - Sofosbuvir and simeprevir cure approved 1/1/2013 1998 - FDA approves Interferon + Ribavirin 1989 - Hepatitis C Virus Identified for HCV treatment 1/1/1989 1/1/1998 2001 - FDA approves Peginterferon alfa-2b 1991 - IFN-alpha is approved for hepatitis C 2014 - Harvoni approved 1/1/2001 treatment by FDA 1/1/1991 10/14/2014 1989 2019 1989 1993 1997 2001 2005 2009 2013 6/8/2016 2016 - Zepatier and Epclusa approved by FDA Peg-IFN/RBV: IFN-only: 55% cure 6-16% cure

Direct-Acting Antivirals: Combination Products  Beginning in 2011, rapid advances in product development for direct-acting antiviral agents that specifically target essential components of viral replication  NS3 protease inhibitors  NS5A polymerase inhibitors  NS5B inhibitors  HUGE advantages:  All oral regimens, 8-24 weeks, well-tolerated  Rapid response in viral load reduction  Well-tolerated with minimal adverse effects:  Headache, fatigue, insomnia, nausea  SVR Rates: 95-99%

Direct-Acting Antivirals: Protease Inhibitors  NS3 Protease Inhibition:  Inhibits cleavage of viral polyprotein into functional protein subunits required for viral replication and assembly  Inhibitors: Glecaprevir, grazoprevir, paritaprevir, simeprevir, voxilaprevir Holmes JA, Thompson AJ. Hep Med. 2015;7:51 — 70

Direct-Acting Antivirals: NS5A/NS5B Inhibitors  NS5B:  RNA polymerase responsible for RNA synthesis  Inhibitors: sofosbuvir, dasabuvir  NS5A:  Modulation of NS5B activity  Role in modulation of host response?  Inhibitors: Daclatasvir, elbasvir, ledipasvir, ombitasvir, pibrentasvir, velpatasvir Holmes JA, Thompson AJ. Hep Med. 2015;7:51 — 70