Managing Hepatitis C in Vermont Module 1: HCV 101

Welcome to the HCV 101 module Please take this brief pre-module quiz Click here for brief pre-module quiz or use this web address: https://forms.gle/gc7ppZpEVfdRfyPU7

This module works a lot better in “presentation” mode Above, go to “Slide Show” then hit “From Beginning” and click-through

Outline The burden of HCV in the world, US, and Vermont HCV biology and pathogenesis Consequences and natural history of HCV infection

Outline The burden of HCV in the world, US, and Vermont HCV biology and pathogenesis Consequences and natural history of HCV infection

Global HCV Epidemiology Globally, 2.8% of humans are infected with HCV This is more than 185 million people Certain areas have even higher prevalence: Eastern Europe (3.1%) Central Asia (5.8%) Sub-Saharan Africa (6.0%) Middle East (Egypt: 14.7%) Petruzziello et al 2016

Global HCV Prevalence From Gower E, Estes C, Blach S, et al. Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol 2014; 61:S52

HCV in the USA In 2019, the prevalence of HCV in the US is 1.3% However, looking at the last 20 years, we are losing ground in the fight against HCV… https://www.cdc.gov/hepatitis/hcv/index.htm

HCV in the USA But then… Discovery of HCV HCV serology test licensed New HCV cases per year Needlestick Safety and Prevention Act But then…

Incidence of hepatitis C, by age group — United States, 2000–2014 “HCV in US reproductive aged women essentially doubled from 2006 to 2014” Things started to worsen around 2010 From 2000–2002, incidence rates for acute hepatitis C decreased among all age groups, except for persons aged 0–19 years; rates remained fairly constant among all age groups from 2002–2010. From 2010 to 2014, the rate of acute hepatitis C increased among persons aged 20–29, 30–39 and ≥60 years. The largest increases were among persons aged 20–29 years (from 0.75 cases per 100,000 population in 2010 to 2.20 cases per 100,000 population in 2014) and persons aged 30–39 years (from 0.60 cases per 100,000 population in 2010 to 1.66 cases per 100,000 population in 2014).  In 2014, among all age groups, persons aged 20–29 years had the highest rate (2.20 cases per 100,000 population) and persons aged 0–19 and ≥60 years had the lowest rate (0.12 cases per 100,000 population) of acute hepatitis C. Source: CDC, National Notifiable Diseases Surveillance System (NNDSS)

HCV in the USA After dropping steadily from the late 1980’s to mid-2000’s, new HCV cases in the USA have markedly increased This is a direct result of the ongoing opioid epidemic and injection drug use Young persons who inject drugs are now the majority of NEW HCV infections However…

Baby Boomers (born in 1945–1965) still account for 75% of HCV in the US Birth Year Group 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 1990+ 1980s 1970s 1960s 1950s 1940s 1930s 1920s <1920 Number with chronic HCV (millions) An estimated 35% of undiagnosed baby boomers with HCV currently have advanced fibrosis or cirrhosis 1. Centers for Disease Control and Prevention. MMWR. 2012;61:1-32; Adapted from Pyenson B, et al. Consequences of Hepatitis C Virus (HCV): Costs of a baby boomer Epidemic of Liver Disease. New York, NY: Milliman, Inc; May 18, 2009. http://www.milliman.com/expertise/healthcare/publications/rr/consequences-hepatitis-c-virus-RR05-15-09.php Milliman report was commissioned by Vertex Pharmaceuticals; 3. McGarry LJ et al. Hepatology. 2012;55(5):1344-1355.

HCV in the USA Young persons who inject drugs are more likely to be acquiring and spreading HCV But “Baby Boomers,” born between 1945-1965, are more likely to be suffering from the long-term consequences of chronic HCV infection

HCV in Vermont Vermont has been heavily effected by the opioid epidemic Correspondingly, HCV is on the rise in Vermont National trends hold true: young persons who inject drugs in VT drive most new infections; VT Baby-Boomers drive most HCV-related morbidity/mortality Source: Vermont Department of Health, National Electronic Disease Surveillance System.

HCV in Vermont Since 2014, there have been approximately 900 cases of HCV newly- reported in Vermont per year Likely many more newly infected patients are unaware and unscreened Patients aged 20-39 are being newly infected at higher rates Rate of newly diagnosed infections in baby boomers has also increased, related to screening efforts

HCV incidence in Vermont by age, 2006-2016 Increasing incidence in VT since 2011 across age groups Source: Vermont Department of Health, National Electronic Disease Surveillance System.

Outline The burden of HCV in the world, US, and Vermont HCV biology and pathogenesis Consequences and natural history of HCV infection

HCV Biology Enveloped, single-stranded RNA virus Outer shell: lipid membrane and E1/E2 proteins, which help viral attachment to hepatocytes Inside: icosahedral protein core filled with RNA genome, NS5B RNA polymerase, NS5A transcription co-factor, and NS3/4 protease “NS” just means non-structural [protein] These viral proteins are the main HCV drug targets

HCV Biology The HCV RNA viral polymerase is error- prone. This results in the generation of frequent mutations that have hampered development of effective hepatitis C vaccines. Moreover, because of this, spontaneous clearance or medical cure of HCV does not confer immunity to HCV…patients can be re-infected.

HCV genotypes Over time, because of ongoing mutations, 6 different HCV genotypes have emerged (and many more subtypes) In the US and Vermont, genotype 1 (and specifically 1a) is most common. Genotypes 2-4 are occasionally seen in Vermont. Some patients have mixed infection with multiple genotypes Knowing the genotype of HCV is important as this helps guide what HCV therapy to use However HCV genotype is only helpful for determining treatment. There is no reason to order a genotype if patient is not going to be treated for HCV. USA HCV genotype mix

HCV Pathogenesis HCV virions main affinity is for hepatocytes in the liver Each infected hepatocyte produces up to 50 virions per day, with as many as 1 trillion virions produced daily by an infected liver HCV does not directly kill the hepatocyte. It is non-cytopathic Hepatic steatosis, oxidative stress, and host immune response are thought to cause the actual liver damage Consequently: the absolute value of serum HCV viral load does not influence the rate of hepatic fibrosis or HCV clinical course HCV virion

HCV Pathogenesis Modifiable factors that increase risk of hepatic fibrosis (and the speed at which hepatic fibrosis occurs): Alcohol use Obesity HIV co-infection Hepatitis B virus (HBV) co-infection Consequently, patients with hepatitis C should be counseled about alcohol use and weight management, and HIV and HBV should be treated appropriately

Outline The burden of HCV in the world, US, and Vermont HCV biology and pathogenesis Consequences and natural history of HCV infection

Hepatocellular Carcinoma Chronic HCV infection leads to increased hepatic fibrosis and eventual cirrhosis and liver cancer Fibrosis Cirrhosis Hepatocellular Carcinoma Fibrous scar tissue within the liver HCC3 Cancer of the liver can develop after years of chronic HCV infection Fibrosis can progress, causing severe scarring of the liver, restricted blood flow, impaired liver function, and eventually liver failure Chronic liver disease includes fibrosis, cirrhosis, and hepatic decompensation; HCC=hepatocellular carcinoma. 1. Highleyman L. Hepatitis C Support Project. http://www.hcvadvocate.org/hepatitis/factsheets_pdf/Fibrosis.pdf. Accessed August 18, 2011; 2. Bataller R et al. J Clin Invest. 2005;115:209-218; 3. Medline Plus. http://www.nlm.nih.gov/medlineplus/enxy.article/000280.htm. Accessed August 28, 2012; 4. Centers for Disease Control and Prevention. http://www.cdc.gov/hepatitis/HCV/HCVfaq.htm. Accessed May 8, 2012.

Natural History of HCV after 20 years 100 patients HIV or EtOH accelerate fibrosis, can be as short as 3 years to cirrhosis Exposure 25% 75% 75 Resolves Chronic Of 100 patients with HCV for 20 years, 15 will get cirrhosis and 4 will have a severe outcome 25 80% 20% 15 Stable Cirrhosis 60 25% 4 Men with 40 years of HCV have a 70% rate Gary Davis 2010 gastroenterology 75% HCC Transplant Death Slowly Progressive 11

Natural History of HCV after 40 years 100 patients Exposure 25% 75% 75 Resolves Chronic Of 100 patients with HCV for 40 years, 26 will get cirrhosis and 7 will have a severe outcome 25 65% 35% 26 Stable Cirrhosis 49 25% 7 Men with 40 years of HCV have a 70% rate Gary Davis 2010 gastroenterology 75% HCC Transplant Death Slowly Progressive 19

Consequences of HCV infection: a silent killer There are now more deaths per year from HCV than HIV/AIDS in the USA Source: US Department of Health and Human Services

HCV 101: Key Points HCV is a very common blood born infection, including in Vermont Rates of HCV infection are on the rise due to the injection drug use epidemic, but the burden of morbidity/mortality from HCV is in “baby boomers”, born from 1945-1965 HCV is an RNA virus that readily mutates and thus a vaccine is unavailable, and prior infection gives no protection from re-infection in the future Untreated, HCV can progress to cirrhosis of the liver and liver cancer, and is a leading cause of death from infection in the USA Next Step: Module 2: Screening for HCV

Congratulations! Please take the post-module quiz here Click here for brief post-module quiz or use this web address: https://forms.gle/1TC8WjJxnkZVAapg9