Learning Objectives: Hepatitis Update. Primary Causes of Chronic Liver Disease in the U.S. Hepatitis Definition. Hepatitis Viruses.

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1 Learning Objectives: Hepatitis Update ASCLS-Michigan March 31, 2016 Dr. Kathleen Hoag Upon attendance of this seminar and review of material provided, the attendees will be able to: 1. List hepatitis viruses transmitted by fecal-oral versus blood and body fluids. 2. Identify current laboratory testing recommendations for viral hepatitis. 3. Describe recent advances in the drug treatment of Hepatitis C Virus infection. Hepatitis Definition Hepatitis is a general term that means inflammation of the liver Common symptoms include fatigue, fever, GI upset, muscle pain, with or without jaundice, but many patients are asymptomatic following exposure and infection with hepatitis viruses Primary Causes of Chronic Liver Disease in the U.S. 54% due to chronic HBV or HCV infection Figure 17.15: Contemporary Clinical Immunology and Serology, Rittenhouse- Olson & DeNardin. Hepatitis Viruses Viruses that specifically infect hepatocytes are a common cause of hepatitis, as well as other viruses that secondarily can cause hepatitis Hepatitis virus infection concern is usually chronic infection leading possibly to cirrhosis and/or liver cancer Hepatitis Viruses Can be grouped by mode of transmission Fecal-oral route = contaminated food/water Hepatitis A (HAV) usually food service workers Hepatitis E (HEV) usually water Blood/body fluids (=Parenteral = other than intestine) Hepatitis B [HBV; +/- Hepatitis D (HDV)] Hepatitis C (HCV) 1

2 Usefulness of Viral Serology Testing (not just Viral Hepatitis) Most viruses are not easily cultured Diagnosis primarily by serological methods (and now molecular testing) Serological tests can: Detect past infections Assess current immune status (acute disease, chronic disease, vaccination immunity, etc.) Monitor the course of infection Generalities of Viral Serology Results Virus-specific antibodies in adult patient serum: IgM isotype indicates a current or recent acute infection IgG isotype indicates a current or past infection, and immunity (in most cases) Virus-specific IgM isotype in newborn (neonate) serum indicates congenital infection (IgG does NOT, because could be from mom) Positive serologic tests for viral Ag or detection of viral DNA or RNA (by molecular diagnostic techniques) indicates current infection Hepatitis A Virus Most common cause of acute viral hepatitis throughout most of the world (including U.S.) Incubation period is 28 days Most infected adults are symptomatic children usually asymptomatic HAV antigens shed in feces during incubation period and early acute disease (prior to symptoms) Disease usually resolves in 1-8 weeks rarely fulminant hepatitis (suddenly severe, causing death) does not become chronic Hepatitis A Virus Serology IgM anti-hav in patient serum indicates acute HAV infection Ab peaks at ~1 month of infection Ab becomes undetectable in 6-12 months High total anti-hav antibody (detects mostly IgG) indicates immunity HAV vaccination available and recommended for travel to endemic areas administered to children in U.S. Intramuscular injections of anti-hav immune globulin prevents disease in exposed individuals (passive immunity) Hepatitis E Virus Contracted from drinking water contaminated with feces (developing countries) Acute, self-limiting disease Not common in U.S. (serological test for IgM anti- HEV has been developed but is not commercially available in U.S.) Major concern: associated with high rate of mortality in pregnant women who become infected, especially during 3 rd trimester (20-30% fatality rate) Hepatitis B Virus Transmitted by HBV-contaminated blood or body fluids (parenteral): sexual contact blood products tattooing or body piercing IV drug needle-sharing perinatal (mom baby) occupational needle stick Immunization available and highly recommended for health care and prison workers mandatory in most U.S. schools now 2

3 Hepatitis B Virus continued HBV has long incubation period prior to disease onset (60-90 days) Highly variable clinical course: Acute hepatitis symptoms in: 30-50% of adults <10% of young children 1-2% of adults develop acute severe liver disease with necrosis (high fatality rate) Chronic HBV infection develops in: 5-10% of infected adults 30-60% of infected children (<4 years old) 90% of infected infants Hepatitis B Virus continued 25% of those with chronic infection become chronic carriers (can transmit disease without knowing it) 300 million chronic carriers worldwide 1 million in U.S. ~1 million deaths per year worldwide Hepatitis B Virus Serology Important viral antigens for monitoring infection: HBcAg = hepatitis B core antigen (a protein surrounding viral DNA in virus core) HBeAg = hepatitis Be antigen (also a protein surrounding viral DNA in virus core) HBsAg = hepatitis B surface antigen (a protein in outer virus envelope and in particles in blood) Hepatitis B Virus Serology HBsAg is the first HBV antigen to appear in serum detectable 2 to 12 weeks after exposure peaks during acute infection levels decline as patient Ab increases (usually undetectable 12 to 20 weeks after symptoms) persistent HBsAg is an indication of chronic or active infection HBeAg appears shortly after HBsAg and indicates high viral replication and a high degree of infectivity HBcAg is not detectable in serum Patient Antibody Response to HBV IgM anti-hbc appears first (= IgM isotype antibody against the HBcAg) used as an indicator of current or recent acute infection useful for detecting core window (= time between disappearance of HBsAg and detectable anti-hbs) IgG anti-hbc appear later and persists for life indicates past infection Anti-HBs appears during recovery persists for years and provides protective immunity failure of infected patient to develop anti-hbs indicates chronic infection this antibody is produced in response to vaccination HBV Serology Interpretation Serologic Results HBsAg Total anti-hbs IgM anti- HBc Anti-HBs Never infected; susceptible Early acute infection (or recent vaccine) Acute infection Late acute infection Past infection/recovery/immunity Chronic infection False positive Past infection/resolved low level chronic infection Vaccine immunity (or 3-6 mo s post-hbig admin.)

4 Hepatitis D Virus (HDV) Can only occur with HBV (which acts as helper virus) Uses HBsAg protein in its outer envelope HDV infection can occur simultaneous with HBV (co-infection) or as a superinfection of HBV HDV infection results in greater risk of fulminant hepatitis or chronic liver disease Patient Antibody Response to HDV IgM anti-hdv appears 6 to 7 weeks after exposure IgG anti-hdv appears during convalescence, then declines after resolution of infection Both IgM anti-hdv and IgG anti-hdv remain high in chronic infection No FDA-approved test in U.S. Hepatitis C Virus (HCV) Major public health problem 1.3% of U.S. population chronically infected 3% worldwide population chronically infected =180 million people, 3.5 million in U.S. Transmitted by contaminated blood IV drug use is a big source blood transfusions or organ transplants prior to 1992 Perinatal transmission about 6% HCV has high mutation rate that allows it to escape immune response and prevents development of effective vaccine HCV Disease Course Incubation period is 7 to 8 weeks Only ~20% of infected persons develop acute symptoms 85% develop chronic infection 20% of these develop liver cirrhosis (scarring) years later those with cirrhosis are at increased risk of developing hepatocellular carcinoma HCV Serology Anti-HCV detected by EIA Ab appears 7 to 8 weeks after exposure EIA has 99% specificity (1% false positives) Serology testing cannot distinguish between recently acquired, chronic, or resolved infection Confirmatory test is necessary: Molecular assay for HCV RNA in patient s serum HCV Molecular Testing Qualitative molecular assay also used for: Earlier detection than EIA (1 week after exposure) Detect infection of babies born to HCVinfected mothers Detect exposure in immunosuppressed individuals Quantitative molecular assay used for viral load testing and to follow response to drug therapy 4

5 HCV Genotyping necessary for proper drug treatment Direct-acting antiviral drug targets in HCV lifecycle Prior to 2014, PEG-IFN and ribavirin for months was recommended treatment NO longer recommended Standard of care is combination direct-acting antivirals (DAA), chosen based upon HCV genotype Genotypes 1a, 1b, 2-6 Genotypes 1a, 1b, 2 most common in U.S. Genotypes 1a & 1b have NS5a inhibitor resistance-associated variants PI = previr NS5a = asvir NPI = buvir Bertino, G. et al The new era of chronic hepatitis C treatment. World Journal of Hepatology 8(2):92-106, Figure 1. Recommended DAA by HCV Genotype Genotypes 1a and 1b*: 1. Elbasvir/grazoprevir for 12 weeks 2. Ledipasvir/sofosbuvir for 12 weeks 3. Paritaprevir/ritonavir/omitasvir plus twicedaily dasabuvir for 12 weeks 4. Simeprevir plus sofosbuvir for 12 weeks 5. Daclatasvir plus sofosbuvir for 12 weeks * For patients with no cirrhosis; for NS5A inhibitor resistanceassociated variants, add ribavirin to all above and increase treatment length to 16 weeks hcvguidelines.org/sites/default/files/hcv-guidance_february_2016_a1.pdf Recommended DAA by HCV Genotype Genotype 2: 1. Sofosbuvir/ribavirin for 12 weeks 2. Daclatasvir/sofosbuvir for 12 weeks Genotype 3: 1. Daclatasvir/sofosbuvir for 12 weeks 2. Sofosbuvir/ribavirin plus weekly PEG-IFN for 12 weeks Genotype 4: 1. Paritaprevir/ritonavir/ombitasvir and ribavirin for 12 weeks 2. Elbasvir/grazoprevir for 12 weeks 3. Ledipasvir/sofosbuvir for 12 weeks Genotypes 5 or 6: Ledipasvir/sofosbuvir for 12 weeks hcvguidelines.org/sites/default/files/hcv-guidance_february_2016_a1.pdf Summary Hepatitis viruses are a serious cause of infectious hepatitis worldwide Serological and molecular tests are key to diagnosis, disease staging, and proper drug selection With new drugs available, there is hope chronic HCV and liver cirrhosis/cancer may be prevented References 1. hcvguidelines.org/sites/default/files/hcv- Guidance_February_2016_a1.pdf. 2. Bertino, G. et al The new era of chronic hepatitis C treatment. World Journal of Hepatology 8(2): y/training.htm. 4. Contemporary Clinical Immunology and Serology by Kate Rittenhouse-Olson & Ernesto DeNardin, First edition, Prentice Hall Press, copyright January 14, 2013; ISBN