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Hepatitis A and B viruses Nicholas Teran, PharmD Infectious Diseases Pharmacy Fellow II University of Houston College of Pharmacy [email protected] November 15th, 2023 Learning objectives • Identify differences in the epidemiology, transmission, and disease progression of hepatitis A virus (HAV...

Hepatitis A and B viruses Nicholas Teran, PharmD Infectious Diseases Pharmacy Fellow II University of Houston College of Pharmacy [email protected] November 15th, 2023 Learning objectives • Identify differences in the epidemiology, transmission, and disease progression of hepatitis A virus (HAV) and hepatitis B virus (HBV) • Classify key serologies for HAV and HBV • Propose pharmacotherapy recommendations based on patient case scenarios Resources • Primary reference • Deming P. Viral Hepatitis. In: DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Posey L. eds. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. McGraw Hill; 2023. • Additional • Terrault NA, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):15601599. • CDC HAV & HBV Hepatitis • Inflammation of the ______ • May be caused by toxins/drugs, alcohol, and infectious etiologies • Marked by elevations in liver biomarkers: • Aspartate transaminase (AST) • Alanine transaminase (ALT) • ________ • Others: • Alkaline phosphatase (ALP) • Gamma-glutamyl transpeptidase (GGT) Image: https://www.istockphoto.com/vector/cartoon-liverdisease-gm1318153315-405373206 Hepatitis A virus (HAV) • Non-enveloped ____ virus in Picornaviridae family • Often leads to acute and self-limiting disease • Rarely may result in fulminant liver failure • Transmitted via fecal-oral route or person-toperson • Preventable by _________ Image: https://www.fda.gov/food/foodborne-pathogens/hepatitis-virus-hav Averhoff F, et al. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. HAV endemicity & outbreaks State-reported HAV outbreak cases 10/2023 Prevalence of HAV around the world Image: Jacobsen KH, Wiersma ST. Hepatitis A virus seroprevalence by age and w orld region, 1990 and 2005. Vaccine. 2010;28(41):6653-6657. Image: https://w ww.cdc.gov/hepatitis/outbreaks/2017March-HepatitisA.htm HAV high risk groups • Drug use • Homelessness • Men who have sex with men (MSM) • Incarceration • Chronic liver disease https://www.cdc.gov/hepatitis/outbreaks/2017March-HepatitisA.htm HAV clinical signs and symptoms Symptoms Hepatitis A virus Hepatitis B virus >70% __________ 70% subclinical/anicteric Common: fever, jaundice, scleral icterus, hepatomegaly Uncommon: splenomegaly, skin rash, arthralgia Uncommon: jaundice, dark urine, white stool, abdominal pain, fatigue, fever, chills, loss of appetite, pruritus Young children (<6y are generally asymptomatic) Lab findings Disease progression ALT>AST elevations (>1000 IU/L) ALT>AST elevations (1000-2000 IU/L) Bilirubin elevation Bilirubin normal-elevation Acute (1-2 weeks, up to 9 months) Prolonged disease in <15% Acute (0-6 months) No chronic infections Chronic (>6 months) Deming P. In DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. HAV disease progression Van Damme P, et al. Nat Rev Dis Primers. 2023;9(1):51. HAV disease progression ALF: acute liver failure Van Damme P, et al. Nat Rev Dis Primers. 2023;9(1):51. Within 5-10 days of symptom onset HAV diagnosis & treatment Diagnosis Serology Symptoms Treatment Acute HAV Anti-HAV IgM + Anti-HAV IgG +/- +/- None, supportive care Prior disease or Vaccine Anti-HAV IgM Anti-HAV IgG + None None Deming P. In DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. Averhoff F, et al. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. HAV prevention/prophylaxis criteria Clinical scenario Pre-exposure Criteria Age <6 months 6 months-40 years >40 years Immunocompromised Chronic liver disease Post-exposure Must be ≤2 weeks of exposure Age <6 months 6 months-40 years >40 years Immunocompromised Chronic liver disease Deming P. In DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. Averhoff F, et al. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Vaccine Immunoglobulin                     HAV prevention/prophylaxis Vaccine Age (Years) No. of Doses ≥1 2 0, 6-12 months 0, 6-18 months ≥18 3 0, 1, 6 months ≥18 (accelerated schedule) 4 0, 7 days, 21-30 days, +12 months Havrix Vaqta ______ HAV/HBV Schedule Pre-exposure (<3 mo) or post-exposure 0.02 mL/kg IM x1 Immunoglobulin* Any Pre-exposure (≤5 mo) 0.06 mL/kg IM x1 *avoid giving with live-attenuated vaccines for up to 5 months Deming P. In DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. Averhoff F, et al. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Patient case - HA HA is 25Y M with a no known past medical history was alerted by CDC officials of a potential HAV outbreak related to a restaurant he frequents and last visited 5 days ago. His does not recall ever having received any HAV vaccinations but records show HBV vaccination. As his pharmacist, what would you recommend at this time? A. B. C. D. Nothing; watchful waiting Recommend Havrix alone Recommend Havrix and immunoglobulin Recommend Twinrix HAV Prevention – CDC resourcs Image: https://www.cdc.gov/hepatitis/outbreaks/images/HepAOutbreakStats.png Hepatitis B virus (HBV) • Double-stranded ____ virus in Hepadnaviridae family • Highly infectious (~50-100x HIV) • Survives and remains infectious outside of the body for ≥7 days • Transmitted via: • Sexual contact • Parenteral • Perinatal transmission • Preventable by _________ Thio C, et al.. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Image: https://www.cdc.gov/vaccines/vpd/hepb/public/photos.html HBV global disease burden Image: https://www.cdc.gov/hepatitis/global/index.htm US HBV death burden, 2021 Image: https://www.cdc.gov/hepatitis/statistics/2021surveillance/hepatitis-b/figure-2.8.htm#print HBV high risk groups • Endemic regions where infection prevalence is >2% • Africa, Asia, Spain, South & Centra America, Eastern Europe, and Caribbean • Infants born to HBsAg-positive mothers • Injection drug use + needle sharing • Incarceration • Coinfections with HIV or HCV • Sexual contacts: MSM, multiple sex partners • Dialysis • ___________________ Thio C, et al.. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. HBV clinical signs and symptoms Symptoms Hepatitis A virus Hepatitis B virus >70% symptomatic 70% subclinical/anicteric Common: fever, jaundice, scleral icterus, hepatomegaly Uncommon: splenomegaly, skin rash, arthralgia Uncommon: jaundice, dark urine, white stool, abdominal pain, fatigue, fever, chills, loss of appetite, pruritus Young children (<6y are generally asymptomatic) Lab findings Disease progression ALT>AST elevations (>1000 IU/L) ALT>AST elevations (1000-2000 IU/L) Bilirubin elevation Bilirubin normal-elevation Acute (1-2 weeks, up to 9 months) Prolonged disease in <15% Acute (0-6 months) No chronic infections Chronic (________) Deming P. In DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. HBV disease progression Acute phase Chronic phase, if HBsAg persists Image: https://health.ucdavis.edu/blog/lab-best-practice/hepatitis-b-serologic-testing-methods/2021/06 Deming P. In DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. Thio C, et al.. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Thio C, et al.. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Component Significance HB surface antigen (HBsAg) Infection (acute or chronic) HB core antigen Infection HB e antigen Increased infectivity/replication DNA Viral load (disease burden) HBV structure – antibody development Component Significance HB surface antigen (HBsAg) Infection (acute or chronic) HB core antigen Infection HB e antigen Increased infectivity/replication DNA Viral load (disease burden) Immunity Component Significance Anti-HBs Recovery/immunity from infection Anti-HBe Decreased infectivity, may suggest good prognosis for recovery Total anti-HBc Measure of chronicity: IgM: indicating acute infection (<6 months) IgG: indicating resolved or chronic infection Deming P. In DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. Thio C, et al.. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. HBV serology interpretations Classification HBsAg Total anti-HBc IgM anti-HBc Anti-HBs Acute infection + + + - Link to hepatitis B care Chronic infection + + - - Link to hepatitis B care Resolved infection - + - + Counsel risk for HBV reactivation risk Vaccine immunity - - - + Ensure completed vaccination series Susceptible - - - - Recommend __________ Deming P. In DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. Thio C, et al.. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Action HBV prevention • Screening recommended for high-risk patients (see slide 19) • ACIP immunization recommendations: • Infants-59 years • ≥60 years + risk factors for HBV* *risk factors not required to receive immunization • International travel to endemic regions ACIP: Advisory Committee on Immunization Practices Thio C, et al.. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. HBV prevention Vaccine Age (Years) No. of Doses Heplisav-B ≥18 2 0, 1 months Engerix-B ≥0 3 0, 1, 6 months Recombivax ≥0 3 0, 1, 6 months PreHevbria ≥18 3 0, 1, 6 months _______ HAV/HBV Accelerated schedule ≥18 3 4 0, 1, 6 months 0, 7 days, 21-30 days, 12 months 6 months-6 years 3 Pediarix DTaP/HBV/IPV Deming P. In DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. Thio C, et al.. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Schedule 0, 2, 4 months When do we treat acute HBV? • Acute infection • 95% cases DO NOT require treatment, only supportive care • Low risk for acute liver failure • Will treat: • Acute liver failure • Severe and protracted symptomatic disease • Total bilirubin >3 mg/dL (or direct bilirubin >1.5 mg/dL) • INR >1.5 • Ascites • Encephalopathy Terrault NA, et al. Hepatology. 2018;67(4):1560-1599. When do we treat chronic HBV? Definition HBsAg ≥6 mo HBeAg ALT Viral load (IU/mL) Liver biopsy Treat? Immunetolerant + + ULN >20,000 Minimal fibrosis/inflammation Monitor LFTs, viral load, HBsAg annually Immuneactive + + ≥2x ULN >20,000 Immuneactive + - ≥2x ULN >2,000 Inactive + - ULN <2,000 ULN: upper limit of normal Terrault NA, et al. Hepatology. 2016;63(1):261-283. Terrault NA, et al. Hepatology. 2018;67(4):1560-1599. Moderate-severe inflammation ± fibrosis No inflammation Variable fibrosis Yes Yes Monitor LFTs, viral load, HBsAg annually Decision tree for chronic HBV treatment HBsAg-positive HBeAg-positive ALT ULN 1-2x ULN ≥2x ULN HBV DNA HBV DNA HBV DNA >20,000 IU/mL < or >20,000 IU/mL >20,000 IU/mL >20,000 IU/mL Monitor Treat Terrault NA, et al. Hepatology. 2018;67(4):1560-1599. Treat if lasting >6 months or presence of fibrosis or moderate-severe inflammation Decision tree for chronic HBV treatment HBsAg-positive HBeAg-negative ALT <2,000 IU/mL Monitor ULN 1-2x ULN ≥2x ULN HBV DNA HBV DNA HBV DNA >2,000 IU/mL Treat if lasting >6 months or presence of fibrosis or moderate-severe inflammation Terrault NA, et al. Hepatology. 2018;67(4):1560-1599. < or >2,000 IU/mL <2,000 IU/mL >2,000 IU/mL Treat Treat if lasting >6 months or presence of fibrosis or moderate-severe inflammation Treatment goal – chronic HBV • Prevention of clinical and histological progression via suppression of HBV replication • Cure or eradication is generally NOT possible due to the closed, circular DNA that persists in hepatocytes • Complications • Contributes to >800,000 deaths annually around the world • ~5-10% will develop hepatocellular carcinoma • ~20-30% will develop _______ CDC HBV treatment Dusheiko G, et al. N Engl J Med. 2023;388(1):55-69. Treatment – nucleoside analogues Agent ________ (Baraclude) Tenofovir disoproxil fumarate (___; Viread) Tenofovir alafenamide (___; Vemlidy) Dose (FYI) Monitoring Warnings Clinical pearls 0.5 mg PO daily Lactate Renal function HIV status Lactic acidosis Adjust CrCL <50 mL/min 300 mg PO daily Lactate Renal function Bone density HIV status Lactic acidosis Osteomalacia Nephropathy Fanconi syndrome Adjust CrCL <50 mL/min Lactic acidosis Adjust CrCL <15 mL/min Lower risk than TDF for bone-mineral disease and nephrotoxicity 25 mg PO daily Lactate Renal function HIV status Terrault NA, et al. Hepatology. 2018;67(4):1560-1599. Lexicomp Treatment – RNA interference Agent Pegylatedinterferon alfa-2a (_______) Terrault NA, et al. Hepatology. 2018;67(4):1560-1599. Lexicomp Dose (FYI) Monitoring 180 mcg SQ weekly CBC, TSH Autoimmune, ischemic, neuropsychiatric, and infectious complications Warnings Clinical pearls Fatigue, mood disturbance, flu-like symptoms, Adverse effects are cytopenia, muscle common aches, autoimmune complications Treatment – non-preferred agents (FYI) Agent Dose (FYI) Warnings Non-preferred Lamivudine 100 mg PO daily Lactic acidosis Pancreatitis Resistance Intolerance Adefovir 10 mg PO daily Lactic acidosis Acute renal failure Fanconi syndrome Resistance Nephrotoxicity Terrault NA, et al. Hepatology. 2018;67(4):1560-1599. Lexicomp Treatment duration Nucleoside analogues • Entecavir • TDF • TAF HBeAg negative Indefinite Terrault NA, et al. Hepatology. 2018;67(4):1560-1599. HBeAg positive ≥12 months after seroconversion (anti-HBe & anti-HBs) with: • Normal ALT • Undetectable HBV Patient case - HB HB is a 56Y F with recently diagnosed HBV. Her PMH includes T2DM, asthma, and CKD. Based on her lab-work below, what antiviral agent would you recommend for chronic treatment? Lab Results Lab Results SCr 2.7 HBsAg + ALT 87 Anti-HBc + AST 56 Anti-HBs - T. bili 5.3 HBeAg + Alk phos 210 HBV DNA A. B. C. D. Lamivudine Tenofovir disproxil fumarate Tenofovir alafenamide PEG-interferon 31,000 IU/mL Hepatitis A and B viruses Nicholas Teran, PharmD Infectious Diseases Pharmacy Fellow II University of Houston College of Pharmacy [email protected] November 15th, 2023 Additional resources