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Chair of Microbiology, Virology, and Immunology Hepatitis Viruses Characteristics of Human Hepatitis Viruses Virus Family/ Genus Size/ Genome Length of Incubation Mechanism of transmission HAV Picornaviridae / Hepatovirus 72 27-30 nm, single-stranged RNA HBV Hepadnaviridae / hepadnavirus 142 nm, circular 50-180 double-stranged days DNA HCV Flaviviridae 30-50 nm single- 14-28 days Parenteral, stranged RNA likely other sources No HDV Unclassified 35-40 nm single- 50 180 stranged RNA days* Parenteral transmission No HEV Caliciviridae 27 34 nm singlestranged RNA Oral-fecal No 15-40 days Mostly oralfecal 6 weeks Parenteral Vaccine Yes Recombinant subunit vaccine Global Prevalence of Hepatitis A Infection HAV Prevalence High Intermediate Low Very Low HEPATITIS A VIRUS Virus Hepatitis A Family Picornaviridae Genus Hepatovirus Virion 27 nm icosahedral Envelope No Genome ssRNA Genome size 7,5kb Stability Heat- and acid-stable Transmission Fecal-oral Prevalence High Fulminant disease Rare Chronic disease Never Oncogenic No Hepatitis A virus particles found in fecal extracts by immunoelectron microscopy. Both full and empty particles are present. The virus is 27 to 29 nm in diameter. (X 125,000.) Genome organisation of HAV Hepatitis A Virus Life Cycle Hepatitis A Transmission Fecal-oral contamination of food or water Food handlers For example. An epidemic of Raw shellfish HAV that occurred in Shanghai, Travel to endemic areas China, in 1988 in which 300,000 people were infected Close personal contact with the virus resulted from Household or sexual contact eating Anadara subcrenata Daycare centers obtained from a polluted river. Blood-borne (rare) Injecting drug users Pathogenesis Pathogenesis of HAV HAV replicates slowly in the liver without producing apparent cytopathological effects (CEPs). In the absence of cytolysis, the virus readily establishes a persistent infection. Jaundice, resulting from damage to the liver Antibody is detected and cell-mediated immune responses to the virus Hepatitis A - Clinical Features Incubation period: Jaundice by age group: Complications: Chronic sequelae: Average 30 days Range 15-50 days <6 yrs, <10% 6-14 yrs, 40%-50% >14 yrs, 70%-80% Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis None Body Fluid Concentration of Hepatitis A Virus in Various Body Fluids Feces Serum Saliva Urine 100 102 104 106 Infectious Doses per ml 108 1010 Clinical Variants of Hepatitis A Infection Asymptomatic (anicteric) disease Children under 6 years of age, > 90% Children from 6-14 years old, 40-50% Symptomatic (icteric) disease Adults and children over 14, 70-80% Typical Serologic Course of Acute Hepatitis A Virus Infection Symptoms ALT Total anti-HAV Fecal HAV 0 IgM anti-HAV 1 2 3 4 5 Months after exposure 6 12 24 Hepatitis A Vaccine Efficacy Studies Site/Age Group Vaccine Efficacy (95% CI) HAVRIX (SKB) 2 doses 360 EL.U. Thailand 1-16 yrs 94% (79%-99%) VAQTA (Merck) 1 dose 25 units New York 2-16 yrs 100% (85%-100%) Vaccine HEPATITIS B VIRUS About 300 million people world-wide are thought to be carriers of HBV, and many carriers eventually die of resultant liver disease. HBV causes acute hepatitis that can vary from a mild and self limiting form to an aggressive and destructive disease leading to postnecrotic cirrhosis. Many HBV infections are asymptomatic (especially in children). Prevalence of HBsAg Carrier State >8% 2-8% <2% WHO HEPATITIS B VIRUS Virus Hepatitis B Family Hepadnaviridae Genus Orthohepadnavirus Virion 42 nm, spherical Envelope Yes (HBsAg) Genome dsDNA Genome size 3,2kb Stability Acid-sensitive Transmission Parenteral Prevalence High Fulminant disease Rare Chronic disease Often Oncogenic Yes Fraction of the blood scrum from a patient with a severe ease of hepatitis. The larger spherical particles, or Dane particles, are 42 nm in diameter and are the complete hepatitis B virus. Also evident are filaments of capsid protein (HBsAg). HEPATITIS B VIRUS: HOW THE VIRUS REPRODUCES ?? 1. First the virus attached to a liver cell membrane. 2. The virus is then transported into the liver cell 3. The core particle then releases it’s contents of DNA and DNA polymerase into the liver cell nucleus. 4. Once within the cell nucleus the hepatitis B DNA causes the liver cell to produce, via messenger RNA; HBs protein, HBc protein, DNA polymerase, the HBe protein, and other undetected protein and enzymes. DNA polymerase causes the liver cell to make copies of hepatitis B DNA from messenger RNA. 5. The cell then assembles ’live’ copies of virus. 6. However because of the excess numbers of surface proteins produced many of these stick together to form small spheres and chains. These can give a characteristic “ ground glass” appearance to blood samples seen under a microscope. 7. The copies of the virus and excess surface antigen are released from the liver cell membrane into blood stream and from there can infect other liver cells. HBV: Replication Reverse transcription: one of the mRNAs is replicated with a reverse transcriptase making the DNA that will eventually be the core of the progeny virion RNA intermediate: HBV replicates through an RNA intermediate and produces and release antigenic decoy particles. Integration: Some DNA integrates into host genome causing carrier state Genome of HBV virus Genome: 3.200 nucleotídes S P C X Open Reading Frames There are 4 open reading frames derived from the same strand (the incomplete + strand) • S - the 3 polypeptides of the surface antigen (preS1, preS2 and S - produced from alternative translation start sites. • C - the core protein • P - the polymerase • X - a transactivator of viral transcription (and cellular genes?). HBx is conserved in all mammalian (but not avian) hepadnaviruses. Though not essential in transfected cells, it is required for infection in vivo. HBV Genome AgHBs Pré S1 Pré S2 DNA Polimerase gene P AgHBc gene C AgHBe Pré C gene S ANTIGEN OF HEPATITIS B VIRUS: HBsAg = surface (coat) protein ( 4 phenotypes : adw, adr, ayw and ayr) HBcAg = inner core protein (a single serotype) HBeAg = secreted protein; function unknown In HBsAg there are some determinants, which are responsible for 10 subtypes of this antigen. “а” determinat is general. There are “d” and “y”, and two additional - “w” and “r”. So, there are four main subtypes: “adr”, “ayr”. Other determinants - f, g, j, n, t, x. “adw”, “ayw”, HBV SPREAD MAINLY BY PARENTERAL ROUTE DIRECT PERCUTANEOUS INOCULATION OF INFECTED SERUM OR PLASMA INDIRECTLY THROUGH CUTS OR ABRASIONS ABSORPTION THROUGH MUCOSAL SURFACES ABSORPTION OF OTHER INFECTIOUS SECRETIONS (SALIVA OR SEMEN DURING SEX) HBV SPREAD MAINLY BY PARENTERAL ROUTE POSSIBLE TRANSFER VIA INANIMATE ENVIRONMENTAL SURFACES VERTICAL TRANSMISSION SOON AFTER CHILDBIRTH (TRANSPLACENTAL TRANSFER RARE) CLOSE, INTIMATE CONTACT WITH AN INFECTED PERSON Pathogenesis and Immunity Virus enters hepatocytes via blood Immune response (cytotoxic T cell) to viral antigens expressed on hepatocyte cell surface responsible for clinical syndrome 5 % become chronic carriers (HBsAg> 6 months) Higher rate of hepatocellular carcinoma in chronic carriers, especially those who are “e” antigen positive Hepatitis B surface antibody likely confers lifelong immunity (IgG anti-HBs) Hepatitis B e Ab indicates low transmissibility Determinants or acute and chronic HBV infection From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia,, WHO IS AT GREATEST RISK FOR HBV INFECTION? DRUG ABUSERS BLOOD PRODUCT RECIPIENTS ACCOUNTS FOR 5-10% POSTRANSFUSION HEPATITIS HEMODIALYSIS PATIENTS PEOPLE FROM SOUTHEAST ASIAN COUNTRIES (70-80%) LAB PERSONNEL WORKING WITH BLOOD PRODUCTS SEXUALLY ACTIVE HOMOSEXUALS PERSONS WITH MULTIPLE AND FREQUENT SEX CONTACTS MEDICAL/DENTAL PERSONNEL HBV 300,000 NEW CASES IN U.S. PER YEAR LIFETIME RISK FOR AVERAGE PERSON IS 5% SEXUAL PROMISCUITY > RISK LIFETIME RISK FOR DENTIST IS 13-28% Jaundice CHARACTERISTICS OF HBV INFECTION INFECTION IS USUALLY SELF LIMITING, COMPLETE RESOLUTION IN 6 MONTHS HOWEVER, WHEN INFECTED 5% ADULTS CHRONIC CARRIERS 20% CHILDREN CHRONIC CARRIERS 80-90% NEONATES AND INFANTS BECOME CHRONIC CARRIERS HBV - Diagnosis Acute Infection HBV DNA HBeAg Anti-HBe Anti-HBs Anti-HBc HBsAg 0 Anti-HBc IgM 2 Months 4 6 Years HBV - Diagnosis Chronic Infection HBV DNA HBeAg Anti-HBe HBsAg Anti-HBc IgG Anti-HBc IgM Months Years PRACTICE HBsAG HBcAB (TOTAL) HBsAB HAV-IGM HCV PAST INFECTION. N. P. P. N. N. PRACTICE HBsAg HBcAB (total) HBsAB HAV-IGM HCV IMMUNIZATION. N. N. P. N. N. PRACTICE HBsAg P. HBcAB (Total) P. HBsAB N. HAV-IGM N. HCV N. MAY BE ACUTE OR CHRONIC. Order Hep. B Core IgM to clarify. The IgM will be positive , If Acute. HBV - Vaccine Vaccine Age Group Dose Volume (μg) Engerix-B Recombivax HB (Optional 2-dose) # Doses (ml) 0-19 yr 20 yr Adults on hemodialysis 10 20 0.5 1.0 3 (mo 0,1,6) 3 (mo 0,1,6) 40 2.0 4 (mo 0,1,2,6) 0-19 yr 20 yr 11-15 yr Adults on hemodialysis 5 10 10 0.5 1.0 1.0 3 (mo 0,1,6) 3 (mo 0,1,6) 2 (mo 0, 4-6) 40 1.0* 3 (mo 0,1,6) Combined HAV and HBV - Vaccine Bivalent HAV and HBV vaccine 1ml contains 720 ELISA Units of inactivated HAV and 20 ug of recombinant HBsAg protein Dosage: 1 ml at 0, 1, 6 months Recommended for all susceptible persons 18 years at risk of exposure to both HAV and HBV, including travelers to areas of high/intermediate endemicity for both viruses Therapeutic Agents Immune Modulators Nucleo(s)tide analog Interferon Lamivudine Thymosin Adefovir dipivoxil Therapeutic vaccines Emtricitabine Entecavir L-dT/ L-dC Clevudine Famciclovir Characteristics of hepatitis C viruses Virus Hepatitis C Family Flaviviridae Genus Hepacivirus Virion 60 nm spherical Envelope Yes Genome ssRNA Genome size 9,4 kb Stability Ether-sensitive, acid-sensitive Transmission Parenteral Prevalence Moderate Fulminant disease Rare Chronic disease Often Oncogenic Yes Model of Human Hepatitis C Virus Lipid Envelope Capsid Protein Nucleic Acid Envelope Glycoprotein E2 Envelope Glycoprotein E1 HCV RNA Structure Transcription, Replication IRES, Translation Structural Non-Structural 5' UTR 3' UTR Structure C E1 E2 Nucleocapsid, Assembly Envelope Proteins, Assembly and Entry Processing p7 NS2 Protease Calcium Channel? NS3 Replication NS4A NS4B NS3 cofactor Serine Protease, Helicase NS5A Phosphoprotein, Replication Replication? IRES = internal ribosomal entry site; UTR = untranslated region; C = nucleocapsid core; E1 = envelope protein 1; E2 = envelope protein 2; NS = nonstructural NS5B RNA-dependent RNA polymerase Hepatitis C: A Global Health Problem 170-200 Million (M) Carriers Worldwide United States 3-4 M Western Europe 5M Eastern Europe 10 M Far East Asia 60 M Southeast Asia 30-35 M Americas 12-15 M Africa 30-40 M Australia 0.2 M HCV - Epidemiology Prevalence In Groups at Risk Recipients of clotting factors before 1987 75 - 90% Injection drug users 70 - 85% Long-term hemodialysis patients 10% Individuals with > 50 sexual partners 10% Recipients of blood prior to 1990 5% Infants born to infected mothers 5% Long-term sexual partners of HCV positive 1 - 5% Health workers after random needlesticks 1 - 2% Current Likelihood of Transmission Transfusion ~ 1 in 1,000,000 Maternal-Infant Mother HIV-negative Mother HIV-positive ~ 5% 15 - 20% Heterosexual partner ~1 in 1,000 per yr Needlestick injury HCV-positive source HCV status unknown ~ 5% ~ 1% HCV ACCOUNTS FOR 90-95% OF POST TRANSFUSION HEPATITIS RISK OF SEXUAL TRANSMISSION LOWER THAN FOR HBV RISK THROUGH CASUAL CONTACT LOW HCV VERTICAL TRANSMISSION POSSIBLE RISK INCREASED IF MOTHER IS POSITIVE FOR HCV RNA RISK INCREASED IF MOTHER IS HIV POSITIVE OVERALL PREVALENCE ESTIMATED AT 1.4% WHO IS AT GREATEST RISK FOR HCV INFECTION? DRUG ABUSERS BLOOD PRODUCT RECIPIENTS (ANTIHCV SCREENING HAS GREATLY REDUCED RISK) HEMODIALYSIS PATIENTS LAB PERSONNEL WORKING WITH BLOOD PRODUCTS SEXUALLY ACTIVE HOMOSEXUALS PERSONS WITH MULTIPLE AND FREQUENT SEXUAL CONTACTS MEDICAL/DENTAL PERSONNEL (3-10% VIA NEEDLESTICK FROM INFECTED PATIENT) Diagnostic Tests Hepatitis C antibody tests Qualitative HCV RNA tests Quantitative HCV RNA tests Genotyping Acute HCV Infection 1000 HCV RNA positive 800 Anti-HCV ALT 600 (IU/L) Symptoms 400 200 Normal ALT 0 0 2 4 6 8 10 12 24 1 2 3 Weeks 4 5 Months Time After Exposure 6 7 HCV Antibody Test Indicates past or present infection Inexpensive, sensitive and specific Poor positive predictive value in low prevalence populations Low sensitivity in immunosuppressed patients Qualitative HCV RNA (PCR) Confirms diagnosis of HCV infection Useful in the early diagnosis of acute hepatitis C Demonstrates the presence of active infection “Gold standard” for documenting response to treatment Potential HCV Therapies Phase I R803 Rigel HCV/MF59 Chiron SCH-6 Schering ANA245 ANADYS Phase II ISIS 14803 Isis E-1 Innogenetics Phase III Viramidine Valeant Albuferon VX-950 Human Genome Vertex Sciences JTK 003 AKROS Oral IFN alpha Pharma Amarillo Biosciences NM283 Idenix HepX-C XTL IDN-6556 Idun Infergen/gamma IFN InterMune Amantadine Endo Labs Solvay Ceplene Maxim VX-497 Vertex Omega IFN Biomedicine Multiferon Viragen Civacir NABI IP-501 Indevus Zadaxin SciClone REBIF Ares-Serono Time to Market HCV-086 ViroPharma/ Wyeth Characteristics of hepatitis D viruses Virus Hepatitis D Family Unclassified Genus Deltavirus Virion 35 nm spherical Envelope Yes (HBsAg) Genome ssRNA Genome size 1,7 kb Stability Acid-sensitive Transmission Parenteral Prevalence Low, regional Fulminant disease Frequent Chronic disease Often Oncogenic ? Hepatitis Delta Virus (HDV) HDV INFECTION PATTERNS COINFECTION ACUTE SIMULTANEOUS INFECTION WITH HBV AND HDV OFTEN RESULTS IN FULMINANT INFECTION (70% CIRRHOSIS) SURVIVORS RARELY DEVELOP CHRONIC INFECTION (< 5%) HDV INFECTION PATTERNS SUPERINFECTION RESULTS IN HDV SUPERINFECTION IN AN HBsAg CARRIER (CHRONIC HBV) CAN OCCUR ANYTIME DURING CHRONIC DISEASE USUALLY RESULTS IN RAPIDLY PROGRESSIVE SUBACUTE OR CHRONIC HEPATITIS HDV - Coinfection ALT HDV RNA IgM anti-HDV IgG anti-HDV HDAg IgM anti-HBc HBsAg IgG anti-HBc anti-HBs Months HDV - Superinfection ALT HDV RNA IgM anti-HDV IgG anti-HDV HDAg HBV DNA HBsAg, IgG anti-HBc Years HDV Transmission: Oral No Percutaneous Common Sexual Yes, rare Perinatal No Incubation period 21 - 45 days Jaundice Unknown Fulminant 2 – 7.5% Diagnostic tests: Acute infection IgM anti-HDV Chronic infection IgG anti-HDV, HBsAg + Immunity Not applicable Case-fatality rate 1 – 2% Chronic infection: Superinfection 80% Coinfection < 5% HEPATITIS E VIRUS Virus Hepatitis E Family Caliciviridae Genus Unnamed Virion 30-32 nm, icosahedral Envelope No Genome ssRNA Genome size 7,6kb Stability Heat-stable Transmission Fecal-oral Prevalence Regional Fulminant disease In pregnancy Chronic disease Never Oncogenic No Epidemiology Suspected from study of waterborne hepatitis in India in 1980 Confirmed by transmission to chimp and human in 1983 Probably accounts for many historical outbreaks of hepatitis Endemic mainly in Asia, Middle East, North Africa Epidemiology Fecal-oral transmission (human to human) Contaminated water supplies in tropical or subtropical developing countries Mainly young adults Can infect primates, swine, sheep, rats Swine may be reservoir of infection in North America (attenuated virus) Maternal-infant transmission occurs and is often fatal Clinical Characteristics Similar to hepatitis A Can cause severe acute hepatitis Subclinical infection is common Attenuated virus from animal reservoirs Low-dose infections often asymptomatic No chronic infection Up to 20% mortality among pregnant women (esp. third trimester) Course of Acute Infection Viral Replication IgM Antibody IgG Antibody ALT Viremia Symptoms Virus in Stool 0 10 20 30 40 50 Time After Infection (days) 60 1 2 (years) Prevention Passive (Immune serum globulin) Does not prevent infection May ameliorate hepatitis Active (Vaccine) Anti-ORF2 prevents infection in chimps and humans Clinical trials in progress HEV Transmission: Oral Common No Percutaneous Unknown Sexual No Perinatal Yes, unknown frequency Incubation period 15 - 60 days Jaundice Common Fulminant <1%, in pregnancy up to 30% Diagnostic tests: Acute infection IgG anti-HEV (seroconversion) Chronic infection Not applicable Immunity Not applicable Case-fatality rate 0,5 – 4 % 1.5 – 21% in pregnant women Chronic infection None HEPATITIS G VIRUS Virus Hepatitis G Family Flaviviridae Genus Unnamed Virion 60 nm, spherical Envelope Yes Genome ssRNA Genome size 9,4 kb Stability Ether-sensitive Transmission Parenteral Prevalence Moderate Fulminant disease ? Chronic disease Yes Oncogenic ? HGV AND GVB-C SHARE 95% AMINO ACID IDENTITY THUS REPRESENT DIFFERENT ISOLATES OF THE SAME HUMAN VIRUS “HEPATITIS C-LIKE VIRUS” CLASSIFIED IN THE FLAVIVIRIDAE FAMILY SAME AS HCV GENETIC ORGANIZATION SIMILAR TO HCV GENONE CONSISTS OF SINGLE-STRANDED RNA MOLECULE OF POSITIVE POLARITY HGV - EPIDEMIOLOGY TRANSMISSABLE BY BLOOD AND BLOOD PRODUCTS PRESENT IN ASYMPTOMATIC BLOOD DONORS WITH NORMAL ALT LEVELS FOUND IN: GENERAL POPULATION 1-2 % HEMOPHILIA PATIENTS 18 % IV DRUG USERS 33 % Patients with chronic Hepatitis B 10 % Patients with chronic Hepatitis C 20% HGV - CLINICAL SIGNIFICANCE RECENT DATA SUGGESTS: HGV INFECTION DOES NOT CAUSE ACUTE HEPATITIS HGV MAY ESTABLISH CHRONIC INFECTIONS FREQUENTLY OCCURS WITH HBC AND HCV INFECTIONS MAY NOTQUALIFY AS A TRUE HEPATITIS VIRUS THE END