1. Chair of Microbiology, Virology, and Immunology
Hepatitis Viruses

2. Characteristics of Human Hepatitis Viruses Mechanism of transmission
Family/ Genus
Size/ Genome
Length of Incubation
Mechanism of transmission
Vaccine
HAV
Picornaviridae / Hepatovirus 72
27-30 nm, single-stranged RNA
15-40 days
Mostly oral-fecal
Yes
HBV
Hepadnaviridae / hepadnavirus
142 nm, circular double-stranged DNA
days
Parenteral
Recom-binant subunit vaccine
HCV
Flaviviridae
30-50 nm single-stranged RNA
14-28 days
Parenteral, likely other sources No
HDV
Unclassified
35-40 nm single-stranged RNA
days*
Parenteral transmission
HEV
Caliciviridae
27 34 nm single-stranged RNA
6 weeks
Oral-fecal

3. Global Prevalence of Hepatitis A Infection
HAV Prevalence
High
Intermediate
Low
Very Low
Global Prevalence of Hepatitis A Infection

4. 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

5. 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.)

6. Genome organisation of HAV
This figure shows the genome organisation of HAV
The genome consist of a long ORF divided into 3 regions;
The structural proteins P1
And the non-structural proteins P2 and P3.
The C-terminal part of VP3, the N-terminal part of VP1, as well as the VP1-2PA junction are the most variable regions and has therefore been used in molecular epidemiological studies.
Based upon sequencing 168 bp within the VP1-2PA Betty Roberston and workers mange to distinguish geographical distributed strains and classified them into genotypes.

7. Hepatitis A Virus Life Cycle

8. Hepatitis A Transmission
Fecal-oral contamination of food or water
Food handlers
Raw shellfish
Travel to endemic areas
Close personal contact
Household or sexual contact
Daycare centers
Blood-borne (rare)
Injecting drug users
Hepatitis A Transmission
For example. An epidemic of HAV that occurred in Shanghai, China, in 1988 in which 300,000 people were infected with the virus resulted from eating Anadara subcrenata obtained from a polluted river.
Slide 45
Routes of Hepatitis A Transmission
Hepatitis A is transmitted primarily via the fecal-oral route by either ingestion of contaminated food or water or person-to-person contact with an individual with acute HAV infection. Examples of fecal-oral transmission from ingestion of contaminated food or water include travel of susceptible individuals to endemic areas of infection, epidemics of infection resulting from ingestion of contaminated shellfish, and epidemics of infection from ingestion of food contaminated by infected food handlers.
Person-to-person transmission occurs most commonly within families and among children in day care centers. Sexual transmission occurs most frequently between men who have sex with men. Blood-borne transmission, although unusual, does occur, primarily in hemophiliacs and injection drug users.
Shapiro CN, Hadler SC. Significance of hepatitis A in children in day care. Semin Pediatr Infect Dis 1990; 1:
Soucie JM, Robertson BH, Bell BP, McCaustland KA, Evatt BL. Hepatitis A virus infections associated with clotting factor concentrate in the United States. Transfusion 1998; 38:
Centers for Disease Control and Prevention. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1999; 48(RR-12):1-38.

9. Pathogenesis

10. 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

11. Hepatitis A - Clinical Features
Incubation period: Average 30 days
Range days
Jaundice by <6 yrs, <10% age group: yrs, 40%-50% >14 yrs, 70%-80%
Complications: Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis
Chronic sequelae: None 7

12. Concentration of Hepatitis A Virus in Various Body Fluids
Feces
Body Fluid
Serum
Saliva
Urine
100
102
104
106
108
1010
Infectious Doses per ml 10

13. 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%
Clinical Variants of Hepatitis A Infection
Slide 47
Clinical Variants of Hepatitis A Infection
Hepatitis A infection can result in either an asymptomatic or symptomatic clinical illness. The illness typically has an abrupt onset with symptoms that can include transient fever, malaise, anorexia, nausea, vomiting, abdominal pain, and jaundice. The likelihood of symptoms and jaundice are related to the patient’s age. Fewer than 10% of children under 6 years of age have jaundice. In contrast, over two-thirds of older children and adults have symptomatic disease with jaundice. The duration of illness is < 2 months in most cases. Complete recovery and the development of natural immunity to reinfection ultimately occur in all infected individuals.
Hadler SC, Webster HM, Erben JJ, Swanson JE, Maynard JE. Hepatitis A in day-care centers: a community-wide assessment. N Engl J Med 1980; 302:
Lednar WM, Lemon SM, Kikpatrick JW, Redfield RR, Fields ML, Kelley PW. Frequency of illness associated with epidemic hepatitis A virus infection in adults. Am J Epidemiol 1985; 122:

14. Typical Serologic Course of Acute Hepatitis A Virus Infection
Fecal
HAV
ALT
IgM anti-HAV
Months after exposure
Symptoms 1 2 3 4 5 6 12 24
Total anti-HAV
Slide 46
Serological Course of Acute Hepatitis A
HAV replicates in the liver, is excreted in bile, and is shed in the stool. Most patients with hepatitis A become symptomatic after an average incubation period of 28 days (range days). Peak infectivity occurs during the two-week period before the onset of elevated aminotransferases and jaundice. Fecal shedding of the virus usually disappears by the time patients become symptomatic. Specific antibodies develop rapidly in patients with HAV infection. IgM antibodies against HAV are usually detectable 5-10 days before the onset of symptoms and can persist for up to 6 months after infection. IgG antibodies, which appear early in the infection, persist indefinitely and confer lifetime protection against reinfection. The diagnosis of acute hepatitis A is made by detecting IgM anti-HAV in the serum.
Skinhøj P, Mathiesen LR, Kryger P, Møller AM. Faecal excretion of hepatitis A virus in patients with symptomatic hepatitis A infection. Scand J Gastroenterol 1981; 16:
Liaw YF, Yang CY, Chu CM, Huang MJ. Appearance and persistence of hepatitis A IgM antibody in acute clinical hepatitis A observed in an outbreak. Infection 1986; 14:
Stapelton JT. Host immune response to hepatitis A virus. J Infect Dis 1995; 171(suppl 1):S9-S14.

15. Hepatitis A Vaccine Efficacy Studies
Site/Age
Efficacy
Vaccine
Group
(95% CI)
HAVRIX Ò
Thailand
94%
(SKB)
1-16 yrs
(79%-99%)
2 doses
360 EL.U.
VAQTA ä
New York
100%
(Merck)
2-16 yrs
(85%-100%)
1 dose
25 units 17

16. 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).

17. Prevalence of HBsAg Carrier State
>8%
2-8%
<2%
Slide 61
Epidemiology of Hepatitis B
Hepatitis B infection is a global health problem. Approximately 350 million people worldwide are chronic carriers of HBV. Chronic hepatitis B is endemic in most parts of Africa, Asia and Alaska, with carrier rate higher than 20%.
In United States, the latest population survey showed prevalence of chronic hepatitis B to be 0.42%. However, in that study, people at high risks, such as those imprisoned or incarcerated, were not surveyed. Hence, the actual prevalence may be even higher.
Kao JH, Chen DS. Global control of hepatitis B virus infection. Lancet Infec Dis 2002;2:
McWuillan GM, et al. Prevalence of hepatitis B virus infection in the United States: the National Health and Nutrition Examination Surveys, 1976 through Am J Public Health Jan;89(1):14-8.
WHO

18. 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

19. 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).

21. HEPATITIS B VIRUS:

22. HOW THE VIRUS REPRODUCES ??
1. First the virus attached to
a liver cell membrane.
2. The virus is then transported
into the liver cell

23. 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.
3. The core particle then releases it’s contents of DNA and DNA polymerase into the liver cell nucleus.

24. 5. The cell then assembles ’live’ copies of virus.

25. 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.
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.

27. 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

28. Genome of HBV virus
Genome: nucleotídes S P C X

29. 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.

30. HBV Genome Pré S1 Pré S2 gene S gene P gene C Pré C AgHBs
DNA Polimerase
gene P
AgHBc
AgHBe
gene C
Pré C

31. 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

32. 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: “adw”, “ayw”, “adr”, “ayr”.
Other determinants - f, g, j, n, t, x.

33. 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) 28

34. 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 29

35. 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

36. Determinants or acute and chronic HBV infection
From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia,,

37. WHO IS AT GREATEST RISK FOR HBV INFECTION?
LAB PERSONNEL WORKING WITH BLOOD PRODUCTS
SEXUALLY ACTIVE HOMOSEXUALS
PERSONS WITH MULTIPLE AND FREQUENT SEX CONTACTS
MEDICAL/DENTAL PERSONNEL
DRUG ABUSERS
BLOOD PRODUCT RECIPIENTS
ACCOUNTS FOR 5-10% POSTRANSFUSION HEPATITIS
HEMODIALYSIS PATIENTS
PEOPLE FROM SOUTHEAST ASIAN COUNTRIES (70-80%) 30

38. 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% 32

39. Jaundice

40. 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 37

41. Acute Infection HBsAg Anti-HBs Anti-HBc Anti-HBc IgM HBeAg HBV DNA
HBsAg
Anti-HBs
Anti-HBc
Anti-HBc IgM
Months Years
HBeAg
HBV DNA
Anti-HBe
HBV - Diagnosis
Slide 80
Serological Markers of Acute HBV Infection
Incubation period of HBV infection ranges from 60 to 180 days. HBsAg is the first serological marker of acute HBV infection. Early in the course of acute HBV infection, markers of active viral replication (HBeAg and HBV DNA), are also detectable. As the patients recover, serum HBV DNA level markedly decrease but may remain detectable by PCR assay for up to several decades, HBeAg to anti-HBe seroconversion occurs and finally HBsAg becomes undetectable. Persistence of HBsAg for more than 6 months indicates progression to chronic HBV infection.
Anti-HBc IgM is the first antibody to be detected and usually persists for several months. It may be the only marker of acute HBV infection during the ‘window’ period after HBsAg is cleared and before anti-HBs is detected. Recovery from acute HBV infection is indicated by the presence of anti-HBc IgG and anti-HBs.

42. Chronic Infection HBV - Diagnosis HBV DNA HBeAg Months Years Anti-HBe
Anti-HBc IgM
Anti-HBc IgG
Anti-HBe
HBsAg
Slide 81
Serological Markers of Chronic HBV Infection
Chronic HBV infection is indicated by the presence of HBsAg persisting for more than 6 months and detection of anti-HBc IgG. During the early phase of chronic HBV infection, markers of HBV replication: HBeAg and high serum HBV DNA levels are also present. Over time, patients seroconvert from HBeAg to anti-HBe, accompanied by decrease in serum HBV DNA levels.

43. PRACTICE HBsAG N. HBcAB (TOTAL) P. HBsAB P. HAV-IGM N. HCV N.
PAST INFECTION.

44. PRACTICE HBsAg N. HBcAB (total) N. HBsAB P. HAV-IGM N. HCV N.
IMMUNIZATION.

45. 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.

46. Vaccine Age Group Dose Volume # Doses
HBV - Vaccine
Vaccine Age Group Dose Volume # Doses
(μg) (ml)
Engerix-B yr (mo 0,1,6)
 20 yr (mo 0,1,6)
Adults on
hemodialysis (mo 0,1,2,6)
Recombivax HB 0-19 yr (mo 0,1,6)
 20 yr (mo 0,1,6)
(Optional 2-dose) yr (mo 0, 4-6)
hemodialysis * 3 (mo 0,1,6)
Slide 95
Dose schedule of HBV vaccine
Two recombinant HBV vaccines are currently available in the United States: Engerix-B (GlaxoSmithKline Biologicals) and Recombivax HB (Merck & Co., Inc.). The two vaccines can be used inter-changeably. Conventional 3-dose schedules include injections at 0, 1, and 6 months for immunocompetent people.
The dose recommended for children and adolescents is lower while that for immunocompromised adults such as dialysis patients is higher.
In adolescents aged 11 to 15 years, Recombivax HB has been approved for use in a 2-dose, 10ug regimen, with the second dose given 4 to 6 months after the first. This 2-dose regimen should increase compliance and reduce costs.
CDC. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: recommendations of the immunization practices advisory committee (ACIP). MMWR 1991;40 (RR-13):1-19.
Koff RS. Hepatitis A, hepatitis B, and combination hepatitis vaccines for immunoprophylaxis. An update. Dig Dis Sci 2002;47:

47. 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
Slide 97
Combined hepatitis A and B vaccines
Many individuals are at risk of acquiring hepatitis A and B. A vaccine that provides protection against both hepatitis A and B reduces the number of injections, offers greater convenience to the vaccinees, and improves compliance.
Twinrix is a bivalent vaccine containing the antigenic components used in producing Havrix A and Engerix-B. A 1.0 mL dose of vaccine contains not less than 720 ELISA Units of inactivated hepatitis A virus and 20 ug of recombinant HBsAg protein. For those aged 18 or older, a dose of 1ml is given at 0, 1, and 6 months.
Twinrix is recommended for individuals who are, or will be, at risk of exposure to both HAV and HBV infection, including travelers to areas of high or intermediate endemicity for both viruses, and patients with chronic liver disease.
Knoll A, Hottentrager B, Kainz J, et al. Immunogenicity of a combined hepatitis A and B vaccine in healthy young adults. Vaccine ;18:

48. Therapeutic Agents Immune Modulators Nucleo(s)tide analog
Interferon Lamivudine
Thymosin Adefovir dipivoxil
Therapeutic vaccines Emtricitabine
Entecavir
L-dT/ L-dC
Clevudine
Famciclovir
Slide 113
Therapeutic agents for chronic hepatitis B
Antiviral therapies can be divided into immune modulators and nucleotide or nucleoside analogues. Currently, only interferon, lamivudine, and adefovir dipivoxil are approved for the treatment of chronic hepatitis B.

49. Characteristics of hepatitis C viruses
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

50. Model of Human Hepatitis C Virus
Lipid Envelope
Capsid Protein
Nucleic Acid
Envelope Glycoprotein E2
HCV was first recognized as a separate entity in 1975 after it was determined that the majority of cases of transfusion-related hepatitis were not caused by the 2 types of hepatitis recognized at the time (hepatitis A and B). The disease was called “non-A non-B” hepatitis until the virus was cloned and sequenced in At that time the virus was renamed hepatitis C virus.
HCV is a linear single-strand RNA virus nanometers in size that belongs to the Flaviviridae family and the Hepacivirus genus. The virus is covered with a lipid envelope and is encased with glycoprotein peplomers or “spikes.”
Envelope Glycoprotein E1

51. IRES = internal ribosomal entry site; UTR = untranslated region;
HCV RNA Structure
IRES, Translation
Transcription, Replication
Structural
Non-Structural
5' UTR
3' UTR
Structure
Processing
Replication C E1 E2
Nucleocapsid, Assembly
Envelope Proteins, Assembly and Entry p7
Calcium Channel?
NS2
NS3
NS4A
Protease
Serine Protease, Helicase
NS3 cofactor
NS4B
NS5A
NS5B
Replication?
Phosphoprotein, Replication
RNA-dependent RNA polymerase
HVC is composed of a single-stranded RNA genome approximately 9.6 kilobases long that encodes a single, large polyprotein of about 3,000 amino acids. This polyprotein is cleaved post-translationally into multiple structural and nonstructural (NS) peptides. The structural peptides include a nucleocapsid core (C), 2 envelope glycoproteins (E1, E2), and a calcium channel (p7). The NS proteins are labeled NS2 through NS5. Although the specific functions of the NS proteins have not been completely characterized, their presumed functions are illustrated in the slide. In particular, the highly conserved NS3 and NS5 segments of the genome contain structured RNA elements that are vital for the initiation of protein translation (both NS3 and NS5) and for RNA transcription (NS3). These structures represent potential attractive targets for anti-HCV therapy.
Hoofnagle JH. Course and outcome of hepatitis C. Hepatology. 2002;36:S21-S29.
Pawlotsky JM, McHutchison JG. Hepatitis C. Development of new drugs and clinical trials: promises and pitfalls. Summary of an AASLD hepatitis single topic conference, Chicago, IL, February 27-March 1, Hepatology. 2004;39:
IRES = internal ribosomal entry site; UTR = untranslated region;
C = nucleocapsid core; E1 = envelope protein 1; E2 = envelope protein 2; NS = non-structural

52. Hepatitis C: A Global Health Problem
Million (M) Carriers Worldwide
Far East Asia
60 M
Western
Europe
5 M
Eastern
Europe
10 M
United States
3-4 M
Southeast Asia
30-35 M
Africa
30-40 M
Americas
12-15 M
Hepatitis C: A Global Health Problem
According to CDC estimates, approximately 3-4 million people in the US are currently infected with the hepatitis C virus (see map). There are, however, a few distinct geographic regions where infection is especially common. In Egypt, for example, HCV infection occurs in 10% to 30% of the general population. Likewise, the prevalence of infection is greater than 10% in certain parts of Asia and high rates of infection have been found in certain geographic regions of Japan, Taiwan, and Italy. In such areas, HCV infection is generally more prevalent among persons over the age of 40 and uncommon under the age of 20. This cohort effect suggests that transmission probably occurred through a practice that has been discontinued, such as traditional folk remedies or reuse of needles for injection. In developing countries, nosocomial transmission is most likely the principal route of HCV infection. Evidence from Egypt, Romania, and other nations, before economic transition, point to various percutaneous practices performed in the context of traditional and nontraditional medical care.
The incidence of acute hepatitis C in the US has decreased during the last decade, from approximately 180,000 cases per year to approximately 30,000 to 50,000 cases per year.
References
Cohen J. The scientific challenge of hepatitis C. Science. 1999;285(5424):26-27.
Alter MJ. Epidemiology of Hepatitis C. Hepatology. 1997;26(suppl 1):62S-65S.
World Health Organization. Weekly epidemiological report. 1999;74: Available at: Accessed February 19, 2003.
Australia
0.2 M

53. Prevalence In Groups at Risk
HCV - Epidemiology
Prevalence In Groups at Risk
Recipients of clotting factors before %
Injection drug users %
Long-term hemodialysis patients 10%
Individuals with > 50 sexual partners 10%
Recipients of blood prior to %
Infants born to infected mothers 5%
Long-term sexual partners of HCV positive 1 - 5%
Health workers after random needlesticks 1 - 2%
Slide 186
Prevalence In Groups at Risk
These data are taken directly from Table 1 of the reference cited and are rounded to the nearest 5%. These numbers are estimates of the already-established prevalence in a particular group, not the prospective risk of infection. This information is useful in highlighting the relative importance of screening various groups for HCV infection.

54. Current Likelihood of Transmission
Transfusion ~ 1 in 1,000,000
Maternal-Infant
Mother HIV-negative ~ 5%
Mother HIV-positive %
Heterosexual partner ~1 in 1,000 per yr
Needlestick injury
HCV-positive source ~ 5%
HCV status unknown ~ 1%
Slide 187
Current Likelihood of Transmission
A recent study of the risk of transmission by blood transfusion concluded that the risk was 1 in 250,000 to 1 in 25,000 per unit [Schreiber GB et al., New Engl J Med 1996;334:1685]. However, the current risk is likely to be lower, particularly away from high-prevalence urban areas. The risk of 1 in 1,000,000 is based on data from a major blood bank in the Midwest. See slide 185.
The risk estimates for needlestick injury are averages from multiple studies.

55. HCV ACCOUNTS FOR 90-95% OF POST TRANSFUSION HEPATITIS
RISK OF SEXUAL TRANSMISSION LOWER THAN FOR HBV
RISK THROUGH CASUAL CONTACT LOW 39

56. 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% 40

57. WHO IS AT GREATEST RISK FOR HCV INFECTION?
SEXUALLY ACTIVE HOMOSEXUALS
PERSONS WITH MULTIPLE AND FREQUENT SEXUAL CONTACTS
MEDICAL/DENTAL PERSONNEL (3-10% VIA NEEDLESTICK FROM INFECTED PATIENT)
DRUG ABUSERS
BLOOD PRODUCT RECIPIENTS (ANTI-HCV SCREENING HAS GREATLY REDUCED RISK)
HEMODIALYSIS PATIENTS
LAB PERSONNEL WORKING WITH BLOOD PRODUCTS 41

58. Lecture Notes
Approximately 60% of cases of hepatitis C are due to injection drug use. Fifteen percent of cases may be sexually transmitted. Ten percent of cases are due to transfusion-related infections. Unknown sources account for approximately 10% of cases and nosocomial, occupational, and perinatal exposure together account for another 5%.1
Reference
1. CDC. Hepatitis C Slide set. Available at: September 25, Accessed: February 5, 2002.

59. Lecture Notes
Approximately 85% of infected individuals will develop chronic hepatitis. Of these, 20% to 50% will progress to develop cirrhosis. One quarter of those with cirrhosis will progress to hepatic decompensation and 1% to 4% will progress to hepatocellular carcinoma. This progression typically takes place over the course of 20 to 30 years.

61. Diagnostic Tests Hepatitis C antibody tests Qualitative HCV RNA tests
Quantitative HCV RNA tests
Genotyping
Slide 222
Diagnostic Tests
A variety of tests are available for the diagnosis and management of patients with chronic hepatitis C. These include antibody tests for detection of anti-HCV, qualitative and quantitative tests for detection of HCV RNA, and various methods of determining the genotype of HCV infection.
Carithers RL Jr, Marquart A, Gretch DR. Diagnostic testing for hepatitis C. Semin Liver Dis 2000; 20:
Pawlotsky JM. Molecular diagnosis of viral hepatitis. Gastroenterology 2002; 122:
Pawlosky JM. Use and interpretation of virological tests for hepatitis C. Hepatology 2002; 36(Suppl 1):S65-S73.

62. Acute HCV Infection Anti-HCV ALT Symptoms Time After Exposure Weeks
400
600
800
1000
ALT
(IU/L) 2 4 6 8 10 12 24 1 3 5
Anti-HCV
Symptoms
Weeks
Months
HCV RNA positive
200 7
Normal ALT
Slide 229
Acute hepatitis C infection
The diagnosis of acute hepatitis C can be quite difficult. Jaundice is infrequent and many patients have few, if any, symptoms. These diagnostic difficulties are compounded by considerable delay between HCV infection and the detection of antibodies in the patient’s serum. This was particularly true for early antibody tests for HCV in which the average time between infection and seroconversion was 16 weeks. This window has been progressively shorted with newer generations of antibody tests. However, even with the most sensitive newer tests the “window period” between HCV infection and seroconversion is at least 6-8 weeks. In contrast, HCV RNA can usually be detected within days after infection.
Carithers RL Jr, Marquart A, Gretch DR. Diagnostic testing for hepatitis C. Semin Liver Dis 2000; 20:
Pawlosky JM. Use and interpretation of virological tests for hepatitis C. Hepatology 2002; 36(Suppl 1):S65-S73.

63. 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
Slide 227
Antibody tests for hepatitis C
Antibody tests for hepatitis C are inexpensive, sensitive and specific for prior HCV infection. In patients with clinical evidence of chronic liver disease, a positive antibody test for HCV has a positive predictive value > 90%. In contrast, in low risk populations, such as blood donors, the positive predictive value for a positive test is extremely low. Antibody tests for HCV have low sensitivity for infection in immunocompromised individuals.
Carithers RL Jr, Marquart A, Gretch DR. Diagnostic testing for hepatitis C. Semin Liver Dis 2000; 20:
Pawlosky JM. Use and interpretation of virological tests for hepatitis C. Hepatology 2002; 36(Suppl 1):S65-S73.

64. 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
Slide 228
Qualitative tests for HCV RNA
Detection of HCV RNA in a patient’s blood confirms the presence of active infection. The most sensitive methods for doing so are the reverse transcription polymerase chain reaction (PCR) and transcription-mediated amplification (TMA). Qualitative tests for HCV RNA are extremely sensitive methods for determining the presence of hepatitis C virus. Most of these tests have a sensitivity of at least 50 IU/ml. Because of their sensitivity, these tests are useful in documenting successful clearance of virus during and after completion of antiviral therapy. To avoid false negative results from these tests, serum or plasma should be separated from whole blood within 4 hours, followed by rapid storage of specimens at –70°C.
Carithers RL Jr, Marquart A, Gretch DR. Diagnostic testing for hepatitis C. Semin Liver Dis 2000; 20:
Pawlotsky JM. Molecular diagnosis of viral hepatitis. Gastroenterology 2002; 122:
Pawlosky JM. Use and interpretation of virological tests for hepatitis C. Hepatology 2002; 36(Suppl 1):S65-S73.

65. Potential HCV Therapies
ViroPharma/
Wyeth
Albuferon
Human Genome
Sciences
VX-950
Vertex
R803
Rigel
HCV/MF59
Chiron
Phase I
JTK 003
AKROS
Pharma
Oral IFN alpha
Amarillo
Biosciences
SCH-6
Schering
HepX-C
XTL
NM283
Idenix
ANA245
ANADYS
Ceplene
Maxim
Multiferon
Viragen
IDN-6556
Idun
Time to Market
ISIS 14803
Isis
Phase II
VX-497
Vertex
Infergen/gamma IFN
InterMune
Civacir
NABI
E-1
Innogenetics
Omega IFN
Biomedicine
IP-501
Indevus
Viramidine
Valeant
Amantadine
Endo Labs
Solvay
REBIF
Ares-Serono
Zadaxin
SciClone
Phase III

66. Characteristics of hepatitis D viruses
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 ?

67. Hepatitis Delta Virus (HDV)

68. HDV INFECTION PATTERNS
COINFECTION
ACUTE SIMULTANEOUS INFECTION WITH HBV AND HDV
OFTEN RESULTS IN FULMINANT INFECTION (70% CIRRHOSIS)
SURVIVORS RARELY DEVELOP CHRONIC INFECTION (< 5%) 51

69. 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 52

70. HDV - Coinfection Months HDV RNA IgM anti-HDV IgG anti-HDV HDAg
IgG anti-HBc
ALT
HBsAg
anti-HBs
IgM anti-HBc
Slide 168
HDV Co-infection
Coinfection with HDV and HBV is characterized by the presence of markers of HDV and HBV during the acute phase. Coinfection is more likely to lead to a fulminant course than acute HBV infection alone.

71. HDV - Superinfection ALT HDV RNA IgG anti-HDV IgM anti-HDV HDAg
HBV DNA
Years
HBsAg, IgG anti-HBc
Slide 169
HDV Superinfection
HDV superinfection occurs in an individual already chronically infected with HBV. Diagnosis is suggested by a negative test for anti-HBc IgM, positive HBsAg, and presence of HDV markers. Clinically, it presents like an acute exacerbation of chronic hepatitis in a HBV carrier, occasionally the course is fulminant. Since the HBsAg carrier permits continuous replication of HDV, the vast majority (over 90%) of HDV superinfection progresses to chronic infection.
Hadziyannis S, et al. The role of the hepatitis delta virus in acute hepatitis and in chronic liver disease in Greece. Prog Clin Biol Res1991;364:51-62.

72. HDV Transmission: Oral No Percutaneous Common Sexual Yes, rare
Perinatal
Incubation period
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%

73. 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

74. 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
Slide 315
Epidemiology
Although HEV was discovered relatively recently, it is likely that it has accounted for most of the large-scale outbreaks of hepatitis around the world. Cases outside of endemic areas are uncommon and sporadic.

75. 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
Epidemiology
Slide 316
Epidemiology
Transmission is not usually directly from human to human, as the attack ratre within households is only about 2% [Smith]. Contaminated water supplies are usually the route of infection in large epidemics. Sporadic cases often have no clear source of infection. The rare individuals who acquire infection from swine seem to have a mild illness due to attenuation of the virus.
Hepatitis E is a dangerous illness in the last trimester of pregnancy, because essentially all newborns acquire the infection from their mothers and the case fatality rate is high (next slide).

76. 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)
Clinical Characteristics
Slide 317
Clinical Characteristics
The clinical spectrum of hepatitis E is similar to that of hepatitis A. Both may cause a severe acute hepatitis, but the infection usually is associated with mild disease. Probably half of infections are subclinical. Neither hepatitis A nor hepatitis E infection becomes chronic. Both have a high case fatality rate in late pregnancy. See slide 6 for a further comparison.

77. Course of Acute Infection10 20 30 40 50 60
Time After Infection (days) 1 2
Viral Replication
IgM Antibody
IgG Antibody
Viremia
ALT
Virus in Stool
(years)
Symptoms
Slide 318
Course of Acute Infection
Virus can be detected in stool for some time prior to the onset of symptoms, accounting for the virus’s success during large-scale outbreaks. IgM antibody may persist for up to a year. IgG antibody can be detected long-term and confers immunity.

78. Prevention Does not prevent infection May ameliorate hepatitis
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
Prevention
Slide 320
Prevention
Worldwide prevention mainly relates to increasing the level of sanitation in developing countries. Travelers to endemic areas can protect themselves by boiling drinking water and eating only thoroughly cooked food.

79. HEV Transmission: Oral Common No Percutaneous Unknown Sexual No
Perinatal
Yes, unknown frequency
Incubation period
days
Jaundice
Common
Fulminant
<1%, in pregnancy up to 30%
Diagnostic tests:
Acute infection
IgG anti-HEV (seroconversion)
Chronic infection
Not applicable
Immunity
Case-fatality rate
0,5 – 4 %
1.5 – 21% in pregnant women
None

80. 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
Oncogenic

81. 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 2

82. HGV - EPIDEMIOLOGY TRANSMISSABLE BY BLOOD AND BLOOD PRODUCTS
PRESENT IN ASYMPTOMATIC BLOOD DONORS WITH NORMAL ALT LEVELS
FOUND IN:
GENERAL POPULATION %
HEMOPHILIA PATIENTS %
IV DRUG USERS %
Patients with chronic Hepatitis B 10 %
Patients with chronic Hepatitis C 20% 2

83. 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 2

84. THE END