1. Hepatitis A-E Viruses
Enock Anassi MD, PharmD

2. Viral Hepatitis - Historical Perspectives
Enterically
transmitted
“Infectious” A E
Viral hepatitis
NANB
Parenterally
transmitted
“Serum” B D C
F, G, TTV
? other 2

3. Type of Hepatitis A B C D E Source of feces blood/ blood/ blood/ feces
virus
blood-derived
blood-derived
blood-derived
body fluids
body fluids
body fluids
Route of
fecal-oral
percutaneous
percutaneous
percutaneous
fecal-oral
transmission
permucosal
permucosal
permucosal
Chronic no
yes
yes
yes no
infection
Prevention
pre/post-
pre/post-
blood donor
pre/post-
ensure safe
exposure
exposure
screening;
exposure
drinking
immunization
immunization
risk behavior
immunization;
water
modification
risk behavior
modification 3

4. Hepatitis A Virus 6

5. HEPATITIS A: signs and symptoms
Nausea and vomiting, anorexia, jaundice
Self limited
No chronic disease
Stool excretion 2 weeks before and 1 week after appearance

6. 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

7. Hepatitis A Infection Typical Serological Course Total anti-HAV Titre
Symptoms
Titre
ALT
Fecal
HAV
IgM anti-HAV 1 2 3 4 5 6 12 24
Months after exposure 9

8. Hepatitis A Virus Transmission
Close personal contact (e.g., household contact, sex contact, child day care centers)
Contaminated food, water (e.g., infected food handlers, raw shellfish)
Blood exposure (rare) (e.g., injecting drug use, transfusion) 11

9. Global Patterns of Hepatitis A Virus Transmission
Disease
Peak Age
Endemicity
Rate
of Infection
Transmission Patterns
High
Low to
Early
Person to person;
High
childhood
outbreaks uncommon
Moderate
High
Late
Person to person;
childhood/
food and waterborne
young adults
outbreaks
Low
Low
Young adults
Person to person;
food and waterborne
outbreaks
Very low
Very low
Adults
Travelers; outbreaks
uncommon 15

11. Laboratory Diagnosis
Acute infection is diagnosed by the detection of HAV-IgM in serum by EIA.
Past Infection i.e. immunity is determined by the detection of HAV-IgG by EIA.

12. Hepatitis A Vaccination Strategies
Epidemiologic Considerations
Many cases occur in community-wide outbreaks
no risk factor identified for most cases
highest attack rates in 5-14 year olds
children serve as reservoir of infection
Persons at increased risk of infection
travelers
homosexual men
injecting drug users 18

13. Hepatitis A Prevention - Immune Globulin
Pre-exposure
travelers to intermediate and high HAV-endemic regions
Post-exposure (within 14 days)
Routine
household and other intimate contacts
Selected situations
institutions (e.g., day care centers)
common source exposure (e.g., food prepared by infected food handler) 27

14. VIRAL HEPATITIS
HEPATITIS B

15. Hepatitis B Virus 28

16. Hepatitis B - Clinical Features
Incubation period: Average days
Range days
Clinical illness (jaundice): <5 yrs, <10% yrs, 30%-50%
Acute case-fatality rate: 0.5%-1%
Chronic infection: <5 yrs, 30%-90% immunocompetent 5 yrs, 1%-5%
Premature mortality from chronic liver disease: 15%-25% 29

17. Spectrum of Chronic Hepatitis B Diseases
1Chronic Persistent Hepatitis - asymptomatic
2. Chronic Active Hepatitis - symptomatic exacerbations of hepatitis
3. Cirrhosis of Liver
4. Hepatocellular Carcinoma

18. Hepatitis B ACUTE CHRONIC- 5-10% <6 months (infection >6months)
Every year 1 to 2 million people die due to an infection by this virus
complications of chronic hepatitis

19. Endemicity

20. Global Patterns of Chronic HBV Infection
High (>8%): 45% of global population
lifetime risk of infection >60%
early childhood infections common
Intermediate (2%-7%): 43% of global population
lifetime risk of infection 20%-60%
infections occur in all age groups
Low (<2%): 12% of global population
lifetime risk of infection <20%
most infections occur in adult risk groups 35

22. Acute Hepatitis B Virus Infection with Recovery
Typical Serologic Course
Symptoms
HBeAg
anti-HBe
Total anti-HBc
Titre
anti-HBs
HBsAg
IgM anti-HBc 4 8 12 16 20 24 28 32 36 52
100
Weeks after Exposure 30

23. Progression to Chronic Hepatitis B Virus Infection
Typical Serologic Course
Acute
(< 6 months)
Chronic
(>6 months)
HBeAg
anti-HBe
HBsAg
Total anti-HBc
Titre
IgM anti-HBc 4 8 12 16 20 24 28 32 36 52
Years
Weeks after Exposure 31

24. Outcome of Hepatitis B Virus Infection
by Age at Infection
100
100 80
Chronic Infection (%) 80 60 60
Chronic Infection
Symptomatic Infection (%) 40
Chronic Infection (%) 40 20 20
Symptomatic Infection
Birth
1-6 months
7-12 months
1-4 years
Older Children
and Adults
Age at Infection 34

25. Interpretation of Serologic Tests in Hepatitis B+

26. Viral Hepatitis and Serology
Type of Viral Hepatitis
Positive Virology
Acute HBV
HBsAg, HBeAg, HBcAb IgM
Acute HBV, windows period
HBcAb IgM
Chronic active HBV
HBsAg, HBeAg, HBcAb IgG
Recovery HBV
HBsAb IgG, HBcAb IgG, Normal ALT
Immunized HBV
HBsAb IgG

27. Serological Marker Hep B
1) HBsAg (Hepatitis B surface antigen):
if positive, person is infectious
Sensitivity = 0.15 ng/ml
Specificity = 99.5%
2) Anti-HBs (Antibody to HBV surface antigen):
indicates immunity to HBV and protection from disease
Protective level is >10 IU/ml

28. Serological Markers Hep B
3) Anti - HBc (Antibody to HBV core antigen):
Total - indicates past or active infection; present whether person is immune or chronic carrier
Specificity = 99.8% to 99.9%
IgM - early indicator of acute infection
No antigen test

29. Serological Marker Hep B
4) HBeAg (Hepatitis Be antigen):
indicates person is highly infectious
Selecting patients for therapy
5) Anti-HBe (Antibody to HBVe antigen):
prognostic for resolution of infection; less infectious; spontaneous seroconversion in 10 to 20% of healthy adults per year

30. Serologic markers – caveats: Precore or HBeAg negative mutants:
Due to mutation in precore (abolishes HBeAg production) or core promoter region (down-regulates HBeAg production)
No effect on viral replication (may be enhanced)
More difficult to treat; greater risk of cirrhosis
Co-infection with HCV may suppress both HBeAg and HBsAg

31. Serologic markers – caveats:
Persistent HBsAg for >6 mos = chronic infection
HBsAg and anti-HBs may co-exist in up to 24% of chronically infected individuals; likely due to mutations in the “a” determinant of the S gene
Surface antigen escape mutants described in infants infected with HBV after HBIG + vaccination and in Liver transplants after prolonged HBIG
Anti-HBc IgM may persist for up to 2 years in 20%; chronically infected individuals may have low titres which rise during acute flares

32. Hepatitis B – Laboratory Tests
Serologic markers – caveats:
Isolated HBcAb may be due to:
Remote infection (immune or chronic carrier)
“Window” period between HBsAg and HBsAb
Co-infection with HCV
False positive test result – HBcAb is marker most prone to false positives
HBV DNA may help sort this out

33. Concentration of Hepatitis B Virus in Various Body Fluids
Low/Not
High
Moderate
Detectable
blood
semen
urine
serum
vaginal fluid
feces
wound exudates
saliva
sweat
tears
breastmilk 1 1 1

34. Hepatitis B Virus Modes of Transmission
Sexual - sex workers and homosexuals are particular at risk.
Parenteral - IVDA, Health Workers are at increased risk.
Perinatal - Mothers who are HBeAg positive are much more likely to transmit to their offspring than those who are not. Perinatal transmission is the main means of transmission in high prevalence populations. 2 2 2

35. Diagnosis
A battery of serological tests are used for the diagnosis of acute and chronic hepatitis B infection.
HBsAg - used as a general marker of infection.
HBsAb - used to document recovery and/or immunity to HBV infection.
anti-HBc IgM - marker of acute infection.
anti-HBcIgG - past or chronic infection.
HBeAg - indicates active replication of virus and therefore infectiveness.
Anti-Hbe - virus no longer replicating. However, the patient can still be positive for HBsAg which is made by integrated HBV.
HBV-DNA - indicates active replication of virus, more accurate than HBeAg especially in cases of escape mutants. Used mainly for monitoring response to therapy.

36. Treatment
Interferon (PEGinterferon-2α) , - for HBeAg +ve carriers with chronic active hepatitis. Response rate is 30 to 40%.
Lamivudine - a nucleoside analogue reverse transcriptase inhibitor. Well tolerated, most patients will respond favorably. However, tendency to relapse on cessation of treatment. Another problem is the rapid emergence of drug resistance.
Entecavir and Adefovir
Successful response to treatment will result in the disappearance of HBsAg, HBV-DNA, and seroconversion to HBeAg.

38. Prevention
Vaccination - highly effective recombinant vaccines are now available. Vaccine can be given to those who are at increased risk of HBV infection such as health care workers. It is also given routinely to neonates as universal vaccination in many countries.
Hepatitis B Immunoglobulin - HBIG may be used to protect persons who are exposed to hepatitis B. It is particular efficacious within 48 hours of the incident. It may also be given to neonates who are at increased risk of contracting hepatitis B i.e. whose mothers are HBsAg and HBeAg positive.
Other measures - screening of blood donors, blood and body fluid precautions.

39. Complications Arthritis Glomerulonephritis Polyarteritis nodosa
Hepatocellular carcinoma

40. Hepatitis D Transmission: parenteral (intravenous drug use mostly)
Subviral satellite because it can propagate only in the presence of hepatitis B
coinfection superinfection
Transmission: parenteral (intravenous drug use mostly)
> 60% develop cirrhosis

41. Hepatitis D (Delta) Virus
 antigen
HBsAg
RNA 19 19 19

42. Hepatitis D Anti-HDV Total (IgG & IgM) available
Incubation time – similar to Hepatitis B
High titires of HDV antibodies indicate ongoing chronic infection
Treatment same as HBV
If acquired as superainfection in chronic HBV there is in severity of infection i.e fulminant hepatitis, chronic hepatitis with rapid progression to cirhosis

43. HBV - HDV Superinfection
Typical Serologic Course
Jaundice
Symptoms
Total anti-HDV
ALT
Titre
HDV RNA
HBsAg
IgM anti-HDV
Time after Exposure 23 23 23

44. Hepatitis D - Prevention
HBV-HDV Coinfection
Pre or postexposure prophylaxis to prevent HBV infection.
HBV-HDV Superinfection
Education to reduce risk behaviors among persons with chronic HBV infection. 25 25 25

45. Hepatitis C Affects each person differently No vaccine available
Many people have the virus and do not even know it
By blood transfusion and IV drug abuse
Intranasal cocaine use, piercing
Type 1 (most resistant) type II and III

46. Hepatitis C - Clinical Features
Incubation period: Average 6-7 wks
Range 2-26 wks
Clinical illness (jaundice): % (20-30%)
Chronic hepatitis: 70%
Persistent infection: %
Immunity: No protective antibody
response identified 8 8 8

47. Chronic Hepatitis C Infection
The spectrum of chronic hepatitis C infection is essentially the same as chronic hepatitis B infection.
All the manifestations of chronic hepatitis B infection may be seen, albeit with a lower frequency i.e. chronic persistent hepatitis, chronic active hepatitis, cirrhosis, and hepatocellular carcinoma.
Waxing and waning aminotransferases (ALT/AST)

48. Hepatitis C Virus Infection
Waxing and Waning ALT/AST
anti-HCV
Symptoms
Titre
ALT
Normal 1 2 3 4 5 6 1 2 3 4
Months
Years
Time after Exposure 10 10 10

49. Risk Factors Associated with Transmission of HCV
Transfusion or transplant from infected donor
Injecting drug use
Hemodialysis (yrs on treatment)
Accidental injuries with needles/sharps
Sexual/household exposure to anti-HCV-positive contact
Multiple sex partners
Birth to HCV-infected mother 11 11 11

50. Hepatitis C Dispelling Myths
Hepatitis C is not spread by:
Casual contact
Hugging/kissing
Sharing eating utensils and drinking glasses
Sneezing/coughing
Shaking hands
Sitting on a toilet seat

51. Prevention Never share drug equipment
Straws, bills, needles, syringes, water, filter, cooker, pipes etc…
Never share tooth brushes/razors or any personal hygiene articles that have blood on them (even tiny amounts).
Practice safer sex

52. Prevention
Always make sure new & sterilized equipment is being used for tattooing & piercing
Make sure ink for tattooing is not being shared
Do not touch dirty needles without proper equipment or following proper procedures

53. 14 14 14

54. Laboratory Diagnosis
HCV antibody - generally used to diagnose hepatitis C infection. Not useful in the acute phase as it takes at least 4 weeks after infection before antibody appears.
HCV-RNA - various techniques are available e.g. PCR and branched DNA. May be used to diagnose HCV infection in the acute phase. However, its main use is in monitoring the response to antiviral therapy.
HCV-antigen - an EIA for HCV antigen is available. It is used in the same capacity as HCV-RNA tests but is much easier to carry out.

55. Treatment Types 1 II and III Type I is resistant than II and III
Acute HCV –alfa- interferon for 6 months also type II and III
Chronic HCV –alfa interferon+ ribavirin or peginterferon +ribavirin
Type I use alfa interferon +Ribavirin for 1 year, Telaprevir, Betapravir
HAV and HBV vaccination.

56. Prevention of Hepatitis C
Screening of blood, organ, tissue donors
High-risk behavior modification
Blood and body fluid precautions 15 15 15

57. Complications Cryoglobulinemia
Membranoproliferative glomerulonephritis
Hepatocellular Carcinoma
Cirrhosis
Alfa interferon is contraindicated with major depression and organ transplant
Ribavirin contraindicated in pregnancy, avoid for 6 months after therapy

58. Treatment Alcoholics should stop for 1 month before starting treatment
Screen for hepatocellular carcinoma every 6 months
Inteferon S/E: flu like syndrome (malasia, HA, fever, myalgia) depression, myelosuppression (neutropenia, anemia)
Ribavirin S/E HA, fatigue, hemolysis

59. Hepatitis E Virus 26 26 26

60. Hepatitis E - Clinical Features
Incubation period: Average 40 days
Range days
Case-fatality rate: Overall, 1%-3% Pregnant women, %-25%
Illness severity: Increased with age
Chronic sequelae: None identified 27 27 27

61. Hepatitis E Virus Infection
Typical Serologic Course
Symptoms
ALT
IgG anti-HEV
Titer
IgM anti-HEV
Virus in stool 1 2 3 4 5 6 7 8 9 10 11 12 13
Weeks after Exposure 28 28 28

62. Epidemiologic Features
Hepatitis E -
Epidemiologic Features
Most outbreaks associated with faecally contaminated drinking water.
Several other large epidemics have occurred since in the Indian subcontinent and the USSR, China, Africa and Mexico.
In the United States and other nonendemic areas, where outbreaks of hepatitis E have not been documented to occur, a low prevalence of anti-HEV (<2%) has been found in healthy populations. The source of infection for these persons is unknown.
Minimal person-to-person transmission. 29 29 29

64. Prevention and Control Measures for Travelers to HEV-Endemic Regions
Avoid drinking water (and beverages with ice) of unknown purity, uncooked shellfish, and uncooked fruit/vegetables not peeled or prepared by traveler.
IG prepared from donors in Western countries does not prevent infection.
Unknown efficacy of IG prepared from donors in endemic areas.
Vaccine? 31 31 31

65. Hepatitis Virus – Molecular Tests
Molecular assays available as follows:
Commercial assays for HBV DNA and HCV RNA
In-house assays for HAV RNA & HDV RNA
No molecular assay for HEV RNA
HCV RNA & HBV DNA, plasma or serum must be separated from cells within 6 hrs and plasma can be stored at 4oC for several days or -70oC for long-term
No licensed tests for diagnostic purposes; all tests are for monitoring or donor screening
HCV RNA will be done in HIV or other immunocompromised patients if requested

66. Nucleic Acid Amplification Tests (NAAT) for Detection of RNA/DNA
Quantitation of RNA or DNA may be reported as copies/ml or IU/ml
Conversion factor for copies/ml to IU/ml is not the same for different assays measuring the same target or different targets
HBV DNA: 5.82 copies/IU
HCV RNA: PCR copies/IU; bDNA: 5.2 copies/IU
Coefficient of variation (COV) may range from 15 to 50%

67. HBV DNA in Clinical Practice
Routine monitoring on therapy to assess response to treatment
Every 3 months X years on oral agents
Every 1 month X 6-12 on PEG/IFN
Routine monitoring off therapy to estimate prognosis and to evaluate need for treatment
Every 6 –12 months normally
Diagnosis of occult HBV infection