1. Viral Hepatitis

2. A large number of viruses can cause hepatitis (EBV, CMV, VZV, HSV, YF, Lassa virus … etc).
There are viruses, however, that only cause hepatitis.
At least five viruses, A through E, and two newly discovered viruses, GBV and TTV, are considered hepatitis viruses.

3. Viral Hepatitis 5 Major Identified Types: Vaccine Preventable
A: oral-fecal transmission
B: sexual fluids & blood to blood
C: blood to blood
D: acquired with B
E: oral-fecal transmission
Vaccine
Preventable
There are also other less common strains

4. Hepatitis viruses differ greatly in their taxonomy, structure, mode of replication and mode of transmission as well as in the course of the disease they cause.
Diseases caused by hepatitis viruses usually do not become clinically apparent until most or all of the liver is infected.
Furthermore, as hepatocytes are killed new cells are created to take their place.
These new cells provide a potentially endless reservoir for additional cycles of viral infection.

5. The specific course, nature and serology of the disease differ for each virus.
These viruses are readily spread because infected people are contagious before, or even without, showing symptoms.
Viral hepatitis has emerged as a major public health problem throughout the world affecting hundreds of millions.

6. Hepatitis A Virus 6

7. Hepatitis A
“Catarrhal jaundice” known to ancient Chinese, Greeks, and Romans.
First reference to “epidemic jaundice” in Minorca, 1745
Infectious hepatitis, a term that was coined in 1912 to describe the epidemic form of the disease.
The viral etiology was suggested in 1931, but the virus was first isolated in 1973 by Feinstone et al using IEM.

8. Pathogenesis and Pathology
Natural infection with HAV usually follows ingestion of virus in fecally contaminated food or drink.
The nature of the host cell receptor that determines tissue tropism has not been elucidated but replication takes place in gut epithelial cells and liver
The virus reaches the liver via the portal system and initiates a rapid acute infection prior to the onset of the immune response (hit and run strategy).
During the incubation period, viremia is observed at about the same time of fecal shedding of HAV which is excreted in bile to be shed in feces.

10. Fecal shedding is detected as early as days after exposure and continues until peak elevation of serum aminotransferases, which coincide with antibody detection.
Viremia is brief and terminates shortly after hepatitis develops whereas feces remain infectious for another 1-2 weeks.
HAV replicates slowly in the liver without causing apparent CPE.

11. Host immune response seems to play a major role in HAV pathogenesis.
Clinical manifestations resulting from damage to the liver occur when antibody is detected and a cell-mediated immune response to the virus occurs.
There is no evidence of extrahepatic site of replication.

12. Events In Hepatitis A Virus Infection1 2 3 4 5 6 7 8 9 10 11 12 13
Weeks
Response
Clinical illness
ALT
IgM
IgG
HAV in stool
Infection
Viremia

13. Pathologic Changes characteristic of HAV
Necrosis and mononuclear cell infiltration of the periportal region with acidophilic degeneration and activation of RE cells of the sinusoids and portal tracts resulting in marked hypertrophy and hyperplasia.
Less common conspicuous parenchymal changes than HBV, less occurrence of steatosis than HCV, and less occurrence of cholestasis than HEV
The damaged hepatic tissue is usually restored within 8-12 weeks.
Confluent hepatic necrosis is a rare potentially progressive lesion that may lead to fulminant hepatitis and death in up to 70% or more of cases.

14. Clinical Features
The course of viral hepatitis may be extremely variable.
Regardless of the etiology, the course of acute viral hepatitis is similar and can be divided into four clinical phases; incubation, prodrome, icterus and convalescence.
Incubation of HAV ranges from 2-6 weeks and is followed by a short prodrome or preicteric phase (2-7 days).
Symptoms usually appear coincident with the initiation of an immune response, as gauged by the appearance of IgM class molecules directed against viral structural proteins.

15. Patients may have a prodorme of viral type illness
Features of hepatitis gradually replace the prodromal illness after 2-7 days.
The urine darkens ad bilirubinuria increases and the stools may be noticeably pale.
Jaundice then develops, first seen in the sclera and later in the skin.
The fever resolves as jaundice becomes established.

17. At this stage, virus excretion ceases and the patient is no longer infectious.
Most patients feel better once the jaundice appears.
After a few days, the appetite returns and the jaundice begin to resolve.
Older children and adults often complain of right upper quadrant pain or discomfort which usually precedes jaundice by 1 to 2 weeks.

18. Fulminant hepatitis occasionally occurs in the first 6-8 weeks of illness
Ascites, a bleeding diathesis, and decerebrate rigidity lead to death in 70-90% of cases.
Mortality rate increases with age and survival is unlikely over the age of 45 years.
Clinical indicators of liver failure are persistent vomiting, rapid decrease in liver size, disturbed behavior, tremor of the outstretched hands and increasing drowsiness.

19. Poor cerebral function is classically demonstrated by showing the patient’s inability to copy a drawing of a five-pointed star, although he or she may be able to copy a square (constructional apraxia).
Hepatitis A commonly causes cholestasis with a rise in alkaline phosphatase to IU.
Occasionally, cholestasis is prolonged with deepening jaundice and severe pruritis persisting for months if untreated.

20. Resolution of uncomplicated viral A hepatitis is slow but patient recovery is complete.
Relapsing hepatitis occurs in 3-20% of cases within 4-15 weeks after resolution of initial symptoms. More than one relapse can occur.
The disease is milder in children and mortality is age related.
Two thirds of cases occur in children and 70% of deaths are in those above 49 years of age.

21. HAV: Clinical Usually mild, especially among children
Loss of appetite, nausea
Cigarette aversion
Abdominal discomfort
Fever to 38.5
Jaundice
Fulminant hepatitis rare
No chronic infection

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

23. Age Specific Mortality
Age group
Case-Fatality
(years)
(per 1000)
<5
3.0
5-14
1.6
15-29
1.6
30-49
3.8
>49
17.5
Total
4.1
Source: Viral Hepatitis Surveillance Program, 8

24. HEPATITIS A

25. HEPATITIS A

26. Laboratory Diagnosis Virus isolation PCR Serology
- Acute infection is diagnosed by the detection of HAV- IgM in serum by EIA.
- Past Infection (immunity) is determined by the detection of HAV- IgG by EIA.

27. Epidemiology
Approximately 40-60% of cases of acute hepatitis are caused by HAV
It is endemic throughout the world and hyperendemic in the developing countries.
Epidemics are common and they are common source epidemics.

28. Geographic Distribution of HAV Infection
[SLIDE 17, SLIDE 18] Global Patterns of Hepatitis A Virus Transmission, Geographic Distribution of HAV Infection*
Worldwide, four different patterns of HAV transmission can be defined on the basis of age-specific seroprevalence data. In general, these transmission patterns correlate with socioeconomic and hygienic conditions. In many developing countries where environmental sanitation generally is poor, nearly all children <9 years of age have evidence of prior HAV infection. In these areas, distinct outbreaks rarely occur and clinical disease related to HAV infection is uncommon. As hygienic conditions improve, transmission shifts to older age groups and the incidence of clinically evident disease increases. In most industrialized countries, low levels of endemic HAV transmission occur. The relatively high prevalence of prior HAV infection among older age groups in these areas is likely to be related to the presence of lower socioeconomic and hygienic conditions in the past. Because most of the population is susceptible to HAV infection, disease outbreaks are relatively common in most of these countries. However, in a few industrialized countries hepatitis A outbreaks are uncommon, and nearly all HAV transmission occurs among drug users and travelers to high endemic areas.
*(Note: The map of anti-HAV prevalence generalizes available data and patterns may vary within countries.)

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

30. Concentration of Hepatitis A Virus
in Various Body Fluids
Feces
Serum
Body Fluids
Saliva
Urine
100
102
104
106
108
1010
Infectious Doses per mL
Source: Viral Hepatitis and Liver Disease 1984;9-22
J Infect Dis 1989;160:

31. 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

32. PREVENTING HEPATITIS A
Hygiene (e.g., hand washing)
Sanitation (e.g., clean water sources)
Hepatitis A vaccine (pre-exposure)
Immune globulin (pre- and post-exposure)
Good hygienic practices and adequate sanitation are important elements in the prevention of HAV infection, particularly in the developing world. However, hepatitis A vaccine is the key component in the overall strategy to prevent HAV infection in the United States. Immune globulin is also available for pre-exposure and post-exposure prophylaxis.

33. Hepatitis A Vaccination Strategy: Epidemiologic Considerations
Many cases occur in community-wide outbreaks
no risk factor identified for 40-50% of cases
highest attack rates in 5-14 year olds
children serve as reservoir of infection
Groups at increased risk of infection
travelers to developing countries
men who have sex with men
illegal drug users
persons with chronic liver disease
[SLIDE 12] Hepatitis A Vaccination Strategy: Epidemiologic Considerations
Epidemiologic features of HAV infection that need to be considered in developing hepatitis A vaccination strategies include the following:
Most hepatitis A in the United States occur in the context of extended community-wide outbreaks in which a large proportion of cases have no identifiable risk factor. In these outbreaks, the highest rates of disease occur among children 5-14 years of age and person-to-person transmission, especially from children to adults, is the primary mode of transmission.
2. The primary groups with an increased risk of infection include the following:
Travelers to developing countries. The risk among such travelers who do not receive IG is about 3-5/1000 per month of stay. These persons should be vaccinated before departure. Persons can be assumed to be protected by 4 weeks after receiving the initial vaccine dose, although the second dose 6 to 18 months later is necessary for long‑term protection. Individuals who will travel to high‑risk areas <4 weeks after the initial dose of vaccine should also be given IG, but at different injection sites. Travelers to high‑risk areas who are allergic to a vaccine component or otherwise elect not to receive vaccine or children less than 2 years old should receive IG.
Men who have sex with men. Hepatitis A outbreaks among MSM have been reported frequently and serosurveys have demonstrated a prevalence of HAV infection among MSM several-fold higher than among control populations.
Illegal drug users. Cross-sectional serologic surveys have demonstrated that IDUs have higher anti-HAV seropositivity that the general US population. Transmission among IDUs likely occurs through percutaneous and fecal-oral routes, e.g., sharing needles, sharing contaminated “works” and having household or other close personal contact with infected persons.
Persons with chronic liver disease. Susceptible persons with chronic liver disease, including persons awaiting or having received liver transplants, may be at increased risk for complications of hepatitis A and should be vaccinated.

34. HEPATITIS A VACCINES Highly immunogenic
97%-100% of children, adolescents, and adults have protective levels of antibody within 1 month of receiving first dose; essentially 100% have protective levels after second dose
Highly efficacious
In published studies, 94%-100% of children protected against clinical hepatitis A after one dose

35. Duration of Protection after Hepatitis A Vaccination
Persistence of antibody: At least 5-8 years among adults and children
Efficacy: No cases in vaccinated children at 5-6 years of follow-up
Mathematical models of antibody decline suggest protective antibody levels persist for at least 20 years
Other mechanisms, such as cellular memory, may contribute

36. Use of Hepatitis A Vaccine for Infants
Hepatitis A vaccine is licensed only for persons aged 1
year and older
Safe and immunogenic for infants without maternal antibody
Presence of passively-acquired maternal antibody blunts immune response, all respond, but with lower final antibody concentrations
Age by which maternal antibody disappears is unclear
still present in some infants at one year
probably gone in vast majority by 15 months

37. RECOMMENDATIONS FOR PERSONS AT INCREASED RISK OF INFECTION
Men who have sex with men
Illegal drug users
International travelers
Persons who have clotting factor disorders
Persons with chronic liver disease
Periodic outbreaks among users of illicit drugs and men who have sex with men have been recognized in the United States, Canada, Europe, and Australia for many years. Since 1996, when the ACIP made the first recommendations for the use of hepatitis A vaccine, routine vaccination of persons at increased risk of infection or its consequences has been recommended. However, these recommendations have not been widely implemented. Hepatitis A vaccination is also recommended, instead of or in addition to IG for persons who travel to areas of high or intermediate hepatitis A endemicity (see slide 10). Other groups for whom hepatitis A vaccination is recommended include persons who have clotting factor disorders and persons with chronic liver disease because of the increased risk of more severe symptoms with hepatitis A.

38. HEPATITIS A VACCINE-(HAVRIX)
Dose:
>18 years old - 1 ml (1440 units), and
6-12 months later
2-18 years old ml (360 units), and
Side effects: Pain at injection site, fever, headache

39. HEPATITIS A VACCINE EFFICACY STUDIES
JAMA 1994;271:1363-4; N Engl J Med 1992;327:453-7
Vaccine
Site/
Age Group N
Vaccine Efficacy
(95 % Cl)
HAVRIX
(GSK)
2 doses
360 EL.U.
Thailand
1-16 yrs
38,157
94%
(79%-99%)
VAQTA Ò  
(Merck)
1 dose
25 units
New York
2-16 yrs
1,037
100%
(85%-100%) Ò
The efficacy of HAVRIX® * was evaluated in a double-blind, controlled, randomized clinical trial in Thailand among 38,157 children 1-16 years of age living in an area with high endemic rates of hepatitis A. Following two doses of vaccine (360 EL.U. per dose) given 1 month apart, the efficacy of vaccine in protecting against clinical hepatitis A was 94% (95% confidence interval [CI], 79%-99%). A double-blind, placebo-controlled, randomized clinical trial using VAQTA® * was conducted among 1,037 children 2-16 years of age living in a single U.S. community with a high rate of hepatitis A. Within 18 days following one dose (25 U) of vaccine, the efficacy in protecting against clinical disease was 100% (95% CI, 85%-100%).
*Use of trade names is for identification only and does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services. 17

40. SAFETY OF HEPATITIS A VACCINE
Most common side effects
Soreness/tenderness at injection site - 50%
Headache - 15%
Malaise - 7%
No severe adverse reactions attributed to vaccine
Safety in pregnancy not determined – risk likely low
Contraindications - severe adverse reaction to previous dose or allergy to a vaccine component
No special precautions for immunocompromised persons
Soreness at the site of injection is the most commonly reported side effect of hepatitis A vaccination (50%). Headache and malaise were reported by 15% and 7% of vaccinees, respectively.
Reviews of data from multiple sources for more than 5 years did not identify any serious adverse events among children or adults that could be definitively attributed to hepatitis A vaccine. The safety of the vaccine will continue to be assessed through ongoing monitoring of data from the Vaccine Adverse Events Reporting System (VAERS) and other surveillance systems.
The safety of hepatitis A vaccination during pregnancy has not been determined; however, because hepatitis A vaccine is produced from inactivated HAV, the theoretical risk to the developing fetus is expected to be low. The risk associated with vaccination should be weighed against the risk of hepatitis A in women who might be at high risk for exposure to HAV.
Hepatitis A vaccine should not be administered to persons with a history of a severe reaction to a dose of hepatitis A vaccine or allergy to a vaccine component. Because hepatitis A vaccine is inactivated, no special precautions are needed when vaccinating immunocompromised persons.

41. FACTORS ASSOCIATED WITH DECREASED IMMUNOGENICITY TO HEPATITIS A VACCINE
Decreased antibody concentration:
- Concurrent administration of IG
- Presence of passively-transferred maternal antibody
- Age
- Chronic liver disease
Decreased seroconversion rate:
- HIV infection (May be related to degree of
immunosuppression)
- Liver transplantation
The presence of anti-HAV at the time of vaccination appears to blunt the immune response. Administration of immune globulin (IG) concurrently with the first dose of hepatitis A vaccine did not decrease the proportion of adults who developed protective levels of antibody compared with adults who had been administered hepatitis A vaccine alone, but the geometric mean antibody concentrations (GMCs) among adults who received IG were lower 1 month after completion of the vaccination series than the GMCs of any adults who had been administered hepatitis A vaccine alone. The reduced immunogenicity of hepatitis A vaccine that occurs with concurrent administration of IG does not appear to be clinically significant. IG and hepatitis A vaccine can be given concurrently if indicated.
Reduced vaccine immunogenicity also has been observed in infants who had passively-transferred antibody because of prior maternal HAV infection and were administered hepatitis A vaccine according to a number of different schedules. In most studies, all infants developed protective levels of antibody, but the final GMCs were approximately 1/3 to 1/10 those of infants born to anti-HAV-negative mothers.
Based on limited data, final antibody concentrations might be lower among older vaccinated persons.
Vaccination of adults with chronic liver disease of viral or nonviral etiology produced seroprotection rates similar to those observed in healthy adults. Final antibody concentrations, however, were substantially lower for each group of patients with chronic liver disease than for healthy adults.
In some studies, administration of hepatitis A vaccine to persons with HIV infection resulted in lower seroprotection rates and antibody concentrations. Among HIV-infected men, those who responded to hepatitis A vaccination had significantly more CD4+ T lymphocytes at baseline compared with those who did not respond. Being HIV positive, however, is not a contraindication for administering hepatitis A vaccine if the person is in a risk group for whom hepatitis A vaccine is recommended.
In one small study, none of the 8 patients who had received a liver transplant responded to hepatitis A vaccination; however, liver transplantation is not a contraindication for administering hepatitis A vaccine.

42. 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