1. HISTORICAL PERSPECTIVE
VIRAL HEPATITIS
HISTORICAL PERSPECTIVE A
“Infectious”
“Serum”
Viral hepatitis
Enterically
transmitted
Parenterally
other E
“NANB” B D C
Before the discovery of hepatitis A virus (HAV) and hepatitis B virus (HBV) during the 1960s and 1970s, patients with viral hepatitis were classified based on epidemiological studies as having either infectious (transmitted person to person by the fecal-oral route) or serum (transmitted by transfusion of blood products) hepatitis. When diagnostic tests for HAV and HBV infections were developed, HAV was found to be the major cause of infectious hepatitis and HBV was found to be the major cause of serum hepatitis. Hepatitis delta virus (HDV), discovered in 1977, is a defective virus requiring the presence of HBV in order to replicate. However, some patients with typical signs and symptoms of viral hepatitis did not have serologic markers of HAV, HBV, or HDV infection and were categorized based on epidemiological characteristics as having either parenterally transmitted non-A, non-B (NANB) hepatitis or enterically transmitted NANB hepatitis. Subsequently, two additional viruses were discovered: hepatitis C virus (HCV) and hepatitis E virus (HEV). HCV is the major cause of parenterally transmitted NANB and HEV is the major cause of enterically transmitted NANB hepatitis. In addition, some patients with typical signs and symptoms of acute viral hepatitis do not have serologic markers of any of these types of viral hepatitis and can be classified as having non-ABCDE hepatitis. New viruses might be discovered in patients with non-ABCDE hepatitis. 2

2. REPORTED CASES OF SELECTED NOTIFIABLE DISEASES PREVENTABLE BY VACCINATION, UNITED STATES, 2001
Hepatitis A
Hepatitis B
Pertussis
Meningococcal disease
H. influenzae, invasive
Mumps
Measles
Source: NNDSS, CDC
10,609
7,843
7,580
2,333
1,597
266
116
Despite the availability of highly effective vaccines and recommendations that have been in place for several years, there were more than 13,000 cases of hepatitis A reported and more than 8,000 cases of hepatitis B reported in 2000, making these diseases among the most frequently reported vaccine-preventable diseases in the United States.

3. HEPATITIS A VIRUS
This is an electron micrograph of HAV that causes hepatitis A. See the next slide for specifics about this virus.

4. HEPATITIS A VIRUS RNA Picornavirus Single serotype worldwide
Acute disease and asymptomatic infection
No chronic infection
Protective antibodies develop in response to infection - confers lifelong immunity
Hepatitis A is caused by HAV, a 27-nm ribonucleic acid (RNA) agent that is classified as a picornavirus. Only one serotype has been observed among HAV isolates collected from various parts of the world. HAV causes both acute disease and asymptomatic infection. HAV does not cause chronic infection. Total antibody to HAV develops in response to infection and confers lifelong immunity from future HAV infection.

5. HEPATITIS A - CLINICAL FEATURES
Jaundice by <6 yrs <10% age group: yrs %-50% >14 yrs %-80%
Rare complications: Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis
Incubation period: Average 30 days Range days
Chronic sequelae: None
The average incubation period for hepatitis A is 30 days, with a range of 15 to 50 days. Patients characteristically have abrupt onset of symptoms which can include fever, malaise, anorexia, nausea, abdominal discomfort, dark urine, and jaundice. The severity of clinical disease associated with HAV infection increases with increasing age; jaundice occurs among less than 10% of children younger than 6 years of age, 40%-50% of older children, and 70%-80% of adults. Complications of hepatitis A include fulminant hepatitis, in which the case fatality rate can be greater than 50% despite medical interventions such as liver transplantation; cholestatic hepatitis, with very high bilirubin levels that can persist for months; and relapsing hepatitis, in which exacerbations can occur weeks to months after apparent recovery. Chronic infection does not occur following HAV infection.

6. EVENTS IN HEPATITIS A VIRUS INFECTION
Clinical illness
Infection
ALT
IgM
IgG
Viremia
Response
HAV in stool
The diagnosis of acute HAV infection is confirmed during the acute or early convalescent phase of infection by the presence of IgM antibodies to HAV (IgM anti-HAV). IgM anti-HAV is generally present 5-10 days before the onset of symptoms and is no longer detectable in the vast majority of patients 6 months later. IgG anti-HAV, which also appears early in the course of infection, remains detectable for the lifetime of the individual and confers lifelong protection against infection. Commercial tests are available for the detection of IgM and total (IgM and IgG) anti-HAV in serum.
In infected persons, HAV replicates in the liver, is excreted in bile, and is shed in the stool. Peak infectivity occurs during the 2-week period before onset of jaundice or elevation of liver enzymes, when the concentration of virus in stool is highest. The concentration of virus in stool declines after jaundice appears. Children and infants can shed HAV for longer periods than adults, up to several months after the onset of clinical illness. Chronic shedding of HAV in feces does not occur; however, shedding can occur in persons who have relapsing illness. Viremia occurs soon after infection and persists through the period of liver enzyme (alanine aminotransferase [ALT]) elevation.
HAV RNA can be detected in the blood and stool of most persons during the acute phase of infection by using nucleic acid amplification methods, such as PCR, and nucleic acid sequencing has been used to determine the relatedness of HAV isolates. These methods, however, are available in only a limited number of research laboratories and are not used generally for diagnostic purposes. 1 2 3 4 5 6 7 8 9 10 11 12 13
Week

7. CONCENTRATION OF HEPATITIS A VIRUS
IN VARIOUS BODY FLUIDS
Feces
Serum
Body Fluids
Saliva
Urine
Feces can contain up to 108 infectious virions per milliliter and are the primary source of HAV. Viremia occurs during the preclinical and clinical phases of illness, and HAV has been transmitted by transfusion (before screening of blood and blood products for HAV was initiated) and by injection drug use. Virus has also been found in saliva and urine during the incubation period in experimentally infected animals, but transmission by saliva or urine has not been reported to occur.
100
102
104
106
108
1010
Infectious Doses per mL
Source: Viral Hepatitis and Liver Disease 1984;9-22
J Infect Dis 1989;160:

8. HEPATITIS A VIRUS TRANSMISSION
GLOBAL PATTERNS OF
HEPATITIS A VIRUS TRANSMISSION
Disease
Rate
Peak Age
of Infection
Transmission
Patterns
Endemicity
High
Low to high
Early childhood
Person to person;
outbreaks uncommon
Moderate
High
Late childhood/
young adults
Person to person;
food and waterborne
outbreaks
Low
Low
Young adults
Person to person;
food and waterborne
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 is generally poor, nearly all children have evidence of prior HAV infection. In these highly endemic areas, outbreaks rarely occur, but the frequency of clinically recognized disease due to HAV infection varies. In some areas, disease rates might be high because of the pervasiveness of the virus in the environment. 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. Because most of the population is susceptible to HAV infection in these industrialized countries, clinically apparent disease is recognized and outbreaks occur. In a few countries, primarily in Scandinavia, hepatitis A outbreaks are uncommon, and nearly all HAV transmission occurs among illegal drug users and travelers to high or intermediate endemic areas.
outbreaks
Very low
Very low
Adults
Travelers; outbreaks
uncommon

9. GEOGRAPHIC DISTRIBUTION OF HEPATITIS A VIRUS INFECTION
HAV infection prevalence is high or intermediate in the areas noted in red, blue, and green. Hepatitis A vaccine is recommended for persons who travel or work in these areas. Yellow indicates the areas where HAV infection prevalence is low (including the United States). HAV infection prevalence is very low in the areas shown in tan.
Note: This slide has been generalized from available data.

10. HEPATITIS A, UNITED STATES
Most disease occurs in the context of community-wide outbreaks
Infection transmitted from person to person in households and extended family settings
- facilitated by asymptomatic infection among children
Some groups at increased risk
specific factor varies
do not account for majority of cases
No risk factor identified for 40%-50% of cases
In the United States, hepatitis A epidemiology can be divided into two periods, before and after about 1996, based on when hepatitis A vaccines became available and recommendations for their use were made. Before hepatitis A vaccines were used, most cases of hepatitis A resulted from person-to-person transmission in households and extended family settings during community-wide outbreaks. The most frequently reported source of infection was either household or sex contact with a person with hepatitis A. Transmission was facilitated by asymptomatic infections among children. During some of these outbreaks, a particular group at increased risk could be identified, such as users of injecting and noninjecting drugs or men who have sex with men. However, cases among persons in these groups did not account generally for the majority of cases. Approximately 50% of persons with hepatitis A did not have a source identified for their infection.

11. ACUTE HEPATITIS A CASE DEFINITION FOR SURVEILLANCE
Clinical criteria An acute illness with:
discrete onset of symptoms (e.g. fatigue, abdominal pain, loss of appetite, intermittent nausea, vomiting), and
jaundice or elevated serum aminotransferase levels
Laboratory criteria
IgM antibody to hepatitis A virus (anti-HAV) positive
Case Classification
Confirmed. A case that meets the clinical case definition and is laboratory confirmed or a case that meets the clinical case definition and occurs in a person who has an epidemiologic link with a person who has laboratory-confirmed hepatitis A (i.e., household or sexual contact with an infected person during the days before the onset of symptoms).
Trends in acute viral hepatitis can be monitored through cases reported to surveillance systems using a standard case definition. The surveillance case definition for acute hepatitis A includes both clinical and laboratory criteria. The clinical criteria consist of an acute illness with discrete onset of symptoms AND presentation of jaundice OR elevated liver enzymes. The laboratory criterion is IgM anti-HAV positivity. In addition, the case definition can be met if the person meets the clinical criteria and had an epidemiological link with a person who has laboratory-confirmed hepatitis A (i.e., household or sex contact with an infected person during the days before the onset of symptoms). All patients who meet this case definition should be reported to the local or state health department. Case reports of acute hepatitis A are then transmitted weekly by state health departments to CDC via the National Electronic Telecommunications System for Surveillance (NETSS).

12. REPORTED CASES OF HEPATITIS A,
UNITED STATES,
In general, the incidence of hepatitis A in the United States has been cyclic, with nationwide increases occurring every 10 to 15 years (the last peak occurred in 1995). Hepatitis A vaccine, licensed in 1995, is now used in hepatitis A childhood immunization programs in certain parts of the United States. Hepatitis A rates have been declining since 1995, and since 1998 have been at historically low levels. The wider use of vaccine is probably contributing to this marked decrease in hepatitis A rates in the United States.
Source: NNDSS, CDC

13. DISEASE BURDEN FROM HEPATITIS A UNITED STATES, 2001
Number of acute clinical cases reported
10,609
Estimated number of acute clinical cases
45,000
Estimated number of new infections
93,000
Because of under-reporting of cases and asymptomatic or unrecognized infection, many more HAV infections occur than are reported each year in the United States. In 2001, there were 10,609 cases reported, but after accounting for under-reporting, an estimated 45,000 acute clinical cases occurred. An estimated total of 93,000 new infections occurred, including asymptomatic infections. According to the Third National Health and Nutrition Examination Survey (NHANES III) conducted during , about one third (31.3%) of the U.S. population has serologic evidence of ever having had HAV infection.
Percent ever infected
31.3%

14. INCIDENCE OF HEPATITIS A BY AGE GROUP IN STATES WHERE VACCINATION IS
RECOMMENDED & CONSIDERED,
Historically, the highest rates were reported among children, adolescents and young adults. Approximately one third of reported cases involved children less than 15 years of age. Since 1998, rates have declined in all age groups.

15. HEPATITIS A RATES, BY RACE/ETHNICITY; 1994 Race/Ethnicity
Rate (per 100,000)
130
121.2
120
110 30
Historically, hepatitis A incidence varied by race/ethnicity, as illustrated here. The highest rates occurred among Native Americans/Alaska Natives and the lowest rates among Asians; rates among Hispanics were higher than among non-Hispanics. Racial/ethnic differences in rates most likely reflected differences in risk factors for infection, such as socioeconomic levels and resultant living conditions (e.g., crowding) and more frequent contact with persons from countries where hepatitis A is endemic (e.g., Mexico and Central America).
20.7 20
10.3 10
5.5
6.4
4.6
Total
Asian
non-Hispanic
non-Hispanic
Hispanic
Native American/
Alaska Native
Black
White
Race/Ethnicity

16. NUMBER OF YEARS REPORTED INCIDENCE OF HEPATITIS A EXCEEDED 10 CASES PER 100,000,
BY COUNTY,
Over the past several decades, the highest rates of hepatitis A have occurred in a limited number of states and counties in the United States. This marked variation of hepatitis A rates from 1987 through 1997 is illustrated on this slide. During this period, the hepatitis A rate in each U.S. county indicated in red exceeded the approximate U.S. average of 10 cases/100,000. It can be seen also that in most counties in the western U.S. during this period , the rate was higher then the average U.S. rate.

17. 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)
Blood exposure (rare) (e.g., injection drug use, rarely by transfusion)
Transmission of HAV generally occurs when susceptible persons put anything in their mouths that has been contaminated with the feces of an infected person. Close personal contact is the most common mode of HAV transmission, as demonstrated by infections among household and sex contacts of persons with hepatitis A and among children in day-care center outbreaks. Contaminated food and water can also serve as vehicles of HAV transmission. HAV transmission can occur when an infected food handler directly handles uncooked or cooked foods. Outbreaks have also been reported in association with foods contaminated before wholesale distribution, such as fresh vegetables contaminated at the time of harvesting or processing. HAV transmission can occur as a result of blood exposures such as injecting drug use or blood transfusion because viremia can occur prior to the onset of illness in infected persons. Screening of blood products for HAV has essentially eliminated the already extremely low risk associated with transfusion.

18. RISK FACTORS ASSOCIATED WITH
REPORTED HEPATITIS A,
, UNITED STATES
From 1990 through 2000, the most frequently reported source of infection was personal contact (household or sex) with an infected person (14%). Two percent of cases involved a child or employee in day-care; 6% of cases were a contact of a child or employee in day-care; 5% of cases reported recent international travel; and 4% of cases reported being part of a recognized foodborne outbreak. Injection drug use was a reported risk factor in 6% of cases; men who have sex with men represented 10% of cases. Forty-six percent of reported hepatitis A cases could not identify a risk factor for their infection.
Note: Risk factor percentages rounded to nearest percent
Source: NNDSS/VHSP

19. 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.

20. PREPARATION OF INACTIVATED HEPATITIS A VACCINES
Cell culture adapted virus grown in human fibroblasts
Purified product inactivated with formalin
Adsorbed to aluminum hydroxide adjuvant
In the United States, highly immunogenic and efficacious inactivated hepatitis A vaccines were first licensed in 1995 by the Food and Drug Administration (FDA). These vaccines are prepared by methods similar to those used for inactivated poliovirus vaccine. Cell culture-adapted virus is propagated in human fibroblasts, purified from cell lysates by ultrafiltration and exclusion gel chromatography or other methods, inactivated with formalin, and adsorbed to an aluminum hydroxide adjuvant.

21. 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 equivalent of one dose
The two inactivated vaccines licensed in the United States, HAVRIX® * (manufactured by GlaxoSmithKline) and VAQTA® * (manufactured by Merck & Co., Inc.), are highly immunogenic. Approximately 97%-100% of children, adolescents, and adults develop protective levels of antibody within 1 month after the first dose of vaccine; essentially 100% of vaccinees develop protective antibody with high geometric mean concentrations after completing the two-dose series. The vaccines are highly efficacious: In published studies, 94%-100% of children were protected against clinical hepatitis A after receiving the equivalent of one dose.
*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.

22. 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

23. HEPATITIS A VACCINES Recommended Dosages of Hepatitis A Vaccines
Age Volume 2-Dose Schedule
Vaccine (yrs) Dose (mL) (mos)
HAVRIX ® # (EL.U.*) , 6-12
>18 1, , 6-12
VAQTA ® ## (U**) , 6-18
> , 6-18
* EL.U. – Enzyme-linked immunosorbent assay (ELISA) units
** Units
# has 2-phenoxyethanol as a preservative
## has no preservative
Both HAVRIX® and VAQTA® should be administered intramuscularly into the deltoid. A needle length appropriate for the vaccinee’s age and size should be used. HAVRIX® is available in two formulations, and the formulation differs according to the person’s age: for persons 2-18 years of age, 720 EL.U. per dose in a two-dose schedule; and for persons greater than 18 years of age, 1,440 EL.U. per dose in a two-dose schedule. VAQTA® is also licensed in two formulations, and the formulation differs according to the person’s age: for persons 2-18 years of age, 25 U in a two-dose schedule; and for persons greater than 18 years of age, 50 U per dose in a two-dose schedule.

24. 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.

25. 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
Among adults and children, studies have demonstrated that detectable antibody persists for at least 5-8 years after completing the vaccination series. Although data regarding long-term efficacy are limited, no cases among vaccinated children were observed in one community at 5-6 years of follow-up. Estimates of antibody persistence derived from mathematical models of antibody decline indicate that protective levels of anti-HAV persist for at least 20 years. Whether other mechanisms such as cellular memory also contribute to long-term protection is unknown.

26. 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.

27. USE OF HEPATITIS A VACCINE FOR INFANTS
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
Hepatitis A vaccine is safe and immunogenic for infants who do not have antibody to HAV that was passively-transferred from a mother who had hepatitis A in the past. A number of studies of infants vaccinated according to different dosages and schedules have shown that the presence of passively-acquired maternal antibody blunts the immune response. 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. Although the age at which this passively-transferred antibody disappears is unclear, it is probably no longer detectable in most infants by 15 months of age. Currently, hepatitis A vaccines are not licensed by the FDA for children under 2 years of age.

28. COMBINED HEPATITIS A HEPATITIS B VACCINE
Approved by the FDA in United States for persons >18 years old
Contains 720 EL.U. hepatitis A antigen and
20 μg. HBsAg
Vaccination schedule: 0,1,6 months
Immunogenicity similar to single-antigen vaccines given separately
Can be used in persons > 18 years old who need vaccination against both hepatitis A and B
Formulation for children available in many other countries
Twinrix® is a combined hepatitis A and hepatitis B vaccine approved in 2001 by the Food and Drug Administration (FDA) for persons 18 years of age or older. Twinrix® contains 720 EL.U. of hepatitis A antigen and 20 μg of hepatitis B surface antigen.
Primary immunization consists of three doses, given on a 0-, 1-, and 6-month schedule, the same schedule as that used for single-antigen hepatitis B vaccine. Immunogenicity of the combined vaccine appears to be similar to that of the single-antigen vaccines when given separately.
Twinrix® can be used for immunization of persons 18 years of age or older who have indications for vaccination against both hepatitis A and hepatitis B, such as users of illicit injectable drugs, men who have sex with men, and persons with clotting factor disorders who receive therapeutic blood products. Formulation for children is available in many other countries.
For international travel, hepatitis A vaccine is recommended for travelers to areas of high or intermediate hepatitis A endemicity (see slide 10). Hepatitis B vaccine is recommended for travelers to areas of high or intermediate hepatitis B endemicity who plan to live or work for at least 6 months in highly endemic countries (see slide 9 in hepatitis B slide set at

29. PRE-VACCINATION TESTING
Considerations:
cost of vaccine
cost of serologic testing (including visit)
prevalence of infection
impact on compliance with vaccination
Likely to be cost-effective for:
persons born in high endemic areas
Older U.S. born adults
Older adolescents and young adults in certain groups (e.g., Native Americans, Alaska Natives, Hispanics, IDUs)
Antibody production in response to HAV infection results in lifelong immunity to hepatitis A and, presumably, to HAV infection. Vaccination of a person who is immune because of prior infection does not increase the risk of adverse events. In populations that are expected to have high rates of prior HAV infection, prevaccination testing might be considered to reduce costs by avoiding vaccination of persons who have prior immunity. Testing of children is not indicated generally because of their expected low prevalence of infection. For adults, the decision to test should be based on the expected prevalence of immunity, the cost of vaccination compared with the cost of serologic testing (including the cost of an additional visit), and the likelihood that testing will not interfere with initiating vaccination. For example, if the cost of screening (including laboratory and office visits) is one third the cost of the vaccine series, then screening potential recipients in populations where the prevalence of infection is likely to be greater than 33% should be cost-effective.
Persons for whom prevaccination testing will likely be most cost-effective include adults who were born in or lived for extensive periods in geographic areas that have a high endemicity of HAV infection, older adolescents and young adults in certain population groups (i.e., Native Americans, Alaska Natives, and Hispanics), and adults in certain groups that have a high prevalence of infection (e.g., injecting drug users[IDU]). In addition, the prevalence might be high enough among all older U.S.-born adults to warrant prevaccination testing. Commercially available tests for total anti-HAV should be used for prevaccination testing. 24

30. POST-VACCINATION TESTING
Not recommended:
High response rate among vaccinees
Commercially available assay not sensitive enough to detect lower (protective) levels of vaccine-induced antibody
Post-vaccination testing is not indicated because of the high rate of vaccine response among adults and children. In addition, testing methods that have the sensitivity to detect low, but protective, anti-HAV concentrations after vaccination are not approved for routine diagnostic use in the United States. 25

31. 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)
IG is a sterile preparation of concentrated antibodies made from pooled human plasma. IG provides protection against hepatitis A through passive transfer of antibody. IG is 80%‑90% effective in preventing clinical hepatitis A when administered before exposure or early in the incubation period after exposure. IG can be used for pre-exposure prophylaxis for travelers to areas of high or intermediate endemicity of hepatitis A, particularly when the planned departure is less than 2-4 weeks later. In this situation, immunity from vaccination might not have developed by the time of departure. Post-exposure prophylaxis with IG is effective if administered within 14 days of exposure. The primary routine indication for post-exposure prophylaxis is for household or other intimate contacts of persons with hepatitis A. In addition, post-exposure prophylaxis might be indicated when hepatitis A cases occur in some institutional settings (e.g., child day-care centers) and after some common source exposures (e.g., persons who ate food prepared by an infected food handler). Local and/or state health departments should be consulted regarding the use of IG for post-exposure prophylaxis in these settings.

32. ACIP RECOMMENDATIONS FOR PREVENTION OF
HEPATITIS A USING HEPATITIS A VACCINE
Inactivated hepatitis A vaccines were first licensed by the FDA and available in the United States in Since then, the Advisory Committee on Immunization Practices (ACIP), as well as the American Academy of Pediatrics and other professional organizations, have made recommendations for use of the vaccine.

33. HEPATITIS A VACCINATION RECOMMENDATIONS: GUIDING PRINCIPLES
Need comprehensive strategy to reduce overall rates
Routine vaccination of children likely to be most effective
Need creative approaches
Formulation not available that would allow integration into infant schedule
The recommendations for hepatitis A vaccination are based on several guiding principles. To reduce overall hepatitis A incidence, it was felt that a comprehensive strategy was needed and that routine vaccination of children should be the cornerstone of this strategy. Herd immunity could play an important role in extending the effects of hepatitis A vaccination of young children to older children and to adults.
Creative approaches, however, were needed because hepatitis A vaccine is not licensed for use in children under 2 years of age, which is the age group in which we generally administer routine vaccinations to children in the United States.

34. INCREMENTAL IMPLEMENTATION OF ROUTINE HEPATITIS A VACCINATION OF CHILDREN
Children living in communities with the highest rates
1999- Children living in states/communities with consistently elevated rates during “baseline period”
All children nationwide
Thus, the ACIP recommendations for routine vaccination of children built on the epidemiology in an incremental fashion, starting with areas in which the disease burden was greatest. In 1996, the ACIP recommended routine vaccination of children living in communities with historically the highest rates, such as Native American and Alaska Native communities.
In 1999, the ACIP took another incremental step, recommending routine vaccination of children living in areas with consistently elevated rates during a defined baseline period.
The third step will be to vaccinate all children nationwide.

35. Reported Hepatitis A Cases, By Year Northern Plains Indian Reservation† South Dakota, 1968-2002
Vaccination program*
Historically, Native American communities had among the highest rates of hepatitis A. Epidemics of hepatitis A typically occurred every 5-10 years and lasted for several years. This slide shows this cyclic pattern on a Northern Plains Indian reservation in South Dakota. The last outbreak occurred in 1991; another outbreak was expected to occur in the mid 1990s. However, a vaccination program among children and adolescents 2-12 years of age was started in 1995 and vaccination of young children has been ongoing since that time. These vaccination efforts appear to have been effective in preventing the anticipated hepatitis A outbreaks. **
* Estimated first dose coverage (children 2-12 years) = 71%
** Preliminary data
† Counties: Bennett, Corson, Dewey, Jackson, Roberts, Shannon, Todd, Ziebach
* † Source: South Dakota Department of Health

36. HEPATITIS A INCIDENCE UNITED STATES AND NATIVE AMERICANS 1990-2001
Vaccine Licensed
Native American
ACIP Recommendation
United States
Historically, the overall national incidence among Native Americans and Alaska Natives was 6-10 times higher than the average rate in the United States. An unprecedented decline in incidence began in the mid-1990s and, for the first time ever, beginning in 1998, the rate among Native Americans and Alaska Natives fell below the average U.S. rate.
Source: NNDSS, CDC

37. 1999 RECOMMENDATIONS FOR HEPATITIS A VACCINATION OF CHILDREN STRATEGY
Further incremental step
Not the same everywhere in the country
Regional recommendations using rate-based criteria during a “baseline period”
Flexible implementation strategies
Children or adolescents
One or more single age cohorts
Selected settings, e.g., day-care
Despite the apparent successes among populations in which children were being vaccinated routinely, there was little apparent impact of this policy on overall rates in the United States because disease in the groups for which vaccination was recommended accounted for a small proportion of cases nationwide. Thus, in 1999 the ACIP took another incremental step in extending its recommendations for routine hepatitis A vaccination of children. These updated recommendations reflect the remarkable geographic variation in hepatitis A rates (see slide 42) and thus are not the same everywhere in the country. Rather, there are different recommendations for different regions, based on average incidence rates during a baseline period ( ) before the recommendations were made. Flexible implementation strategies could be used that focus on children or adolescents, one or more single age cohorts, or vaccination in selected settings (e.g., day-care).

38. INCIDENCE OF HEPATITIS A BY REGION,
UNITED STATES,
Baseline
For the purposes of vaccination recommendations, three U.S. regions were defined based on historical epidemiological patterns: areas with consistently low rates of disease, areas with moderately elevated rates, and areas with consistently elevated rates over more than a 30-year period.
Because the epidemiological pattern of each region did not change over time, but considerable year-to-year fluctuations in rates occurred within each region, the average rate between 1987 and 1997 was chosen as the baseline period by which to define the regions. ACIP defined states with consistently elevated rates of hepatitis A as those with greater than or equal to an average of 20 cases per 100,000 during the baseline period. States with moderately elevated rates were defined as those with rates between 10 and 20 cases per 100,000; states with low rates were defined as those with an average of fewer than 10 cases per 100,000 during this baseline period.

39. 1999 ACIP RECOMMENDATIONS FOR ROUTINE
HEPATITIS A VACCINATION OF CHILDREN
Children Who Should be Routinely Vaccinated
- living in states, counties, and communities where the average hepatitis A rate was  cases/100,000 during baseline period.
Children Who Should be Considered for
Routine Vaccination
- living in states, counties, and communities where the average hepatitis A rate was <20 but  cases/100,000 during the baseline period.
The current ACIP recommendations, published in 1999, recommend that children living in areas where rates of hepatitis A were at least twice the national average; that is, greater than or equal to 20 cases per 100,000 during the baseline period ( ) should be routinely vaccinated.
The ACIP also recommends that routine vaccination be considered for children living in areas where rates of hepatitis A were greater than the national average but lower than twice the national average; that is, rates of at least 10, but fewer than 20 cases per 100,000 during the baseline period ( ).

40. 1999 ACIP RECOMMENDATIONS FOR STATEWIDE ROUTINE HEPATITIS A VACCINATION OF CHILDREN
Rate > 20/100,000*
Recommended
Rate 10-20/100,000*
Considered
Rate < 10/100,000*
Not statewide
This slide shows the states where the 1999 recommendations applied. Areas with consistently elevated rates during the baseline period, in which routine vaccination of children is recommended, included 11 states, mostly in the western United States. Areas in which routine vaccination of children should be considered included 6 states. Hepatitis A cases reported from these 17 states accounted for about 50% of cases during the baseline period and represented about one third of the U.S. population. No statewide recommendation for routine vaccination of children was made for the remaining states.
* Based on average incidence rate during baseline period ( )

41. Hepatitis A Incidence, United States,*
1995 vaccine licensure
1996 ACIP recommendations
1999 ACIP recommendations
2002 rate* = 2.9
This slide depicts hepatitis A incidence from 1980 to In 1995, hepatitis A vaccine was licensed by the FDA and became available in the United States. In 1996, the ACIP published the first national recommendations for vaccine use in hepatitis A prevention. These recommendations were updated and extended in Hepatitis A incidence has been falling, beginning in 1998, to below recorded historical lows, even compared with national hepatitis surveillance that was first begun in the 1960s. The provisional 2002 rate of 2.9 per 100,000 represents a 67% decline from the previously recorded lowest rate of 8.9 cases per 100,000 in 1983.
*2002 rate provisional

42. Incidence of Hepatitis A by U.S. Region, 1990-2002*
86%
89%
50%
With respect to the baseline period ( ) before any statewide recommendations for routine hepatitis A vaccination, the 2002 rate in states where routine vaccination is recommended declined by 86%. Rates declined by 89% in states where childhood vaccination is to be considered. Rates declined by 50% in states where there is no statewide recommendation for routine vaccination of children.
*2002 rate provisional

43. DOSES OF PEDIATRIC HEPATITIS A VACCINE PURCHASED BY PUBLIC SECTOR
BY U.S. REGION,
Since 1998, pediatric hepatitis A vaccine purchases in the public sector steadily increased, particularly in areas covered by the 1999 ACIP recommendations. By 2001, purchases reached 164 doses per 1,000 children in states where hepatitis A vaccination is recommended and 93 doses per 1,000 children in states where vaccination is to be considered. In 2002, a total of almost 3.5 million doses of pediatric hepatitis A vaccine were purchased by all states.

44. Summary of Hepatitis A Incidence by Region:
Baseline, 2001, and 2002
Rate/100,000
Baseline
2001
2002*
Recommended
25.9
4.5
3.6
Considered
16.1
3.8
1.8
No statewide
5.6
3.4
2.8
% Baseline Cases
% Cases 2001
This slide compares hepatitis A incidence by U.S. region and shows that declines have been concentrated in the areas of the country in which routine vaccination of children is occurring. The table shows the 86% decline, with respect to average baseline incidence, in states in which routine vaccination is recommended. In addition, the table shows, respectively, the 89% and 50% declines in states where vaccination is to be considered and in states where there are no vaccination recommendations. These declines are reflected in the distribution of reported cases. At baseline, for example, 48% of cases were reported from states in which routine vaccination is recommended, which includes 22% of the U.S. population. In 2002, the majority of cases are in states with no statewide recommendation.
*2002 rate provisional

45. Hepatitis A Incidence 1987-97 average incidence 2002 incidence
> = 20
5 - 9
0 - 4
Rate per 100,000
The change in incidence from the baseline period to 2002 can be seen dramatically in this state and county map of the United States. During the baseline period of , there were many counties, particularly in the west, with rates averaging 20 or more cases per 100,000. By 2002, there were few counties with rates of 5 or more cases per 100,000.

46. HIGHEST HEPATITIS A RATES
TOP 10 STATES WITH THE
HIGHEST HEPATITIS A RATES 7
Connecticut 33
Utah
Kansas 30
Washington 6
Maryland 24
Oklahoma
Massachusetts
South Dakota
Texas 21
Idaho 5
Florida
Nevada
California 20
Rhode Island 40
New Mexico 8
Arizona
Oregon 12
Georgia 45
Alaska 14
D.C. 48
Rate
Avg. rate
THEN
NOW
1987 -
1997
2001
A comparison of the 10 states with the highest average rates in the baseline period ( ) and in 2001 illustrates two points. First, the overall declines in hepatitis A rates can be appreciated: The 2001 rates, even in the states with the highest rates, are substantially lower than the rates during the baseline period. Second, most of the states on the 2001 list had historically low hepatitis A rates. Only two states, California and Arizona, are included on both lists, and the 2001 cases were no longer concentrated in the west and southwest.

47. HEPATITIS A RATE, BY AGE AND GENDER
UNITED STATES, 1990
Female
Male
Age
<5
10.1
11.9
5-9
26.7
26.7
10-14
17.7
17.2
15-19
12.8
14.1
20-24
16.1
20.4
25-29
15.8
22.2
30-34
11.4
17.7
35-39
7.9
13.5
40-44
In 1990, the largest proportion of cases occurred in children aged 5-14 years. Approximately the same number of cases occurred among males compared to females.
6.4
10.3
45-49
5.6
7.7
50-54
4.4
5.9
55-59
3.8
5.9
60+
2.8
3.4
Rate

48. HEPATITIS A RATE, BY AGE AND GENDER
UNITED STATES, 2001
Female
Male
Age
<5
2.2
2.5
5-9
4.7
4.7
10-14
3.5
3.6
15-19
2.8
3.4
20-24
3.8
6.3
25-29
3.6
7.5
30-34
2.8
9.3
35-39
2.3
8.7
40-44
2.1
6.1
Currently, most hepatitis A, albeit at lower rates than in previous years, is occurring among adults, as illustrated in this slide of 2001 incidence by age and gender. Incidence is particularly high among adult men. This is primarily a reflection of disease among adults in certain groups at increased risk, especially men who have sex with men and users of illicit drugs.
45-49
2.2
5.6
50-54
2.6
5.2
55-59
2.4
3.6
60+
2.4
2.8
Rate

49. Male : Female Rate Ratio
HEPATITIS A INCIDENCE BY GENDER,
UNITED STATES,
Male 18 2
Female 16
1.8
Ratio
1.6 14
1.4 12
1.2 10
Male : Female Rate Ratio
Cases per 100,000 1 8 \
0.8 6
0.6
Since 1996, the female to male ratio has increased, from 1:4 in to more than 1:8 in This ratio is primarily a reflection of an increasing number of cases associated with outbreaks among men who have sex with men and illegal drug users. 4
0.4 2
0.2
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
Year

50. ACIP RECOMMENDATIONS PERSONS AT INCREASED RISK OF INFECTION, 1996
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.

51. STD Treatment Guidelines MMWR May 10, 2002 51(RR06)
“Vaccination against hepatitis is the most effective means of preventing sexual transmission
of hepatitis A and B.”
The complete set of guidelines for the treatment of patients who have sexually transmitted diseases (STDs) were developed by CDC after consultation with a group of professionals knowledgeable in the field of STDs who met in Atlanta on September 26-28, Included in the guidelines is language that stresses that hepatitis A and hepatitis B vaccinations are critical in the care of men who have sex with men.

52. Integration of services for high-risk adults
Reports of converging epidemics (STD, HIV, hepatitis) impacting MSM, IDU, and others at risk
Integration of services that target MSM, IDU, and others at risk saves $$$ and improves services
As the previous slide noted, hepatitis A outbreaks have been reported for several years among MSM, IDUs and other groups at risk of viral hepatitis. Other diseases and infections among these populations have occurred over the last several years, as well. It makes good public health sense to integrate services for these populations; a “one-stop-shopping” approach that assures a more comprehensive level of care.

53. Lack of integrated prevention activities leads to…
Individuals infected with HIV, hepatitis and other STDs remain undiagnosed, untreated and uninformed
Infected and uninformed have higher levels of risky behavior and continue to transmit
Counseling is mistakenly based on limited diagnosis
and individuals at risk for HAV and HBV don’t get immunized
If integrated prevention services are lacking, individuals infected with HIV, hepatitis and other STDs will remain undiagnosed, untreated and uninformed. Uninfected and uninformed clients might have higher levels of risky behavior and could continue to transmit. A lack of integrated services increases the chance that counseling is mistakenly based on limited diagnosis and therefore inadequate counseling occurs. Subsequently, individuals at risk for HAV and HBV infections fail to get immunized.

54. HEPATITIS A IN THE UNITED STATES -2002
National rate lowest yet recorded
Continued monitoring needed to determine if low rates sustained and due to vaccination
Evaluation of age-specific rates to assess impact of vaccination strategy
Rates increasing in some states
Occurring among adults in high risk groups (e.g. MSM, drug users)
Hepatitis A rates in the United States reached their lowest level in Some of the decline is likely a reflection of the periodic fluctuations seen in hepatitis A incidence without any interventions. Continued surveillance is needed to determine the extent to which these low rates are due to hepatitis A vaccination. Hepatitis A rates have increased in some states, primarily among adults in high-risk groups, such as men who have sex with men (MSM) and illegal drug users, emphasizing the need for better strategies to provide vaccine to these high-risk adults.

55. HEPATITIS A VACCINATION IN THE UNITED STATES CHALLENGES FOR THE FUTURE
Continue implementation of the current recommendations for vaccination of children
Sustain vaccination in face of falling rates
Further reduce incidence
Vaccination of high-risk adults
Vaccination of children nationwide
Important challenges will be to sustain vaccination in the face of falling disease rates and to continue to improve hepatitis A vaccination coverage among children. Without ongoing vaccination, hepatitis A incidence rates in areas that historically had consistently elevated rates will return to pre-vaccination-era levels because the fundamental epidemiological characteristics that resulted in these elevated rates have not changed.
To further reduce incidence, we will need to do a better job of vaccinating adults in high-risk groups. Ultimately, vaccination of all children nationwide can be considered. This final incremental step would be facilitated by the availability of a vaccine that can be used in children younger than 2 years old and a combination vaccine that includes hepatitis A vaccine.