Transcript Prevention of Hepatitis A during outbreaks and post-exposure Paolo Bonanni Department of Public Health University of Florence, Italy.

Prevention of Hepatitis A
during outbreaks
and post-exposure
Paolo Bonanni
Department of Public Health
University of Florence, Italy
Hepatitis A: epidemiological patterns
Endemicity Age of infected
Risk groups
level
subjects
for clinical disease
High
< 5 years
Intermediate
5-15 years
Low
> 20 years
Children
Many
Contacts of
cases;
travellers;
drug users;
homosexuals
Outbreaks
Rare
Common: community-wide;
food-borne (shellfish); waterborne; close personal contact
Occasional: day-care
centers;
food-borne (shellfish);
water-borne;communitywide; close personal contact
Source: WHO, 1995 (modified)
Epidemiological shift in
seroprevalence of anti-HAV
Seroprevalence of
anti-HAV (%)
100
80
Improvement in
hygiene
60
40
20
0
10
20
30
Age (years)
40
50
(from Van Damme P, 1994)
Epidemiological changes of
hepatitis A infection
• Consequence of improved hygiene and sanitation,
better socio-economic situation, changes in family
size
• Reduced circulation of HAV at young age and
growing number of susceptibles in younger age
groups and adults
• End result is a higher possibility for outbreaks to
occur and a more severe disease since infection is
often acquired by adolescents and adults
Outbreak of hepatitis A in a canteen in
Genoa (Italy), 1993
Epidemiological investigation
Asymptomatic = 1
Primary cases = 52
Total no. of cases = 56
Symptomatic = 51
Secondary cases = 4
Total no. of anti-HAV negative employees = 468
(37% of all workers)
Attack rate = 11.1%
(Bonanni P et al., Abstracts IX Triennial International Symposium
on Viral Hepatitis. April 21-25, 1996, Rome, Italy, pp. 65)
Why is this old disease of growing
importance?
The exposure is changing due to:
– dining out culture
– preference for exotic food, fast food, etc.
– growing trend to send young children to day care
(at an earlier age)
 if we are not travelling to hepatitis A,
hepatitis A is travelling to us!
 Changing migration patterns
 increasing number of people on the move
Importation of hepatitis A
• Foreign born mobile populations and the children
born to first generation migrants are an increasing
population cohort in many European countries,
including Italy
• Immigrants residing in these countries visit
annually their country of birth
• their children born in low endemic countries
contract HAV on holiday in parents’ country
• these children cause secondary infections upon
their return
General measures for hepatitis A
prevention
• In household settings:
– good personal hygiene (hand washing practices)
– attention to proper food preparation
• At the community level
– provision of safe drinking water
– proper disposal of sanitary waste
– good hand washing practices among food
handlers and good food-handling techniques
– surveillance of water beds for shellfish
– control of the commercial distribution of
shellfish from unsupervised areas
Impact of general prophylaxis
measures on HAV epidemiology
Fundamental to reduce the overall
circulation of the virus, but often unable to
put outbreaks under control, especially in
situation of high promiscuity and common
use of toilet facilities by many people (e.g.
day care centres and closed communities)
Use of standard immune globulin
during hepatitis A outbreaks
Demonstration of about 85% efficacy in post-exposure
prophylaxis when given within 14 days after exposure
(Mosley JW et al., Am J Epidemiol 1968; 87: 539-550), but:
• Ig was often unable to stop community-wide
outbreaks, probably due to the limited time of
protection compared to the usual lenght of epidemics
• Ig is often difficult to obtain in stocks for use in the
population
• Ig are not well accepted because they are obtained
from human blood
• the concentration of anti-HAV in Ig has declined in the
last decades as a consequence of decreased viral
circulation
Effectiveness of human immune globulin
or vaccine in controlling outbreaks of
hepatitis A
Depends on:
• how well the community at risk is defined
• how high is the coverage achieved with the
intervention
• the efficacy of the intervention at the
individual level
• the phase of the outbreak when the
intervention is implemented
Impact of hepatitis A vaccine during
outbreaks
1) Public health perspective: ability of the
intervention to shorten the duration of the
outbreak, although cases may still occur in
vaccinees
2) Individual perspective: ability of vaccination
to avoid secondary infections in contacts of
cases
Experience of hepatitis A vaccination
during an outbreak in a nursery school
of Tuscany, Italy
- background • Start of the outbreak in late October, 1996 in a nursery
school located in a village of Tuscany, local health
district n. 11 (total population about 80,000 subjects)
• Yearly incidence of hepatitis A in the area 1985-1995:
2.5/100,000 population
• 41 children attended the nursery school
• Index case: child returning from Albania
• Confirmation of cases by detection of IgM anti-HAV
(Bonanni P. et al., Epidemiology and Infection 1998; 121: 377–380)
Experience of hepatitis A vaccination during
an outbreak in a nursery school
of Tuscany, Italy
- results • 11 cases (5 in children and 6 in household contacts)
detected by December 6, 1996
• Start of an immunisation programme without use of
immunoglobulin on December 7, 1996
• 33 schoolchildren (2 parents’ refusals), 11/36
cohabitant children, all 6 adult school-workers and
10/78 adult household contacts were vaccinated
• 2 vaccinated schoolchildren developed hepatitis A
5 and 7 days after immunisation, respectively
• 3 children vaccinated with unspecific gastroenetritis
turned to clear hepatitis A within few days
(Bonanni P. et al., Epidemiology and Infection 1998; 121: 377–380)
Experience of hepatitis A vaccination during
an outbreak in a nursery school
of Tuscany, Italy
- results and discussion • 2 cases of hepatitis A occurred among cohabitant
immunised children 7-10 days after a single dose of vaccine,
respectively
• All other children completed the vaccination course
• Last case of hepatitis A detected on February 7, 1997
• Overall number of cases detected: 11 in schoolchildren
(attack rate = 26.8%) and 10 in their household contacts
(attack rate on all cohabitants, irrespective of
susceptibility: = 9%)
• Two cases occurred in grandmothers of schoolchildren
• Role of vaccination in the extinction of the outbreak highly
likely
(Bonanni P. et al., Epidemiology and Infection 1998; 121: 377–380)
Large-scale hepatitis A vaccination during an
outbreak in Genoa, 1997 (1)
• First case of hepatitis A detected in an immigrant
child returning from a travel to his original country
• Another case occurred two weeks later in a child
attending the same nursery school of the index case
• Vaccination programme started immediately,
involving 26/29 children attending the school
• Two further cases occurred within 3 weeks in
contacts of previous cases who attended two other
schools
Bruzzone B.M., Abstracts of the 7th National Congress of Travel and Migration Medicine, 1999
Large-scale hepatitis A vaccination during an
outbreak in Genoa, 1997 (2)
• Vaccination was extended to children of 17 nursery
schools of the historical centre of the city (1453/2033 71% subjects -were immunized) and offered to
susceptible family members, teachers and school
operators
• Eight further cases occurred after vaccination: 5 in the
first school involved (3 in immunised children within 12
days, and 2 in non-vaccinated subjects) and 3 in the
second school involved (2 in vaccinees within 2 days
and 1 non immunised)
• One year later a new imported case occurred in one of
the school involved in the vaccination programme: no
further cases, in spite of several contacts
Bruzzone B.M., Abstracts of the 7th National Congress of Travel and Migration Medicine, 1999
Efficacy of hepatitis A vaccine in prevention of
secondary hepatitis A infection: a randomised trial
- background • Hepatitis A vaccine was used in susceptible family
contacts (age 1-40 years) of acute hepatitis A cases in a
trial performed in Naples in 1997
• Index cases were defined as IgM anti-HAV+ subjects with
primary infection, ALT ≥ twice the upper normal value
and hospitalised within 1 week of onset of symptoms
• Household contacts participating in the study were
randomly assigned to treatment (1 dose of HA vaccine) or
to no treatment according to the week of enrolment
• Their blood was drawn at time of enrolment and at day
14 and 45 of follow-up. IgM anti-HAV positive subjects at
day 0 and 14 were classified as co-primary cases
(Sagliocca et al., Lancet 1999; 353: 1136-1139)
Efficacy of hepatitis A vaccine in prevention of
secondary hepatitis A infection: a randomised trial
- results • Out of 356 eligible cases, 146 agreed to participate
• 351 their household contacts underwent blood tests
• All those assigned to the treatment group received a vaccine
dose within 8 days from onset of symptoms in index cases
(56% within 4 days)
• 132 contacts (37.6%) were already immune, and 9 were coprimary cases
• Hepatitis A vaccine showed a 79% protective efficacy (95%
c.i.: 7-95%) in the prevention of secondary hepatitis A when
households were considered
• Efficacy was 82% (95% c.i.: 20-96%) when household
contacts were analysed as independent participants
(Sagliocca et al., Lancet 1999; 353: 1136-1139)
Efficacy of hepatitis A vaccine in prevention of
secondary hepatitis A infection: a randomised trial
- considerations • Vaccination was required in 18 participants to prevent one
secondary infection (the number may vary according to
number of immune subjects)
• The study was stopped before reaching the foreseen sample
size (160 households in the two arms) because of ethical
considerations (demonstration of efficacy)
• The rate of non-participation to the study was higher in less
educated subjects, but this probably did not affect efficacy
• Efficacy may be underestimated (non-continuos exposure of
contacts due to hospitalisation of cases within 1 week of
disease onset)
(Sagliocca et al., Lancet 1999; 353: 1136-1139)
Problems and opportunities of use for hepatitis A
vaccine during outbreaks and post-exposure (1)
Problems
• No direct comparison between vaccine and immune globulin
during outbreaks or for the prevention of secondary cases has
been performed (it would require a large number of subjects).
Experimental studies of vaccine efficacy during outbreaks are
not available and would imply ethical problems should a notreatment group be included
• Since the data from the only clinical trial reported in the
literature regarded early identified contacts of cases,
prophylaxis based on vaccine use alone implies that systems
are in place for HAV cases to be detected rapidly so that
contacts can receive the vaccine within 7 days of exposure
• Vaccination during outbreaks has been sometimes successful
and sometimes delayed in its effects. The coverage in those at
higher risk is a crucial point for the success of the strategy
Problems and opportunities of use for hepatitis A
vaccine during outbreaks and post-exposure (2)
Opportunities
• Hepatitis A vaccine has been shown to be highly effective in
pre-exposure prophylaxis. The relatively long incubation
period of hepatitis A is the basis for its use during outbreaks
• The ‘number needed to treat’ with prophylaxis to prevent
one case (depending upon prevalence of susceptibility,
secondary attack rate following exposure, effectiveness of
intervention and rate of clinical disease in the age group
exposed) is less than 20 in adults (less than 10 if secondary
attack rate is ≥ 20). In children, the number is greater
(frequently asymptomatic infection)
• Hepatitis A vaccine offers long-time protection. Its effect
outlasts the outbreak and might be successfully followed by
the implementation of routine vaccination of children and/or
adolescents in the affected area
Effectiveness of hepatitis A in a former
frequently affected community - 9 years of
follow-up (Kiryas Joel community of Monroe, NY)
(Werzberger et al., Vaccine 2002; 20: 1699-1701)
• Efficacy field trial of hepatitis A vaccine performed in 1991
• Two epidemics, one lasting 3 years and the other 1.5 years
during the 6.5 years preceding the vaccine trial
• No case in any vaccine recipient later than day 16 after
vaccination
• Since 1991, 2-year olds routinely receive HA vaccine
• Pre-vaccination pattern of frequent epidemics has
disappeared, though sporadic cases were reported through
1997 in non-vaccinees
• Cases continued to be reported in 4 sister communities
sharing a special bus route up to the end of 1999-2000
Conclusions (1)
• Hepatitis A vaccine is one of the most immunogenic
vaccines available
• Its excellent efficacy in pre-exposure prophylaxis has
been documented by several studies
• Vaccination has been used in the course of outbreaks and
for the prevention of secondary cases.
• Active prophylaxis usually shortened the course of
outbreaks where coverage of a well-defined target
population was high
• No clinical trial on the effectiveness of HA vaccination
during outbreaks (in comparison with human normal
immune gloubulin) is available
• Although used in the past for post-exposure prophylaxis,
immune globulin preparations have probably decreased
their antibody concentrations, are difficult to get and are
not well accepted due to their origin from human blood
Conclusions (2)
• The only clinical trial of vaccine used for postexposure prophylaxis showed good efficacy (about
80%). Confidence intervals are wide, but high
numbers of subjects to be studied are very difficult
to obtain
• In communities experiencing recurrent epidemics
the use of vaccination seems also justified by the
high secondary attack rates and the consequent
acceptable cost-effectiveness profile
• However, in areas where hepatitis A represents a
public health problem, the implementation of
routine vaccination of children and/or adolescents
seems, in the long term, the most reasonable way to
put outbreaks under control
Summary of actions when an outbreak
occurs (“rapid is beautiful”)
1) Rapid identification of the source
2) Rapid identification of the population to be targeted by
vaccination (contacts of cases and people attending
institutions where infection has occurred)
3) Quick information campaign on the infection, the way it is
spread and the possibility of prevention by vaccination and
by good hygiene practices
4) Rapid creation of a task force in charge of the programme
5) Rapid administration of the first vaccine dose to the target
population
6) Maintenance of records of vaccinated people
7) Review of the campaign (initial number of cases, N°
immunised/target population, time to control the outbreak,
N° of cases in vaccinees and their timing, N° of boosters)