WP_CRP_ICP_BVM_020_eng (2.889Mo)

Transcription

(~P)CRP/ICP/BVM/020
REPORT
~IENTIFIC
l'
GROUP ON VIRAL HEPATITIS B AND ITS
RELATED LIVER DISEASES
Nagasaki, Japan
29 September - 2 October 1982
Not for sale
Printed and Distributed
by the
Regional Office for the Western Pacific of the
World Health Organization
Manila, Philippines
December 1982
)
Note
The views expressed in this report are those of the participants and
do not necessarily reflect the policy of the World Health Organization.
This report has been prepared by the Regional Office for the
Western Pacific of the World Health Organization for Governments of
Member States in the Region and for the participants of the Scientific
Group on Viral Hepatitis B and its Related Liver Diseases which was
held in Nagasaki, Japan, 29 September to 2 October 1982.
CON'l1ENTS
1.
INTRODUCTION .. .................................... ·i" .......................................... ..
1
2.
BACKGROUND INFORMATION .................. , ........................................ ,. .. ..
1
Hepatitis B infection in th! Region •••••••••••••••
1
Distribution of sub-types ........................ .
HBV and chronic liver diseafe ••••••••.•••••••••••.
3
4
HBV infection and primary i
hepatocellular carcinoma •• ~ ••••••••••.•.•••••.•.•.
5
DIAGNOSTIC TECHNIQUES FOR DETECT~NG
HEPATITIS B INFECTION .................. "I" ........ ,. .................................. ,.
7
Detection of HBsAg ••••••• ~ .••••••.•••••••••••.....
Production of reagents ••••.••••••.•••••••••••.••••
Quality control programmes I • • • • • • • • • • • • • • • • • • • • • • • •
9
10
COUNTRY OR AREA REPORTS .............. ~ .............................................. ..
10
2.1
2.2
2.3
2.4
3.
3.1
3.2
3.3
4.
........................... ......................... .
,.
4.1 China
4.2 Fiji
4.3 French Polynesia ••••••••• !••••••••••••••••••••••••
4.4 Hongkong •••••••••••••••• ·1' ........................... ..
4.5 Japan ...................................... •1""" ........................................ ..
4.6 Malaysia ,. . . . . . . . . . . . . . . . . . ""i . . . . . . . . . . . . . . . . . . . . . . . . . . ..
. . . . . . . . . . . . . . . . . . . . . . .
1. . . . . . . . . . . . . . . . . . . . . . . . . . . .
.
............... ............................... .
.............. ....................... .... .
4.7
New Caledonia
4.8 Philippines
"
"
4.9 Repub 1 ic 0 f Korea ................... ,. ••• ,.,. ... ,.,. ............... .
4.10 Singapore ........ ,..,. ............................. ,. •••
it • • • • • • • • • • • ,. . . . . . . . . . . oO_' .... .
4.11 Viet Nam ,. •••
~
oO . . . . oOoO • • • • • •
5.
THE IMPORTANCE OF
MATERNAL/INF~
PREVENTION OF MATERNAL/INFANT
7.
HEPATITIS B VACCINE
7.1
7.2
7.3
7.4
10
11
14
17
18
19
20
26
27
29
32
TRANSMISSION
OF HBV IN THE REGION ......... • 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ,. . . . .
6.
9
~RANSMISSION
.
.. ............ .
. . . . . . ,. • • • •1 . . . . . . . . . . . . . . . . . . " • • ,. • • • • •
34
34
35
Hepatitis B 22 particle ~accines ••••••••••••••••••
Polypeptide vaccines .•. j ......................... .
Alternative sources of H,sAg ••.•••••••••••.•••••••
Proposed requirements for the safety and
potency testing of hepat~tis B vaccines •••••••••••
37
C~IER
STATE •••••••••••••••
40
·············1···························
40
8.
ELIMINATION OF THE CHRONIC
9.
RECOMMENDATIONS
35
36
38
- ii -
ANNEX 1 - LIST OF MEMBERS, CONSULTANTS,
OBSERVERS AND SECRETARIAT ••••••••••••••••••••
43
ANNEX 2 - PROVISIONAL AGENDA •••••••••••••.•....•••.•.••
49
ANNEX 3 - OPENING SPEECH OF THE REGIONAL DIRECTOR ••••••
51
ANNEX 4 - APPROPRIATE WAYS AND MEANS OF ESTABLISHING
SUITABLE MECHANISMS FOR COLLABORATIVE
STUDIES IN HEPATITIS AND ITS RELATED
LIVER DISEASES •• ••• •••• •• •• • •• •• •••• •• •• • •• •
54
1.
INT~ODUCTION
I
The WHO stieutific Group on Vira~ Hepatitis B and Its Related Liver
Diseaae., wet in Nagasaki, Japan, fr~ 29 September to 2 October 1982. The
meetill& WaS ~ by the Regional Di?l'tor of the WHO RegiQnal Office for
the Western Pacific, Dr H. Nakajima, ~o welcomed the participants and
thanked the Japanese organizations whi~h had assisted in the preparation
and presentation of the meeting. Afte~ a further address of welcome by the
Preaident of Na,asaki University, Prof~ssor Fukumi, Dr Paik, operational
officer, explained its background and pbjective,.
At ita sbth Session in Manila inl198l, the Western Pacific Advisory
Committee on Medical Research had invi~ed Dr K. Nishioka of the Tokyo
Metropolitan Institute of Medical Scie~ces to address it on the topic of
hepatitis B. As a result, the WPACMR ~ad recommended that a meeting be
held to assess the extent of the problfm, to define areas which required
further research and to explore the st,ps needed to establish a regional
research programme. A Scientific Grou~ was accordingly convened by the
Regional Director.
I
The specific objectives of the
Gr~up
were:
(1) to review significant progre~s that has been made in the specific
diagnosis of viral hepatitis with a vi~w to standardizing the use of
specific screening procedures for mark1rs of hepatitis B infection on a
regional basis, which would make cross~ountry comparisons of data easier
and more meaningful;
(2) to review the incidence of a1d factors favouring perinatal
transmission of hepatitis B and its sigfificance in different areas of the
Region, and to discuss measures to int~rupt perinatal transmission of
hepatitis B surface antigen (HBsAg);
(3) to review the pathogenic rOlel of hepatitis B infection,
especially the persistent carrier state in chronic liver diseases such as
chronic hepatitis, liver cirrhosis and ~epatocellular carcinoma in the
Region;
(4) to recommend ways and means of establishing suitable mechanisms
for collaborative studies, aiming at ev,ntual reduction of chronic liver.
disease in tha .. ,ion.
The group elected Dr Nishioka, Cha~rman of the meeting,
Professor Chilli." Vice Chairman and prof,ssor Oon, Rapporteur.
I
2.
2.1
BACKGROUNI) INFORMATION
Hepatitie B infection in the Regi01
Hepatitis B infection is a major P~liC health problem in this region
of the world and is responsible for cons'derable morbidity and mortality.
The virus is hyperendemic in most countries in the Region and a large
- 2 -
proportion of the population are known to be chronic carriers. Many of
these people are suffering from or are likely to develop long term sequelae
such as chronic active hepatitis, liver cirrhosis or primary hepatocellular
carcinoma.
(1)
Chronic carriers of hepatitis B virus (HaV).
Of the estimated 215 million chronic carrie~s in the world,
approximately 168 million or 78% reside in Asia and the Western Pacific
(see Table 1)
Table 1.
Estimated number of carriers of HBV in the world
Region
Population
(millions)
Carriers of HBV
%
Number (millions)
Africa
441
6.0
26.5
United States of America
and Canada
338
0.5
1.8
South America
228
0.6
1.4
2 437
6.9
168.0
Europe
480
1.0
4.8
Oceania
22
2.0
0.4
320
4.0
12.8
Asia
Union Soviet Socialist
Republic
The most recent population estimates and carrier rates of some of the
major countries/areas in the WHO Western Pacific Region are shown in
Table 2.
- 3 -
Table 2.
Population and HB carrier rates in some countries in the Region
Population
(millions)
Australia
HVB carriers
(actual numbers)
15.0
0.1
15 000
933.0
8.9
82 666 000
4.6
9.6
442 000
114.9
2.7
3 102 000
Malaysia
12.3
9.4
1 139 000
Mongolia
1.5
12.2
192 000
Philippines
46.3
11.0
3 098 000
Republic of Korea
37.0
9.7
3 590 000
2.3
3.8
88 000
China
Hongkong
Japan
Singapore
2.2
HBV Carriers
(%)
Distribution of sub-types
Interesting differences in the pattern of distribution of the four
major sub-types of HBV exist throughout the Region. A recent map analysis
by Dr Nishioka and his colleagues shows three characteristic zones;
HBsAg/ayw is the predominant sub-type in West Asia (USSR, China
(Xinjiang), North India, Iran and Israel, and extends to the Mediterranean
and North, Central and Western Africa.
HBsAg/idr is found commonly in North-east Asia (the main islands of
Japan, Korea, the Han ethnic group in China, Lao People's Democratic
Republic, Thailand and Malaysia. Tamilnadu and Nepal are the border
between the adr and ayw zones.
HBsAg/adw is found in Okinawa and Amami Islands of Japan, China
(Taiwan), the Philippines, Indonesia, some parts of southern China, the
southwest coast of India, the east coast of Africa and coast of the islands
of the Pacific and Indian oceans.
- 4 -
Although the sub-types have proved extremely useful epidemiological
and anthropological markers, there is no evidence that they are associated
with important biological difference.. For practical purpose., infection
with anyone sub-type appears to produce immunity against each of the
others. This is particularly relevant as it suggests that a vaccine made
from a single sub-type may be effective throughout the Region.
3.1
HBV and chronic liver disease
Hepatitis B markers, particularly HBsAg, are detected more frequently
in patients with chronic liver disease such as chronic active hepatitis,
liver cirrhosis, and primary hepatocellular carcinoma than among age and
sex matched controls.
Table 3 shows the results of a WHO-sponsored collaborative study in
which standardized techniques were used to measure the prevalence of HBsAg
and antibody to hepatitis B surface antigen (anti-HBs) among patients with
liver disease and controls in the Western Pacific Region.
Table 3
Healthy adults
Subject with chronic liver
disease
HBsAg
(% )
anti-HBs
(% )
Total
(;0
HBsAg
(%)
anti-HBs
Total
(% )
(% )
Australia
0.5
2.3
2.8
8.1
2.5
10.&
China
3.1
34.6
37.7
27.6
28.2
55.8
12.2
43.3
55.5
63.3
16.7
80.0
Japan
2.7
18.4
21.1
29.6
13.2
42.8
Malaysia
5.2
20.6
25.8
13.3
13.3
26.&
Philippines
13.6
38.6
52.2
34.6
48.0
82.6
Papua New
Guinea
18.0
43.0
61.0
44.7
21.9
66.5
Republic of
Korea
12.0
33.5
45.5
48.5
20.3
68.8
7.1
21.9
29.0
36.8
16.8
53.6
Hong Kong
Singapore
I
I
- 5 -
3.4
HBV infection and primary hepatocellular carcinoma
Primary hepatocellular carcinoma (PHC) is a COmmon tumour in this
region and has a very high mortality. When patients with the disease are
tested for the presence of markers of HBV infection, a significantly higher
proportion of subjects with PHC are found to be chronic carriers of HBV
(see Table 4).
Table 4.
Prevalence of HB8Ag in patients with primary
hepatocellular carcinoma and matched controls
from different parts of the world
Number
HBsAg + (%)
Attribu- \
Relative
risks
table risk*
Controls
Primary hepatocellular carcinoma
Number
HBsAg + (%)
Asia
1 063
526
(49.5)
10 180
556
(5.5)
16.8
46.6
Africa
1 317
765
(58.0
2 463
219
(8.9)
14.2
54.0
Oceania
32
23
(71.9)
100
18
(18.0)
11.7
65.7
America
83
34
(41.0)
6 526
21
(0.3)
230.9
40.8
192
91
(47.4)
982
14
(1.4)
63.5
46.7
2 687
1 439
(53.6)
20 251
828
(4.0
27.0
51.4
Europe
Total
*The attributable risk is a measure of the percentage of PHC cases
which can be attributed to HBV infection in a particular population and is
defined by the formula: E(R-l) where E is the proportion of the population
l+E(R-15
with evidence of chronic HBV infection.
- 6 -
since the association between chronic HBV infection and the
development of long term sequelae such as chronic hepatitis, liver
cirrhosis and PHC provide the rationale for mass immunization campaigns it
is worth stating the evidence upon which this conclusion is reached.
(1) There is a geographical correlation between areas where
hepatitis B infection is highly endemic and where PHC prevalence is also
high.
(2)
The risk of developing PHC has been shown to be relatively
constant in endemic and non-endemic areas among male persistent carriers of
HBsAg. (The annual death rate from PHC varies from 250 to 500 per 100 000
in these populations. Given a gross estimate of about 200 million HBsAg
persistent carriers in the world, the annual incidence of PHC has been
calculated to be about 350 000 cases, making HBV-related PHC one of the
more prevalent cancers in the world.)
(3) The frequency of finding HBsAg in PHC patients is much higher
than in matched controls living in the same area. In some areas with low
prevalence of infection, the ratio may be as high as 100:1.
(4) Acute HBV infection precedes, and persistent or chronic active
hepatitis B usually accompanies, the development of PHC.
(5) Chronic infection with HBV may lead to cirrhosis. Prospective
studies have shown that HBsAg-positive patients with cirrhosis develop
primary liver cancer with high frequency, in contrast to HBsAg-negative
patients with cirrhosis.
(6) In other prospective studies of male HBsAg carriers and matched
controls over a 4-5 year period, the risk of developing PHC was over 1000
times higher among the HBsAg carriers.
(7) HBV-DNA has been shown to become integrated into the genomes of
hepatocytes, hepatocellular carcinoma cells, and in some PHC cell lines
established in cell culture. In addition, RNA molecules containing
HBV-specific sequences have been detected in these cells. Integrated
HBV-DNA has also been reported in non-transformed liver cells.
(8) Viruses similar in composition and morphology to HBV have been
detected in lower animals, the woodchuck (Marmota monax), the ground
squirrel (Spermophilus beecheyi), and Pekin ducks (Anas domesticus), both
in China and in commercial flocks in the United States of America that had
their origin in ducks transported from China many years ago. The duck
hepatitis virus is transmitted "vertically", and infected ducklings may
have persistent viraemia. As with HBV, prsistent infection revealed by
circulating surface antigen is common also in woodchucks,and primary
hepatocellular carcinoma often occurs in woodchucks and Pekin ducks. As in
human PHC, the carcinoma is usually associated with chronic hepatitis and
sometimes with liver cirrhosis. The surface and core antigens of these
agents have some features in common with HBV.
- 7 -
3.
DIAGNOSTIC TECHNIQUES FOR DETECTING HEPATITIS B INFECTION.
The structure of hepatitis B virus 1S shown diagramatically in
figure 1. The hepatitis B V1r10n is a double shelled structure measuring
42 nm in diameter. It is composed of an outer coat measuring about 7 nm
in in diameter and bearing a mosaic of antigens known as the hepatitis B
surface antigens (HBsAg) which are responsible for defining the subtype of
the virus and induce neutralizing (protective) antibodies (anti-HBs). The
outer coat encloses an icosohedral inner core measuring 27 nm in diameter,
which possesses two antigens, the hepatitis B core antigen (HBc Ag) and a
second antigen which is probably a component of HBcAg, the hepatitis Be
antigen (HBe Ag). Both antigens stimulate specific antibody responses
which are useful for the diagnosis of HBV infection but, as they are
directed against internal components of the virus, play no role in
protection against reinfection. A wide range of techniques is now
available for detection of HBsAg, HBc Ag, HBe Ag and total and
class-specific antibodies directed against them. In the Western Pacific
Region, the full battery of tests is restricted to a handful of reference
laboratories, most of which are located in developed countries.
A synopsis of the interpretation of the presence of various
permutations of serological markers is given in Table 5.
Figure 1.
INNER CO/Q£
NBc A,9
\H--+-+--HEk A$
- 8 -
Table 5.
HBsAg*
HBeAG
+
+
+
+
+
Anti-HBe
Interpretation of the presence of combinations of
serological markers of the hepatitis B virus
Anti-HBc
Anti-HBs**
Intepretation
Infectivity of blood
Incubation period or
early acute period
during hepatitis B
high
+
Acute hepatitis B
or chronic carrier***
high
+
+
Late during hepatitis
B or chronic state
low
+
+
+
none
+
+
Convalescent from
acute hepatitis B
infection
Recovered from past
hepatitis B infection
+
+
none
Inmunized without
infection, repeatedly
exposed to HBsAg without
infection or recovered from
past hepatitis B infection
Recovered from past hepatitis B infection with undetectable anti-HBs* early
convalescent or chronic
infection
questionable
*All positive for HBsAg are acutely or chronically infected with HBV.
**All positive for anti-HBs are immune to hepatitis B
***The titre of anti-HBc and/or the immunological class of the anti-HBc
may differentiate between the convalescent phase, persistent carrier, or
chronic infection (see text).
For a more detailed treatment of this subject, readers are referred to:
Deinhardt, F. and Gust, 1.0. "Viral hepatitis", Bulletin of the World
Health Organization, 60 (5): 661-691 (1982)
- 9 -
3.1
Detection of HBsAg
For practical purposes, the single most important test of HBV
infection is the detection of HBsAg. The Scientific Group agreed that
every country/area should have at least one laboratory capable of
detecting this antigen by a technique at least as sensitive as reversed
passive haemagglutination (RPHA). Four tests fall into this category;
RPHA, immune adherence haemagglutination (lARA), enzyme immunoabsorbent
assay (ELISA) and radioimmunoassay (RIA).
Provided good quality reagents are used, each of these tests is
extremely sensitive. Specificity can be checked by the use of appropriate
controls and by neutralizing positive results with appropriate antisera.
Of the four tests mentioned, RIA is the most sensitive. However,
because it requires facilities for handling and disposing of radioactive
materials and expensive equipment, it is restricted to laboratories in
developed countries. Of the remaining tests, the most simple and easiest
to perform is RPHA, which is now widely used in developing countries. The
reagents have a long shelf life, are convenient to use, and require no
special equipment. Both of the remaining tests require multiple
manipulations and rather more sophisticated techniques than RPHA, although
ELISA assays are becoming easier to perform and are growing in popularity.
Table 6.
Sensitivity
A comparison of the most sensitive methods
for detection of HBsAg
Specificity
Order of
simplicity
Shelf
life
s;::?al equipment needed
g _ counter
RIA
4+
4+
2
weeks
RPHA
3-4+
4+
1
months
!AHA
3-4+
4+
3
months
ELISA
3-4+
4+
3
months
3.2
Production of reagents
In many countries/areas of the Region, testing for HBsAg and the
sequelae of chronic HBV infection is limited by inability to purchase
diagnostic reagents due to lack of funds. As tests of high sensitivity and
specificity can be produced by competent and well equipped laboratories,
the Scientific Group suggested that emphasis be placed upon local
- 10 -
development of reagents by national and regional laboratories. They called
upon WHO to facilitate this process by developing appropriate training
courses and providing fellowships for local workers to allow them to
develop expertise in the production and testing of reagents.
The advent of hybrodoma technology and the development of monoclonal
antibodies to group and strain specific antigens of HBsAg promise to
revolutionalize the diagnosis of hepatitis B infection and should bring the
cost of testing within the reach of most countries.
3.3
Quality control programmes
To ensure that testing for HBsAg {and other markers of HBV infection}
is performed properly, it is important that proficiency testing programmes
be developed on both a national and a regional basis. The WHO
collaborating centres provide a useful network for establishing such
programmes and have access to a range of test panels and otber reference
reagents prepared by WHO.
4.
4.1
COUNTRY OR AREA REPORTS
China
Viral hepatitis is a common problem in China and produces serious
consequences for public health and a major loss of manpower. Last year,
the Government called upon medical institutions to make s greater effort to
control hepatitis and to develop methods of preventing infection with SBV.
In response to this, a Hepatitis Advisory Committee composed of
epidemiologists, virologists, physicians and members of the Ministry of
Public Health, was established and a network of laboratories at province
and municipality level established. Two national hepatitis reference
centres have been designated by WHO to assist with these studies.
4.1.2
Acute viral hepatitis
Acute hepatitis is less important in public health terms tban the
long-term sequelae of chronic infection.
4.1.3 Prevalence of markers of HBV infection
In 1980, more than 200,000 sera were collected from different parts of
China and tested for HBsAg and anti-HBs infection by RPHA and PHA. The
prevalence of HBsAg overall was 8% with a higher incidence in males than
females. An additional 40% of the population showed evidence of past
infection (i.e. anti-HBs, anti HBc or both). Two patterns of the
age-specific prevalence of HBsAg were detected, the first with a peak
between 5-10 years and a steady decline in later life, the second showing a
similar pattern but with a second peak between 35-45 years. Using the
insensitive 1D test for HBeAg, 27% of carriers of HBsAg were found to be
positive.
- 11 -
,
4.1.3
Perinatal transmission of HBV
From 1980 to 1982, 16,908 pregnancies were investigated. HBsAg was
detected (by RPHA or RIA) in 908 women (5.3%), of whom 26% were HBeAg
positive by immunodiffusion. HBsAg was detected in the cord blood of about
11% of carrier women but never from the babies blood, collected at the same
time by heel prick. HBsAg was detected in the breast milk of 14% of
carrier women.
Of 76 babies born to carrier mothers, 25 were infected in the first
six month of life (one month 5.2%, three months 17%, six months 33%).
Infection was more common inHBeAg positive mothers (85%) than mothers
whose blood contained anti-HBe (25%).
4.1.4
Other points of interest
Prevention of perinatal transmission of HBV is now regarded as an
urgent matter in China and the development and testing of vaccines is
receiving high priority. Studies on the production of a local 22 nm
particle vaccine have been conducted for the past five years. The vaccine
appears to be safe, antigenic and have negligible side effects.
Large-scale production is now under-way. In addition, several other
vaccines produced in the United States (NIH and MSD) and Japan (Green Cross
and Kitasato Institute) are under trial.
4.2
Fiji
Fiji is a small island group situated in the Pacific Ocean about 2000
miles Northeast of Sydney, Australia. Approximately 95% of the population
live in two main islands, Viti Levu and Vanua Levu, the majority in the
capital, Suva. The Fijian population, which numbers approximately 625,000,
is of considerable interest as almost half are Melanesians while the other
half are Indians, descendants of the indentured laborers introduced at the
turn of the century. The two groups live quite separately and there is
little intermarriage.
4.2.1
Hepatitis is a common problem but is poorly notified, less than one
third of the cases being reported to the public health authorities The
prevalence of the disease during the period 1974-1980 is shown in Table 7.
- 12 -
Table 7
SEX
RACE
Year
Fijian
Indian
Others
M
TOTAL
DEATHS
F
1974
90
42
8
89
51
140
10
1975
116
47
12
107
68
175
3
1976
70
60
15
93
65
145
2
1977
92
84
7
129
54
164
3
1978
57
44
14
81
34
115
4
1979
100
53
7
105
55
160
5
1980
109
72
53
146
90
236
1
These figures indicate that hepatitis is disproportionately more
common among the small European population and that the caSe fatality rate,
among these sufficiently ill to be admitted to hospital, is about 2.5%. At
present, tests are not routinely carried out to determine the etiology of
each episode of hepatitis.
4.2.2
Prevalence of markers of HBV infection
There is a marked difference in the pattern of HBV infection in the
two major population groups. Whereas HBV is hyperendemic among Fijians, it
is relatively uncommon infection among the Indian population. For example,
in the period 1980-1981, a total of 10,372 blood donors were screened for
HBsAg, of whom 6329 were Fijians, 2317 Indians and 1726 others. The
prevalence of HBsAg in the two groups was 4.3%, 1.1% and 3.7%
respectively. These differences in the epidemiology of hepatitis B
infection among the two groups are shown dramatically in a study of the
specific prevalence of markers of hepatitis A and B infection carried out
several years ago.
- 13 -
100
VITI
76
L.EVu - FIJII/AIS
0'---0
I7NT/-
#AV
.e--••
HBs I1g r /Inti -!lit.-
O------~·----~--~I------~------~'L-----~------~
0-9
lO-l/f
I~-I"
ao-2'f
30 39
~ -~~
5(1-$9'
liCE (>"£17;\"5")
100
--0
VITI LEW - INOIHNS
__--------.----~e~--~.~~
0-9
10-1+
'''-19
~-2P
.30-)Y
;:7(;£ (YE/l/{S)
- 14 -
The high rate of HBV infection in Fijians of Melanesian origin is
similar to that observed in other Melanesian population such as Papua New
Guinea, Solomon Islands and Vanuatu, while the low rate of infection among
Indians is similar to what is observed in much of India and Sri Lanka.
These findings suggest that the two populations have remained essentially
separste for the past 80-90 years. From a public health point of view, the
data are also interesting in that they indicate that the existence of a
large pool of chronic carriers in a community does not necessarily provide
a health risk to other susceptible groups.
4.2.3
Chronic liver disease and primary hepatocellular carcinoma
During the period 1974-1980, 393 patients with cirrhosis of the liver
were detected at the Colonial War Memorial Hospital in Suva of whom 181
were Fijians and 179 Indians, suggesting that factors other than chronic
hepatitis B infection are responsible for liver cirrhosis in the latter
group. The mortality from the disease was high, 69 patients (17.6%) dying
during the study period.
In the past three years, a serious attempt has been made to detect
cases of primary hepatocellular carcinoma. This has been a most important
study as, prior to 1979, PHC was regarded as rare among the Pacific Island
populations. With the assistance of outside consultants, a cancer registry
has been established and post-mortems are being performed whenever
possible. As a result, during the period 1 November 1979 - 31 October
1981, 30 cases of PHC were diagnosed of whom 27 were Fijians.
4.2.4
In Fiji, more than 90% of the blood used for transfusion is collected
in two urban centres, Suva and Lautoka. This blood is screened for HBsAg
by RPHA and antigen positive blood discarded. No screening is carried out
in the smaller rural centres.
4.3
French Polynesia
Consists of widely scattered islands of different sizes housing a
variety of ethnic groups. Most of the information available comes from the
most populous island, Tahiti, which has an excellent health service and
collects and publishes data on infectious diseases.
4.3.1
The number of cases of hepatitis notified during the period 1978-1981
is shown in Table 8.
- 15 -
Table 8.
Prevalence of acute viral hepatitis in Tahiti
Year
Number of cases
1978
71
2
(2.8%)
69
1979
205
3
(1.5%)
202
1980
177
6
(3.4%)
171
1981
180
11
(6.1%)
169
Hepatitis B
Others
The disease is extremely uncommon among the Polynesian population but
is relatively common among French soldiers stationed in Papeete,
\
particularly among new arrivals from France. Hepatitis is responsible for
more than 9% of admissions to the army hospital; however most of these
cases are hepatitis A.
4.3.2
Several studies on the prevalence of HBV infection have been carried
out in French Polynesia with the collaboration of the Institut Louis
Halarde, the Yale School of Public Health and Tropical Medicine and the
WHO Collaborating Centre for Virus Reference and Research, Fairfield
Hospital, Melbourne.
These studies have involved Tahiti, the Tuamotu and Gambier
archipelago, the Australes Islands and the Marquise Islands. The results
are shown in Table 9.
- 16 -
Table 9.
Prevalence of HBsAg in different population
groups in French Polynesia
HBsAg
Total
population
Numbers of
sera examined
Metropolitan
-
52
0
Administration
-
44
1 (2,2 %)
Pregnant
-
719
62(8,6 %)
-
2 137
76 0,6 %)
Takapoto
140
83
8 (9,5 %)
Reao
243
237
5 (2,1 %)
TUAMOTU
Abe
109
68
14 (20,6 %)
GAMBIER
Tikehau
207
89
8 (8,9 X)
Rikitea
447
190
Maiao
220
143
35 (32,1%)
Archipelago
islands or
category
TAHITI
women
Blood donors
8 (4 %)
Rimatara
813
112
37 (33 %)
AUSTRALES
Islands
Rapa
398
330
170 (54,2 %)
MARQUISES
Hiva Oa
170
120
24 (20 %)
What is most interesting is the marked difference in the prevalence of
HBSAg among different groups of Polynesians, ranging from a low of 4% on
the island of Rikitea to a high of 54.2% on the island of Rapa. These
differences are not due to differences in techniques or to sampling
errors. The reasons are unknown but may reflect the proportion of HBsAg
carrier women in the population who are HBeAg positive and thus highly
infectious. On the other hand, the differences may represent the existence
of strains of HBV with different biological properties.
-17-
4.3.3
Few data are available about the prevalence of chronic liver disease.
During the period 1980-1981, 224 malignant tumours were detected in Tahiti
of which 6 (2.7%) were hepatocellular carcinoma. Only one of these was
HBsAg positive.
4.3.4
Several sens1t1ve techniques are available in Tahiti for the detection
of HBsAg. These include RPHA, ELISA and RIA. Tests for anti-HAY and
anti-HAY IgM are also undertaken. Hepatitis B immunoglobulin (HBIG)
prepared by the French National Centre for Blood Transfusion is available
as is hepatitis B vaccine prepared by the Pasteur Institute. All blood
intended for transfusion is screened by RPHA and positive units are
discarded.
4.4
Hong Kong
Hong Kong has a population of almost 5 million people of whom 98% are
of Chinese descent.
4.4.1
Acute viral hepatitis is an increasing problem. In 1980, 1534 cases
were notified, an incidence of 30.5 per 100,000 population. The case
fatality rate among notified caSes was 2.4%. This compares with an
incidence of 21.8 per 100,000 in 1976 and a case fatality rate of 4.6%.
A study of 236 patients with acute viral hepatitis admitted to a
single hospital indicated that 25.8% had hepatitis A, and 41.5% had
hepatitis B. The remaining 32.3% of patients were assumed to have non-A,
non-B hepatitis.
4.4.2
From January to June 1979, a sera-epidemiological study of HBV
infection was performed on 674 children and adults hospitalized for
diseases other than hepatitis and on 15,660 blood donors aged between 16
and 40 years. HBsAg was detected by RPHA and anti-HBs by RIA. The overall
carrier rate was 9.6% with a higher prevalence in males (11.8%) than
females (6.1%). The prevalence of HBsAg rose sharply (3.3% in the 0-10 age
group; 9.4% in the 11-13 years age group), reaching a peak of 11.4% in the
21-30 age group. A similar rise in the prevalence of anti-HBs was a180
noted, suggesting that infection is acquired throughout life and is
particularly common in the 11-13 age group.
HBe Ag was detected in 47.5% of carrier blood donors, and in 54.3% of
pregnant women catriers. Of 37 babies born to carrier mothers, all of the
22 born to HBeAg positive women were infected within six months of delivery
compared with 5 of 13 babies born to HBeAg negative mothers. Perinatal
transmission was found to be most important. HBsAg was detected by RIA in
98.3% of vaginal specimens and 95.3% of infant gastric aspirates obtained
at birth.
- 18 -
4.4.3
In 1980, the death rate from chronic liver disease and cirrhosis in
Hong Kong was 7.8 per 100,000 making it the 10th most Common cause of
death. A total of 2, 293 patients with liver cirrhosis were admitted to
hospital. of 80 patients with postnecrotic cirrhosis but without PHC
coming to autopsy, 87.5% were HBsAg positive.
In the same year, there were 833 deaths from PHC of which 679 (83.9%)
were in males. PHC is the third most common malignancy in Hong Kong and
the second commonest cause of death due to malignancy (17.9 per 100,000).
Two studies on the prevalence of HBsAg in patients with PHC have been
performed, one retrospective, the other prospective. HBsAg was detected in
93% of the former group and 90% of the latter.
4.4.4
Screening of donated blood for HBsAg has been mandatory since 1975.
The test currently employed is RPHA. Prior to this a prospective study of
patients receiving multiple blood transfusion showed that at least 20%
developed hepatitis Band 16.7% non-B hepatitis, probably non-A, non-B.
HBIG is available from overseas sources but is not produced locally.
Limited quantities of the Mercke, Sharpe and Dohme hepatitis B vaccine
(H-B vax), are available and three other vaccines (Japanese Green Cross,
Pasteur Institute and Netherlands Red Cross) are under trial. Plans are
under way to develop a strategy of immunization. However, until large
quantities of vaccine are available at reasonable prices, it may only prove
possible to offer vaccine to high risk groups.
4.5
Japan
Hepatitis and chronic liver diseases are major health problems in
Japan and are receiving considerable attention. A number of research and
task forces have been established by the Ministry of Health.
4.5.1
According to figures obtained by the task force, in 1979,
approximately 180,000 cases of hepatitis occurred in Japan, an incidence of
134.7 per 100,000. Serological studies showed that 40% of these were
hepatitis A, 20% non-A, non-B
In addition, there were 4,000 cases of
fulminant hepatitis (3.4 per 100,000), of which 50% were due to infection
with HBV.
4.5.2
Of 342,107 blood donors (16-64 years), 1.9% were HBsAg positive by
RPHA (Sasaki), while in Kyushu, 2.8% of 145,076 donors were positive by the
same technique. The prevalence of HBeAg among carriers is highest in the
young, (35% at 16-19 years) and decreases with increasing age (9% from
50-64 years).
- 19 -
The prevalence of HBeAg in carrier women of childbearing age is
17.7%. Studies in Tokyo and Sendai showed that between 85 and 93% of
children born to HBeAg positive mothers became carriers of HBVL In the
Tokyo study, intravenous injection of free HBIG immediately after birth,
followed by intramuscular injection of HBIG and HB vaccine, appears to have
successfully interrupted transmission of infection in 50 babies born to
HBeAg positive mothers.
4.5.3
Chronic liver disease and PHC
These are common diseases in Japan at present. In 1979, it was
estimated that there were 1,100,000 patients with chronic hepatitis (755
per 100,000), 219,000 with liver cirrhosis (188.0 per 100,000), and 20,000
with PHC (17.2 per 100,000). From 30% to 50% of these people were chronic
carriers of HBV. Liver cancer is the third most Common tumour in men and
fourth most common in women in Japan.
In 1979 there were 30,327 deaths from chronic liver disease and PHC in
Japan, representing 4.4% of all deaths. Over the age of 40, it is the 4th
most COmmon case of death after neoplasma, crebrovascular diseases and
heart disease. Approximately 1 in 10 deaths between the ages of 40 and 65
in Japan is due to chronic liver disease or PHC and at least half of these
are associated with chronic hepatitis B infection.
4.5.4
In Japan, screening of blood donors for HBsAg was commenced in 1968.
Since 1976, a sensitive RPHA has been adopted at all Japan Red Cross blood
centres with a consequent decrease in post-transfusion hepatitis due to
HBV. However, about 9-10% of multitransfused subjects can be expected to
develop non-A, non-B hepatitis.
As a result of education and improved hospital practices, including
the use of single-dose needles and syringes, the yearly incidence of HBV
infection in certain high risk groups over the period 1972-1981 has fallen
(e.g. dialysis units from 25% to 3.6%, medical staff from 5% to 0.6%,
non-medical community from 2.7% to 0.3%).
4.6
Malaysia
A limited amount of data is available from Malaysia, as there is no
routine surveillance programme and no liver task force. Most of the
information which is available comes from studies carried out at the
National Blood Bank and the General Hospital in Kuala Lumpur.
4.6.1
Approximately 2,100 patients with hepatitis are admitted to the Kuala
Lumpur General Hospital each year of whom 14.3% have hepatitis B, the rest
non-B hepatitis. The case fatality rates in the two groups are 4.9% and
1.2% respectively. Most cases are in the 13-44 age group. Non-B hepstitis
is most common among Malays whereas hepatitis B appears to occur with equal
frequency among Malays, Chinese and Indians.
- 20 -
4.6.2
Prevalence of HBV infection
An early study of the prevalence of HBsAg and anti-HBs in healthy
blood donors reported figures of 5.5% and 50.1% respectively
In a subsequent study using a more sensitive test for HBsAg (RPHA),
the prevalence of HBsAg in blood donors was found to be 9.4%. The carrier
rate was higher in Chinese (14.8%) than in Malays (7.4%) or Indians
(6.0%). A total of 62.2% of carrier donors have detectable levels of HBeAg
circulating in their blood.
4.6.3
Approximately 1,200 patients with non-alcoholic liver cirrhosis and
900 patients with PHC are seen at the General Hospital in Kuala Lumpur each
year. The majority of patients are aged between 45 and 64 years and the
case fatality rate for both diseases is 18.5%. Cirrhosis is mOre common
among the Indian population while the majority of cases of PHC are Chinese.
4.6.4
No HBIG or hepatitis B vaccine is available in Malaysia and no
intervention studies are being planned. Blood intended for transfusion is
usually screened by RIA or RPHA except in rural areas. The reagents used
are purchased from overseas manufacturers. Although there is considerable
interest in the problem of chronic hepatitis B infection, further
development in this field will be impossible unless local laboratories can
be provided with or develop the capacity to produce their own reagents.
4.7
New Caledonia
New Caledonia is a large island lying in the Pacific Ocean 1,000 miles
northeast of Brisbane, Australia. Its population of 150,000 people is a
mixture of Melanesians (40%) Europeans (40%), Polynesians (10%) and other
racial groups (10%).
4.7.1
Acute viral hepatitis is a moderate problem with an annual incidence
of 78 per 100,000 of the population.
The distribution of cases of hepatitis during the period 1979-1981 is
shown in Table 10.
- 21 -
Table 10
Year
Melanesian
European
Polynesian
Others
Total
1979
36
20
20
6
102
1980
37
22
18
12
III
1981
75
29
24
13
141
I
Micro ELISA tests for anti-HAV IgM have been available during this
period and the proportion of cases in each year due to HAV infection was
26.5%, 23.4% and 32.6% in 1979, 1980 and 1981 respectively. Most of these
episodes were confined to young Europeans who had recently arrived in the
island.
In New Caledonia, the diagnosis of acute viral hepatitis is
complicated by the occurrence of two other diseases which cause acute liver
damage: leptospirosis and dengue. Over the three-year period 1979-1981,
22 patients with leptospirosis presented with hepatitis while during the
1979 outbreak of dengue 4, 48% of cases gave evidence of acute liver damage.
4.7.2
The prevalence of HBsAg among men and women in the four major racial
groups was studied using sera collected from voluntary blood donors and
from women attending ante-natal clinics. The results are shown in Table 11.
Table 11.
Prevalence of HBsAg in various groups in New Caledonia
Females
Males
Number tested
HBsAg{%)
Number tested
IIBsAg{%)
Melanesians
447
8.9
413
6
Europeans
812
1.1
557
1
Polynesians
160
11.0
393
6.1
33
1.8
79
8.8
Others
- 22 -
In addition to the above study, a systematic investigation has been
performed to determine the prevalence of HBV infection among defined
populations of Melanesians and Polynesians. The populations surveyed were:
(a) Melanesians in the community of Touho, a town located on the
north-east coast of New Caledonia. Touho is rural and has s
population of 492 people.
(h) Melanesians and Polynesians on the island of Ouvea. Ouvea is a
coral atoll in the Loyalty group of islands, which are
administratively part of New Caledonia. The island has a population
of 2,421 and is located about 100 kms from the mainland.
Although New Caledonia and Ouvea were probably settled
contemporaneously by Melanesians about 3000 years ago, the population of
Ouvea is unique, because, over the past few centuries, Polynesians have
become integrated in the community.
The island has two languages, Melanesian and Polynesian, and the
inhabitants live in distinct Melanesia, Polynesian and mixed villages.
The prevalence of markers of HBV infection in the two groups is shown
in Tables 12 and 13.
- 23 -
Table 12.
Sex and age group
Prevalence of hepatitis B surface antigen (HBsAg) in
the populations of Ouvea and Touho, New Caledonia
Ouvea Melanesians
Ouvea Polynesians
Touho Melanesians
Males
20-24
25-34
35-44
45-54
55-64
> 65
9/29
10/52
8/50
7/38
2/37
3/22
( 31.0)*
09.2)
06.0)
08.4)
( 5.4)
(13.6)
0/25
7/43
1/32
5/34
1/15
3/15
06.3)
0.1)
(14.7)
(6.7)
(20.0)
0/8
0/22
0/20
1/16
0/17
0/7
(6.3)
Total
39/228
(17.1)
17/164
00.4)
1/90
0.1)
20-24
25-34
35-44
45-54
55-64
65
7/48
6/68
2/57
5/57
0/47
3/27
04.6)
(8.8)
(3.5)
(8.8)
1/36
2/55
3/34
5/44
0/30
4/38
(2.8)
(3.6)
(8.8)
(11.4)
00.5)
0/5
0/26
0/20
0/13
0/10
0/6
Total
23/304
(7.6)
15/237
(6.3)
0/80
62/532
01. 7)
32/401
(8.0)
1/170
Females
>
Males and females
*
Per cent in parenthesis
01.1)
(0.6)
- 24 -
Table 13.
Sex and age group
Prevalence of antibody to hepatitis B core
antigen(anti-HBC) in the populations
of Ouvea and Touho, New Caledonia
Ouvea Melanesians
Ouvea Polynesians
Touho Melanesians
Males
20-24
25-34
35-44
45-54
55-64
65
27/29
47/52
42/50
36/38
32/37
21/22
(93.1)*
(90.4)
(84.0)
(94.7)
(86.S)
(95.5)
18/25
40/43
30/32
30/34
14/15
14/15
(72.0)
(93.0)
(93.8)
(88.2)
(93.3)
(93.3)
1/8
10/22
9/20
4/16
9/17
6/7
(12.5)
(45.5)
(45.0)
(25.0)
(52.9)
Total
205/228
(89.9)
146/164
(89.0)
39/90
(43.3)
20-24
25-34
35-44
45-54
55-64
)65
41/48
64/68
51/57
48/57
43/47
23/27
(85.4)
(94.1)
(89.5)
(84.2)
(91.5)
(85.2)
29/36
47/55
31/34
37/44
25/30
31/38
(80.6)
(85.5)
(91.2)
(84.1)
(83.3)
(81.6)
2/5
13/26
9/20
6/13
7/10
4/6
(40.0)
(50.0)
(45.0)
(46.2)
(70.0)
Total
270/304
(88.8)
200/237
(84.4)
41/80
(51.3)
475/532
(89.3)
346/401
(86.3)
80/170
(47.1)
>
(85.
n
Females
Males and females
(66.
n
* Per cent in parentheses
It is generally believed that the ratio of HBsAg carriers to subjects
with detectable levels of circulating antibody (anti HBc or anti HBs) in a
community is a reflection of the age of the population at the time
infection is acquired. A number of studies have shown that, if infection
occurs early in life when a child's immunological system is relatively
immature, there is a high probability that the child will become a chronic
carrier.
The data from Touho suggest that hepatitis B infection in this
community is largely acquired in adult lite, a situation which is unusual
in tropical countries.
The lower rates of anti HBc among younger people can be interpreted to
suggest that there has been some major change in the pattern of hepatitis B
virus infection in recent years. Such a decline could also be due to a
change in child-bearing or chi1d-reating practices.
,
- 25 -
4.7.3
Chronic hepatitis and liver cirrhosis unrelated to heavy alcohol
intake are common in New Caledonia. In 1981, 9 new cases were diagnosed by
laparoscopy. New Caledonia has an excellent cancer registry and during the
period 1977-1981, 43 cases of PHC were detected, representing an incidence
of more than 6 per 100,000 per year. Cases occurred from 23-78 years with
a mean of 55.8 years, and were more common among men (35 cases) than women
(3 cases).
The age distribution of cases and estimated age-specific incidence of
the disease are shown in Table 14.
Table 14.
(years)
PHC in New Caledonia, 1977-1981
PHC
Population
20-29
1
21 456
4.7
30-39
1
17 758
5.6
40-49
7
12 892
54.3
50-59
16
8 013
199.7
60-69
15
5 267
284.8
3
2 854
108.1
Age
70 +
Cases per 100,000
*Estimated on basis of 1976 census figures.
HBsAg was detected in 48.5% of patients with PHC but its frequency
differed according to racial group.
(Melanesians, 61.9%, Polynesians 50%,
other racial groups 40%, Europeans 0%.)
4.7.4
A variety of serological tests are performed at the Pasteur
Institute in New Caledonia. These include tests for HBsAg (RPHA) ,
anti-HBs, anti-HBc, HBeAg and anti-HBe (ELISA). All blood donations are
screened for HBsAg by RPHA and positive units are discarded.
- 26 -
A study of the frequency of perinatal transmission of HBV infection is
underway, coupled with a study of the value of scrupulous cleansing of the
baby at delivery in preventing infection.
HBIG is neither produced nor administered in New Caledonia; however,
hepatitis B vaccine (Pasteur Institute) is available and used in high risk
populations (laboratory workers, nurses, patients and staff in dialysis
units, etc.)
4.8
Philippines
A liver study group has been established in the Philippines involving
staff of the University of the Philippines and the Philippine General
Hospital, Manila.
4.8.1
No accurate statistics exist on the magnitude of the problem in the
Philippines. In a recent hospital- based study, the relative contributions
of hepatitis A. hepatitis B and non-A. non-B hepatitis were 37%, 40%
and 23%.
4.8.2
The prevalence of HBsAg has been investigated in four rural
communities and varies from 8-16%. As in China. two patterns of prevalence
of HBsAg are described, the first with a peak in early childhood and a
gradual decline with increasing age, the second showing another but smaller
peak in the 30-39 age group. The prevalence of infection with HBV is
related to socioeconomic status. Whereas. the average prevalence of HBsAg
in poor areas is 12-15%, among higher socioeconomic groups such as medical
students it is only 2%.
4.8.3
There are no reliable data on the incidence of chronic hepatitis or
cirrhosis in the Philippines at present. Approximately 50 new patients
with liver cirrhosis are admitted to the gastrointestinal clinic of the
UP-PGH Hospital each year.
PHC is a major problem and is the most common malignancy (17%)
recorded at the UP-PCH hospital where over 8,000 autopsies are performed
each year. PHC is also responsible for 1-3% of admissions to the
Department of Medicine. The estimated rate of PHC per 100,000 population
varies from 14.4 to 103.8 according to age. The prevalence of HBsAg among
patients with PHC is 74% compared with 15% in matched controls.
4.8.4
Tests for HBsAg (RPHA and RIA), anti-HBs (PHA and RIA), anti-HBc,
HBeAg and anti-HBe (RIA) used by the liver study group are provided by the
Tokyo Metropolitan Institute of Medical Science and the Japan Hepatitis
Foundation. It is hoped to develop the capability to produce good quality
reagents locally. Some screening for HBsAg has been carried out by the
Ministry of Health and tests are available through one private laboratory.
although the cost is high.
J
- 27 -
Studies of perinatal transmission of HBV are in progress. To date 60%
of infants born to HBeAg positive carrier mothers have become carriers
within a year of birth compared with 2% of babies born to anti-HBe positive
mothers. Studies on the importance of mUltiple use of syringes during
immunization campaigns, transfusion of non-screened blood, unclean
techniques for paramedical procedures, acupuncture, ear lobe pricking,
childhood circumcision, barber shops and sexual promiscuity in the
transmission of HBV infection are under-way. Strategies for reducing
infection which are under consideration include:
mass education of field workers in the need for aseptic techniques
and altered practices;
extending the sc·reening of blood intended for transfusion (at
present only 10% is screened);
collection of plasma from chronic carriers and anti-HBs from
healthy donors for the production of HB vaccine and HBIG.
Initially, it may be necessary for these procedures to be carried
out overseas.
testing of marriage applicants and pregnant women for HBsAg with a
view to immunizing seronegative spouses of carriers and babies born
to carrier mothers.
4.9
Republic of Korea
Data on the overall prevalence of liver disease are not available but
excellent information has been obtained from studies in several large
hospitals and from mass screening programmes. Of 31,646 inpatients treated
in general hospitals in four parts of the country, 12-27% (average 21%)
were suffering from liver disease (acute hepatitis 20% chronic hepatitis
22%, liver cirrhosis 31%, PHC 23%).
4.9.1
The mean age of patients with hepatitis is 31 years. In a prospective
study of 353 patients with acute hepatitis, 68% were found to have
hepatitis B (by the detection of HBsAg by RIA or the development of
anti-HBc or anti-HBs); the remainder had non-B hepatitis.
4.9.2
In a study of healthy people aged from 3 months to 75 years in rural
and urban areas of the country, the prevalence of HBsAg was found to be
6.6%. An additional 59.1% of the population had detectable levels of
artti-HBs or anti-HBc (all tests by RIA). Other studies have shown an HBsAg
prevalence of 7-18% depending on the group tested.
- 28 -
4.9.3
The major features of a series of patients with chronic liver disease
or PHC admitted to five of large general hospitals are shown in Table 15.
Table 15
Type of liver disease
Mean age
Male/female
ratio
HBsAg
positive
Chronic hepatitis
40 years
3:8:1
75%
Cirrhosis
44 years
3:8:1
91%
PHC
50 years
9:1
87%
I
Serological evidence of HBV infection was assayed in sera from
112 Korean patients with PHC and from 63 age and sex-matched controls.
Serological evidence of HBV infection was found in 100% of PHC patients and
in 97% of controls.
A total of 87% of PHC patients were positive for
HBeAg compared with 14% of controls. Hepatitis B e antigen (HBeAg) was
detected in a high percentage (38%) of HBsAg positive PHC patients. but in
none of the nine HBSAg positive control individuals. Serum AFP was
detectable in 83% of PHC patients but in only one of 63 controls
(1.5%).These results suggeset that chronic infection with HBV may be the
major factor in the development of PHC in the country.
For the purpose of establishing the entity of asymptomatic anicteric
hepatitis, a mass screening survey of SGOT levels was performed on 1906
healthy Korean personnel. Of these, 42 had SGOT levels of greater than 50
units on 2 examinations and 32 were available for liver biopsy. Of these,
24 (75%) had a persisting parenchymal lesion justifying the designation of
chronic active hepatitis.
In a previous study, the most common sign of snicteric hepstitis had
been the presence of s palpable liver. Thus, clinically healthy appearing
Korean personnel were screened by palpable liver and 14 cases detected.
Ten of these showed normal levels of SGOT. Five out of these 10 caseS had
evidence of chronic active hepatitis. Since several of the personnel with
anicteric hepatitis had normal SGOT levels, the total incidence of
anicteric hepatitis in the country is probably of the order of 2%. three
quarter of whom appear to have chronic active hepatitis.
- 29 -
4.9.4
In 1971 a study was carried out to determine the prevalence of
post-transfusion hepatitis when unscreened donor blood was used. A total
of 9S patients were adequately followed up and of these 45 (48%) developed
post-transfusion hepatitis. The risk of developing the disease was highest
in those who received more than 10 units of blood (80%) and lowest in those
receiving only a single unit (17.4%). The HBsAg carrier rate among the
donors used was 5.3%. Of those patients who received HBsAg positive blood,
63% developed hepatitis compared with 38% of patients who received only
HBsAg negative blood. It should be noted that the method used for
detection of HBsAg at that time was agar gel diffusion. Currently all
donor blood is screened by RPHA.
A recent study in Seoul has shown that 9.8% of pregnant women are
carriers of HBsAg and 41% of these are HBeAg positive. The incidence of
perinatal transmission and the effect of HBIG administered in a dose of
0.5 ml at birth are under investigation. HB!G produced by Mercke, Sharpe
and Oohme and Cutter Laboratories are available in the Republic of Korea as
are the hepatitis B vaccines produced by Mercke, Sharpe and Oohme and the
Pasteur Institute.
In addition, a 22 nm particle hepatitis B vaccine is being produced
locally by a process of concentration, acid pepsin digestion and gradient
ultracentrifugation. This vaccine is currently being evaluated in man.
4.10 Singapore
Singapore is a multiracial country, with a total land area of 616.3
square kilometers and a population of 2.4 million people. This population
consists of 76% Chinese, 15% Malays, 7% Indians and 2% other races. Over
the last ten years the population has increased from 2.1 to 2.4 million
persons and the death rate has remained about the same
Singapore enjoys a
good health system and life expectancy is now 71 years. The average family
is a four member unit and public hospitals provide the bulk of health care.
4.10.1
Viral hepatitis has been a notifiable disease since 1977. The
incidence of the disease appears to be rising - whereas only 855 cases were
notified during the period 1977-1979, 1001 casese were reported in 1980 and
this trend is continuing. The case fatality rate among hospitalized
patients is 1.4%. The ratio of males to females is 2.3:1 and the average
duration of hospitalization is 9.3 days.
The major etiological agents responsible for hepatitis in Singapore at
present are HAV 30%, HBV 46%, and non-A, non-B agents 24%.
4.10.2
The average prevalence of HBsAg in Singapore is 8% indicating that
approximately 200,000 members of the population are chronic carriers of the
the virus. The prevalence of markers of HBV infection in early life has
been studied by RIA and the results are shown in Table 16.
- 30 -
Table 16.
Prevalence of hepatitis B markers in early life
I
I
I
HBsAg
Age
I in
Sex
years
<. 1
M
F
1-2
M
F
3-5
M
I
I
6-8
F
IM
I
I~
F
9-11
Number of
children
tested
Number of
children
positive
I: M
,I
F
I
Percentage
Number of
children
tested
Number of
children
positive
13
3
1l.S
4.3
100
58
26
22
26.0
37.9
109
69
48
30
7
2
14.6
6.7
46
30
10
4
21. 7
13.3
48
30
34
28
5
0
14.7
0
33
28
8
1
24.2
3.6
34
28
37
19
8
1
21.6
5.3
36
19
12
5
33.3
26.3
37
18
7
7
18.9
5.6
35
18
13
4
266
165
40
7
15.0
4.2
250
153
69
36
I
i
I
I
:
I
I
!
Number of
children
Number of
children
tested
Percentage
110
70
I
TOTAL
Anti-HBs
Anti-HBc
Percentage
positive
25
26
22.9
37.7
i
7
4
14.6
13.3
I
4
1
11.8
3.6
36
19
7
0
19.4
0
37.1
22.2
37
18
6
3
16.2
16.7
27.6
23.5
264
164
49
34
I
I
i
i
18.6
20.7
i
I
I
I
- 31 -
The marked predominance of male carriers is worthy of note. In spite
of these findings, clinical hepatitis is extremely rare in childhood.
The prevalence of the markers in three adult groups, healthy adult
male ~lood ~o~ors (mean age 45 years), healthy women attending a family
plann1ng c11n1c (mean age 34 years), and hospital staff (mean age 34 years)
is shown in Table 17.
Table 17.
Prevalence of hepatitis B markers in adults
Population
Number tested
HbsAg
Anti-HBc
Anti-Rbs
1.
Male blood donors
396
6%
5D
7D
2.
Females attending
family planning
clinic
319
7%
43%
44%
3.
Hospital staff
468
4%
31%
29%
4.10.3
I
Chronic liver disease and PRC
In 1980, 538 patients with chronic liver disease or cirrhosis were
investigated. Of these, 71.4% were Chinese, 5.4% Malays and 19.5%
Indians. The incidence of chronic liver disease was 46 per 100,000. About
80% of patients with chronic hepatitis and 600 of patients with cirrhosis
were HBsAg positive; males outnumbered females by 3:1 and the average
duration of hospitalization was 11.1 days.
Of the five leading causes of death, malignancy is second only to
cardiac causes and accounts for 20% of all deaths in the country. Primary
liver cancer is the third most common malignancy in the country and the
incidence for all races is 29 (males) and 8 (females) per 100,000 per year.
90% of primary liver cancers are due to PHe, 5% to cholangiocarcinomas
and the rest are undifferentiated carcinomas of indeterminate origin. PHC
is a very severe disease; the one-year survival rate in the absence of
treatment is less than 5%. If surgical resections are possible, the
one-year sutvival is raised to 60% but recurrences are common within twelve
months.
In case-control studies of 56 PRC patients, 39% were RBsAg positive
and 91.2% were snti-HBc positive by RIA compared with figures of 9% and 75%
for patients with other malignancies (colon, breast, lung, lymphoma).
These differences are statistically significant.
- 32 -
The development of PHC in a small proportion of patients exposed to
oncogenic agents, raises the question of whether defective immunological
responses, induced by the environment of a defective immune Tr gene, ar~
responsible for the chronic carrier state and subsequent PHC. In Sin~Aporp
a study has been carried out to define the immune status of patients with
PHC, chronic carriers of HBV, patients with acute hepatitis B and their
families. There was no particular H-LA relationship with acute viral
hepatitis Bj however, a strong correlation existed between the detection of
alpha fetoprotein, HBsAg and HI-A BS. HL-A BlS occurred in 567. of AFP
negative patients. HI-A B17 was associated with the presences of anti-HRs.
4.10.4
A study of perinatal transmission of HB'! has been underway for
the past three years. A final evaluation in August 1982 showed that of
2 273 maternal prede1ivery sera, 100 were HBsAg positive. A total of
58 babies born to antigen positive mothers have been studied. Vertical
transmission was seen in 43 babies. The presence of HBeAg in maternal sera
was the most important predictor of subsequent transmission. Data on
details of breast feed, Apgar scoring, vaginal delivery vs Caesarian
section delivery, nursing in incubators away from the mother are now under
analysis.
The availability of safe effective vaccines against hepatitis B is of
special interest to countries such as Singapore. The Government is about
to produce a 22 nm particle vaccine in collaboration with workers from the
Pasteur Institute Paris. Detailed studies of the cost effectiveness of
different immunization strategies and the need to pre screen recipients are
underway. Measures to reduce the spread of infection by improvements in
hygiene and nursing and medical practice are under consideration.
4.11
Viet Nam
4.11.1
The incidence of acute viral hepatitis in Viet Nam is estimated to be
120 per 100,000 population. In Bach Mai Hospital, Hanoi, the number of
cases seen per year and the case fatality rate is as shown in Table 18.
Table 18.
Year
1975
1976
1977
1978
1979
1980
1981
Cases
333
256
295
213
236
220
251
Deaths
11
16
18
12
8
13
10
3.3
6.2
6.1
5.6
3.4
5.9
4.0
Case fatality
rate (% )
- 33 -
Few data are available on the etiology of viral hepatitis in
Viet Nam. The prevalence of HBsAg has been studied by CIEP in over
2,000 patients admitted to three different hospitals and found to be from
3-5.5%, which is similar to its prevalence in the general population. As
high titres of HBsAg are usually present early in the illness, these data
imply that the majority of cases are either hepatitis A or non-A, non-B
hepatitis.
4.11.2
Prevalence of markers of HBV infection.
A number of studies on the prevalence of HBsAg have been carried out
by CIEP. The results are shown in Table 19.
Since 1980, a number of tests have been carried out by third
generation techniques and the prevalence of HBsAg in medical staff hospital
patients and blood donors shown to be 9.4%, 13.2% and 15.7% respectively.
The predominant subtypes found in Viet Nam are ayw (58%) adw (20%) and adr
(20%): ayw is rare (2%).
4.11.3
Both disease are common but precise data on the frequency and the
presence of markers of HBV infection are lacking.
4.11.4
The most common test for HBsAg is still CIEP using locally produced
reagents. HBIG and HB vaccine are not yet available. Blood donors are
screened for HBsAg by CIEP and positive units are not transferred.
Table 19
i
Population studied
A.
4,015
507
150
200
38 750
4.1
5.1
5.8
8.5
5.8
300
300
7.0
4.1
253
222
250
3.7
5.4
5.3
Kindergarten children
Hanoi City
Quang Minh
C.
HBsAg detected (:0
Healthy blood donors
Bach Mai Hospital
Viet Duc Hospital
University of Medicine Hospital
Da Nang Hospital
Institute of Blood Transfusion
(Ho Chi Minh City)
B.
Number
Other groups
Northern Highlands
Plains population
Citizens of Hue
I
- 34 -
5.
THE IMPORTANCE OF MATERNAL/INFANT TRANSMISSION
OF HBV IN THE REGION
Transmission of HBV infection from carrier mothers to their babies is
an important factor in the perpetuation of the virus. The HBsAg positive
rate in pregnant women varies from country to country and may be as low as
0.1% in countries such as Australia and as high as 50% in some Pacific
Islands.
According to studies on the detection of HBV markers among babies born
to HBsAg positive mothers in Japan, 26.5% became carriers. As there are
1 550 000 births in a year in Japan, a carrrier rate of about 2.5%,
approximately 10 000 babies, probably become carriers by maternal/infant
transmission every year. On a global basis, it can be estimated that more
than 600 000 babies born each year will become carriers in their first year
of life. The presence of HBeAg in the mothers blood is the best marker for
predicting whether maternal/infant transmission will occur as about 90% of
babies of HBeAg positive mothers become carriers.
6.
PREVENTION OF MATERNAL/INFANT TRANSMISSION
There are some reports on the prevention of matternal/infant
transmission by the use of high titered HBIG. About 500 cases are reported
in the world. There are two methods of administering high titered HBIG:
Single administration at birth or repeated administrations over the first
few months of life. Both methods are quite effective. According to
Beasley's large controlled study in China (Taiwan), repeated administration
is more effective than single administration. The methods and results of
Dr Yano's study on maternal/infant transmission of HBV in Japan were
presented at the meeting. Briefly, HBIG supplied by Nichiyaku Co. and
Green Cross Co. was given intramuscularly in a dose of 300-400 iu within 24
hours after birth. A second dose was given when the babies level of
anti-HBs began to disappear, and a passive immunization state was kept for
one year. With this schedule, good results were obtained, however, it may
be necessary to alter this schedule for practical use. HBIG has been given
to 168 babies of HBeAg positive mothers so far. Of these, 15 babies became
carriers, giving a protective efficacy of 91%. Out of 168 babies, 89
babies were observed for over one year, and 30 babies were observed for
over two years. There was no increase in the carrier rate among the babies
observed for this period. This result is excellent considering that 90% of
non-treated babies born to HBeAg positive mothers become carriers.
Studies are also in progress to assess the value of combined treat.ent
with HBIG and hepatitis B vaccine and the optimal dose and timing of thase
preparations. Further data are needed before the optimal schedule can be
decided.
- 35 -
7.
HEPATITIS B VACCINE
From the data presented to date, it is clear
need for a cheap, safe, effective vaccine against
vaccines have been produced and are either in use
following review of the situation is taken from a
discussion held in Munich in May 1982.
7.1
that there is a major
hepatitis B. Several
or under trial. The
WHO round-table
Hepatitis B 22 particle vaccines.
The failure to grow the hepatitis B virus in tissue culture has
prevented the development of conventional vaccines. Attention has
therefore been directed to the use of other preparations for active
immunization, including the use of inactivated hepatitis B surface antigen
purified from the plasma of asymptomatic human carriers. Since HBsAg leads
to the production of protective surface antibody as shown by serological
surveys and experimental transmission studies, purified 22 nm spherical
surface antigen particles have been developed as vaccines. Although it is
generally accepted that the preparations of the 22 nm sub-unit particles,
when pure, are free from nucleic acid and therefore non-infectious, the
fact that the starting material is human plasma obtained from persons
infected with hepatitis B virus means that extreme caution must be
exercised to ensure their freedom from all harmful contaminating material,
including host components.
Progress in the safety and efficacy testing of plasma-derived subunit
vaccines has been rapid. The safety, immunogenicity and high protective
efficacy of two such preparations have been demonstrated by large-scale
placebo-controlled, randomized, double-blind trials in several susceptible
populations and among staff and patients from haemodialysis units and
health care personnel.
A study was reported of an attempt to prevent the development of the
carrier state of hepatitis B surface antigen in children living in a high
prevalence area. Three doses of a subunit vaccine were given
subcutaneously at monthly intervals to 335 children aged less than
six months and two years. A comparison group of 267 children in
18 villages received diphtheria/tetanus/poliomyelitis vaccine. After
12 months, four children
(1/7%) in the vaccinated group were carriers of
the surface antigen compared with 14 (7.2%) in the control group, an
efficacy of 85%. The surface antibody response in the children who were
actively immunized was not significantly influenced by age or sex, and
maternal antibody acquired passively did not appear to interfere with
active immunization. This study if of particular significance in that it
demonstrates the feasibility of preventing infection early in life, which
often leads to the persistent carrier state. It has been previously
suggested that an important factor in the association between hepatitis B
infection and primary hepatocellular carcinoma may lie in an early age of
infection.
- 36 -
Various other studies with this type of vaccine are in progress, and from
the results obtained to date it is established that the acquisition of
anti-RBs is synonymous with protection against infection with hepatitis B
virus. However, 22 nm hepatitis B surface antigen particle vaccine has
several disadvantages:
pooled plasma with high titre of hepatitis B surface antigen (often
e antigen positive) is required in large quantity from persistent
asymptomatic carriers, and each carrier donor cannot be
characterized on an individual basis;
supply of suitable plasma may be difficult to secure in the long
term;
live virus containment facilities are required for production of
the vacc ine ;
the manufacturing process is lengthy, extending over a period of 65
weeks, during which possible extraneous/adventitious agents and
other contaminants must be removed;
the vaccine is very expensive;
strict safety testing of the vaccine is required, at least for the
present, including tests for residual infectivity of hepatitis B
virus in susceptible chimpanzees as recommended by the WHO Expert
Committee on Biological Standardization, 1981.
7.2
Polypeptide vaccines
(a)
Separated polypeptide
To overcome SOllie of these problems, "second generation" hepatitis B
polypeptide vaccines containing hepatitis B specific antigenic determinants
asaociated with a nonglycosylated polypeptide with a molecular weight of
25 000 and a glycosylated polypeptide with a molecular weight of 30 000
have been prepared and tested for safety, immunogenicity snd protective
efficacy in susceptible chimpanzees. The advantages of such a polypeptide
vaccine, derived from any source, include precise biochemical
characterization, absolute eaclusioa of genetic material of viral origin
and exclusion of host or donor-derived substances. Disadvantages of
polypeptide vaccines include low yield if strong ionic detergents are u.ed.
(b)
Aggregated polypeptides
The purification of viral coat subunits in large quantitiea
presents considerable problems, particularly with viruses possessing a
lipoprotein envelope, in which the immunogenic components are integral
membrane proteins, highly hydrophobic, insoluble in aqueous media and
requiring drastic treatment with detergents. The extraction of the
antigenic polypeptides by a non-ionic detergent resolved one of the
problems. However, polypeptides in 1II0nomeric form in high concentrations
of detergent are poorly antigenic. Consequently, a method of detergent
removal that allows membrane polypeptides to reassociate into water-soluble
- 37 -
protein micelles was developed. Protein miscelles are aggregates of
polypeptides arranged so that the hydrophobic regions are sequestered in
the interior of the aggregates with the hydrophilic residue on the surface,
so that the micelles are water-soluble. Comparison in mice of the
immunogenicity of the micelles with the 22 nm particle vaccine showed tha·t,
at all the dose levels tested, the micelles elicited a greater protective
surface antibody response than the intact particles. Tests of safety and
efficacy in non-human primates have been satisfactorily completed.
7.3
Alternative sources of HBsAg
(a)
Vaccines prepared from antigen "producer" cell lines.
Antigen sources other than from human carriers of hepatitis B virus
are becoming available. These include heteroplid HBsAg secreting cells
derived from primary hepatocellular carcinoma. The HBSAg obtained in this
way is non-infectious, of relatively simple biochemical composition, the
cell lines can be characterized, techniques are available to ensure freedom
from contaminating nucleic acid and potent inactivating agents are
available. It should be noted that the cell lines sre transformed and show
heterotransplantability; therefore developments in this area must be viewed
with caution.
(b)
Vaccine prepared by recombinant DNA technology
Particularly attractive sources of antigenic material would be
prokaryotic cells expressing hepatitis B surface antigen proteins as a
result of cloning of hepatitis B viral DNA; production of HBsAg by this
method has been reported by several groups. Expression of hepatitis B
proteins has also been achieved in various eukaryotic cells, inCluding
human simian and rodent. Sources such as transformed heterotransplantable
HBsAg-producing cell lines have not yet been licensed by national control
authorities for vaccine production. Expression of hepatitis B surface
antigen in yeast cells has also been reported. These developments are
potentially important for large-scale in vitro production of vaccines
produced by recombinant DNA technology.
(c) Synthetic hepatitis B peptide vaccines
The development of synthetic vaccines is an exciting prospect
offering many advantages in attaining the ultimate goal of chemicslly
synthesized multivalent vaccines to replace many current bacterial and
viral vaccines which often contain many irrelevant microbial antigenic
determinants, proteins and other material that contaminate the essential
immunogen and which mey lead to untoward side-effects. As a result of work
in progress since 1966, the conceptual way to synthetic vaccines was open,
since the feasibility for such an approach had been demonstrated in studies
with tobacco mosaic virus. Examples of immunization with a synthetic
peptide were publiShed recently including diphtheria toxin and
Streptococcus pyogenes K protein. possible approaches to the development
of chemically synthesized hepatitis B vaccines were described a few years
ago by several groups and current progress suggests that such synthetic
peptide vaccines may be within reach. The identification of an 892 base
pair region along the DNA strand of hepatitis B virus with the ~
- 38 -
determinants in cloned DNA frangments made possible the determination of
the full sequence of the 226 amino acids comprising the 25,000 molecular
weight polypeptide of hepatitis B surface antigen. The corresponding
sequence for the ~ subtype suggested a variation of 16 amino acids. With
the help of computer programmes, the internal and external residues of the
proteins with their known structure and hydrophilic regions were predicted
and corresponding peptides were chemically synthesized. Such synthetic
peptides with the amino acid sequences of hepatitis B surface antigen are
being tested in several laboratories for immunogenicity.
Such single peptides of precisely known composition and structure are
proving useful in determining the localization of antigenic epitopes within
the HBsAg protein. In addition two synthetic cyclic peptides which contain
the amino acid sequence analogous to position 117 through 137 of the major
HBsAg protein were found to inhibit the reaction of human anti- HBsAg
idiotype with its anti-idiotype antiserum. These findings reported by
Kennedy et a1 support the view that a conformational antigenic determinant
is present in these synthetic peptides similar to that found on the HBsAg
as it occurs in man.
It is possible that synthetic peptides may be employed, in the
future, as vaccines although mixtures of more than one of the peptides may
be required. Of the many questions which remain to be answered, the
critical issues are whether antibodies induced by synthetic immunogens will
be protective and whether immunogens will be protective and immunity will
persist. Studies in susceptible chimpanzees with such "synthetic vaccines"
have begun.
7.4
Proposed requirements for the safety and potency testing of
hepatitis B vaccines
Detailed consideration of requirements for the control of hepatitis B
vaccines has so far only been given to vaccines containing HBsAg derived
from human plasma. In order to help control authorities to ensure that
imported vaccines satisfy requirements for safety and efficacy, WHO has
formulated requirements. In some countries manufacturers and national
control authorities have collaborated in the preparation of guidelines for
the production of safe and effective vaccines. A summary of the laboratory
tests appropriate to control the safety and potency of hepatitis B vaccines
prepared from human plasma is given below.
Other sources of HBsAg have been considered for the preparation of
"second generation" hepatitis B vaccines. Such sources include:
(1)
products obtained by recombinant DNA technology, i.e. HBsAg
prepared by gene expression in procaryotic or eUkaryotic cells;
(2)
Synthetic peptides either alone or linked to a carrier molecule',
(3)
Antigen derived from primary hepatocellular carcinoma or other
transformed cell lines.
•
- 39 -
,
It is premature to define the criteria for the standardization and
control of products prepared from these sources of antigen. Careful
consideration will have to be given to the testing requirements for these
products based on the nature of the product and its method of manufacture.
For instance, it is clear that, if developed, vaccines which incorporate
HBsAg from transformed cell lines would present considerable problems in
terms of accepptability. Control tests would need to provide evidence that
the final products are completely free from cellular DNA.
Tests recommended at various stages in the preparation of hepatitis B
vaccine from human plasma are specified in the WHO requirements and include:
(1)
Bacterial sterility tests (at various stages of production)
(2)
Tests in cell cultures (plasma pools)
(3)
Tests in mice (plasma pools)
(4)
Tests in embryonated egss - allantoic and yolk sac route (plasma
pools)
(5)
Test for human immunoglobulins (purified inactivated bulk)
(6)
Assay for blood group substances and corrersponding antibodies
(purified inactivated bulk).
(7)
Test for HBsAg antigen protein (purified inactivated bulk)
(8)
Tests for agents used in purification and inactivation (purified
inactivated bulk)
(9)
Pyrogen testing in rabbits (final bulk)
(10)
Tests in chimpanzees for infectious hepatitis B virus (final
bulk)
As hepatitis B virus cannot be propagated in tissue culture,
the only method available for the detection of residual
infections virus is by inoculation of the final bulk preparation
into chimpanzees. In some countries each batch is tested in
4 chimpanzees. However, other countries plan only to test a
designated number of early production batches.
(11)
General safety test in mice and guinea pigs (final product)
(12)
Mouse potency test (final product)
(13)
Identity test for hepatitis B antigen in final vaccines
(14)
Quantitative radioimmunoassay for HBsAg in final vaccine
These proposed requirements will need to be reviewed as more
experience is gained with the use of vaccines in the field. Further
consideration is required for the establishment of suitable references for
the control of hepatitis B vaccines.
- 40 -
It should be noted that the chimpanzee safety test is of limited value
and quite impractical in some countries. An alternative test based on the
level of residual formalin is under consideration. Work is also in
progress to develop an international standard hepatitis B vaccine so that
the activity of each vaccine can be expressed in terms of international
units per mgm of HBsAg. Work is also underway to establish standards for
the purity of vaccine based on analysis by CDS polyanylamide gel
electrophoresis and to establish standard assay for potency.
These assays are urgently needed so that the results obtained by
different vaccine manufacturers can be compared.
8.
ELIMINATION OF THE CHRONIC CARRIER STATE
Prevention of the late sequelae of chronic hepatitis B infection by
immunizing susceptible infants will take many years to take effect. In the
meantime, large numbers of chronic carriers will develop chronic hepatitis,
cirrhosis or PHC and many of these will die.
As a result, there is a great interest in attempts to eradicate the
carrier state by the use of antiviral agents, either alone or In
combination. Several studies were reported in which large doses of a or b
interferon were administered daily for one week, then reduced doses daily
for three weeks. Both preparations produced a marked decrease in the
levels of circulating DNA Polymerase during the first week of treatment but
these levels tend to rebound during subsequent weeks. Decrease in DNA
Polymerase levels was accompanied by a transient rise in AST and ALT levels
and a fall in the number of leucocytes and platelets in the blood. All
these changes were reversed by Cessation of treatment.
Treatment with both a and b interferon was accompanied by fever,
chills, malaise and 10s8 of appetite but the symptoms were never
sufficiently severe to cause treatment to be stopped.
Studies are also in progress in Japan to assess the value of ara-A
and ara-AMP in eradication of the carrier state. Both compounds are
administered by intravenous infusion for four weeks in doses of
10 mm/kilo/day for one week and 5 mgm/kilo/day for the next three weeks.
The results of these and other studies are awaited with interest.
9.
RECOMMENDATIONS
After considering all the working papers before it, the Scientific
Group made the following recommendations to the Regional Director.
•
- 41 -
Hepatitis B infection is one of the major public health problema of
the Region because of the high incidence of chronic liver disease and
primary hepatocellular carcinoma among persistent carriers of the virus.
The Group reco_nds that the Regional Director should exercise every
effort~
to encourage the colle~tion and dissemination of reliable data on
the incidence of the carrier state and the frequency of long-term
sequelae of infection;
to stimulate the production and distribution of standardized
reagents for the diagnosis of hepatitis B infection; and
to encourage operational, field and basic research aimed at
prevention of the carrier .tate and its sequelae.
Specifically, the Group recommended
that~
(1) A three-tier network of WHO-designated laboratories should be
established on an interregional, regional and national basis.
The interregional centres should be responsible for:
the development, evaluation and distribution of reference reagents,
standard procedures for the production of reagents, standard
methods of detecting hepatitis B infection, and the development of
teaching programmes and training manuals;
the transfer of these skills to regional laboratories.
Regional laboratories should be responsible for the transfer of
these skills to national laboratories, the distribution of reference
and, where relevant, working reagents, and the development of regional
quality control programmes.
National laboratories would be ultimately responsible for the
development of training and quality control programmes and the
production of working reagents on a national basis.
(2) WHO should cooperate
in conducting workshops in the Region
aimed at training staff in the detection of HBsAg by RPHA and ELISA.
As a second stage, designated local workers should be trained 10 that
they will develop the capability to perform other tests and produce
reagents and kits for use on a local or national basis.
(3) A small regional task force should be convened on an ad hoc basis
from representatives of WHO-affiliated institutions with special
expertise in the field of viral· hepatitis. The responsibility of the
Task Force should be:
- 42 -
to act a8 a catalyst for WHO's regional programme by:
collecting and analysing data;
defining areas which require further research and assisting in
the development of collaborative research proposals;
closely reviewing progress in vaccine development and its.
application in the Region, especially in preventing
transmission from mothers to their babies;
reviewing other data on intervention ~tudies and advisjng the
Regionsl Director on the need for additional studies;
coordinating research in the Region;
encouraging the sharing of data and the effective use of
resources.
- 43 -
ANNEX 1
LIST OF MEMBERS, CONSULTANTS, OBSERVERS AND SECRETARIAT
1.
CHINA
MEMBERS
Dr Zhu Rui Yong
Director
Shanghai Cancer Institute
270 Dong Ang Road
Shanghai 200032
Dr Tao Yixun
Vice Director
Shanghai Municipal Institute
for Medical Laboratory
Shanghai
Dr Liu Chungpai
Institute of Virology
Chinese Academy of Medical Sciences
Beijing
Dr Wang Chao
Health and Epidemiology
Prevention Department
Ministry of Public Health
Beijing
FIJI
Dr Karem Singh
Consultant Pathologist
Department of Pathology
CWM Hospital
Suva
FRENCH POLYNESIA
Professor Agrege Durosoir
c/o Monsieur Ie Haut-Commisaire
de la Republique
fran~aise
Direction des Services de Sante
Papeete
HONG KONG
Dr Ek Yeoh
Medical and Health Department
Sunning Plaza
Hysan Avenue
Hong Kong
- 44 -
Annex 1
JAPAN
Dr K. Nishioka
Vice President
Tokyo Metropolitan Institute
of Medical Sciences
3-18 Honkomagome
Bunkyo-ku
Tokyo 113
Professor H. Suzuki
Department of Internal Medicine
Yamanashi Medical College
Kofu
Dr Michitami Yano
Chief
Department of Gastroenterology
Nagasaki Chuo National Hospital
1001 Kubarago
Omura City
Nagasaki
MALAYSIA
Dr (Mrs) Dora Tan
Head
Virology Uni t
Institute of Medical Research
Kuala Lumpur
NEW CALEDONIA
Dr G. Le Gonidec
Pasteur Institute
Boite postale 61
Noumea
PHILIPPINES
Dr Augusto Lingao
Department of Medicine
University of the Philippines/
Philippine General Hospital
Medical Center
Taft Avenue
Ermita, Metro Manila
REPUBLIC OF KOREA
Professor Whan Kook Chung
Catholic Medical Centre
Myong Dong
Seoul
Dr Chung Yong Kim
Professor
Chief, Gastroenterology Division
College of Medicine
Seoul National University
Seoul
- 45 -
Annex 1
SINGAPORE
Dr Chan So Ha
Department of Microbiology
Faculty of Medicine
University of Singapore
Singapore 0316
Professor Oon Chong Jin
Associate Professor of Medicine
Consultant Physician
University Department of Medicine (1)
Faculty of Medicine
University of Singapore
Singapore 0316
VIET NAM
Dr Dao Dinh Duc
Deputy Head
Infectious Diseases Department
Bach Mai Hospital
Hanoi
2.
CONSULTANTS
Dr Ian Gust
Fairfield Hospital
Queen's Memorial Infectious
Disease Hospital
Yarra Bend Road
Fairfield, Victoria
Australia 3078
Professor Shigenobu Nagataki
Chairman
The First Department of
Internal Medicine
Nagasaki University
Nagasaki 852
Japan
Professor T. Oda
Faculty of Medicine
University of Tokyo
7-3-1 Hongo, Bunkyo-Ku
Tokyo 113
Japan
- 46 -
Annex 1
Consultants (cont'd)
Dr H. Yokouchi
Director
Nagasaki Chuo National Hospital
1001 Kubarago
Omura City 856
Nagasaki
Japan
3.
OBSERVERS
Dr Ni Chengrui
Beijing 2nd Infectious
Diseases Hospital
Beijing Children's Hospital
Beijing
People's Republic of China
Dr Toshihiko Koji
Department of First Internal Medicine
Medical School
Nagasaki City
Japan
Professor M. Kayumi
Department of llamunology
Jichi Medical School
Tochigi-ken
Japan 329-04
Dr Toshio Shikata
Department of Pathology
National Institute of Health
10-35 2-Chome
Kamiosaki, Shinagawa-Ku
Tokyo 141
Japan
Dr M. Simizu
Blood Bank
Tokyo Metropolitan Institute
of Medical Sciences
3-18 Hongkomagome
Bunkyo-ku
Tokyo 113
Japan
- 47 -
Annex 1
Observers (cont'd)
Dr S. Sumorhardjo
West Nusa Tenggara Provincial Hospital
J. I. Pejangjik 6
Mataram, West Nusa
Tenggara
Indonesia
Dr J. Maynard
Director
WHO Collaborating Centre
for Reference and REesearch
for Viral Hepatitis
Phoenix, Arizona 85014
United States of America
Mr Byung-Yang Moon
Member
National Assembly
Health Committee
1-440 Yeouido-Dong
Yeoungdeungpo-ku
Seoul 150
Republic of Korea
Dr Shanghi Rhee
Member
National Assembly
Health Committee
1-440 Yeouido-Dong
Yeoungdeungpo-ku
Seoul 150
Republic of Korea
4.
SECRETARIAT
Dr H. Nakajima
Regional Director
WHO Regional Office
for the Western Pacific
P. O. Box 2932
Manila
Philippines
Dr F. Assaad
Director
Division of Communicable Diseases
WHO Headquarters
1211 Geneva 27
Switzerland
II
- 48 -
II
" "I
Annex 1
Secretariat (cont'd)
Dr 1. Geizer
Regional Adviser
in Health Laboratory Services
WHO Regional Office
P. O. Box 2932
Manila
Philippines
Dr Hu Ching Li
Regional Adviser in
Maternal and Child Health
WHO Regional Office
P. O. Box 2932
Manila
Philippines
Dr Allan Linsell
Division of Epidemiology
and Biostatistics
International Agency tor
Research on Cancer
Lyon
France
Dr Y. H. Paik (Operational Officer)
Chief, Research Promotion and Development
WHO Regional Office
P. O. Box 2932
Manila
Philippines
Dr T. Umenai
Regional Adviser in
Communicable Diseases
WHO Regional Office
P. O. Box 2932
Manila
Philippines
II
II
II
"•
11
- 49 -
ANNEX 2
PROVISIONAL AGENDA
Wednesday
29 September 1982
Registration
Opening of the Session:
Director's address
Regional
Orientation to the Scientific Group
(Dr Y. H. Paik)
Adoption of the Agenda
Plenary session
Overview of epidemiology of
hepatitis B in the Western
Pacific Region (Dr K. Nishioka)
l
Specific screening techniques for
markers of hepatitis B infection
(Dr K. Nishioka)
Review of the progress in prevention
in hepatitis B vaccines
(Professor Oon Chong Jin)
Measures to interrupt perinatal
transmission of hepatitis B
(Dr M. Yano)
Thursday
30 September 1982
Review of pathogenic role of HB
infection especially the persistent
carrier state in chronic liver diseases
and primary hepatocellular carcinoma
(Professor H. Suzuki)
country reports
Friday, 1 October 1982
country reports (continued)
Appropriate ways and means of establishing
suitable mechanisms for collaborative
studies in hepatitis and its related liver
diseases (Dr F. Assaad)
Meeting of directors of WHO collaborating
centres
I
I
- 50 -
..
ii
II
Annex 2
Saturday
2 October 1982
Field visits
Plenary session
II
Examination and adoption of
reco1lllllendations
Closing ceremony
II
Ii
Ii
I
I
i
1
)1
- 51 -
ANNEX 3
OPENING SPEECH OF THE REGIONAL DIRECTOR AT THE
SCIENTIFIC GROUP ON VIRAL HEPATITIS B
AND ITS RELATED LIVER DISEASES
NAGASAKI, JAPAN, 29 SEPTEMBER - 2 OCTOBER 1982
Distinguished Members,
Ladies and Gentlemen,
It is in my capacity as Director of the World Health Organization
Regional Office for the Western Pacific that I have the privilege of
welcoming you to this Scientific Group on Viral Hepatitis B and Its Related
Liver Diseases.
I wish to express my grateful thanks to the Government of Japan for
agreeing to host this meeting in Nagasaki and to Dr Yokouchi, Director of
the Nagasaki National Chuo Hospital, and his staff for their valuable
assistance in organizing the meeting.
The Nagasaki Chuo National Hospital has a distinguished record of
achievement and activities in clinical services and research for liver
diseases and it was recently designated as a WHO Collaborating Centre for
Research on Hepatitis. I am sure that the members of this group will have
a chance to observe this hospital during the meeting. It is therefore
appropriate that this institute should host an international meeting like
this in the historical and beautiful city of Nagasaki in collaboration with
another WHO Collaborating Centre for hepatitis in Japan - The Tokyo
Metropolitan Institute of Medical Sciences.
According to the studies carried out by Dr Nishioka, Director of the
WHO Collaborating Centre for Reference and Research on hepatitis at the
Tokyo Metropolitan Institute of Medical Sciences, it is estimated that
there are at least 210 million hepatitis B virus carriers in the world,
170 million of whom are in the Asia-ocenia area. The 1970s saw rapid
advances in relation to the etiology, epidemiology and immunology of
hepatitis. There has also been significant progress in specific methods of
screening viral markers of hepatitis B infection. All the epidemiological
studies using hepatitis B antigens have clearly shown a causative
association between persistent infection of HB virus and
clinico-pathological changes ranging from hepatitis through liver cirrhosis
to primary hepatocellular carcinoma. The development of liver biopsy
methods has contributed to the classification of liver diseases based on
histological findings, while the measurement of serum enzymes has
elucidated the existence of anicteric hepatitis. Also noteworthy are the
new studies by our Japanese colleagues on the administration of hepatitis B
immunoglobulin shortly after birth to provide protection against infection
early in lfe, which often leads to a persistent carrier state. The most
important means of achieving widespread prevention of hepatitis B is now
active immunization with purified 22 Nanometer particles of surface antigen.
Hepatitis vaccines have been shown in several countries to be safe,
immunogenic and effective in prevention of the disease.
- 52 -
Annex 3
Although other cocarcinogenic influences, including genetic,
immunological and environmental factors, may be necessary for the induction
of hepatocellular carcinoma, the persistent HB virus has been shown to be a
significant oncogenic factor in primary hepatocellular carcinoma.
Studies in many countries have demonstrated an excessive prevalence of
hepatitis B surface antigen in patients with liver cirrhosis and primary
hepatocellular carcinoma as compared with matched control groups.
Hepatitis B virus carriers are, therefore, assumed to constitute a high
risk group liable to develop chronic hepatitis, liver cirrhosis and liver
cancer. If this is the case, the incidence not only of hepatitis But also
of this form of cancer may be reduced greatly, by control of this viral
infection.
The high rate of infection with hepatitis B and also of hepatocellular
carcinoma in the Western Pacific Region points to the urgent need to
develop a closely knit functional network of collaborative research
activities in the Region.
In developing a collaborative programme, the
first step to be taken in many developing member states would be the
development of research infrastructure and capability through institution
strengthening and training of workers.
In order to do this, it will be extremely important to standardize and
widely distribute the low-cost but sensitive reagents for detection of
hepatitis virus markers to permit a field epidemiological study, which
would measure the extent and patterns of hepatitis prevalence, as well as
meaningful international comparison of data. There are still many things
awaiting clarification in the field of hepatitis. The route for vertical
transmission from infected mothers and newborn infants is not clear, and
factors involved in the development into a chronic carrier state should be
elucidated. Measures to interrupt perinatal and horizontal transmission
during infancy, which have already been initiated in Japan, merit further
evaluation. In this connexion, further efforts are needed to make a
low-cost immunoglobulin with a high titre of antibody to hepatitis B
surface antigen. The long-term outcome of hepatitis B infection acquired
early in life should be studied with particular attention to the role of
hepatitis B virus in hepatocellular carcinoma.
Although the efficacy of hepatitis B vaccines has been proved in many
countries, these vaccines are still so very expensive, because of the
lengthy and elaborate manufacturing process, that countries which need them
badly cannot afford them. Ironically, sources of positive donor plasma
sufficient to produce large quantities of vaccine are disproportionately
located in countries which have the least capability to produce vaccine for
their own use. Sound immunization strategies are therefore necessary to
ensure selective immunization for high risk groups according to prevailing
local patterns of hepatitis B prevalence.
To this effect, many well controlled trials with hepatitis B vaccines
in Member States should be encouraged.
..
53
International collaboration in the field of viral hepatitis research
has already been developed and it is urged that such collaboration should
continue. WHO, as the directing and coordinating authority on
international health work, will play the role of catalyst.
With these brief reflections, I will conclude by wishing you a most
interesting and successful meeting and by expressing the hope that the
final outcome of this meeting will contribute in due course to the
formulation of a strategy for collaborative need-based research on this
preventable disease - viral hepatitis - which is essential if we are to
reach our long-term goal of Health for All by the Year 2000.
Thank you.
_ 54 _
ANNEX 4
APPROPRIATE WAYS AND MEANS OF ESTABLISHING SUITABLE
MECHANISMS FOR COLLABORATIVE STUDIES IN HEPATITIS
AND ITS RELATED LIVER DISEASES
High quality scientific research work, of both fundamental and applied
nature, in several disciplines is essential for the achievement of the goal
of the WHO programme on the prevention and control of disease. The
biomedical and operational research currently in progress in many excellent
national laboratories and institutes is valued and encouraged by WHO and
the Organization plays a role in the initiation and support of such
programmes. The practical application of fundamental advances to disease
prevention and control is an area in which WHO, through its collaborating
centres, plays a leading role. WHO is anxious to encourage and coordinate
collaborative research progammes in the field of viral hepatitis aimed at
improvements in diagnosis, epidemiological understanding, prophylaxis and
therapy.
Research on viral hepatitis and its sequelae brings to the fore:
(a)
the constraints under which research - especially when it deals
with human subjects - has to be conducted; and
(b)
the pressing need for WHO to assume its leading coordinating role
to meet the.e constraints.
CONSTRAINTS TO COLLABORATIVE RESEARCH - WHO's ROLE
The constraints facing research on hepatitis can be summarized under
the following headings:
1.
Conceptual
The place of research on hepatitis within the total picture of WHO's
collaborative research effort, and the priority it assumes, have to be
clearly defined. Hepatitis is a global problem, but, admittedly, it
assumes different priorities in different regions.
The general aim and the expected outcome of a collaborative research
effort should be clearly outlined in terms of direct or eventual impact on
prevention and control of the disease.
The study protocols, clear and unambiguous, should detail what is to
be done, how it is to be done, by whom, where, on what subjects (in case
humans are involved), what materials and methods are to be used and over
what period. Protocols should, in addition, outline how all these efforts
would answer the questions that have led to the collaborative research.
II,
ss
Annex 4
WHO is in the best position to bring together workers from various
disciplines working on the same subject and obtain a consensus on how best
to tackle a problem.
2.
Technological
Only methods and materials that represent the latest in design and/or
development and have received the scientific world's endorsement can be
used in collaborative studies, for example:
reagents that have been tested and approved in more than one WHO
collaborating centre;
vaccines that meet WHO requirements;
study designs that comply with WHO guidelines or manuals; etc.
Through its network of collaborating centres, WHO is in the best
position to secure the most appropriate teChnology.
3.
Ethical
In the field of communicable diseases, intervention involving humans
is judged in terms of:
potential benefits versus possible risks; and
ultimate use to prevent/control a disease in question.
In research on hepatitis, the following examples may be given:
the hepatitis B vaccine in use in the WHO collaborative study in
Burma has been tested on animal models, in human volunteers and in
large-scale trials in humans; and
the investigation for HBeAg in the same study to determine
eligibility for vaccination.
An added ethical problem in hepatitis research is the dichotomy
between prevalence of the disease and the location of centres of
excellence. The centres of excellence in hepatitis research are almost
exclusively located in the highly industrialized countries, while the high
prevalence of the disease, the high carrier rate and the high frequency of
chronic liver disease (including hepatocelular carcinoma) are all in the
tropical developing world.
_ S6 _
Annex 4
WHO is in the unique position of being able - because of its
coordinating role - to secure an ethical design without sacrificing
scientific rigour. Furthermore, working on behalf of all Member States, WHO
has the mandate to bring together workers from the developing as well as
the developed world to find solutions to problems of worldwide importance.
4.
Managerial
For WHO to sponsor a collaborative study the necessary manpower,
adequate physical facilities, and a sound management structure shuld first
be secured. WHO can play an important role in training scientists, in
upgrading physical facilities .ad, through visits of scientists and
continued exchange of information, in upholding sound management of
research.
5.
Funding
In only a few instances would collaborative research be entirely
funded by participating laboratories/institutes. In most cases, WHO is
called upon to play its catalytic role in securing funds from interested
donor agencies. WHO has been actively pursuing this course to finance
research bearing on its priority programmes; its own research budget is too
small to provide anything but seed money.
MANAGEMENT OF COLLABORATIVE RESEARCH WITHIN WHO
Over a period of years WHO has evolved mechanisms for delineating
areas of collaborative research, of setting priorities within these areas,
and of selecting concrete proposals within a set priority.
The Constitution of the World Health Organization requires its
Executive Board to submit to the World Health Assembly for consideration
and approval a general programme of work covering a specific period. At
its Sixty-ninth session, in January 1982, the Executive Board confirmed
that the Seventh Genral Programme of Work for the period 1984-1989
constituted WHO's support to the Global Strategy of Health for All by the
Year 2000 and submitted it to the Thirty-fifth World Health Assembly, which
approved it with full acclaim, in May 1982.
Within the Seventh General Programme of Work, Disease Prevention and
Control comes under the major programme area (one of four on the classified
list of programmes) of Health Science and Technology. Health science and
technology, as an association of methods, techniques and equipment,
together with the research required to develop them, constitute the content
of a health system. Health science and technology programmes will,
therefore, deal with:
the identification of technologies that are already appropriate for
delivery by the health system infrastructure;
_ 57 _
Annex 4
the research required to adapt and/or develop technologies that are
not yet appropriate for delivery;
the transfer of appropriate technologies;
the search for behavioural alternatives to technology; and
the related aspects of social control of health science and
technology.
They will thus involve a high degree and wide variety of scientific
research, aimed at the validation, generation and application of knowledge,
and will include the identification of standards and norms.
Within Disease Prevention and Control, control of communicable
diseases calls for, among other things, the development and improvement of
methods used to help define problems, establish priorities and indicate
appropriate and timely action. Problem identification will enable
research to be undertaken to develop new and improved tools for prevention
and control. Selection of, and research on, diagnostic, prophylactic and
therapeutic substances of recognized quality, safety and efficacy enable
health systems to concentrate resources on those most relevant.
Within the broad outlines given in the Seventh General Programme of
Work, medium-term programmes are elaborated to form the basis of the
programme and budget. The WHO Virus Diseases medium-term programme
represents the pooled efforts of WHO regional offices and headquarters. It
is based on a study by the Directors of WHO Collaborating Centres for
Reference and Research on Viral Diseases in 1981. 1 The medium-term
programme stresses the magnitude of the viral hepatitis problem and
emphasizes in particular the risk of chronic disease and hepatocellular
carcinoma to chronic carriers of hepatitis B virus surface antigen
(HBsAg). It outlines in· broad terms areas of priority in hepatitis B
research. Emphasis is placed on the use of modern biotechnology, f?r
example: DNA hybridization and DNA recombinant techniques, synt~es1s of
polypeptide synthesis, etc. Stress is also laid on the sound tr1al of new
procedures or products.
For hepatitis B research the framework of WHO's
a:ti~n a~H~ea~~8until
the end of the presen: decade ha~ b:~nc~:!~e:o::d s!~e~~is~~ in ~ember
network of collaboratlng anhd n~t~?n this framework as a collaborative
States to implement researc Wlt 1n
effort.
llaborating Centres for Virus
lMeeting of Directors of WHO Co
h
19S1 (~~QIV~~I~~·l).
h Geneva, 2-6 Nove~ ~~
Reference and ReSeare ,
_ 58 _
Annex 4
IMPLEMENTATION
In implementing a research programme, various methods may be
followed. The following is only one example, based on the accumulated
experience of other programmes. It described a step-by-step programme and
can be summarized as follows:
1.
Definition of the problem in terms of:
Magnitude of the disease problem;
gaps in knowledge that need research, set within a priority system;
technologies available that can be applied in research;
appeal to public health authorities, medical profession and funding
agencies; and
rough estimate of cost and cost-effectiveness.
This task is usually entrusted to a scientific group or similar
meeting of scientists from a number of disciplines, convened by WHO. Two
such groups have been convened by WHO, one in May 1982 in Munich,l and
the present meeting.
2.
Preparation of a concrete proposal (or set of proposals) for a
collaborative research effort. A small number of scientists, preferably:
from among the Directors of WHO Collaborating Centres, to maintain
the communication facilities that exist between the Collaborating
Centres and the Organization, and among themselves; and
those it is anticipated will take an active part in the study,
either directly or through technological support or follow-up;
are given the task of preparing the proposals with the understanding
that:
they will defend the proposals wh en sub'
mltte d to relevant bodies
and other scientists; and
they will present it to donor
.
agencles, international organizations
and governments.
1J .
olnt WHO/Max v p t
Hepatitis Munich 26·28 e tenkofer-Institute
Round Table Discussion on
, - May 1982.
,
- 59 -
Annex 4
To carr~ ou~ these functions it may be advisable to .elect from the
The focal
pOint w~uld prefe~abl~ ~e the director of an institute that can provide the
managerlal.and SCientifiC back-up, and ideally be the director of a WHO
Collaborating Centre.
st~rt one SC1entlst from that small group as the focal point.
3.
Endorsement by the WHO Adivsory Committee on Medical Research (ACMR)
Depending on the pr~o~ity acco~ded to research - or different aspects of •
research - on hepatitis B and its related diseases by the regional offices
pro~osals can be submitted to Regional ACMRs. The proceedings of the
'
Regional ACMRs are presented to the Global ACMR for adoption and further
endorsement if the case arises.
Endorsement by the ACMR puts research on hepatitis in its proper
prospective within WHO's collaborative research context. When first
discussed, it may therefore be advisable to have the focal point, mentioned
above, to present and defend research proposals.
4.
Provision of a management structure for the implementation of a
research programme. A small group of world-renowned scientists who are
directly involved in research on hepatitis may be called upon to manage the
WHO collaborative research. The composition of the group would preferably
be rotating and the members partly from the scientific group mentioned
under (2) above. The group would give the general outline for protocols
for studies, and would screen protocols submitted to WHO, i.e. provide peer
review.
5.
Securing of financial back-up. WHO, regionally and globally, would
approach interested donor agencies to secure funding over a reasonable
period of time. WHO may calIon the focal point mentioned under (2), or
members of the group mentioned under (4), to present the subject matter to
donor agencies, i.e. take part in promoting fund raising.
D.
Coordination of research. WHO would approach interested governments
and competent institutes to participate in collaborative research.
Especially in case of contacting governments, the WHO regional offices are
the best suited for the purpose. Again, WHO may calIon outside scientists
(see points 2 and 4) to help in coordinating research.
7.
Evaluation of the research effort.
Evaluation is very important to:
ensure a sustained high level of scientific work; and
secure continued funding.
An independent group of scientists of different disciplines (see
point 1) would review on-going research and submit its report to the WHO
ACMR, to participating parties and to donor agencies. Publication in
world-known scientific journals provides excellent support.

WP_CRP_ICP_BVM_020_eng (2.889Mo)

Transcription

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