WP_CRP_ICP_BVM_020_eng (2.889Mo)
Transcription
WP_CRP_ICP_BVM_020_eng (2.889Mo)
(~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 Acute viral hepatitis 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 Other points of interest 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 Acute viral hepatitis 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 Prevalence of markers of HBV infection 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 Chronic liver disease and primary hepatocellular carcinoma 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 Other points of interest 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 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 Prevalence of markers of HBV infection 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 Chronic liver disease and primary hepatocellular carcinoma 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 Other points of interest 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 Acute viral hepatitis 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 Prevalence of markers of HBV infection 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 Other points of interest 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 Acute viral hepatitis 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 Chronic liver disease and PHC 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 Other points of interest 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 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 Prevalence of markers of HBV infection 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 liver disease and PHC 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 Other points of interest 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 Acute viral hepatitis 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 Prevalence of markers of HBV infection 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 Chronic liver disease and PHC 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 Other points of interest 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 Acute viral hepatitis 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 Prevalence of markers of HBV infection 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 Chronic liver disease and PHC 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 Other points of interest 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 Acute viral hepatitis 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 Prevalence of markers of HBV infection 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 Other points of interest 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 Acute viral hepatitis 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 Chronic liver disease and PHC Both disease are common but precise data on the frequency and the presence of markers of HBV infection are lacking. 4.11.4 Other points of interest 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 Department of Internal Medicine 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 Department of Internal Medicine 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 Department of Internal Medicine 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 for the Western Pacific P. O. Box 2932 Manila Philippines Dr Hu Ching Li Regional Adviser in Maternal and Child Health WHO Regional Office for the Western Pacific 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 for the Western Pacific P. O. Box 2932 Manila Philippines Dr T. Umenai Regional Adviser in Communicable Diseases WHO Regional Office for the Western Pacific 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.