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Seroepidemiology of hepatitis B virus infection in Saudi Arabian children: A baseline survey for mass vaccination against hepatitis B
Journal of Infection (1992) 24, 197-2o6
EPIDEMIOLOGY
S e r o e p i d e m i o l o g y o f h e p a t i t i s B v i r u s i n f e c t i o n in S a u d i A r a b i a n c h i l d r e n : a b a s e l i n e s u r v e y for m a s s v a c c i n a t i o n against hepatitis B F. Z. AI-Faleh, *11 E. A. Ayoola,* M. Arif,* S. Ramia,* R. A1-Rashed,* M. A1-Jeffry,~ M. A1-Mofarreh,$ M. A1-Karawi~ and M. AI-Shabrawy*
*College of Medicine and King Khalid University Hospital, tMinistry of Health, :~Social Insurance Hospital, and ~Riyadh Armed Forces Hospital, Riyadh, Saudi Arabia Accepted for publication 22 August 1991 Summary Saudi Arabia is considered to be an area of endemic hepatitis B virus (HBV) infection. By adult age, 7 % persons have hepatitis B surface antigen (HBsAg) and about 7o % have one or m o r e H B V markers. In order to provide a baseline for the integration of hepatitis B vaccine into the extended p r o g r a m m e of immunisation (EPI), a populationbased survey of H B V markers was made among Saudi children. T h e overall prevalence of H B s A g was 6"7%, with at least one H B V marker being positive in 19'7 % persons tested. T w o peaks of H B V prevalence were observed in the 7- and ioyear-old children respectively. T h e prevalence of H B s A g was steady in all age groups with identifiable but insignificant peaks in children aged 4 and 7 years respectively. Despite the apparent homogeneity of the Saudi population, the prevalence rates of H B V varied a m o n g the regions and were higher in urban dwellers. T h e r e was no significant difference in the H B s A g prevalence for the sexes (7'3 ~o for males and 6.0 ~o for females). Socioeconomic factors and family size did not significantly influence the prevalence of H B V among children. O f 307 HBsAg-positive children, 55 (17"9%) were positive for HBeAg. T h e early acquisition of H B V in the Saudi population is confirmed. T h e most effective strategy for H B V control, therefore, is by mass vaccination of all Saudi infants. An extension of the immunisation p r o g r a m m e so as to include all pre-school children should further reduce the reservoir of H B V in Saudi Arabia. A repetition of a similar survey after 5 and IO years should be made in order to measure this reduction. Introduction
Hepatitis B virus (HBV) infection, with its chronic sequelae of cirrhosis of the liver and hepatocellular carcinoma (HCC), constitutes a major health problem in countries where H B V is hyperendemic. 1-4 Studies among Saudi Arabian adults have established the high prevalence of H B V in the general population and the significant contribution by H B V to acute viral hepatitis and chronic l i v e r d i s e a s e ) -s T h e a v a i l a b i l i t y o f safe a n d efficacious v a c c i n e s h a s led to t h e f e a s i b i l i t y o f effective c o n t r o l o f H B V i n f e c t i o n , e s p e c i a l l y in a r e a s o f h i g h p r e v a l e n c e w h e r e il Address correspondence to: Professor F. Z. A1-Faleh,Department of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia. oi63-4453/92/o2oi97 +09 $03.00/0
© I99Z The British Society for the Study of Infection
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most chronic H B V carriers acquire the infection very early in life. 9 It is n o w generally accepted that an appropriate strategy in such circumstances involves the vaccination of infants. Based on this strategy and the epidemiology of H B V in the general population, the government of Saudi Arabia p r o p o s e d the integration of H B V vaccination into its extended p r o g r a m m e of immunisation (EPI) and also mass vaccination of all pre-school and school children. 1° As part of the p r o g r a m m e , precise determination of the epidemiology of H B V in Saudi children was considered m a n d a t o r y in view of the paucity of s,,t~ch available information, la In order to provide this information, and to obtain baseline data for the vaccination programme, we report here the results of a p o p u l a t i o n - b a s e d survey aimed at determining the age-specific prevalence of hepatitis B virus markers among children aged I-IO years.
Location, population and methods Study location Covering about 2.2 million km 2 and located in the Arabian Peninsula, Saudi Arabia has an estimated population of Io million people, almost equally distributed among the u r b a n and rural areas. Significant socioeconomic progress within the last two decades is manifested b y a well-developed road network, telecommunications, water supply and distribution of electricity as well as a comprehensive health care delivery system t h r o u g h o u t the country. T h e s e have lessened the differences b e t w e e n the rural (village or town of less than 30000 people) and urban populations. In some villages, water is obtained from deep wells within c o m p o u n d s or from distribution b y water tankers. T h e r e is no difference b e t w e e n rural and u r b a n people with regard to ethnicity or to cultural and religious practices. In m a n y areas, about 2o-3o % of the population are Bedouins with a nomadic life style and who live mostly in tents which are not registered. T h e health care delivery system divides the country into I4 administrative regions each of which comprises a group of primary health care centres ( P H C C ) . T h e catchment for each P H C C is derived from a cluster of households located within well-defined boundaries. Each household has a registration file in the P H C C in which all demographic and health records of family m e m b e r s are kept. T h e projected total n u m b e r of households was estimated as 1816373 with an average family size of seven. 12 Sample size T h e national census has estimated that about 25 ~/o of the population (i.e. 2"5 million) are children aged from I to Io years, proportions of males and females being approximately equal. O n the assumption that the prevalence of H B s A g in Saudi children might be about I o - 2 o % with a standard error of o'oo5, the sample size required for the study was calculated to be 36oo. In order to a c c o m m o d a t e the proportion of tent dwellers (Bedouins) 2o % was added, giving a projected total of 432o. It was decided to survey Io % of the estimated total households (i.e. x816), recruiting not m o r e than two children from each household.
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S a m p l i n g strategy T h e sampling m e t h o d often used for surveys of i m m u n i s a t i o n was modified so as to include the strategy of probability proportionate to size. 13 T h e sample size for each zone was calculated according to the ratio of the zonal population to the national census. D e p e n d i n g on the sample size, one or two u r b a n areas and an equal number of rural areas within the same zone were randomly selected (Fig. I). Within each area, clusters were defined by the boundaries of the catchment of the respective P H C C and households within these clusters were r a n d o m l y selected and visited by well-trained survey teams who carried an introductory letter from the Ministry of Health encouraging co-operation from parents. In each household visited, one or two children aged i - i o years were recruited into the study. N o n e of the eligible children refused to participate. Collection o f data and blood s a m p l e s T h e field word was u n d e r t a k e n in D e c e m b e r 1989 and J a n u a r y 199o. After i n f o r m e d consent had been obtained, details of age, sex and educational status of each of the recruited children were recorded. In addition, the number of children in the family, the position of the participant, the occupation and the
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educational qualification of the father or guardian were recorded. T h e investigators noted the type of house. T h e r e a f t e r , about 5-zo ml blood were obtained from the child by venesection. S e r u m was separated by centrifugation, coded and stored at - 7 o °C until n e e d e d for testing. Laboratory methods Hepatitis B surface antigen (HBsAg), antibody to HBsAg (anti-HBs) and antibody to core antigen (anti-HBc) were tested by E L I S A with the use of commercially available test kits (Organon Teknika). Samples which were HBsAg positive were tested for hepatitis B e antigen (HBeAg) and its antibody (anti-HBe) by means of E L I S A kits from Organon Teknika. Socioeconomic stratification T h e socioeconomic status of the child was taken as that of the father or guardian and classified from the 'socioeconomic score' derived from the type of house ( m u d built or tent I, apartment or ordinary house 2, villa 3); the father's education (primary or grade school or less I, s e c o n d a r y / h i g h school 2, University or professional qualification 3). T h e father's occupation was scored from I to 6 according to the nature of his work, e.g. labourer z, trader 2, etc. A score of less than 4 from a m a x i m u m score of I2 was classified as low socioeconomic status, 5-8 as middle and above 9 as upper class. Statistical analysis Chi-square (X2) and Fisher's exact probability tests were used to compare proportions. Definition Participants who were HBsAg positive were classified as ' H B s A g carriers', while possession of any H B V m a r k e r (HBsAg, anti-HBc, anti-HBs) was considered as evidence of H B V exposure (past or present). Results Overall prevalence A m o n g 4575 children studied, the prevalence of HBsAg was 6"7 %. T h e H B V exposure rate was I9"7 % (Table I). Comparison of urban and rural inhabitants indicated significant differences in respect of the prevalence rates of H B s A g (P = o.o2) and for H B V exposure (P = 0"007) (Table I). Age and sex-specific prevalence As shown in Fig. 2, the highest rate of HBsAg positivity (9"7 %) was in the age group of I year. Thereafter, the rate declined, and varied between 5"~ ~o and 7"8 ~o with no significant peak of infection. Although the overall prevalence rate of HBsAg was higher among males than females, the difference was not statistically significant (Table I). Comparison of the rates for the various age groups revealed no significant difference between the sexes. W h e n exposure rates were compared, however,
Hepatitis B virus infection
2OI
T a b l e I l i b V markers among Sauce children Per cent positive for Number tested
HBsAg
Anti-HBc
Anti-HBs anti-HBs
Anti-HBc + marker
any
Sex
Male Female Location Urban
2458 2117
7"3 6"0
4.2 4"1
5"7 6"0
3'0 3"0
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5"1 4"9 7"3 5"8
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18"O 17"4 23"4 19"7
Age (years) 1-3 4-6 7-10 All ages
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(Age in years) Fig. 2. Prevalence of H B V markers in Saudi children. ( • ) , H B s A g ; ([]), a n t i - H B c ; ([]), antiH B s ; ([]), a n t i - H B c + H B s . N u m b e r tested = 4575.
significant differences were f o u n d for the age-groups o f 2 years ( P = 0"007) and IO years ( P = 0"03) (Fig. 3). In children aged 3 and 4 years, the e x p o s u r e rates were h i g h e r in the u r b a n residents than in their rural c o u n t e r p a r t s ( P = o ' o o I , 0"003, respectively) (Fig. 4).
HBV prevalence according to regions T a b l e II summarises the prevalence of H B V infection in the various regions. T h e lowest prevalence o f H B s A g was o b s e r v e d in Najran, despite the high prevalence of 9"6-I7 % in the n e i g h b o u r i n g regions o f A l b a h a , Asir and Gizan.
Infective pool (HBeAg positivity) a m o n g Saudi children O f 3o7 H B s A g - p o s i t i v e samples, 55 (I7"9 %) were positive for H B e A g . T h e r e was no significant difference (P = 0"3) b e t w e e n the f r e q u e n c y o f H B e A g in the
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males (36 of i8o children) and that in the females (I9 of I27 children). T h e r e was no significant clustering of HBeAg in any particular region or age groups (Table III). Socioeconomic factors, family size and I-IBV prevalence
HBsAg was present in 7"5 % (80 of Io7I), 6.o % (gz of I54I) and 7 % (I33 of I9I I) of children in the ' u p p e r ' , ' m i d d l e ' and 'lower' socioeconomic classes respectively, there being no significant difference. Of 52 unclassifiable children, two (3"8 %) were HBsAg positive. Similarly, there was no classrelated difference in the HBV exposure rates. Of the children from small (I-5), m e d i u m (6-I0) and large ( > Io) families, 6 % o f 2 I o z , 7"z % of I983 and 8.2 % of 29z children respectively were HBsAg positive; 6"7% of I98 with unavailable data were positive also. T h e differences among the groups were insignificant.
Hepatitis B virus infection
203
Table II Prevalence of HBsAg and H B V markers among Saudi children
according to regions Percent positive for Region
Areas
Number tested
Central
Riyadh Qassim Hail A1-Hafouf/ Dammam Qarayat Tabouk Madina Makkah Jeddah Taif Aseer A1-Baha Gizan
8oo 2oi 209 573
8"6 3"5 2"9 3'1
177 15o 35o 240 456 4°0 476 I45 283
9"0 I 2"8 5"7 5"8 3'7 7'5 lO' 3 7'6 8'8
Eastern Northwestern Southwestern Southern
HBsAg
Any marker i9.8 22"9
6'2 9"6 40' I 53"3 13"4 13"8 i8-o z i-3 I8-o I4"5 27'9
Table III Frequency of HBeAg among HBsAg-positive Saudi children Number tested (number positive for HBeAg) in each age group Province/ region Central Eastern North-western South-western Southern Total
I-3 years
4-6 years
7-1o years
17 (4) 7 (I) 2o (4) 23 (6) z6 (I) 93 (16)
35 (3) 6 (I) 16 (4) I9 (5) 27 (5) lO3 (20)
30 (6) 5 (2) I9 (5) 19 (3) 38 (3) II1 (19)
Total 82 (13) I8 (4)
55 (I3) 61 (IO) 91 (9) 3O7 (55)
Discussion
Hepatitis B virus (HBV) infection is endemic in Saudi Arabia, where about 7"4% adults are positive for HBsAg and about 6o % have evidence of past H B V infections) '6'n'14 This population-based study shows that 6"7 % Saudi children are HBsAg positive and about 2o % have been exposed to HBV. This further confirms that H B V infection is acquired very early in life in this population, a pattern which is common in all areas of endemic HBV. Earlier studies involving relatively small numbers of Saudi children, gave conflicting reports with respect to sex-related differences in H B V prevalence. For example, in a limited study in Riyadh, the sexes had an approximately equal prevalence, 15 whereas in Gizan male outnumbered female children 2 to I in prevalence. 14 Our results indicate no significant sex difference in either the HBsAg carrier rate or that for H B V exposure. Although a significant
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preponderance of HBV carriers in males were reported from Africa and the Far East, the sex differences vary remarkably in magnitude from country to country and also within each population. 4' 9.16 Although it has been speculated that the intersex variation in HBV antigenaemia in older age groups may be attributed to more efficient HBsAg clearance in females, 17 the precise reasons for these variations are yet to be established. It is generally accepted that horizontal transmission is the major mode of infection in endemic areas outside East Asia. 18'19 T h e observation in our study of relatively high prevalence among infants (i year old), however, suggests the possibility of significant HBV transmission during the perinatal period or soon after. 2° This may relate to the HBsAg status of the mothers as was demonstrated in the Gambia. 19 Irrespective of the HBeAg status, vertical (mother to child) transmission takes place in Saudi Arabia. 21,22 Even so, the relative contribution to the HBV-infected pool in the Saudi population is low. ~4 T h e absence of any significant peak of HBV prevalence at school age suggests that intrafamilial spread, through close contact, may be an important mode of HBV transmission. Kissing of newborns and children by friends and relatives is a major cultural practice among the Saudis. ~ Despite the homogeneity of the Saudi population with respect to habits, cultural practices and socioeconomic factors, there was a marked regional variation in HBV prevalence (Table II). Generally, the southern regions of Saudi Arabia had greater endemic HBV rates compared to those of others (e.g. Hail). With an overall HBsAg carrier rate of I9 % and an exposure rate of 53 %, Tabouk in the Northwestern province of Saudi Arabia may be regarded as hyperendemic focus of HBV infection. Variation within homogeneous populations is well recorded but remains unexplained. 19'2a.2~ T h e dynamics of HBV exposure in different populations vary and may be influenced by interaction with populations of neighbouring countries. This concept is supported indirectly by the relatively high prevalence in regions (e.g. Tabouk, Gizan) which share boundaries with Jordan and Yemen, where HBV is endemic. T h e infective pool of persons is assessed by determining the prevalence of HBeAg. 25 In this survey, HBeAg was found in about I 7 % , being evenly distributed among both sexes and all ages. This is similar to the observation among Saudi adults, in whom the incidence is about IO %,~4 but is different from the rates of 5o-90 % reported for African children. ~9'25 We found no relationship between HBV prevalence and socioeconomic status or family size. This lack of association is not surprising in view of the fact that the population has retained its tradition and cultural habits despite the socioeconomic development in the last two decades. Furthermore, those classifiable as belonging to the 'upper class' have continual interaction and share similar habits and cultural practices with relatives in the villages. It is apparent from the above that socioeconomic development alone could not reduce transmission of HBV or its prevalence in the Saudi population. Therefore, the mass vaccination programme recently introduced in Saudi Arabia is justified and remains the best method of control under prevailing circumstances. ~° As indicated by the pattern of HBV infection in the Saudi children, HB vaccine should not only be integrated into the expanded
Hepatitis B virus infection
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p r o g r a m m e o f i m m u n i s a t i o n ( E P I ) , b u t all p r e - s c h o o l c h i l d r e n s h o u l d b e v a c c i n a t e d f o r t h e n e x t f e w y e a r s in o r d e r to r e d u c e t h e r e s e r v o i r o f H B V i n f e c t i o n in t h e s e c h i l d r e n a n d s u b s e q u e n t l y t h e p r e v a l e n c e o f c h r o n i c liver diseases i n c l u d i n g h e p a t o c e l l u l a r c a r c i n o m a in t h e p o p u l a t i o n o f S a u d i A r a b i a . Comparison of the present findings with those of similar surveys planned for t h e f u t u r e (in 5 a n d IO y e a r s ) , will p r o v i d e u s e f u l i n f o r m a t i o n o n t h e e f f e c t i v e n e s s o f t h e p r o g r a m m e o f m a s s i m m u n i s a t i o n a g a i n s t h e p a t i t i s B. (This study is part of a research project supported by the Ministry of Health, K i n g d o m of Saudi Arabia. We thank all the Directors-General of Health of Saudi Arabia and the Supervisors of the Primary Health Care Units for their co-operation and assistance.) References
1. Beasley RP, Hwang LY, Chein CS et al. Hepatocellular carcinoma and hepatitis B virus : a prospective study in 22707 men in Taiwan. Lancet 198I ; ii: 1129-1133. 2. Heyward WL, Bender TR, Lancer AP, Francis DP, McMahon BJ, Maynard JE. Serological markers of hepatitis B virus and alpha-fetoprotein levels preceding primary hepatocellular carcinoma in Alaskan Eskimos. Lancet 1982 ; ii: 889-89I. 3. Viola LA, Barrison IG, Goleman JC et al. Natural history of liver disease in chronic hepatitis B surface antigen carriers. Survey of lOO patients from Great Britain. Lancet 1981; ii: II56-II59. 4. Ayoola EA. Viral hepatitis in Africa. In: Zuckerman AJ, Ed. Viral hepatitis and liver diseases. New York: Alan R. Liss, I61-I69. 5. E1-Hazmi MAF, A1-Faleh FZ, Warsy AS. Epidemiology of viral hepatitis among the Saudi population: a study of viral markers in Kahiber. Saudi Med J I986; 7: I22-I29. 6. A1-Faleh FZ. Hepatitis B infection in Saudi Arabia. Ann Saudi Med I988 ; 8: 474-48o. 7. Shobosky OA, Serebeer FE. The aetiology of acute viral hepatitis in the western region of Saudi Arabia. Tram R Soc Trop Med Hyg 1987; 8x : 219-z21. 8. Ashraf SJ, Arya C, Sayed M e t al. A profile of primary hepatocellular carcinoma patients in Gizan area of Saudi Arabia. Cancer 1986; 58: 2163-2168. 9. Barin F, Perrin J, Chotard J e t al. Cross sectional and longitudinal epidemiology of hepatitis B in Senegal. Prog Med Virol I98I; 27: I48-I62. IO. A1-Faleh FZ, A1-Jefri M, Ayoola EA. Mass vaccination against hepatitis B in Saudi Arabia. The 199o Symposium on Viral Hepatitis and Liver Diseases, April 4-8, 199° , Houston, Texas, U.S.A. (Abstr. 227). I I. Abdurrahman MA. Hepatitis B infection and immunization: a review. Saudi Med J 1984; 5: 369-376. I2. National populations Atlas of Kingdom of Saudi Arabia. King Saud University, Riyadh, Saudi Arabia I98I: I9. 13. Henderson RJ, Sundereson T. Cluster sampling immunization coverage: a review of experience with a simplified method. Bull W H O I982; 6o: 253-260. 14. Arya SC, Ashraf SJ, Parade CM et al. Hepatitis B virus in Gizan, Saudi Arabia. J IVied Virol 1985; 17: 267-274. 15. Ramia S, Bakir TS, Hossain A et al. Prevalence and subtype of hepatitis B surface antigen (HBsAg) in the Saudi population. Trop Geogr Med 1986; 38: 63-69. 16. Tabor E, Bayley AC, Cairis J, Pelleu L, Gerety RJ. Horizontal transmission of hepatitis B virus among children and adults in five rural villages in Zambia..7 Med Virol 1985 ; 15: 113-12o. 17. Szmuness W, Harley EJ, Ikram H, Stevens CE. Sociodemographic aspects of the epidemiology of hepatitis B. In: Vyas GN, Cohen SN, Schmid R, Eds. Viral hepatitis : a contemporary assessment of aetiology, epidemiology, pathogenesis and prevention. Philadelphia : Franklin Institute Press, 1978: 297-320. 18. Prince AM, White T, Polloch N e t al. Epidemiology of hepatitis B infection in Liberian infants. Infect Immun 1981; 32: 675-68o.
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19. Whittle HC, Bradley A K , McLauchlan K et al. Hepatitis B virus infection in two Gambian villages. Lancet I983 ; i: I2O3-I2o6. 20. Marinier E, Barrois V, Larouze B e t al. lack of perinatal transmission of hepatitis B virus infection in Senegal, West Africa. J Pediatr I985 ; IO6: 843-849. 2 I. Basalamah AH, Serebour F, Kazim E. Materno-foetal transmission of hepatitis B in Saudi Arabia. J Infect I984; 8: 200-204. zz. Ramia S, Abduljabbar F, Bakir T M , Hossain A. Vertical transmission of hepatitis B surface antigen in Saudi Arabia. Ann Trop Paediatr I984; 4: 213-21623. Gust ID, Dimitrakakis M, Zommet P. Studies on hepatitis B surface antigen and antibody in Nauris. Distribution amongst Nauruans. A m J Trop Med Hyg I978 ; z7: Io30-Io36. 24. Schreeder U T , Bender TR, McMahon BJ et al. Prevalence of hepatitis B in selected Alaskan Eskimo villages. A m J Epidemiol I983; I I 8 : 543-569. 25. Shobelasky O. Prevalence of markers of hepatitis B virus infection in various countries: W H O Collaborative Study. Bull W H O I98o; 58: 621-628.
EPIDEMIOLOGY
S e r o e p i d e m i o l o g y o f h e p a t i t i s B v i r u s i n f e c t i o n in S a u d i A r a b i a n c h i l d r e n : a b a s e l i n e s u r v e y for m a s s v a c c i n a t i o n against hepatitis B F. Z. AI-Faleh, *11 E. A. Ayoola,* M. Arif,* S. Ramia,* R. A1-Rashed,* M. A1-Jeffry,~ M. A1-Mofarreh,$ M. A1-Karawi~ and M. AI-Shabrawy*
*College of Medicine and King Khalid University Hospital, tMinistry of Health, :~Social Insurance Hospital, and ~Riyadh Armed Forces Hospital, Riyadh, Saudi Arabia Accepted for publication 22 August 1991 Summary Saudi Arabia is considered to be an area of endemic hepatitis B virus (HBV) infection. By adult age, 7 % persons have hepatitis B surface antigen (HBsAg) and about 7o % have one or m o r e H B V markers. In order to provide a baseline for the integration of hepatitis B vaccine into the extended p r o g r a m m e of immunisation (EPI), a populationbased survey of H B V markers was made among Saudi children. T h e overall prevalence of H B s A g was 6"7%, with at least one H B V marker being positive in 19'7 % persons tested. T w o peaks of H B V prevalence were observed in the 7- and ioyear-old children respectively. T h e prevalence of H B s A g was steady in all age groups with identifiable but insignificant peaks in children aged 4 and 7 years respectively. Despite the apparent homogeneity of the Saudi population, the prevalence rates of H B V varied a m o n g the regions and were higher in urban dwellers. T h e r e was no significant difference in the H B s A g prevalence for the sexes (7'3 ~o for males and 6.0 ~o for females). Socioeconomic factors and family size did not significantly influence the prevalence of H B V among children. O f 307 HBsAg-positive children, 55 (17"9%) were positive for HBeAg. T h e early acquisition of H B V in the Saudi population is confirmed. T h e most effective strategy for H B V control, therefore, is by mass vaccination of all Saudi infants. An extension of the immunisation p r o g r a m m e so as to include all pre-school children should further reduce the reservoir of H B V in Saudi Arabia. A repetition of a similar survey after 5 and IO years should be made in order to measure this reduction. Introduction
Hepatitis B virus (HBV) infection, with its chronic sequelae of cirrhosis of the liver and hepatocellular carcinoma (HCC), constitutes a major health problem in countries where H B V is hyperendemic. 1-4 Studies among Saudi Arabian adults have established the high prevalence of H B V in the general population and the significant contribution by H B V to acute viral hepatitis and chronic l i v e r d i s e a s e ) -s T h e a v a i l a b i l i t y o f safe a n d efficacious v a c c i n e s h a s led to t h e f e a s i b i l i t y o f effective c o n t r o l o f H B V i n f e c t i o n , e s p e c i a l l y in a r e a s o f h i g h p r e v a l e n c e w h e r e il Address correspondence to: Professor F. Z. A1-Faleh,Department of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia. oi63-4453/92/o2oi97 +09 $03.00/0
© I99Z The British Society for the Study of Infection
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most chronic H B V carriers acquire the infection very early in life. 9 It is n o w generally accepted that an appropriate strategy in such circumstances involves the vaccination of infants. Based on this strategy and the epidemiology of H B V in the general population, the government of Saudi Arabia p r o p o s e d the integration of H B V vaccination into its extended p r o g r a m m e of immunisation (EPI) and also mass vaccination of all pre-school and school children. 1° As part of the p r o g r a m m e , precise determination of the epidemiology of H B V in Saudi children was considered m a n d a t o r y in view of the paucity of s,,t~ch available information, la In order to provide this information, and to obtain baseline data for the vaccination programme, we report here the results of a p o p u l a t i o n - b a s e d survey aimed at determining the age-specific prevalence of hepatitis B virus markers among children aged I-IO years.
Location, population and methods Study location Covering about 2.2 million km 2 and located in the Arabian Peninsula, Saudi Arabia has an estimated population of Io million people, almost equally distributed among the u r b a n and rural areas. Significant socioeconomic progress within the last two decades is manifested b y a well-developed road network, telecommunications, water supply and distribution of electricity as well as a comprehensive health care delivery system t h r o u g h o u t the country. T h e s e have lessened the differences b e t w e e n the rural (village or town of less than 30000 people) and urban populations. In some villages, water is obtained from deep wells within c o m p o u n d s or from distribution b y water tankers. T h e r e is no difference b e t w e e n rural and u r b a n people with regard to ethnicity or to cultural and religious practices. In m a n y areas, about 2o-3o % of the population are Bedouins with a nomadic life style and who live mostly in tents which are not registered. T h e health care delivery system divides the country into I4 administrative regions each of which comprises a group of primary health care centres ( P H C C ) . T h e catchment for each P H C C is derived from a cluster of households located within well-defined boundaries. Each household has a registration file in the P H C C in which all demographic and health records of family m e m b e r s are kept. T h e projected total n u m b e r of households was estimated as 1816373 with an average family size of seven. 12 Sample size T h e national census has estimated that about 25 ~/o of the population (i.e. 2"5 million) are children aged from I to Io years, proportions of males and females being approximately equal. O n the assumption that the prevalence of H B s A g in Saudi children might be about I o - 2 o % with a standard error of o'oo5, the sample size required for the study was calculated to be 36oo. In order to a c c o m m o d a t e the proportion of tent dwellers (Bedouins) 2o % was added, giving a projected total of 432o. It was decided to survey Io % of the estimated total households (i.e. x816), recruiting not m o r e than two children from each household.
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S a m p l i n g strategy T h e sampling m e t h o d often used for surveys of i m m u n i s a t i o n was modified so as to include the strategy of probability proportionate to size. 13 T h e sample size for each zone was calculated according to the ratio of the zonal population to the national census. D e p e n d i n g on the sample size, one or two u r b a n areas and an equal number of rural areas within the same zone were randomly selected (Fig. I). Within each area, clusters were defined by the boundaries of the catchment of the respective P H C C and households within these clusters were r a n d o m l y selected and visited by well-trained survey teams who carried an introductory letter from the Ministry of Health encouraging co-operation from parents. In each household visited, one or two children aged i - i o years were recruited into the study. N o n e of the eligible children refused to participate. Collection o f data and blood s a m p l e s T h e field word was u n d e r t a k e n in D e c e m b e r 1989 and J a n u a r y 199o. After i n f o r m e d consent had been obtained, details of age, sex and educational status of each of the recruited children were recorded. In addition, the number of children in the family, the position of the participant, the occupation and the
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educational qualification of the father or guardian were recorded. T h e investigators noted the type of house. T h e r e a f t e r , about 5-zo ml blood were obtained from the child by venesection. S e r u m was separated by centrifugation, coded and stored at - 7 o °C until n e e d e d for testing. Laboratory methods Hepatitis B surface antigen (HBsAg), antibody to HBsAg (anti-HBs) and antibody to core antigen (anti-HBc) were tested by E L I S A with the use of commercially available test kits (Organon Teknika). Samples which were HBsAg positive were tested for hepatitis B e antigen (HBeAg) and its antibody (anti-HBe) by means of E L I S A kits from Organon Teknika. Socioeconomic stratification T h e socioeconomic status of the child was taken as that of the father or guardian and classified from the 'socioeconomic score' derived from the type of house ( m u d built or tent I, apartment or ordinary house 2, villa 3); the father's education (primary or grade school or less I, s e c o n d a r y / h i g h school 2, University or professional qualification 3). T h e father's occupation was scored from I to 6 according to the nature of his work, e.g. labourer z, trader 2, etc. A score of less than 4 from a m a x i m u m score of I2 was classified as low socioeconomic status, 5-8 as middle and above 9 as upper class. Statistical analysis Chi-square (X2) and Fisher's exact probability tests were used to compare proportions. Definition Participants who were HBsAg positive were classified as ' H B s A g carriers', while possession of any H B V m a r k e r (HBsAg, anti-HBc, anti-HBs) was considered as evidence of H B V exposure (past or present). Results Overall prevalence A m o n g 4575 children studied, the prevalence of HBsAg was 6"7 %. T h e H B V exposure rate was I9"7 % (Table I). Comparison of urban and rural inhabitants indicated significant differences in respect of the prevalence rates of H B s A g (P = o.o2) and for H B V exposure (P = 0"007) (Table I). Age and sex-specific prevalence As shown in Fig. 2, the highest rate of HBsAg positivity (9"7 %) was in the age group of I year. Thereafter, the rate declined, and varied between 5"~ ~o and 7"8 ~o with no significant peak of infection. Although the overall prevalence rate of HBsAg was higher among males than females, the difference was not statistically significant (Table I). Comparison of the rates for the various age groups revealed no significant difference between the sexes. W h e n exposure rates were compared, however,
Hepatitis B virus infection
2OI
T a b l e I l i b V markers among Sauce children Per cent positive for Number tested
HBsAg
Anti-HBc
Anti-HBs anti-HBs
Anti-HBc + marker
any
Sex
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(Age in years) Fig. 2. Prevalence of H B V markers in Saudi children. ( • ) , H B s A g ; ([]), a n t i - H B c ; ([]), antiH B s ; ([]), a n t i - H B c + H B s . N u m b e r tested = 4575.
significant differences were f o u n d for the age-groups o f 2 years ( P = 0"007) and IO years ( P = 0"03) (Fig. 3). In children aged 3 and 4 years, the e x p o s u r e rates were h i g h e r in the u r b a n residents than in their rural c o u n t e r p a r t s ( P = o ' o o I , 0"003, respectively) (Fig. 4).
HBV prevalence according to regions T a b l e II summarises the prevalence of H B V infection in the various regions. T h e lowest prevalence o f H B s A g was o b s e r v e d in Najran, despite the high prevalence of 9"6-I7 % in the n e i g h b o u r i n g regions o f A l b a h a , Asir and Gizan.
Infective pool (HBeAg positivity) a m o n g Saudi children O f 3o7 H B s A g - p o s i t i v e samples, 55 (I7"9 %) were positive for H B e A g . T h e r e was no significant difference (P = 0"3) b e t w e e n the f r e q u e n c y o f H B e A g in the
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males (36 of i8o children) and that in the females (I9 of I27 children). T h e r e was no significant clustering of HBeAg in any particular region or age groups (Table III). Socioeconomic factors, family size and I-IBV prevalence
HBsAg was present in 7"5 % (80 of Io7I), 6.o % (gz of I54I) and 7 % (I33 of I9I I) of children in the ' u p p e r ' , ' m i d d l e ' and 'lower' socioeconomic classes respectively, there being no significant difference. Of 52 unclassifiable children, two (3"8 %) were HBsAg positive. Similarly, there was no classrelated difference in the HBV exposure rates. Of the children from small (I-5), m e d i u m (6-I0) and large ( > Io) families, 6 % o f 2 I o z , 7"z % of I983 and 8.2 % of 29z children respectively were HBsAg positive; 6"7% of I98 with unavailable data were positive also. T h e differences among the groups were insignificant.
Hepatitis B virus infection
203
Table II Prevalence of HBsAg and H B V markers among Saudi children
according to regions Percent positive for Region
Areas
Number tested
Central
Riyadh Qassim Hail A1-Hafouf/ Dammam Qarayat Tabouk Madina Makkah Jeddah Taif Aseer A1-Baha Gizan
8oo 2oi 209 573
8"6 3"5 2"9 3'1
177 15o 35o 240 456 4°0 476 I45 283
9"0 I 2"8 5"7 5"8 3'7 7'5 lO' 3 7'6 8'8
Eastern Northwestern Southwestern Southern
HBsAg
Any marker i9.8 22"9
6'2 9"6 40' I 53"3 13"4 13"8 i8-o z i-3 I8-o I4"5 27'9
Table III Frequency of HBeAg among HBsAg-positive Saudi children Number tested (number positive for HBeAg) in each age group Province/ region Central Eastern North-western South-western Southern Total
I-3 years
4-6 years
7-1o years
17 (4) 7 (I) 2o (4) 23 (6) z6 (I) 93 (16)
35 (3) 6 (I) 16 (4) I9 (5) 27 (5) lO3 (20)
30 (6) 5 (2) I9 (5) 19 (3) 38 (3) II1 (19)
Total 82 (13) I8 (4)
55 (I3) 61 (IO) 91 (9) 3O7 (55)
Discussion
Hepatitis B virus (HBV) infection is endemic in Saudi Arabia, where about 7"4% adults are positive for HBsAg and about 6o % have evidence of past H B V infections) '6'n'14 This population-based study shows that 6"7 % Saudi children are HBsAg positive and about 2o % have been exposed to HBV. This further confirms that H B V infection is acquired very early in life in this population, a pattern which is common in all areas of endemic HBV. Earlier studies involving relatively small numbers of Saudi children, gave conflicting reports with respect to sex-related differences in H B V prevalence. For example, in a limited study in Riyadh, the sexes had an approximately equal prevalence, 15 whereas in Gizan male outnumbered female children 2 to I in prevalence. 14 Our results indicate no significant sex difference in either the HBsAg carrier rate or that for H B V exposure. Although a significant
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preponderance of HBV carriers in males were reported from Africa and the Far East, the sex differences vary remarkably in magnitude from country to country and also within each population. 4' 9.16 Although it has been speculated that the intersex variation in HBV antigenaemia in older age groups may be attributed to more efficient HBsAg clearance in females, 17 the precise reasons for these variations are yet to be established. It is generally accepted that horizontal transmission is the major mode of infection in endemic areas outside East Asia. 18'19 T h e observation in our study of relatively high prevalence among infants (i year old), however, suggests the possibility of significant HBV transmission during the perinatal period or soon after. 2° This may relate to the HBsAg status of the mothers as was demonstrated in the Gambia. 19 Irrespective of the HBeAg status, vertical (mother to child) transmission takes place in Saudi Arabia. 21,22 Even so, the relative contribution to the HBV-infected pool in the Saudi population is low. ~4 T h e absence of any significant peak of HBV prevalence at school age suggests that intrafamilial spread, through close contact, may be an important mode of HBV transmission. Kissing of newborns and children by friends and relatives is a major cultural practice among the Saudis. ~ Despite the homogeneity of the Saudi population with respect to habits, cultural practices and socioeconomic factors, there was a marked regional variation in HBV prevalence (Table II). Generally, the southern regions of Saudi Arabia had greater endemic HBV rates compared to those of others (e.g. Hail). With an overall HBsAg carrier rate of I9 % and an exposure rate of 53 %, Tabouk in the Northwestern province of Saudi Arabia may be regarded as hyperendemic focus of HBV infection. Variation within homogeneous populations is well recorded but remains unexplained. 19'2a.2~ T h e dynamics of HBV exposure in different populations vary and may be influenced by interaction with populations of neighbouring countries. This concept is supported indirectly by the relatively high prevalence in regions (e.g. Tabouk, Gizan) which share boundaries with Jordan and Yemen, where HBV is endemic. T h e infective pool of persons is assessed by determining the prevalence of HBeAg. 25 In this survey, HBeAg was found in about I 7 % , being evenly distributed among both sexes and all ages. This is similar to the observation among Saudi adults, in whom the incidence is about IO %,~4 but is different from the rates of 5o-90 % reported for African children. ~9'25 We found no relationship between HBV prevalence and socioeconomic status or family size. This lack of association is not surprising in view of the fact that the population has retained its tradition and cultural habits despite the socioeconomic development in the last two decades. Furthermore, those classifiable as belonging to the 'upper class' have continual interaction and share similar habits and cultural practices with relatives in the villages. It is apparent from the above that socioeconomic development alone could not reduce transmission of HBV or its prevalence in the Saudi population. Therefore, the mass vaccination programme recently introduced in Saudi Arabia is justified and remains the best method of control under prevailing circumstances. ~° As indicated by the pattern of HBV infection in the Saudi children, HB vaccine should not only be integrated into the expanded
Hepatitis B virus infection
205
p r o g r a m m e o f i m m u n i s a t i o n ( E P I ) , b u t all p r e - s c h o o l c h i l d r e n s h o u l d b e v a c c i n a t e d f o r t h e n e x t f e w y e a r s in o r d e r to r e d u c e t h e r e s e r v o i r o f H B V i n f e c t i o n in t h e s e c h i l d r e n a n d s u b s e q u e n t l y t h e p r e v a l e n c e o f c h r o n i c liver diseases i n c l u d i n g h e p a t o c e l l u l a r c a r c i n o m a in t h e p o p u l a t i o n o f S a u d i A r a b i a . Comparison of the present findings with those of similar surveys planned for t h e f u t u r e (in 5 a n d IO y e a r s ) , will p r o v i d e u s e f u l i n f o r m a t i o n o n t h e e f f e c t i v e n e s s o f t h e p r o g r a m m e o f m a s s i m m u n i s a t i o n a g a i n s t h e p a t i t i s B. (This study is part of a research project supported by the Ministry of Health, K i n g d o m of Saudi Arabia. We thank all the Directors-General of Health of Saudi Arabia and the Supervisors of the Primary Health Care Units for their co-operation and assistance.) References
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19. Whittle HC, Bradley A K , McLauchlan K et al. Hepatitis B virus infection in two Gambian villages. Lancet I983 ; i: I2O3-I2o6. 20. Marinier E, Barrois V, Larouze B e t al. lack of perinatal transmission of hepatitis B virus infection in Senegal, West Africa. J Pediatr I985 ; IO6: 843-849. 2 I. Basalamah AH, Serebour F, Kazim E. Materno-foetal transmission of hepatitis B in Saudi Arabia. J Infect I984; 8: 200-204. zz. Ramia S, Abduljabbar F, Bakir T M , Hossain A. Vertical transmission of hepatitis B surface antigen in Saudi Arabia. Ann Trop Paediatr I984; 4: 213-21623. Gust ID, Dimitrakakis M, Zommet P. Studies on hepatitis B surface antigen and antibody in Nauris. Distribution amongst Nauruans. A m J Trop Med Hyg I978 ; z7: Io30-Io36. 24. Schreeder U T , Bender TR, McMahon BJ et al. Prevalence of hepatitis B in selected Alaskan Eskimo villages. A m J Epidemiol I983; I I 8 : 543-569. 25. Shobelasky O. Prevalence of markers of hepatitis B virus infection in various countries: W H O Collaborative Study. Bull W H O I98o; 58: 621-628.