Key words: HBV, Taiwan, epidemiology, vaccination program, hepatitis B vaccine

Transcription

1 Original Article 521 Forecasting the Declining Rate of Chronic Hepatitis- Carrier Status at a Taiwanese University: Twenty Years after Implementation of an Universal HV Vaccination Program in Taiwan Fu-Hsiung Su, MS; Hsiao-Yun Huang 1, PhD; Hong-Jer Chang 3, PhD; Jin-Ju Jeng 2, S; Yi- Hui Liu 3, A; Chih-Dao Chen, MD ackground: Prior to the introduction of universal hepatitis virus (HV) vaccination in Taiwan in 1984, 15-20% of the general population were chronic HV carriers. Methods: We forecasted and quantified the declining HV carrier rate 20 years subsequent to the implementation of universal HV vaccination in Taiwan. At a Taiwanese university, 28,763 freshmen tested for serum HsAg level were divided into ten age cohorts by date of birth, from July 1976 to June 1986 inclusive. Comparisons of HsAg carrier rates according to gender were examined with the Z test. Regression methods and a time series model were applied to our sample to forecast trends in changes to the HsAg carrier rate Results: for the next five years. Regression analysis demonstrated a trend toward declining HsAg-positive carrier rates. The HsAg carrier rate for male students decreased from 16.8% (for those born between July 1976 and June 1977) to 2.2% (for those born between July 1985 and June 1986). The carrier rate for their female counterparts over the same period declined from 12.2% to 2.4%. The HsAg carrier rate for male participants was significantly greater than that of their female counterparts for certain years during the test period. The results of time series analysis suggests the HsAg carrier status rate will approach zero for students born after July 1987 (expected to enrol in the university in 2006). Conclusions: Our data demonstrate that in order for the HV carrier rate to approximate zero, universal vaccination programs need to continue for at least 21 years. (Chang Gung Med J 2007;30:521-8) Key words: HV, Taiwan, epidemiology, vaccination program, hepatitis vaccine Hepatitis- infection, a global health issue, is particularly prevalent in developing countries. ased on serological evidence, it has been estimated that each year, approximately two billion individuals From the Department of Family Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan; 1 Department of Statistics and Information Science; 2 Student Health Center, Fu Jen Catholic University, Taipei, Taiwan; 3 Institute of Long-Term Care, National Taipei College of Nursing, Taipei, Taiwan. Received: Aug. 2, 2006; Accepted: Mar. 23, 2007 Correspondence to: Dr. Chih-Dao Chen, Department of Family Medicine, Far Eastern Memorial Hospital. 21, Sec. 2, Nanya S. Rd., anciao City, Taipei County 220, Taiwan (R.O.C.) Tel.: ext. 4206; Fax: ; cdchen@mail.femh.org.tw

2 Fu-Hsiung Su, et al Forecasting HV rate at a college in Taiwan 522 worldwide succumb to hepatitis- infections they contracted in the past. (1) Of these, perhaps 350 million appear to be chronic carriers, of whom possibly one million die annually from cirrhosis and/or hepatocellular carcinoma. (2) Listed among the hyperendemic countries, Taiwan appears quite significant in that it features one of the highest HsAg carrier rates in the world, with perhaps 15 to 20% of the general population being carriers. (3-5) In 1984 Taiwan became one of the first countries to implement an universal hepatitis- vaccination program for newborns. (6,7) Vaccination for newborns of carrier mothers was implemented in July 1984 and was extended to include all neonates in The program reached somewhere between 84 and 94 percent of the population. At the commencement of the vaccination program, the HV carrier rate among children was 9.8 percent. (6) Five years later, the HsAg seropositivity rate for children under five years of age had decreased to 2%. (8) After ten years (1994), the HV carrier rate among children had decreased to 1.3 percent. (6,9) After sixteen years (the year 2000), a significant trend toward decreasing HsAg carrier rates-from 20.3% (those born in 1976) to 3.4% (born in 1986)-was reported for high-school students in eastern Taiwan. (10) Such studies show the HV infection and carrier rates have been declining since the launch of this mass vaccination program, (6,7) although the long-term efficacy of a mass HV vaccination program such as this remains a question of great concern for publichealth officials. In this article, we report HV infection trends for ten birth cohorts of Taiwanese university students, for the decades prior and subsequent to 1984, the year when Taiwan s national hepatitis- vaccination campaign for neonates commenced. The results of this study confirm that the effect remained significant 20 years after the first cohort received HV vaccinations, which were ongoing thereafter. Furthermore, we observe that unvaccinated children have also benefited from the hepatitis- vaccination program. METHODS National vaccination program Taiwan s nationwide program of HV vaccination started in July 1984 and for the first two years of the program, only newborns of HsAg-positive mothers were immunized. From July 1986 onwards, all infants were immunized. The program was extended to preschool children in , to primary school children in , to teenagers in , and to adults in on a fee-forservice basis. eginning in October 1990, the freeof-charge H vaccination program was expanded to include all children up to first grade. Since July 1991, the vaccine records of elementary-school entrants have been checked to confirm H vaccination, and non- or incompletely vaccinated elementary school students have been monitored and given a full-cycle of catch-up vaccinations. Participants The study data were collected from Fu-Jen Catholic University, a private university located in northern Taiwan. Using birth place information available in university records, it was determined that the majority (72.6%) of the students in the study were from northern Taiwan (including 59.3% from the Greater Taipei Metropolitan Area) with only 13.2% from central Taiwan, 10.8% from southern Taiwan, and 3.4% from eastern Taiwan and the outlying islands. According to the university s policy, all students were required to undergo a compulsory health screening examination prior to entering university. In total, 28,763 students (12,244 males and 16,519 females), including both graduate and undergraduate levels, completed the health check. Since the mass vaccination program was implemented in July 1984 and conducted in the same month each year, the students were grouped according to their date of birth, with groups stretching from July of a particular year to June of the subsequent year (Table 1). As a result, a total of ten birth cohorts over a period extending from July 1976 to June 1986 were included for analysis in this study. Since the year 2000, an annual survey of serum HsAg status has been conducted for members of the freshman class of Fu-Jen University in September of each year as part of a general youth cohort representative health check-up. All blood samples were transported in a refrigerator to a central laboratory for testing. The serum HsAg level was determined using a commercially available enzyme immunoassay kit (Abbott Laboratories, North Chicago, IL, USA). A regression method was

3 523 Fu-Hsiung Su, et al Forecasting HV rate at a college in Taiwan Table 1. The HsAg Carrier Rate for Taiwanese University Students orn between July 1976 and June 1986 irth HbsAg (+) status in tested population Year of birth cohort Male % (N) 95% CI Female % (N) 95% CI All % (N) 95% CI p-value / / % (55) 12.8~ % (37) 8.5~ % (92) 11.9~ / / % (51) 9.7~ % (31) 5.5~ % (82) 8.5~ / / % (64) 9.6~ % (59) 8.0~ % (123) 9.6~ / / % (84) 8.6~ % (69) 6.9~ % (153) 8.4~ / / % (130) 8.7~ % (114) 7.0~ % (244) 8.3~ / / % (197) 8.4~ % (175) 5.5~ % (372) 7.0~ / / % (171) 7.4~ % (173) 5.1~ % (344) 6.3~ / / % (101) 4.4~ % (133) 4.1~ % (234) 4.5~ / / % (85) 3.7~ % (79) 2.4~ % (164) 3.1~ / / % (29) 1.4~ % (49) 1.7~ % (78) 1.8~ Total 28,763 students 7.9% (967) 7.4~ % (919) 5.3~ % (1886) 6.3~6.9 applied to derived serum HsAg data in order to evaluate any trends displayed in the rate of detected Hs Ag positivity. Comparisons of HsAg carrier rates by gender were performed by means of the Z test. Any difference between data sets was considered significant if the probability of difference was less than A time series statistical method was applied to predict trends in HV infection carrier rates in our sample population. Initially, HsAg carrier rate trends among study participants were interpreted as a non-stationary time series. However, the data were also transformed to constitute a stationary time series by simple differencing. In the mathematical model, {x 1 } was denoted as the HsAg carrier time series. The simple differencing of {x 1 } was denoted by x 1 where x 1 = x 1 x t-1. Thus, subsequent to performing model-building and modelsearching procedures, the ARIMA(2,1,0) model as described by Shumway RH and colleagues was selected as best fitting the data elicited by the study. (11) RESULTS The data showed overall prevalence of HsAg positivity among the students was 6.6% (95% CI: ) [7.9% for males (95% CI: ) and 5.6% (95% CI: ) for females]. There was a significant trend (p < 0.001) toward a decreasing HsAg carrier rate among students at the study university from 14.6% (95% CI: ) to 2.3% (95% CI: ) over the ten-year study period (Table 1). For male students, the HsAg carrier rate declined from 16.8% (95% CI: ) in 1976 to 2.2% (95% CI: ) in 1985; the corresponding figures for females declined from 12.2% (95% CI: ) to 2.4% (95% CI: ), respectively. The reduction was more obvious among male students (Fig. 1). The HsAg carrier rate for male students was significantly greater than that of the female students in the 1977 cohort (p = 0.035), the 1981 cohort (p < 0.001), the 1982 cohort (p < 0.001) and the 1984 cohort (p < 0.001) (Table 1). With the application of the time series method, the ARIMA(2,1,0) model could be rewritten as X t = 1.5X t X t Xt-3 + W t where X t denoted the data value at time t and W t denoted random white noise. Applying this model to predicting trends in the prevalence of HsAg carrier status for this student population (Fig. 2), assuming that there were no interfering factors and that any trend was continuous, the positivity rate for HsAg among students was projected to approach zero for the 1987 cohort, a group comprising students born between 07/01/1987 and 06/30/1988 and expected to enrol in the university in 2006 (Fig. 3). A specific regression method was also applied to evaluate any trend in the HsAg positivity rate with respect to time. Here, Y i denoted the HsAg

4 Fu-Hsiung Su, et al Forecasting HV rate at a college in Taiwan 524 positivity rate and Xi denoted the year. The result showed that a simple linear regression line HsAg positive rate (%) irth cohort (year) male female total Fig. 1 The HsAg carrier rate for Taiwanese university students born between July 1976 and June Rate of HsAg carrier (%) ARIMA(2,1,0) predicted lack line: Actual data plotted line Dot line: ARIMA model predicted trend Fig. 2 The trend in HsAg carrier rates for this student population. Yi = Xi could be fitted to the data. The regression coefficient associated with Xi proved to be negative, indicating that the HsAg positivity rate was declining with time over the test period (Table 2). DISCUSSION From our observations, there appeared to be an abrupt decline in HsAg carrier incidence from the 1976 cohort (14.6%) to the 1977 cohort (10.7%). Subsequently, a steady decline in the HsAg carrier rate from the 1977 cohort to the 1984 cohort was observed. The students in these cohorts as much as seven years old at the time the HV mass-vaccination program commenced. This finding is consistent with a previous study, which looked at children born up to 6 years before the start of the program. (10) Since vertical transmission (the perinatal route) was not modified for these students, the significant reduction in H infection between the 1977 and the 1983 cohorts could be due to a decline in horizontal Rate of HsAg carrier (%) ARIMA(2,1,0) forecast lack line: Actual forecasting line Dot line: Upper and lower forecasting limit Cohortl987:Date of birth (07/01/ /30/1988); Cohortl989:(07/01/ /30/1990);Cohortl990:(07/01/ /30/1991) Fig. 3 Forecasting the trend in HsAg carrier rates for this student population. Table 2. Regression Model of HsAg Carrier Rate for Taiwanese University Freshmen orn between July 1976 and June 1986 Unstandardized Standardized Model coefficients coefficients t Significance Standard error eta 1 (Constant) Year of the research 1.225E Dependent Variable: proportion (percentage) of population that is HsAg (+)

5 525 Fu-Hsiung Su, et al Forecasting HV rate at a college in Taiwan transmission of the virus. (12) We postulate that the obvious decline in the HsAg carrier rate between the 1977 cohort and the 1983 cohort, particularly between the 1981 and 1983 cohorts, might reflect the impact of subsequent catch-up programs, e.g. in the period between 1987 and 1991 (children born between 1981 and 1991 had access to the self-pay preschool program) and the free-of-charge vaccination program for children under seven starting in At the commencement of the national hepatitis- vaccination program in 1984, the completion rate for the total 4-dose HV vaccine was 81.6% for the infants of HV carrier mothers and 9.5% for all newborns. (13) In other words, some carrier mothers were not screened and some newborns of carrier mothers were not vaccinated. Furthermore, unvaccinated children born to non-carrier mothers still exhibited a chance of acquiring HV infection in early childhood from older carriers. (10) Hence the decline of the HsAg positivity rate noted between the 1984 and 1985 cohorts should not only be attributed to the vertical (perinatal) effect of the mass vaccination program; consideration should also be given to the possible horizontal effect of the program as a cause for the decline. Our observations suggest the HV mass-vaccination program successfully reduced horizontal transmission to older children up to age 7, in addition to contributing to the reduction in transmission of hepatitis among children of the same age. (6) Some previous studies have reported the blocking of both vertical and horizontal HV transmission. (6,10) We likewise conclude that twenty years subsequent to the commencement of Taiwan s mass HV vaccination program, the program s effect of reducing horizontal and vertical transmission of HV is still evident, thus the relative efficacy of the vaccination program would appear to have persisted for nearly twenty years. Similar to results of previous studies, (3-5,10,14) our study has revealed that the HsAg carrier rate was higher among males than females. Furthermore, it has been reported that males were more likely to become HsAg carriers following infection than their female counterparts. (3,10,14) Fang JW and his colleagues have suggested that girls responded with a higher anti-hs titre compared with boys after receiving the HV vaccine. (15) As infants and throughout early childhood, male toddlers are typically reported to be more active than their female counterparts and, thus may experience a greater number of opportunities for unwitting parenteral exposure than would appear to be the case for agematched female individuals. (16) These findings have demonstrated that universal vaccination can be used to control vertical and horizontal transmissions of HV infection and the sequelae of chronic HV infection. Given that the chronic HV infection rate has declined in the years following the implementation of Taiwan s mass HV vaccination program, we wished to predict the approximate stage at which HV infection can be virtually eradicated or reduced to a minimal level. The result of time-series analysis indicates that the HV carrier rate will approach zero for the 1987 cohort (students born after 07/01/1987), should the current declining trend in HV carrier rates continue unchanged. Lu SN and colleagues reported the prevalence of HsAg decreased from 12.5% in 1984 to 5.4% in 1991 in one rural township in central Taiwan. (17) In a small district of the Taipei metropolitan area, the HsAg prevalence decreased from 7.3% in surveys done in , to 2% in (18) It is clear that the prevalence of HsAg in rural areas was much higher than urban areas. (17) In 1998, the Department of Health in Taiwan also forecast that if the HV vaccination coverage rate of 90% of all newborns can be maintained, by the year 2010 the carrier rate in Taiwan could be expected to decline to < 0.1%. (19) However, we predicted the carrier rate of HsAg positivity among our student population would decline to a minimal level by the year The discrepancy between our findings and the data presented by the Department of Health might be due to the fact that the majority of our student population was from the greater Taipei metropolitan area and from more affluent families, which means that they likely had easier access to health resources than the general population. Another limitation of the present study is that this mathematical model does not take into account the subsequent catch-up programs and decline of vaccine induced immune memory. Some investigators have pointed out that the possible progressive decline of serum anti-h levels for previously vaccinated individuals over the period following vaccination may be associated with increased likelihood of the developing new H infections over

6 Fu-Hsiung Su, et al Forecasting HV rate at a college in Taiwan 526 time. (20-22) McMahon J and colleagues also suggest that the decline of vaccine-induced memory was greatest for the group aged 0-4 years as compared with other age groups. (23) As a consequence, our results may underestimate the actual HsAg carrier rate in the general population of young adults. Nevertheless, given the results of previous studies 5-, 10- and 16-years post mass vaccination, (6,8-10) using a time-series mathematical model, our data show a continual decrease in the rate of chronic HV infection twenty years subsequent to mass HV vaccination. In addition, it is often suggested that HV infection is the primary aetiology of hepatocellular carcinoma among individuals from many countries, including Taiwan. Therefore, one could say that this study suggests that this mass vaccination program in Taiwan is, to the best of our knowledge, the first occasion where a vaccine may actually prevent a certain type of human cancer. (24) This study confirms the efficacy of a mass HV vaccination program and that the impact of such vaccination remains for at least 20 years subsequent to vaccination. The results suggest that HV vaccination (in Taiwan) not only reduced the perinatal and horizontal transmission of HV among children born after the program commenced, but that such vaccination might also reduce the risk of horizontal transmission of HV to children born up to seven years prior to the commencement of the program. We also predict that the HV infection rate can be reduced to a rather minimal level in 21 years (the 1987 birth cohort expected to enrol in 2006) following the implementation of an universal HV vaccination program among the student population. Clearly, comprehensive, universal HV vaccination programs should be launched in a number of other countries, especially for those for which this virus and associated infections are endemic. REFERENCES 1. Kane MA, Clement J, Hu D. Hepatitis. In: Jamison DT, Mosley WH, Measham AR, obadilla J, eds. Disease Control Priorities in Developing Countries. 1st ed. New York: Oxford University Press, 1993: Mast EE, Alter MJ, Margolis HS. Strategies to prevent and control hepatitis and C virus infections: a global perspective. Vaccine 1999;17: Chen DS, Sung JL. Hepatitis virus infection and chronic liver disease in Taiwan. Acta Hepatogastroenterol 1978;25: Wu JS, Chen CH, Chiang YH, Lee YC, Lee MH, Ko YC, Hu HT. Hepatitis virus infection in Taiwan with reference to anti-hc virus HsAg and anti-hs. J Formosan Med Assoc 1980;79: Sung JL, Chen DS, Lai MY, Yu JY, Wang TH, Wang CY, Lee CY, Chen SH, Ko TM. Epidemiological study of hepatitis virus infection in Taiwan. Chin J Gastroenterol 1984;1: Chen HL, Chang MH, Ni YH, Hsu HY, Lee PI, Lee CY, Chen DS. Seroepidemiology of hepatitis virus infection in children: ten years of mass vaccination in Taiwan. JAMA 1996;276: Hsu HM, Lu CF, Lee SC, Lin SR, Chen DS. Seroepidemiologic survey for hepatitis virus infection in Taiwan: the effect of hepatitis mass immunization. J Infect Dis 1999;179: Tsen YJ, Chang MY, Hsu HY, Lee CY, Sung JL, Chen DS. Seroprevalence of hepatitis infection in children in Taipei, 1989: five years after a mass hepatitis vaccination program. J Med Virol 1991;34: Chang MH, Chen CJ, Lai MS, Hsu HM, Wu TC, Kong MS, Liang DC, Shau WY, Chen DS. Universal hepatitis vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 1997;336: Lin HH, Wang LY, Hu CT, Huang SC, Huang LC, Lin SS, Chiang YM, Liu TT, Chen CL. Decline of hepatitis carrier rate in vaccinated and unvaccinated subjects: sixteen years after a newborn vaccination program in Taiwan. J Med Virol 2003;69: Shumway RH, Stoffer DS. Time Series Regression and ARIMA Models. In: Shumway RH, Stoffer DS, eds. Time Series Analysis and Its Applications. 1 st ed. New York: Springer-Verlag, 2000: Hsu SC, Chang MH, Ni YH, Hsu HY, Lee CY. Horizontal transmission of hepatitis virus in children. J Pediatr Gastroenterol Nut 1993;16: Wong WCW, Tsang KK. A mass hepatitis vaccination programme in Taiwan: its preparation, results and reasons for uncompleted vaccinations. Vaccine 1994;12: Lin HH, Wu JS, Lu CF, Wong CK. Hepatitis virus infection among aboriginal children in eastern Taiwan. J Formos Med Assoc 1992;91: Fang JW, Lai CL, Chung HT, Wu PC, Lau JY. Female children respond to recombinant hepatitis vaccine with a higher titre than male. J Trop Pediatr 1994;40: Lin HH, Lin SS, Chiang YM, Chiang YM, Wang LY, Huang LC, Huang SC, Liu TT. Trend of hepatitis virus infection in freshmen classes at two high schools in Hualien, Taiwan from 1991 to J Med Virol 2002;67: Lu SN, Chen CH, Chen TM, Lee PL, Wang JH, Tung HD, Hung CH, Lee CM, Changchien CS. Hepatitis virus infection in adolescents in a rural township--15 years sub-

7 527 Fu-Hsiung Su, et al Forecasting HV rate at a college in Taiwan sequent to mass hepatitis vaccination in Taiwan. Vaccine 2006;24: Ni YH, Chang MH, Huang LM, Chen HL, Hsu HY, Chiu TY, Tsai KS, Chen DS. Hepatitis virus infection in children and adolescents in a hyperendemic area: 15 years after mass hepatitis vaccination. Ann Intern Med 2001;135: Department of Health. Public Health in Taiwan, Republic of China. The Executive Yuan 1998;2: Coursaget P, Yvonnet, Chotard J, Sarr M, Vincelot P, N doye R, Diop-Mar I, Chiron JP. Seven-year study of hepatitis vaccine efficacy in infants from an endemic area (Senegal). Lancet 1986;2: Poovorawan Y, Sanpavat S, Chumdermpadetsuk S, Safary A. Long-term hepatitis vaccine in infants born to hepatitis e antigen positive mothers. Arch Dis Child Fetal Neonatal Ed 1997;77:F Lu CY, Chiang L, Chi WK, Chang MH, Ni YH, Hsu HM, Twu SJ, Su IJ, Huang LM, Lee CY. Waning immunity to plasma-derived hepatitis vaccine and the need for boosters 15 years after neonatal vaccination. Hepatology 2004;40: McMahon J, ruden DL, Petersen KM, ulkow LR, Parkinson AJ, Nainan O, Khristova M, Zanis C, Peters H, Margolis HS. Antibody levels and protection after hepatitis vaccination: results of a 15-year follow up. Ann Intern Med 2005;142: Zuckerman AJ. Prevention of primary liver cancer by immunization. N Engl J Med 1997;336:

8 , Z 16.8% ( ) 2.2% ( ) % 2.4% ( 2006 ) 21 ( 2007;30:521-8) Tel.: (02) ; Fax: (02) ; cdchen@mail.femh.org.tw