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Reduction in hepatitis B virus seroprevalence among U.S.-born children of foreign-born Asian parents—Benefit of universal infant hepatitis B vaccination
Vaccine 27 (2009) 5942–5947
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Reduction in hepatitis B virus seroprevalence among U.S.-born children of foreign-born Asian parents—Benefit of universal infant hepatitis B vaccination夽,夽夽 Carrie M. Shuler a,b,∗ , Anthony E. Fiore c , Ruth Neeman a , Beth P. Bell c , Wendi Kuhnert d , Sandra Watkins e , Kimberly Kilgour e , Kathryn E. Arnold a a
Notifiable Diseases Epidemiology Section, Georgia Department of Human Resources, Division of Public Health, Atlanta, GA, United States Epidemic Intelligence Service, Centers for Disease Control and Prevention, Atlanta, GA, United States c Division of Viral Hepatitis, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, United States d Hepatitis Laboratory, Division of Viral Hepatitis, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, United States e Georgia Public Health Laboratory, Georgia Department of Human Resources, Division of Public Health, Atlanta, GA, United States b
a r t i c l e
i n f o
Article history: Received 24 March 2009 Received in revised form 18 July 2009 Accepted 23 July 2009 Available online 11 August 2009 Keywords: Hepatitis B immunizations Pediatrics
a b s t r a c t We demonstrate that after implementation of recommendations for universal infant hepatitis B vaccination, HBV infection prevalence among children of foreign-born Asian parents in Georgia declined dramatically; horizontal transmission of infection within households has occurred infrequently; and the vast majority of infants and children have received the recommended hepatitis B vaccinations. These results provide evidence of the success of the hepatitis B infant vaccination program and highlight its potential impact on reducing chronic HBV infection morbidity and mortality among U.S. populations at high risk. Published by Elsevier Ltd.
1. Introduction Chronic infection with hepatitis B virus (HBV) is a leading cause of chronic liver disease and liver cancer worldwide. In the United States, an estimated 1 million–1.25 million persons (0.4% of the U.S. population) are living with chronic HBV infection [1]. These persons are potentially infectious and serve as the main reservoir for continued HBV transmission within the community [1,2]. Acute HBV infection can lead to chronic infection at any age, but infants and young children are more likely to experience chronic infection, compared with adults; ≥90% of perinatal infections lead to chronic infections, compared with approximately 5% of infections among adolescents or adults [3–6]. Hepatitis B vaccine licensed in the United States in 1982 is a safe and effective way to prevent infection. Vaccination beginning at birth or during early infancy has been the cornerstone of prevention efforts [1,2,7–12]. Specific recommendations for infants born to women with chronic HBV infection include the first dose of hepatitis B vaccination and hepatitis B immune globulin (HBIG) at birth [1,12]. 夽 This work was presented in part at the Infectious Disease Society of America Conference: October 9–12, 2003: San Diego, California. 夽夽 The findings and conclusions in this report are those of the author(s) and do not necessarily represent the views of the Centers for Disease Control and Prevention. ∗ Corresponding author at: 2680 NW Thurman Street, Portland, Oregon 97210, United States. Tel.: +1 503 206 8037; fax: +1 503 227 7213. E-mail address: carrie [email protected] (C.M. Shuler). 0264-410X/$ – see front matter. Published by Elsevier Ltd. doi:10.1016/j.vaccine.2009.07.087
The prevalence of chronic HBV infection, indicated by the presence of hepatitis B surface antigen (HBsAg) in serum, is 5–15% worldwide, compared with 0.5% overall in the United States [1,13–16]. These high rates of chronic infection have been attributed to transmission from infected mother to newborn during the perinatal period and from household members with chronic HBV infection to young children [17–19]. Studies conducted in the United States before hepatitis B vaccine was available indicated that children of Southeast (SE) Asian immigrant women had >100 times the estimated rate of infection, compared with nonAsian children [20]. Studies conducted during the 1980s after hepatitis B vaccine licensure demonstrated that high rates of HBV infection among Asian children born in the United States persisted [17–19,21]. Low rates of maternal screening and infant vaccination, as well as horizontal transmission from infected household members to children born to HBsAg-negative women, were demonstrated in multiple investigations conducted among groups at higher risk for HBV infection [6,17,18,22]. These results supported policy changes focused on providing protection against HBV infection for all infants regardless of maternal HBsAg status. In 1988, the Advisory Committee on Immunization Practices (ACIP) recommended HBsAg screening for all pregnant women [9]. In 1991, to prevent horizontal transmission in households and to further reduce missed opportunities to prevent HBV infection, ACIP recommended hepatitis B vaccination for all infants, preferably beginning at birth and regardless of the HBsAg status of the mother
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[2,9]. By 2002, a total of 43 states required hepatitis B vaccination for public school or child care participation [23], and the incidence of acute (i.e., symptomatic) HBV infection among children had declined by 89% [20]. However, the majority of HBV infections among infants and young children are asymptomatic; measures of acute infection cannot capture continuing transmission of HBV infection to infants and children. We performed a follow-up seroprevalence study during 2001–2004 in an Asian immigrant community in Georgia to evaluate the impact of universal maternal HBsAg screening and infant vaccination in preventing HBV infection among U.S.-born children of foreign-born Asian parents. Our three objectives were to determine the seroprevalence of HBV infection among children of foreign-born Asian parents born in the United States during the post universal vaccination recommendation periods, to examine the association between infection among U.S.-born children and the presence of a chronically infected person in their household, and to determine vaccination status among children of foreignborn Asian parents. 2. Materials and methods
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year the foreign-born participants entered the United States, and whether they considered themselves refugees or immigrants. The number of persons per bedroom was also recorded as a measure of household density or crowding. With parental consent for children aged <18 years, all vaccine providers including physicians and public health clinics as well as schools and the Georgia Registry of Immunization Transactions and Services (GRITS) were contacted or reviewed to determine the number and timing of hepatitis B vaccinations. The parent or guardian during the enrollment interview was also asked to show their copy of the child’s vaccination history. To evaluate whether changes in hepatitis B vaccination practices over time were attributable to the 1991 policy and not to improved access to health care, another recommended childhood vaccination [diphtheria, pertussis (whole cell or acellular) and tetanus, DTP/DTaP] was used as a referent practice. Parents were offered the option of topical anesthetic for their children prior to venipuncture. Whole blood (5–10 ml) was obtained in serum-separator tubes, centrifuged within 4 h, and the serum decanted, transferred, and promptly tested at Georgia Public Health Laboratory (GPHL). Serum was subsequently frozen at −20 ◦ C and transported in batches to CDC for confirmatory serologic testing.
2.1. Subjects 2.2. Serology Study enrollment criteria required that households include a parent born in Korea, China, Laos, Cambodia, or Vietnam, and one or more U.S.-born children aged ≥12 months (study children). These countries of origin were chosen because of their high HBV endemicity rates [14,16] and the size of the immigrant population in Georgia. Households were recruited by using multiple methods. We estimated 272 children born in the U.S. after 1991 would be needed to demonstrate a reduced HBV seroprevalence from an expected 12% among high risk groups without vaccination to 2% or less among children born after the universal vaccination recommendations. We initially identified eligible households by focusing on children born during 1992–2001 by linking vital records data to the state’s Refugee Health Program of the Georgia Department of Human Resources (DHR). We also worked closely with the Center for Pan-Asian Community Services (CPACS), a nonprofit organization that provides social, legal, and health-care services to Asian persons in greater Atlanta, including vaccination for approximately 500 children/year. We mailed eligible families a letter of invitation in both English and the relevant language. We also solicited families who visited CPACS and at religious festivals, worksites, and health fairs, and through friends, media announcements, church groups, and health clinics in Asian communities in four Georgia counties (Clayton, DeKalb, Fulton, and Gwinnett). Recruitment, enrollment, interviewing, specimen collection, and venipuncture of eligible family members were coordinated by a nurse-phlebotomist. CPACS served as the main point of contact, provided details about the study, and facilitated scheduling of the initial consultation with translation services, if needed. During the first appointment, written informed consent was sought, and if the qualifying child and the child’s mother agreed to participate, the household was given the option of completing the questionnaire and undergoing venipuncture immediately. If all household members were not available for this meeting, an appointment was scheduled within 2 weeks, either at the home or at CPACS, to obtain blood from other household members. Children younger than age 1 year were excluded from the study. The Georgia DHR Institutional Review Board (IRB) and the Centers for Disease Control and Prevention (CDC) IRB approved the study. The participants were enrolled during May 2001–September 2004. Information was obtained on the age, sex, birthplace, relationship to the U.S.-born child, hepatitis B vaccination history, the
The GPHL and CDC’s Division of Viral Hepatitis tested serum samples (Ortho-Clinical Diagnostics, Rochester, NY) for total antibody to hepatitis B core antigen (anti-HBc) and antibody to hepatitis B surface antigen (anti-HBs); anti-HBc-positive samples were tested for HBsAg and for IgM antibody to hepatitis B core antigen (IgM anti-HBc). HBsAg-positive samples were also tested for hepatitis B e antigen (HBeAg), a marker of higher HBV concentrations and higher infectivity. Participants with evidence of any HBV infection were categorized into chronic or resolved infection. Chronic infection was defined by the presence of HBsAg and the absence of IgM antiHBc; those persons were referred for treatment. Resolved infection was defined by the presence of anti-HBc without HBsAg. Immunity because of vaccination was defined as ≥10 milli-international units/ml (MIU/ml) anti-HBs in serum and undetectable levels of anti-HBc. Participants were offered hepatitis B vaccine if they had no history of hepatitis B vaccination, were HBsAg-negative, and had undetectable levels of anti-HBs and anti-HBc. For families with a chronically infected member, counseling regarding risks for chronic HBV infection, the need for vaccination among susceptible household members, and treatment options were provided. 2.3. Statistical analyses The focus of the data analysis was to calculate the point prevalence of HBV infection among children born since the 1991 universal vaccination recommendations and to identify predictors associated with infection. Because of the limited number of children with the outcome of interest (chronic or resolved HBV infection), adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated by using exact measures in SAS® version 9.1 (SAS Institute Inc., Cary, NC). Predictors of infections among the study children were evaluated in multivariate models by controlling for household members (mother, father, other adult or other child) with chronic infections. 2.4. Vaccination status Documented hepatitis B vaccine doses and DTP/DTaP doses were used to calculate vaccination status. Vaccination status of the study children was broken down into a hepatitis B vaccine birth dose (defined as a dose on or one day after birth), 3 doses of either
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Table 1 Characteristics of Study Participants (N = 989). Foreign-born children/adultsa (n = 635; median age = 38 years)
Country of originb Cambodia (n = 89; 14.0%)
China (n = 61; 9.6%)
Korea (n = 122; 19.2%)
Laos (n = 75; 11.8%)
Vietnam (n = 288; 45.4%)
Age category (years) 1–20—72 (11.3%) 21–30—96 (15.1%) 31–40—243 (38.3%) 41–50—122 (19.2%) >50—102 (16.1%)
5 (5.6) 18 (20.2) 38 (42.7) 18 (20.2) 10 (11.2)
4 (6.6) 6 (9.8) 23 (37.7) 13 (21.3) 15 (24.6)
8 (6.6) 9 (7.4) 59 (48.4) 33 (27.0) 13 (10.7)
5 (6.7) 21 (28.0) 17 (22.7) 17 (22.7) 15 (20.0)
50 (17.4) 42 (14.6) 106 (36.8) 41 (14.2) 49 (17.0)
Refugee—292 (46.0%) Immigrant—339 (53.4%) Median year entering U.S. High household densityc —297 (46.8%) Number of household members (median, range) Number of households—198
65 (73.0) 23 (25.8) 1984 43 (48.3) 6 (2–13) 30
1 (1.6) 60 (98.4) 1993 25 (41.0) 6 (3–14) 18
1 (0.8) 121 (99.2) 1989 14 (11.5) 4 (2–8) 54
61 (81.3) 11 (14.7) 1982 31 (41.3) 6 (3–10) 24
164 (56.9) 124 (43.1) 1993 184 (63.9) 6 (3–17) 72
Study childrend (n = 354; median age = 6 years)
n = 68; 19.2%
n = 27; 7.6%
n = 91; 25.7%
n = 54; 15.3%
n = 114; 32.2%
Age Born before 1992—63 (17.8) Born after 1991—291 (82.2)
17 (25) 51 (75)
2 (7) 25 (93)
24 (26) 67 (74)
13 (24) 41 (76)
7 (6) 107 (94)
High household densityc —121 (34.2%) Born before 1992—18 (14.8) Born after 1991—103 (85.1)
29 (42.6) 10 (34) 19 (66)
10 (37.0) 0 (0) 10 (100)
6 (6.6) 1 (17) 5 (83)
21 (38.9) 5 (24) 16 (76)
55 (48.2) 2 (4) 53 (96)
a Study participant not born in the United States or was aged ≥21 years = 635) at enrollment—72 foreign-born children aged <21 years 59 foreign-born adults, and four U.S.-born adults (aged 21, 23, 23, and 58 years). b If U.S.-born, maternal country of origin. c ≥1.7 Family members per bedroom (i.e., median for population). d Study participant born in the United States and was aged <21 years at enrollment.
Table 2 Hepatitis B virus infection status by country of origin. Foreign-born children/adultsa (n = 635; median age = 38 years)
Country of originb
Chronic infection—67 (10.6%) Resolved infection—291 (45.8%) Immune after vaccine—92 (14.5%) No markers—185 (29.1%)
Cambodia (n = 89; 14.0%) 13 (14.6) 38 (42.7) 11 (12.4) 27 (30.3)
China (n = 61; 9.6%) 6 (9.8) 32 (52.5) 9 (14.8) 14 (23.0)
Korea (n = 122; 19.2%) 4 (3.3) 42 (34.4) 19 (15.6) 57 (46.7)
Laos (n = 75; 11.8%) 8 (10.7) 39 (52.0) 7 (9.3) 21 (28.0)
Vietnam (n = 288; 45.4%) 36 (12.5) 140 (48.6) 46 (16.0) 66 (22.9)
Cambodia
China
Korea
Laos
Vietnam
Study childrenc , d (n = 354; median age = 6 years) Chronic infectione —3 (0.8%) Resolved infectione — (1.1%)
n = 68; 19.2% 1 (1.5) 3 (4.4)
n = 27; 7.6% 0 (0) 0 (0)
n = 91d ; 25.7% 0 (0) 0 (0)
n = 54; 15.3% 1 (1.9) 0 (0)
n = 114d ; 32.2% 1 (0.9) 1 (0.9)
Immune after vaccine—168 (47.5%) Born before 1992—28 (16.7) Born after 1991—140 (83.3)
28 (41.2) 62 (21.4) 22 (78.6)
17 (63.0) 2 (11.8) 15 (88.2)
46 (51.1) 11 (23.9) 35 (76.1)
19 (35.2) 5 (26.3) 14 (73.7)
58 (51.3) 4 (6.9) 54 (93.1)
No markers—177 (50.0%) Born before 1992—31 (17.5) Born after 1991—146 (82.5)
36 (52.9) 8 (22.2) 28 (77.8)
10 (37.0) 0 (0) 10 (100)
44 (48.4) 13 (29.5) 31 (70.5)
34 (63.0) 7 (20.6) 27 (79.4)
53 (46.5) 3 (5.7) 50 (94.3)
Children with household member with chronic infection—92 (25.9%) Born before 1992—14 (15.2) Born after 1991—78 (84.8)
25 (36.8) 7 (28.0) 18 (72.0)
7 (25.9) 0 (0) 7 (100)
9 (9.9) 3 (33.3) 6 (66.7)
15 (27.8) 4 (26.7) 11 (73.3)
36 (31.6) 0 (0) 36 (100)
Children with household member with resolved or chronic infection—310 (87.6%) Born before 1992—56 (18.0) Born after 1991—254 (81.9)
66 (97.1) 17 (25.8) 49 (74.2)
23 (85.2) 2 (8.7) 21 (91.3)
57 (62.6) 18 (31.6) 39 (68.4)
52 (96.3) 12 (23.1) 40 (76.9)
112 (98.2) 7 (6.2) 105 (93.8)
a Study participant not born in the United States or was aged ≥21 years (n = 635) at enrolment —foreign-born children aged <21 years (n = 72), foreign-born adults (n = 559), and U.S.-born adults (n = 4). b If U.S.-born, maternal country of origin. c Study participant born in the United States and was aged <21 years at enrollment. d Two children (Korean and Vietnamese) HBsAg–/anti-HBc–/anti-HBs inconclusive. e Not expanded into age categories because of small numbers.
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Table 3 Multivariate analysis—predictors of chronic or resolved Hepatitis B Virus (HBV) infections among U.S.-born children (n = 341).a . Selected risk factor
Infected children (n = 7) no. (%)
Born before 1992 Mother HBsAg+ Father HBsAg+c Other adult HBsAg+ Other child HBsAg+
4 (57.1) 6 (85.7) 2 (28.6) 0 (0.0) 1 (14.3)
Adjusted odds ratio 9.5 63.2b 4.9 6.1b 2.7
95% CI 1.0–121.9 6.3–Undef. 0.3–66.4 0–81.8 0.05–409.0
P value 0.056 <0.0001 0.4 1.0 1.0
CI = confidence interval; HBsAg = hepatitis B surface antigen. Bold entries highlight the two significant predictors of HBV infection identified in the study. a Category excludes 13 children whose mothers’ HBV status was unknown. b Indicates a median unbiased estimate. c Category excludes 54 children whose fathers’ HBV status was not known.
vaccine by age 1 year, and 3 doses of either vaccine by date of study enrollment. 3. Results 3.1. Participant characteristics A total of 989 persons were enrolled in the study, including 563 adults (aged ≥21 years) and 426 children (aged <21 years). Only four adults were U.S.-born and 72 children (17%) were foreign-born; therefore, 354 children were considered study children (U.S.-born, aged <21 years), and 635 participants were foreign-born or adult participants (nonstudy children). Thirteen U.S.-born children were excluded from the risk factor analysis because the biologic mother’s HBV infection status was unknown. Only 88 persons, including infants age less than 1 year, from 198 families were not enrolled but included in the total number of household members listed by the head of the household. The characteristics of the participants by ethnicity, including age, immigrant/refugee status, recruitment method, household density, and number of household members are displayed in Table 1. Of the 989 participants, 222 (22.4%) were recruited through vital records, and 692 (69.9%) were enlisted through churches, friends, or the media. Approximately 82.8% of the study children were aged <10 years. The largest proportion of study participants was from Vietnam; this ethnic group constituted 42.3% (238/563 not shown) of the adult study population and 32.2% of the 354 study children. Refugee status varied substantially by country of origin, as did how the household was recruited into the study. Seventy-five percent of Cambodian participants were recruited into the study by friends. Chinese and Vietnamese participants learned about the study through letters sent by using vital record data to locate names and addresses. Korean and Laotian participants came to the study through information provided by their church. Eighty-eight percent of the 354 study children lived in a household with at least one person with serologic evidence of chronic or resolved HBV infection. The proportion of study children living in a household with a chronically infected person was 25.9% overall, and ranged from 9.9% among Korean children to 36.8% among Cambodian children (Table 2). 3.2. HBV infection status and characteristics of U.S.-born children with markers of infection Sixty-seven (10.6%) of the 635 foreign-born children or adult participants were chronically infected; 291 (45.8%) had evidence of resolved infection; 92 had (14.5%) evidence of immunity from vaccination; and 185 (29.1%) had no markers of HBV infection and were considered susceptible (Table 2). Three (0.9%) of the 354 study children had chronic infections, and four (1.1%) had serologic evidence of resolved infections (Table 2). Six (85.7%) of the seven children with current or resolved infections, including the three with chronic infections, had a chronically infected mother.
Four (57.1%) of the seven infected study children were born before 1992. Three of the four had serologic evidence of resolved infection and had unknown hepatitis B vaccination status. One (25%) child was chronically infected, born to an HBeAg-positive mother, and had not received the recommended 3 doses of hepatitis B vaccine until age 11. Birth records for the three children with markers of HBV infection born in the United States after 1991 were reviewed. Two children had chronic infections, and one child had resolved infection. All three were born to HBsAg-positive mothers, but only one of the mothers was HBeAg-positive. All three children received vaccine ≤24 h after birth. However, only two were administered HBIG, and only one (the nonchronically infected child) received both vaccine and HBIG immediately upon delivery. 3.3. Risk factors for HBV infection Twenty-nine of 35 (82.9%) children born to a chronically infected mother had no evidence of HBV infection; 25 (71.4%) were fully vaccinated by age 1 year and 30 (85.7%) by date of study enrollment. Of the 306 children born to mothers who were HBsAg-negative at the time of delivery, 305 (99.7%) had no evidence of infection; 185 (60.5%) were fully vaccinated by age 1 year, and 276 (90.2%) by date of study enrollment. Predictors of infection among the study children, controlling for chronic infection among household members, were being born to a chronically infected mother (AOR: 63.2; 95% CI: 6.3–undefined) and being born before 1992 (AOR: 9.5; 95% CI: 1.0–121.9); with a P value of 0.056 being born before 1992 approaches statistical significance. Having a chronically infected father, other adult, or child in the household was not statistically associated with infection among the study children (Table 3). The seroprevalence of infection was not significantly different among children of different ethnicity, sex, or household size. 3.4. Hepatitis B vaccination status Only three (4.8%) of the 63 study children born in the United States before 1992 had a history of 3 doses of hepatitis B vaccine by age 1 year; 32 (50.8%) had completed the recommended series by the date of study enrollment. Of the 291 children born after the universal infant vaccination recommendation, 215 (73.9%) had completed the 3-dose series by age 1 year, and 284 (97.6%) had received all 3 doses by the date of study enrollment. None of the children born before 1992 and 96 (33%) of the children born after 1991, had documentation of a dose of vaccine within one day of birth. A significantly higher proportion of children born after 1991 had been vaccinated by age 1 year or by date of study enrollment, compared with children born before 1992 (P < .01). In contrast completion of the DTP/DTaP 3-dose series by age 1 year (86% among children born before 1992 vs. 91% among children born after 1991) and by study enrollment (100% among children born before 1992 vs. 99.7% among children born
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after 1991) did not differ significantly between the two age groups.
4. Discussion We report results of an HBV seroprevalence survey conducted among Asian immigrant communities in Georgia, modeled after a study conducted in 1985 among a similar population during the era before the routine use of hepatitis B vaccine during infancy [18]. Despite a high prevalence of infected mothers and other infected household members, children born in the United States of foreignborn Asian parents, after routine infant hepatitis B vaccination was recommended in 1991, were rarely infected with HBV. Although the prevalence of chronic HBV infection among foreign-born adults was 11% in both the 1985 study and this study, only 0.8% of the U.S.-born children in our study had chronic HBV infection, compared with 4.3% of the children in the 1985 study; an 81% reduction [18]. The overall HBV infection burden among children decreased as well, with only 1.1% of children born after 1991 having evidence of resolved infection, compared with 12.5% of the children studied in 1985. Children born in the United States after 1991 were more likely to have received the recommended 3 doses of the hepatitis B vaccine during infancy, compared with the children born before the recommendation was made. Vaccination coverage was extremely high among our study children, but could have been timelier among 26.1% of the children who had not completed the 3-dose series by age 1 year. These data are the first to show the impact of routine vaccination programs among U.S.-born children of Asian immigrants, and demonstrate that children vaccinated during infancy remain protected from infection despite the frequent presence of household and community members with chronic HBV infection. Our results provide evidence of reductions in both perinatal and horizontal transmissions among vaccinated U.S.-born children [10,15,24]. Having a chronically infected mother was still the strongest predictor of infection, yet in our study, only six (17.1%) out of 35 children born to chronically infected mothers had evidence of infection. In 1985, 17 (54.8%) out of 31 children born to chronically infected mothers had evidence of infection, highlighting the reduction in perinatal HBV transmission after the hepatitis B vaccination recommendations. During the previous Georgia study, 45% of chronically infected children did not have a chronically infected mother, indicating that infection occurred through horizontal transmission and living with a chronically infected child was a predictor of infection in 1985 [18]. In contrast, six of seven children with chronic or resolved HBV infection identified in this study had a chronically infected mother, and no chronic infections were identified in the household of the seventh. The presence of a household member with chronic infection other than the mother was not associated with infection among our study children. As with any cross-sectional seroprevalence study, the interpretation of these data has limitations. The date of HBV infection was unknown, but among foreign-born participants, infection was assumed to have been acquired in their native countries. For those with resolved infection, we cannot know if, when, or for how long they might have been infectious to other household members. We cannot determine why the children with chronic or resolved infection had not been protected by vaccination. However, breakthrough infections have been noted in the majority of efficacy studies conducted among infants born to infected women, especially among infants born to women with higher viral loads [3,4,25,26] Unlike the 1985 study, our study participants were not randomly selected. If chronically infected persons were preferentially enrolled or sought out study participation, the prevalence of HBV infection in the study population might have been falsely elevated. However, possibly, persons known to be infected could have avoided participation
because of preconceived ideas of treatment or fear of stigmatization. Eligible immigrant households were determined by birth certificate records but follow-up was challenging; addresses had often changed between birth and the start of the study. Additional study subjects were recruited through social and media outlets. Our sample of 354 U.S.-born children including 291 born after the 1991 vaccination recommendations adequately powered our study. Hepatitis B vaccination is the foundation for prevention of HBV infection and its sequelae of chronic liver disease, cancer, and cirrhosis [4,27]. Studies in countries with a high seroprevalence of HBV infection (e.g., Taiwan) have revealed the benefit of infant vaccination by demonstrating a decrease in HBV seroprevalence and liver cancer [27–32]. In the United States in 2005, dramatic declines in hepatitis B incidence rates (80% since 1966) were reported among children aged <15 years [33]. The 1991 universal infant vaccination recommendation resulted in a protected and highly vaccinated cohort of children [32]. High vaccination coverage rates in the United States in 2005 confirmed the success of the hepatitis B vaccination program; 93% of children aged 19–35 months were vaccinated against HBV infection [33]. The high vaccination and low infection rates in the post-1991 age cohort in our study are consistent with these national trends. However, this study is the first conducted among Asian immigrant populations in the United States to demonstrate substantial reductions in the burden of HBV infection among children. Nonetheless, the high prevalence of HBV infection among Asian immigrant adults indicates that continued efforts are needed to maintain high vaccination coverage among children in Asian immigrant families. In addition, the study demonstrates the importance of programs to ensure vaccination of susceptible household contacts living with HBV-infected persons and provide medical referrals for those who have chronic hepatitis B. Acknowledgments We thank the staff at the Center for Pan-Asian Community Services for their work in recruiting eligible participants, the families and children for their cooperation and willingness to provide serology, and the manufacturers of EMLA® (AstraZeneca L.P., Wilmington, Delaware) cream donated to facilitate a more comfortable venipuncture. References [1] Centers for Disease Control Prevention. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Recommend Rep 2005;54(RR-16):1–23. [2] Centers for Disease Control Prevention. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Recommend Rep 1991;40(RR–13):1–19. [3] Hyams KC. Risks of chronicity following acute hepatitis B virus infection: a review. Clin Infect Dis 1995;20:992–1000. [4] Beasley RP, Hwang Ly, Lee GC, et al. Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 1983:1099–102. [5] McMahon BJ, Alward WL, Hall DB. Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state. J Infect Dis 1985;151(4):599–603. [6] Shepard CW, Finelli L, Fiore AE. Epidemiology of hepatitis B and hepatitis B virus infection in United States children. Pediatr Infect Dis J 2005;24:755–60. [7] Mahoney FJ, Woodruff BA, Erben JJ, et al. Effect of a hepatitis B vaccination program on the prevalence of hepatitis B virus infection. J Infect Dis 1993;167:203–7. [8] Centers for Disease Control Prevention. Recommendations of the Immunization Practices Advisory Committee (ACIP): inactivated hepatitis B virus vaccine. MMWR Morb Mortal Wkly Rep 1982;31, 317-318, 327–328. [9] Centers for Disease Control Prevention. Recommendations of the Immunization Practices Advisory Committee (ACIP): prevention of perinatal transmission of hepatitis B virus: prenatal screening of all pregnant women for hepatitis B surface antigen. MMWR Morb Mortal Wkly Rep 1988;37, 341–346, 351.
C.M. Shuler et al. / Vaccine 27 (2009) 5942–5947 [10] Centers for Disease Control Prevention. Update: recommendations to prevent hepatitis B virus transmission—United States. MMWR Morb Mortal Wkly Rep 1995;44:574–5. [11] Centers for Disease Control Prevention. Update: recommendations to prevent hepatitis B virus transmission—United States. MMWR Morb Mortal Wkly Rep 1999;48:33–4. [12] Committee on Infectious Diseases. Universal hepatitis B immunization. Pediatrics 1992;89:795–800. [13] Tong MJ, Hwang SJ. Hepatitis B virus infection in Asian Americans. Gastroenterol Clin North Am 1994;2:523–35. [14] Centers for Disease Control Prevention. Screening for hepatitis B virus infection among refugees arriving in the United States 1979–1991. MMWR Morb Mortal Wkly Rep 1991;40(45):784–6. [15] Ni YH, Chang MH, Huan LM, et al. Hepatitis B virus infection in children and adolescents in a hyperendemic area: 15 years after mass hepatitis B vaccination. Ann Int Med 2001;135:796–800. [16] Custer B, Sullivan SD, Hazlet TK, et al. Global epidemiology of hepatitis B virus. J Clin Gastroenterol 2004;38:S158–68. [17] Hurie MB, Mast EE, Davis JP. Horizontal transmission of hepatitis B virus infection to United States-born children of Hmong refugees. Pediatrics 1992;89:269–73. [18] Franks AL, Berg CJ, Kane MA, et al. Hepatitis B virus infection among children born in the United States to Southeast Asian refugees. N Engl J Med 1989;321:1301–5. [19] Mahoney FJ, Lawrence M, Scott C, et al. Continuing risk for hepatitis B virus transmission among Southeast Asian infants in Louisiana. Pediatrics 1995;96:1113–6. [20] Armstrong GL, Mast EE, Wojczynski M, Margolis HS. Childhood hepatitis B virus infections in the United States before hepatitis B immunization. Pediatrics 2001;108:1123–8. [21] Pon EW, Ren H, Margolis H, et al. Hepatitis B virus infection in Honolulu students. Pediatrics 1993;92:574–8.
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[22] Silverman NS, Darby MJ, Ronkin SL, et al. Hepatitis B prevalence in an unregistered prenatal population. JAMA 1991;266:2852–5. [23] Immunization Action Coalition. Hepatitis B prevention mandates. St Paul, MN: Immunization Action Coalition; 2007. Available at http://www.immunize.org/laws/hepb.htm. [24] Perz JR, Elm JL, Fiore AE, et al. Near elimination of hepatitis B virus infections among Hawaii elementary school children after universal infant hepatitis B vaccination. Pediatrics 2006;118:1403–8. [25] Wong VC, Ip HH, Reesink HW, Lelie PN, et al. Prevention of the HBsAg carrier state in newborn infants of mothers who are chronic carriers of HBsAg and HBeAg by administration of hepatitis B vaccine and hepatitis B immunoglobulin. Lancet 1984;8383:921–6. [26] Beasley RP, Hwang LY. Postnatal infectivity of hepatitis B surface antigencarrier mothers. J Infect Dis 1983;147:185–90. [27] Chang Mh, Chen CH, Lai MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 1997;336:1855–9. [28] Lin HH, Wang L, Hu C, et al. Decline of hepatitis B carrier rate in vaccinated and unvaccinated subjects sixteen years after newborn vaccination program in Taiwan. J Med Virol 2003;69:471–4. [29] Tsebe KV, Burnett RJ, Hlungwani HP, et al. The first five years of universal hepatitis B vaccination in South Africa: evidence for elimination of HBsAg carriage in under 5-year-olds. Vaccine 2001;19:3919–26. [30] Centers for Disease Control Prevention. Achievements in public health: hepatitis B vaccination—United States 1982–2002. MMWR Morb Mortal Wkly Rep 2002;51:549–52. [31] Margolis HS, Coleman PJ, Brown RE, et al. Prevention of hepatitis B virus transmission by immunization. JAMA 1995;274:1201–8. [32] Shepard CW, Simard EP, Finelli L, et al. Hepatitis B virus infection: epidemiology and vaccination. Epidemiol Rev 2006;28:112–25. [33] Centers for Disease Control and Prevention. Surveillance for acute viral hepatitis—United States, 2005. MMWR Surveill 2007;56(SS-3):1–24.
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Reduction in hepatitis B virus seroprevalence among U.S.-born children of foreign-born Asian parents—Benefit of universal infant hepatitis B vaccination夽,夽夽 Carrie M. Shuler a,b,∗ , Anthony E. Fiore c , Ruth Neeman a , Beth P. Bell c , Wendi Kuhnert d , Sandra Watkins e , Kimberly Kilgour e , Kathryn E. Arnold a a
Notifiable Diseases Epidemiology Section, Georgia Department of Human Resources, Division of Public Health, Atlanta, GA, United States Epidemic Intelligence Service, Centers for Disease Control and Prevention, Atlanta, GA, United States c Division of Viral Hepatitis, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, United States d Hepatitis Laboratory, Division of Viral Hepatitis, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, United States e Georgia Public Health Laboratory, Georgia Department of Human Resources, Division of Public Health, Atlanta, GA, United States b
a r t i c l e
i n f o
Article history: Received 24 March 2009 Received in revised form 18 July 2009 Accepted 23 July 2009 Available online 11 August 2009 Keywords: Hepatitis B immunizations Pediatrics
a b s t r a c t We demonstrate that after implementation of recommendations for universal infant hepatitis B vaccination, HBV infection prevalence among children of foreign-born Asian parents in Georgia declined dramatically; horizontal transmission of infection within households has occurred infrequently; and the vast majority of infants and children have received the recommended hepatitis B vaccinations. These results provide evidence of the success of the hepatitis B infant vaccination program and highlight its potential impact on reducing chronic HBV infection morbidity and mortality among U.S. populations at high risk. Published by Elsevier Ltd.
1. Introduction Chronic infection with hepatitis B virus (HBV) is a leading cause of chronic liver disease and liver cancer worldwide. In the United States, an estimated 1 million–1.25 million persons (0.4% of the U.S. population) are living with chronic HBV infection [1]. These persons are potentially infectious and serve as the main reservoir for continued HBV transmission within the community [1,2]. Acute HBV infection can lead to chronic infection at any age, but infants and young children are more likely to experience chronic infection, compared with adults; ≥90% of perinatal infections lead to chronic infections, compared with approximately 5% of infections among adolescents or adults [3–6]. Hepatitis B vaccine licensed in the United States in 1982 is a safe and effective way to prevent infection. Vaccination beginning at birth or during early infancy has been the cornerstone of prevention efforts [1,2,7–12]. Specific recommendations for infants born to women with chronic HBV infection include the first dose of hepatitis B vaccination and hepatitis B immune globulin (HBIG) at birth [1,12]. 夽 This work was presented in part at the Infectious Disease Society of America Conference: October 9–12, 2003: San Diego, California. 夽夽 The findings and conclusions in this report are those of the author(s) and do not necessarily represent the views of the Centers for Disease Control and Prevention. ∗ Corresponding author at: 2680 NW Thurman Street, Portland, Oregon 97210, United States. Tel.: +1 503 206 8037; fax: +1 503 227 7213. E-mail address: carrie [email protected] (C.M. Shuler). 0264-410X/$ – see front matter. Published by Elsevier Ltd. doi:10.1016/j.vaccine.2009.07.087
The prevalence of chronic HBV infection, indicated by the presence of hepatitis B surface antigen (HBsAg) in serum, is 5–15% worldwide, compared with 0.5% overall in the United States [1,13–16]. These high rates of chronic infection have been attributed to transmission from infected mother to newborn during the perinatal period and from household members with chronic HBV infection to young children [17–19]. Studies conducted in the United States before hepatitis B vaccine was available indicated that children of Southeast (SE) Asian immigrant women had >100 times the estimated rate of infection, compared with nonAsian children [20]. Studies conducted during the 1980s after hepatitis B vaccine licensure demonstrated that high rates of HBV infection among Asian children born in the United States persisted [17–19,21]. Low rates of maternal screening and infant vaccination, as well as horizontal transmission from infected household members to children born to HBsAg-negative women, were demonstrated in multiple investigations conducted among groups at higher risk for HBV infection [6,17,18,22]. These results supported policy changes focused on providing protection against HBV infection for all infants regardless of maternal HBsAg status. In 1988, the Advisory Committee on Immunization Practices (ACIP) recommended HBsAg screening for all pregnant women [9]. In 1991, to prevent horizontal transmission in households and to further reduce missed opportunities to prevent HBV infection, ACIP recommended hepatitis B vaccination for all infants, preferably beginning at birth and regardless of the HBsAg status of the mother
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[2,9]. By 2002, a total of 43 states required hepatitis B vaccination for public school or child care participation [23], and the incidence of acute (i.e., symptomatic) HBV infection among children had declined by 89% [20]. However, the majority of HBV infections among infants and young children are asymptomatic; measures of acute infection cannot capture continuing transmission of HBV infection to infants and children. We performed a follow-up seroprevalence study during 2001–2004 in an Asian immigrant community in Georgia to evaluate the impact of universal maternal HBsAg screening and infant vaccination in preventing HBV infection among U.S.-born children of foreign-born Asian parents. Our three objectives were to determine the seroprevalence of HBV infection among children of foreign-born Asian parents born in the United States during the post universal vaccination recommendation periods, to examine the association between infection among U.S.-born children and the presence of a chronically infected person in their household, and to determine vaccination status among children of foreignborn Asian parents. 2. Materials and methods
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year the foreign-born participants entered the United States, and whether they considered themselves refugees or immigrants. The number of persons per bedroom was also recorded as a measure of household density or crowding. With parental consent for children aged <18 years, all vaccine providers including physicians and public health clinics as well as schools and the Georgia Registry of Immunization Transactions and Services (GRITS) were contacted or reviewed to determine the number and timing of hepatitis B vaccinations. The parent or guardian during the enrollment interview was also asked to show their copy of the child’s vaccination history. To evaluate whether changes in hepatitis B vaccination practices over time were attributable to the 1991 policy and not to improved access to health care, another recommended childhood vaccination [diphtheria, pertussis (whole cell or acellular) and tetanus, DTP/DTaP] was used as a referent practice. Parents were offered the option of topical anesthetic for their children prior to venipuncture. Whole blood (5–10 ml) was obtained in serum-separator tubes, centrifuged within 4 h, and the serum decanted, transferred, and promptly tested at Georgia Public Health Laboratory (GPHL). Serum was subsequently frozen at −20 ◦ C and transported in batches to CDC for confirmatory serologic testing.
2.1. Subjects 2.2. Serology Study enrollment criteria required that households include a parent born in Korea, China, Laos, Cambodia, or Vietnam, and one or more U.S.-born children aged ≥12 months (study children). These countries of origin were chosen because of their high HBV endemicity rates [14,16] and the size of the immigrant population in Georgia. Households were recruited by using multiple methods. We estimated 272 children born in the U.S. after 1991 would be needed to demonstrate a reduced HBV seroprevalence from an expected 12% among high risk groups without vaccination to 2% or less among children born after the universal vaccination recommendations. We initially identified eligible households by focusing on children born during 1992–2001 by linking vital records data to the state’s Refugee Health Program of the Georgia Department of Human Resources (DHR). We also worked closely with the Center for Pan-Asian Community Services (CPACS), a nonprofit organization that provides social, legal, and health-care services to Asian persons in greater Atlanta, including vaccination for approximately 500 children/year. We mailed eligible families a letter of invitation in both English and the relevant language. We also solicited families who visited CPACS and at religious festivals, worksites, and health fairs, and through friends, media announcements, church groups, and health clinics in Asian communities in four Georgia counties (Clayton, DeKalb, Fulton, and Gwinnett). Recruitment, enrollment, interviewing, specimen collection, and venipuncture of eligible family members were coordinated by a nurse-phlebotomist. CPACS served as the main point of contact, provided details about the study, and facilitated scheduling of the initial consultation with translation services, if needed. During the first appointment, written informed consent was sought, and if the qualifying child and the child’s mother agreed to participate, the household was given the option of completing the questionnaire and undergoing venipuncture immediately. If all household members were not available for this meeting, an appointment was scheduled within 2 weeks, either at the home or at CPACS, to obtain blood from other household members. Children younger than age 1 year were excluded from the study. The Georgia DHR Institutional Review Board (IRB) and the Centers for Disease Control and Prevention (CDC) IRB approved the study. The participants were enrolled during May 2001–September 2004. Information was obtained on the age, sex, birthplace, relationship to the U.S.-born child, hepatitis B vaccination history, the
The GPHL and CDC’s Division of Viral Hepatitis tested serum samples (Ortho-Clinical Diagnostics, Rochester, NY) for total antibody to hepatitis B core antigen (anti-HBc) and antibody to hepatitis B surface antigen (anti-HBs); anti-HBc-positive samples were tested for HBsAg and for IgM antibody to hepatitis B core antigen (IgM anti-HBc). HBsAg-positive samples were also tested for hepatitis B e antigen (HBeAg), a marker of higher HBV concentrations and higher infectivity. Participants with evidence of any HBV infection were categorized into chronic or resolved infection. Chronic infection was defined by the presence of HBsAg and the absence of IgM antiHBc; those persons were referred for treatment. Resolved infection was defined by the presence of anti-HBc without HBsAg. Immunity because of vaccination was defined as ≥10 milli-international units/ml (MIU/ml) anti-HBs in serum and undetectable levels of anti-HBc. Participants were offered hepatitis B vaccine if they had no history of hepatitis B vaccination, were HBsAg-negative, and had undetectable levels of anti-HBs and anti-HBc. For families with a chronically infected member, counseling regarding risks for chronic HBV infection, the need for vaccination among susceptible household members, and treatment options were provided. 2.3. Statistical analyses The focus of the data analysis was to calculate the point prevalence of HBV infection among children born since the 1991 universal vaccination recommendations and to identify predictors associated with infection. Because of the limited number of children with the outcome of interest (chronic or resolved HBV infection), adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated by using exact measures in SAS® version 9.1 (SAS Institute Inc., Cary, NC). Predictors of infections among the study children were evaluated in multivariate models by controlling for household members (mother, father, other adult or other child) with chronic infections. 2.4. Vaccination status Documented hepatitis B vaccine doses and DTP/DTaP doses were used to calculate vaccination status. Vaccination status of the study children was broken down into a hepatitis B vaccine birth dose (defined as a dose on or one day after birth), 3 doses of either
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Table 1 Characteristics of Study Participants (N = 989). Foreign-born children/adultsa (n = 635; median age = 38 years)
Country of originb Cambodia (n = 89; 14.0%)
China (n = 61; 9.6%)
Korea (n = 122; 19.2%)
Laos (n = 75; 11.8%)
Vietnam (n = 288; 45.4%)
Age category (years) 1–20—72 (11.3%) 21–30—96 (15.1%) 31–40—243 (38.3%) 41–50—122 (19.2%) >50—102 (16.1%)
5 (5.6) 18 (20.2) 38 (42.7) 18 (20.2) 10 (11.2)
4 (6.6) 6 (9.8) 23 (37.7) 13 (21.3) 15 (24.6)
8 (6.6) 9 (7.4) 59 (48.4) 33 (27.0) 13 (10.7)
5 (6.7) 21 (28.0) 17 (22.7) 17 (22.7) 15 (20.0)
50 (17.4) 42 (14.6) 106 (36.8) 41 (14.2) 49 (17.0)
Refugee—292 (46.0%) Immigrant—339 (53.4%) Median year entering U.S. High household densityc —297 (46.8%) Number of household members (median, range) Number of households—198
65 (73.0) 23 (25.8) 1984 43 (48.3) 6 (2–13) 30
1 (1.6) 60 (98.4) 1993 25 (41.0) 6 (3–14) 18
1 (0.8) 121 (99.2) 1989 14 (11.5) 4 (2–8) 54
61 (81.3) 11 (14.7) 1982 31 (41.3) 6 (3–10) 24
164 (56.9) 124 (43.1) 1993 184 (63.9) 6 (3–17) 72
Study childrend (n = 354; median age = 6 years)
n = 68; 19.2%
n = 27; 7.6%
n = 91; 25.7%
n = 54; 15.3%
n = 114; 32.2%
Age Born before 1992—63 (17.8) Born after 1991—291 (82.2)
17 (25) 51 (75)
2 (7) 25 (93)
24 (26) 67 (74)
13 (24) 41 (76)
7 (6) 107 (94)
High household densityc —121 (34.2%) Born before 1992—18 (14.8) Born after 1991—103 (85.1)
29 (42.6) 10 (34) 19 (66)
10 (37.0) 0 (0) 10 (100)
6 (6.6) 1 (17) 5 (83)
21 (38.9) 5 (24) 16 (76)
55 (48.2) 2 (4) 53 (96)
a Study participant not born in the United States or was aged ≥21 years = 635) at enrollment—72 foreign-born children aged <21 years 59 foreign-born adults, and four U.S.-born adults (aged 21, 23, 23, and 58 years). b If U.S.-born, maternal country of origin. c ≥1.7 Family members per bedroom (i.e., median for population). d Study participant born in the United States and was aged <21 years at enrollment.
Table 2 Hepatitis B virus infection status by country of origin. Foreign-born children/adultsa (n = 635; median age = 38 years)
Country of originb
Chronic infection—67 (10.6%) Resolved infection—291 (45.8%) Immune after vaccine—92 (14.5%) No markers—185 (29.1%)
Cambodia (n = 89; 14.0%) 13 (14.6) 38 (42.7) 11 (12.4) 27 (30.3)
China (n = 61; 9.6%) 6 (9.8) 32 (52.5) 9 (14.8) 14 (23.0)
Korea (n = 122; 19.2%) 4 (3.3) 42 (34.4) 19 (15.6) 57 (46.7)
Laos (n = 75; 11.8%) 8 (10.7) 39 (52.0) 7 (9.3) 21 (28.0)
Vietnam (n = 288; 45.4%) 36 (12.5) 140 (48.6) 46 (16.0) 66 (22.9)
Cambodia
China
Korea
Laos
Vietnam
Study childrenc , d (n = 354; median age = 6 years) Chronic infectione —3 (0.8%) Resolved infectione — (1.1%)
n = 68; 19.2% 1 (1.5) 3 (4.4)
n = 27; 7.6% 0 (0) 0 (0)
n = 91d ; 25.7% 0 (0) 0 (0)
n = 54; 15.3% 1 (1.9) 0 (0)
n = 114d ; 32.2% 1 (0.9) 1 (0.9)
Immune after vaccine—168 (47.5%) Born before 1992—28 (16.7) Born after 1991—140 (83.3)
28 (41.2) 62 (21.4) 22 (78.6)
17 (63.0) 2 (11.8) 15 (88.2)
46 (51.1) 11 (23.9) 35 (76.1)
19 (35.2) 5 (26.3) 14 (73.7)
58 (51.3) 4 (6.9) 54 (93.1)
No markers—177 (50.0%) Born before 1992—31 (17.5) Born after 1991—146 (82.5)
36 (52.9) 8 (22.2) 28 (77.8)
10 (37.0) 0 (0) 10 (100)
44 (48.4) 13 (29.5) 31 (70.5)
34 (63.0) 7 (20.6) 27 (79.4)
53 (46.5) 3 (5.7) 50 (94.3)
Children with household member with chronic infection—92 (25.9%) Born before 1992—14 (15.2) Born after 1991—78 (84.8)
25 (36.8) 7 (28.0) 18 (72.0)
7 (25.9) 0 (0) 7 (100)
9 (9.9) 3 (33.3) 6 (66.7)
15 (27.8) 4 (26.7) 11 (73.3)
36 (31.6) 0 (0) 36 (100)
Children with household member with resolved or chronic infection—310 (87.6%) Born before 1992—56 (18.0) Born after 1991—254 (81.9)
66 (97.1) 17 (25.8) 49 (74.2)
23 (85.2) 2 (8.7) 21 (91.3)
57 (62.6) 18 (31.6) 39 (68.4)
52 (96.3) 12 (23.1) 40 (76.9)
112 (98.2) 7 (6.2) 105 (93.8)
a Study participant not born in the United States or was aged ≥21 years (n = 635) at enrolment —foreign-born children aged <21 years (n = 72), foreign-born adults (n = 559), and U.S.-born adults (n = 4). b If U.S.-born, maternal country of origin. c Study participant born in the United States and was aged <21 years at enrollment. d Two children (Korean and Vietnamese) HBsAg–/anti-HBc–/anti-HBs inconclusive. e Not expanded into age categories because of small numbers.
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Table 3 Multivariate analysis—predictors of chronic or resolved Hepatitis B Virus (HBV) infections among U.S.-born children (n = 341).a . Selected risk factor
Infected children (n = 7) no. (%)
Born before 1992 Mother HBsAg+ Father HBsAg+c Other adult HBsAg+ Other child HBsAg+
4 (57.1) 6 (85.7) 2 (28.6) 0 (0.0) 1 (14.3)
Adjusted odds ratio 9.5 63.2b 4.9 6.1b 2.7
95% CI 1.0–121.9 6.3–Undef. 0.3–66.4 0–81.8 0.05–409.0
P value 0.056 <0.0001 0.4 1.0 1.0
CI = confidence interval; HBsAg = hepatitis B surface antigen. Bold entries highlight the two significant predictors of HBV infection identified in the study. a Category excludes 13 children whose mothers’ HBV status was unknown. b Indicates a median unbiased estimate. c Category excludes 54 children whose fathers’ HBV status was not known.
vaccine by age 1 year, and 3 doses of either vaccine by date of study enrollment. 3. Results 3.1. Participant characteristics A total of 989 persons were enrolled in the study, including 563 adults (aged ≥21 years) and 426 children (aged <21 years). Only four adults were U.S.-born and 72 children (17%) were foreign-born; therefore, 354 children were considered study children (U.S.-born, aged <21 years), and 635 participants were foreign-born or adult participants (nonstudy children). Thirteen U.S.-born children were excluded from the risk factor analysis because the biologic mother’s HBV infection status was unknown. Only 88 persons, including infants age less than 1 year, from 198 families were not enrolled but included in the total number of household members listed by the head of the household. The characteristics of the participants by ethnicity, including age, immigrant/refugee status, recruitment method, household density, and number of household members are displayed in Table 1. Of the 989 participants, 222 (22.4%) were recruited through vital records, and 692 (69.9%) were enlisted through churches, friends, or the media. Approximately 82.8% of the study children were aged <10 years. The largest proportion of study participants was from Vietnam; this ethnic group constituted 42.3% (238/563 not shown) of the adult study population and 32.2% of the 354 study children. Refugee status varied substantially by country of origin, as did how the household was recruited into the study. Seventy-five percent of Cambodian participants were recruited into the study by friends. Chinese and Vietnamese participants learned about the study through letters sent by using vital record data to locate names and addresses. Korean and Laotian participants came to the study through information provided by their church. Eighty-eight percent of the 354 study children lived in a household with at least one person with serologic evidence of chronic or resolved HBV infection. The proportion of study children living in a household with a chronically infected person was 25.9% overall, and ranged from 9.9% among Korean children to 36.8% among Cambodian children (Table 2). 3.2. HBV infection status and characteristics of U.S.-born children with markers of infection Sixty-seven (10.6%) of the 635 foreign-born children or adult participants were chronically infected; 291 (45.8%) had evidence of resolved infection; 92 had (14.5%) evidence of immunity from vaccination; and 185 (29.1%) had no markers of HBV infection and were considered susceptible (Table 2). Three (0.9%) of the 354 study children had chronic infections, and four (1.1%) had serologic evidence of resolved infections (Table 2). Six (85.7%) of the seven children with current or resolved infections, including the three with chronic infections, had a chronically infected mother.
Four (57.1%) of the seven infected study children were born before 1992. Three of the four had serologic evidence of resolved infection and had unknown hepatitis B vaccination status. One (25%) child was chronically infected, born to an HBeAg-positive mother, and had not received the recommended 3 doses of hepatitis B vaccine until age 11. Birth records for the three children with markers of HBV infection born in the United States after 1991 were reviewed. Two children had chronic infections, and one child had resolved infection. All three were born to HBsAg-positive mothers, but only one of the mothers was HBeAg-positive. All three children received vaccine ≤24 h after birth. However, only two were administered HBIG, and only one (the nonchronically infected child) received both vaccine and HBIG immediately upon delivery. 3.3. Risk factors for HBV infection Twenty-nine of 35 (82.9%) children born to a chronically infected mother had no evidence of HBV infection; 25 (71.4%) were fully vaccinated by age 1 year and 30 (85.7%) by date of study enrollment. Of the 306 children born to mothers who were HBsAg-negative at the time of delivery, 305 (99.7%) had no evidence of infection; 185 (60.5%) were fully vaccinated by age 1 year, and 276 (90.2%) by date of study enrollment. Predictors of infection among the study children, controlling for chronic infection among household members, were being born to a chronically infected mother (AOR: 63.2; 95% CI: 6.3–undefined) and being born before 1992 (AOR: 9.5; 95% CI: 1.0–121.9); with a P value of 0.056 being born before 1992 approaches statistical significance. Having a chronically infected father, other adult, or child in the household was not statistically associated with infection among the study children (Table 3). The seroprevalence of infection was not significantly different among children of different ethnicity, sex, or household size. 3.4. Hepatitis B vaccination status Only three (4.8%) of the 63 study children born in the United States before 1992 had a history of 3 doses of hepatitis B vaccine by age 1 year; 32 (50.8%) had completed the recommended series by the date of study enrollment. Of the 291 children born after the universal infant vaccination recommendation, 215 (73.9%) had completed the 3-dose series by age 1 year, and 284 (97.6%) had received all 3 doses by the date of study enrollment. None of the children born before 1992 and 96 (33%) of the children born after 1991, had documentation of a dose of vaccine within one day of birth. A significantly higher proportion of children born after 1991 had been vaccinated by age 1 year or by date of study enrollment, compared with children born before 1992 (P < .01). In contrast completion of the DTP/DTaP 3-dose series by age 1 year (86% among children born before 1992 vs. 91% among children born after 1991) and by study enrollment (100% among children born before 1992 vs. 99.7% among children born
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after 1991) did not differ significantly between the two age groups.
4. Discussion We report results of an HBV seroprevalence survey conducted among Asian immigrant communities in Georgia, modeled after a study conducted in 1985 among a similar population during the era before the routine use of hepatitis B vaccine during infancy [18]. Despite a high prevalence of infected mothers and other infected household members, children born in the United States of foreignborn Asian parents, after routine infant hepatitis B vaccination was recommended in 1991, were rarely infected with HBV. Although the prevalence of chronic HBV infection among foreign-born adults was 11% in both the 1985 study and this study, only 0.8% of the U.S.-born children in our study had chronic HBV infection, compared with 4.3% of the children in the 1985 study; an 81% reduction [18]. The overall HBV infection burden among children decreased as well, with only 1.1% of children born after 1991 having evidence of resolved infection, compared with 12.5% of the children studied in 1985. Children born in the United States after 1991 were more likely to have received the recommended 3 doses of the hepatitis B vaccine during infancy, compared with the children born before the recommendation was made. Vaccination coverage was extremely high among our study children, but could have been timelier among 26.1% of the children who had not completed the 3-dose series by age 1 year. These data are the first to show the impact of routine vaccination programs among U.S.-born children of Asian immigrants, and demonstrate that children vaccinated during infancy remain protected from infection despite the frequent presence of household and community members with chronic HBV infection. Our results provide evidence of reductions in both perinatal and horizontal transmissions among vaccinated U.S.-born children [10,15,24]. Having a chronically infected mother was still the strongest predictor of infection, yet in our study, only six (17.1%) out of 35 children born to chronically infected mothers had evidence of infection. In 1985, 17 (54.8%) out of 31 children born to chronically infected mothers had evidence of infection, highlighting the reduction in perinatal HBV transmission after the hepatitis B vaccination recommendations. During the previous Georgia study, 45% of chronically infected children did not have a chronically infected mother, indicating that infection occurred through horizontal transmission and living with a chronically infected child was a predictor of infection in 1985 [18]. In contrast, six of seven children with chronic or resolved HBV infection identified in this study had a chronically infected mother, and no chronic infections were identified in the household of the seventh. The presence of a household member with chronic infection other than the mother was not associated with infection among our study children. As with any cross-sectional seroprevalence study, the interpretation of these data has limitations. The date of HBV infection was unknown, but among foreign-born participants, infection was assumed to have been acquired in their native countries. For those with resolved infection, we cannot know if, when, or for how long they might have been infectious to other household members. We cannot determine why the children with chronic or resolved infection had not been protected by vaccination. However, breakthrough infections have been noted in the majority of efficacy studies conducted among infants born to infected women, especially among infants born to women with higher viral loads [3,4,25,26] Unlike the 1985 study, our study participants were not randomly selected. If chronically infected persons were preferentially enrolled or sought out study participation, the prevalence of HBV infection in the study population might have been falsely elevated. However, possibly, persons known to be infected could have avoided participation
because of preconceived ideas of treatment or fear of stigmatization. Eligible immigrant households were determined by birth certificate records but follow-up was challenging; addresses had often changed between birth and the start of the study. Additional study subjects were recruited through social and media outlets. Our sample of 354 U.S.-born children including 291 born after the 1991 vaccination recommendations adequately powered our study. Hepatitis B vaccination is the foundation for prevention of HBV infection and its sequelae of chronic liver disease, cancer, and cirrhosis [4,27]. Studies in countries with a high seroprevalence of HBV infection (e.g., Taiwan) have revealed the benefit of infant vaccination by demonstrating a decrease in HBV seroprevalence and liver cancer [27–32]. In the United States in 2005, dramatic declines in hepatitis B incidence rates (80% since 1966) were reported among children aged <15 years [33]. The 1991 universal infant vaccination recommendation resulted in a protected and highly vaccinated cohort of children [32]. High vaccination coverage rates in the United States in 2005 confirmed the success of the hepatitis B vaccination program; 93% of children aged 19–35 months were vaccinated against HBV infection [33]. The high vaccination and low infection rates in the post-1991 age cohort in our study are consistent with these national trends. However, this study is the first conducted among Asian immigrant populations in the United States to demonstrate substantial reductions in the burden of HBV infection among children. Nonetheless, the high prevalence of HBV infection among Asian immigrant adults indicates that continued efforts are needed to maintain high vaccination coverage among children in Asian immigrant families. In addition, the study demonstrates the importance of programs to ensure vaccination of susceptible household contacts living with HBV-infected persons and provide medical referrals for those who have chronic hepatitis B. Acknowledgments We thank the staff at the Center for Pan-Asian Community Services for their work in recruiting eligible participants, the families and children for their cooperation and willingness to provide serology, and the manufacturers of EMLA® (AstraZeneca L.P., Wilmington, Delaware) cream donated to facilitate a more comfortable venipuncture. References [1] Centers for Disease Control Prevention. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Recommend Rep 2005;54(RR-16):1–23. [2] Centers for Disease Control Prevention. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Recommend Rep 1991;40(RR–13):1–19. [3] Hyams KC. Risks of chronicity following acute hepatitis B virus infection: a review. Clin Infect Dis 1995;20:992–1000. [4] Beasley RP, Hwang Ly, Lee GC, et al. Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 1983:1099–102. [5] McMahon BJ, Alward WL, Hall DB. Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state. J Infect Dis 1985;151(4):599–603. [6] Shepard CW, Finelli L, Fiore AE. Epidemiology of hepatitis B and hepatitis B virus infection in United States children. Pediatr Infect Dis J 2005;24:755–60. [7] Mahoney FJ, Woodruff BA, Erben JJ, et al. Effect of a hepatitis B vaccination program on the prevalence of hepatitis B virus infection. J Infect Dis 1993;167:203–7. [8] Centers for Disease Control Prevention. Recommendations of the Immunization Practices Advisory Committee (ACIP): inactivated hepatitis B virus vaccine. MMWR Morb Mortal Wkly Rep 1982;31, 317-318, 327–328. [9] Centers for Disease Control Prevention. Recommendations of the Immunization Practices Advisory Committee (ACIP): prevention of perinatal transmission of hepatitis B virus: prenatal screening of all pregnant women for hepatitis B surface antigen. MMWR Morb Mortal Wkly Rep 1988;37, 341–346, 351.
C.M. Shuler et al. / Vaccine 27 (2009) 5942–5947 [10] Centers for Disease Control Prevention. Update: recommendations to prevent hepatitis B virus transmission—United States. MMWR Morb Mortal Wkly Rep 1995;44:574–5. [11] Centers for Disease Control Prevention. Update: recommendations to prevent hepatitis B virus transmission—United States. MMWR Morb Mortal Wkly Rep 1999;48:33–4. [12] Committee on Infectious Diseases. Universal hepatitis B immunization. Pediatrics 1992;89:795–800. [13] Tong MJ, Hwang SJ. Hepatitis B virus infection in Asian Americans. Gastroenterol Clin North Am 1994;2:523–35. [14] Centers for Disease Control Prevention. Screening for hepatitis B virus infection among refugees arriving in the United States 1979–1991. MMWR Morb Mortal Wkly Rep 1991;40(45):784–6. [15] Ni YH, Chang MH, Huan LM, et al. Hepatitis B virus infection in children and adolescents in a hyperendemic area: 15 years after mass hepatitis B vaccination. Ann Int Med 2001;135:796–800. [16] Custer B, Sullivan SD, Hazlet TK, et al. Global epidemiology of hepatitis B virus. J Clin Gastroenterol 2004;38:S158–68. [17] Hurie MB, Mast EE, Davis JP. Horizontal transmission of hepatitis B virus infection to United States-born children of Hmong refugees. Pediatrics 1992;89:269–73. [18] Franks AL, Berg CJ, Kane MA, et al. Hepatitis B virus infection among children born in the United States to Southeast Asian refugees. N Engl J Med 1989;321:1301–5. [19] Mahoney FJ, Lawrence M, Scott C, et al. Continuing risk for hepatitis B virus transmission among Southeast Asian infants in Louisiana. Pediatrics 1995;96:1113–6. [20] Armstrong GL, Mast EE, Wojczynski M, Margolis HS. Childhood hepatitis B virus infections in the United States before hepatitis B immunization. Pediatrics 2001;108:1123–8. [21] Pon EW, Ren H, Margolis H, et al. Hepatitis B virus infection in Honolulu students. Pediatrics 1993;92:574–8.
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[22] Silverman NS, Darby MJ, Ronkin SL, et al. Hepatitis B prevalence in an unregistered prenatal population. JAMA 1991;266:2852–5. [23] Immunization Action Coalition. Hepatitis B prevention mandates. St Paul, MN: Immunization Action Coalition; 2007. Available at http://www.immunize.org/laws/hepb.htm. [24] Perz JR, Elm JL, Fiore AE, et al. Near elimination of hepatitis B virus infections among Hawaii elementary school children after universal infant hepatitis B vaccination. Pediatrics 2006;118:1403–8. [25] Wong VC, Ip HH, Reesink HW, Lelie PN, et al. Prevention of the HBsAg carrier state in newborn infants of mothers who are chronic carriers of HBsAg and HBeAg by administration of hepatitis B vaccine and hepatitis B immunoglobulin. Lancet 1984;8383:921–6. [26] Beasley RP, Hwang LY. Postnatal infectivity of hepatitis B surface antigencarrier mothers. J Infect Dis 1983;147:185–90. [27] Chang Mh, Chen CH, Lai MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 1997;336:1855–9. [28] Lin HH, Wang L, Hu C, et al. Decline of hepatitis B carrier rate in vaccinated and unvaccinated subjects sixteen years after newborn vaccination program in Taiwan. J Med Virol 2003;69:471–4. [29] Tsebe KV, Burnett RJ, Hlungwani HP, et al. The first five years of universal hepatitis B vaccination in South Africa: evidence for elimination of HBsAg carriage in under 5-year-olds. Vaccine 2001;19:3919–26. [30] Centers for Disease Control Prevention. Achievements in public health: hepatitis B vaccination—United States 1982–2002. MMWR Morb Mortal Wkly Rep 2002;51:549–52. [31] Margolis HS, Coleman PJ, Brown RE, et al. Prevention of hepatitis B virus transmission by immunization. JAMA 1995;274:1201–8. [32] Shepard CW, Simard EP, Finelli L, et al. Hepatitis B virus infection: epidemiology and vaccination. Epidemiol Rev 2006;28:112–25. [33] Centers for Disease Control and Prevention. Surveillance for acute viral hepatitis—United States, 2005. MMWR Surveill 2007;56(SS-3):1–24.