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Pediatrics International (2015) 57, 401–405
doi: 10.1111/ped.12528
Original Article
Hepatitis B (HB) immunoglobulin plus HB vaccine for intrauterine HB virus infection Kentaro Iwasawa,1 Ayano Inui,1 Tomoyuki Tsunoda,1 Takeo Kondo,1 Manari Kawamoto,1 Tsuyoshi Sogo,1 Haruki Komatsu2 and Tomoo Fujisawa1 1 Division of Hepatology and Gastroenterology, Children’s Center for Health and Development, Saiseikai Yokohamashi Tobu Hospital and 2Department of Pediatrics, Sakura Hospital, Toho University School of Medicine, Sakura, Chiba, Japan Abstract
Background: Vaccination against hepatitis B virus (HBV) infection in infants born to hepatitis B surface antigen (HBsAg)-positive mothers using HB immunoglobulin (HBIG) and hepatitis B (HB) vaccine was launched in Japan in 1985. Infants testing positive for HBsAg at 1 month of age are considered to have prenatally acquired the infection and are usually excluded from the prevention program. Infants born to HB e antigen (HBeAg)-positive mothers are at a high risk of perinatally acquiring the infection. In this study, long-term outcome was evaluated in children with prenatal HBV infection who received the HBIG and HB vaccine in Japan. Methods: Newborns of both HBsAg- and HBeAg-positive carrier mothers received HBIG within 48 h of birth and at 2 months of age. Subsequently, three doses of recombinant HB vaccine were given at 2, 3, and 5 months of age. Outcome was compared between the following two groups: infants who completed the vaccination program, even if they were HBsAg positive at 1 month of age (n = 15), and infants who did not (n = 51). Results: Seroconversion from HBeAg to anti-HBe antibody (HBeAb) before 3 years of age was observed in five children (33%) who completed the vaccination program and in two (4%) who did not (P = 0.005). In 2/5 children who completed the vaccination program and achieved HBeAb seroconversion, seroconversion from HBsAg to anti-HBs antibody was also noted. Conclusion: This specific vaccination program for children with prenatal HBV infection has the potential to alter immune tolerance to HBV.
Key words fetomaternal infection, hepatitis B, immunotherapy, perinatal care, transmission, vaccine.
According to the World Health Organization (WHO) recommendation, by 2010 all countries in the world should have had routine hepatitis B virus (HBV) immunization coverage at a 90% level nationwide, with at least 80% coverage in every district.1 Despite these recommendations, hepatitis B (HB) vaccination is not currently a part of routine vaccination programs in a few lowincidence countries, including Japan, where an “at-risk” strategy is utilized that involves selective vaccination of infants who are born to HB surface antigen (HBsAg)-positive mothers. Perinatal transmission from HBsAg-carrier mothers to their infants may result in chronic HBV infection.2 HBsAg becomes detectable in the blood after an incubation period of 4–10 weeks.3,4 Therefore, 1-month-old HBsAg-positive infants born to HBV-carrier mothers are usually considered to have prenatally acquired the infection. In Japan, these infants usually receive no further
Correspondence: Ayano Inui, MD PhD, Division of Hepatology and Gastroenterology, Children’s Center for Health and Development, Saiseikai Yokohamashi Tobu Hospital, Shimosueyoshi 3-6-1, Tsurumi, Yokohama, Kanagawa 230-0012, Japan. Email: [email protected] .or.jp Received 17 September 2013; revised 28 August 2014; accepted 8 October 2014.
© 2014 Japan Pediatric Society
immunoprophylaxis against HBV. But we believed that active immunization upregulates cellular immune responses and therefore will lead to HBe and HBs seroconversion in these children. We have continued immunoprophylaxis in the patients described here, since 1995, and therefore their long-term clinical course was able to be compared retrospectively with those who did not receive immunoprophylaxis.
Methods Vaccination program
The Japanese “at-risk” vaccination program against mother-toinfant transmission of HBV was launched in 1985. Since then, all pregnant women have been screened for HBsAg. Those positive for HBsAg are further tested for the HB e antigen (HBeAg). Hepatitis B immunoglobulin (HBIG; 200IU/mL; Dried HB Globulin-Nichiyaku; Nihonseiyaku, Takeda, Japan) is given within 48 h of birth and at 2 months of age to newborns of HBeAg-positive carrier mothers. In addition, three doses of recombinant HB vaccine (Bimmugen, 5 μg/0.25 mL; KAKETSUKEN-Astellas, Tokyo, Japan) are given at 2, 3, and 5 months of age. Vaccination is not recommended if serum HBsAg positivity is detected at 1 month of age in children born
402
K Iwasawa et al.
to HBeAg-positive HBV-carrier mothers because of the difficulty in eradicating chronic HBV infection.
Results
Patients
The subject characteristics are listed in Table 1. All children in both groups were born to HBeAg-positive mothers. Boys accounted for 8/15 children (53%) in the accomplishment group and 31/51 children (61%) in the dropout group. The median age was 5.0 years old (range, 1.0–16 years) in the accomplishment group and 10.0 years (range, 1.0–25 years) in the dropout group. The median follow-up period was 4.8 years (range, 1–16 years) and 6.9 years (range, 0.5–17 years) in the accomplishment group and dropout group, respectively. Although the difference in the follow-up period was not statistically significant, the median age in the dropout group was higher than that in the accomplishment group. Hepatitis B virus was typeable in all 15 children (100%) in the accomplishment group and in 47/51 children (92%) in the dropout group. No differences were found in genotype distribution between the groups. In both groups, genotype C was most frequent (accomplishment group, 14/15, 93% vs dropout group, 43/47, 91%). Median serum alanine transaminase (ALT) at 1 month of age was 143 IU/L (range, 16–215 IU/L) in seven children in the accomplishment group. Serum ALT was measured in 5/51 children in the dropout group at 1 month of age. Median serum ALT was 17 IU/L (range, 8–42 IU/L). The median serum HBeAg titer at 1 month of age was 171.5 s/co (range, 0–1201.2 s/ co) in six children in the accomplishment group. The serum HBeAg titer was measured in only 2/51 children in the dropout group at 1 month of age (138.5 and 296 s/co, respectively). Serum HBV-DNA was not measured in all infants at 1 month of age. HBV infection was diagnosed on serum HBsAg positivity.
From April 1995 to May 2013, 15 children who were identified as HBsAg positive at 1 month of age, despite receiving HBIG (200 IU/mL) within 48 h of birth, were included and followed up until May 2013. After informed consent was obtained from the parents, the vaccination program was conducted (HBIG 200 IU/mL + HB vaccine 5 μg at 2 months of age, followed by recombinant HB vaccine 5 μg at 3 and 5 months of age). Two children received two extra doses at 7 or 8 months and at 11 months of age, and one child received an additional dose at 6 months of age at the request of their parents. These children were included in the accomplishment group. From April 1987 to May 2013, 51 children with chronic HBV infection due to mother-to-infant transmission were referred. These infants were also included in this study. These children comprised the dropout group. In this group, 30 children (59%) had received HBIG within 48 h of birth but, in most subjects, serum HBsAg testing was positive at 1 month of age. Therefore, no subsequent preventive treatment was given. For the other 21 children (41%), no precise records of immunization history were available or the dose and/or timing of HBIG treatment were inappropriate. Mothers of all these infants were HBeAg-positive HBV carriers. The study protocol conformed to the guidelines of the 1975 Declaration of Helsinki, as reflected in a priori approval by the institution’s human research committee. Serology and virology
The HBV seromarkers were measured using enzyme-linked immunoassay (ELISA) commercial kits. Serum HBV-DNA was quantitatively analyzed using branched DNA probe assay before 1998, transcription mediated amplification assay between 1999 and 2001, Roche PCR assay between 2002 and 2007 and COBAS TaqMan HBV test version 2.0 (Roche Diagnostics, Tokyo, Japan) since 2008. Results were expressed in log copies/mL in the range 1.8–9.1. HBV genotypes (A−F) were measured on ELISA using commercial kits (HBV Genotype EIA; Institutes of Immunology, Tokyo, Japan) and PCR-Invader assay with genotype-specific probes.5 Subgenotypes of B were determined on sequence analysis, restriction fragment length polymorphism,6–8 and PCRInvader assay.5 Follow-up was conducted at the outpatient clinic, and every 4–6 months HBeAg, anti-HBe, and HBV-DNA were measured. When serum HBV was 5 log copies/mL); four children (27%) had chronic hepatitis (abnormal ALT for at least 6 months); three children (20%) were anti-HBepositive inactive carriers (normal ALT and HBV-DNA
Pediatrics International (2015) 57, 401–405
doi: 10.1111/ped.12528
Original Article
Hepatitis B (HB) immunoglobulin plus HB vaccine for intrauterine HB virus infection Kentaro Iwasawa,1 Ayano Inui,1 Tomoyuki Tsunoda,1 Takeo Kondo,1 Manari Kawamoto,1 Tsuyoshi Sogo,1 Haruki Komatsu2 and Tomoo Fujisawa1 1 Division of Hepatology and Gastroenterology, Children’s Center for Health and Development, Saiseikai Yokohamashi Tobu Hospital and 2Department of Pediatrics, Sakura Hospital, Toho University School of Medicine, Sakura, Chiba, Japan Abstract
Background: Vaccination against hepatitis B virus (HBV) infection in infants born to hepatitis B surface antigen (HBsAg)-positive mothers using HB immunoglobulin (HBIG) and hepatitis B (HB) vaccine was launched in Japan in 1985. Infants testing positive for HBsAg at 1 month of age are considered to have prenatally acquired the infection and are usually excluded from the prevention program. Infants born to HB e antigen (HBeAg)-positive mothers are at a high risk of perinatally acquiring the infection. In this study, long-term outcome was evaluated in children with prenatal HBV infection who received the HBIG and HB vaccine in Japan. Methods: Newborns of both HBsAg- and HBeAg-positive carrier mothers received HBIG within 48 h of birth and at 2 months of age. Subsequently, three doses of recombinant HB vaccine were given at 2, 3, and 5 months of age. Outcome was compared between the following two groups: infants who completed the vaccination program, even if they were HBsAg positive at 1 month of age (n = 15), and infants who did not (n = 51). Results: Seroconversion from HBeAg to anti-HBe antibody (HBeAb) before 3 years of age was observed in five children (33%) who completed the vaccination program and in two (4%) who did not (P = 0.005). In 2/5 children who completed the vaccination program and achieved HBeAb seroconversion, seroconversion from HBsAg to anti-HBs antibody was also noted. Conclusion: This specific vaccination program for children with prenatal HBV infection has the potential to alter immune tolerance to HBV.
Key words fetomaternal infection, hepatitis B, immunotherapy, perinatal care, transmission, vaccine.
According to the World Health Organization (WHO) recommendation, by 2010 all countries in the world should have had routine hepatitis B virus (HBV) immunization coverage at a 90% level nationwide, with at least 80% coverage in every district.1 Despite these recommendations, hepatitis B (HB) vaccination is not currently a part of routine vaccination programs in a few lowincidence countries, including Japan, where an “at-risk” strategy is utilized that involves selective vaccination of infants who are born to HB surface antigen (HBsAg)-positive mothers. Perinatal transmission from HBsAg-carrier mothers to their infants may result in chronic HBV infection.2 HBsAg becomes detectable in the blood after an incubation period of 4–10 weeks.3,4 Therefore, 1-month-old HBsAg-positive infants born to HBV-carrier mothers are usually considered to have prenatally acquired the infection. In Japan, these infants usually receive no further
Correspondence: Ayano Inui, MD PhD, Division of Hepatology and Gastroenterology, Children’s Center for Health and Development, Saiseikai Yokohamashi Tobu Hospital, Shimosueyoshi 3-6-1, Tsurumi, Yokohama, Kanagawa 230-0012, Japan. Email: [email protected] .or.jp Received 17 September 2013; revised 28 August 2014; accepted 8 October 2014.
© 2014 Japan Pediatric Society
immunoprophylaxis against HBV. But we believed that active immunization upregulates cellular immune responses and therefore will lead to HBe and HBs seroconversion in these children. We have continued immunoprophylaxis in the patients described here, since 1995, and therefore their long-term clinical course was able to be compared retrospectively with those who did not receive immunoprophylaxis.
Methods Vaccination program
The Japanese “at-risk” vaccination program against mother-toinfant transmission of HBV was launched in 1985. Since then, all pregnant women have been screened for HBsAg. Those positive for HBsAg are further tested for the HB e antigen (HBeAg). Hepatitis B immunoglobulin (HBIG; 200IU/mL; Dried HB Globulin-Nichiyaku; Nihonseiyaku, Takeda, Japan) is given within 48 h of birth and at 2 months of age to newborns of HBeAg-positive carrier mothers. In addition, three doses of recombinant HB vaccine (Bimmugen, 5 μg/0.25 mL; KAKETSUKEN-Astellas, Tokyo, Japan) are given at 2, 3, and 5 months of age. Vaccination is not recommended if serum HBsAg positivity is detected at 1 month of age in children born
402
K Iwasawa et al.
to HBeAg-positive HBV-carrier mothers because of the difficulty in eradicating chronic HBV infection.
Results
Patients
The subject characteristics are listed in Table 1. All children in both groups were born to HBeAg-positive mothers. Boys accounted for 8/15 children (53%) in the accomplishment group and 31/51 children (61%) in the dropout group. The median age was 5.0 years old (range, 1.0–16 years) in the accomplishment group and 10.0 years (range, 1.0–25 years) in the dropout group. The median follow-up period was 4.8 years (range, 1–16 years) and 6.9 years (range, 0.5–17 years) in the accomplishment group and dropout group, respectively. Although the difference in the follow-up period was not statistically significant, the median age in the dropout group was higher than that in the accomplishment group. Hepatitis B virus was typeable in all 15 children (100%) in the accomplishment group and in 47/51 children (92%) in the dropout group. No differences were found in genotype distribution between the groups. In both groups, genotype C was most frequent (accomplishment group, 14/15, 93% vs dropout group, 43/47, 91%). Median serum alanine transaminase (ALT) at 1 month of age was 143 IU/L (range, 16–215 IU/L) in seven children in the accomplishment group. Serum ALT was measured in 5/51 children in the dropout group at 1 month of age. Median serum ALT was 17 IU/L (range, 8–42 IU/L). The median serum HBeAg titer at 1 month of age was 171.5 s/co (range, 0–1201.2 s/ co) in six children in the accomplishment group. The serum HBeAg titer was measured in only 2/51 children in the dropout group at 1 month of age (138.5 and 296 s/co, respectively). Serum HBV-DNA was not measured in all infants at 1 month of age. HBV infection was diagnosed on serum HBsAg positivity.
From April 1995 to May 2013, 15 children who were identified as HBsAg positive at 1 month of age, despite receiving HBIG (200 IU/mL) within 48 h of birth, were included and followed up until May 2013. After informed consent was obtained from the parents, the vaccination program was conducted (HBIG 200 IU/mL + HB vaccine 5 μg at 2 months of age, followed by recombinant HB vaccine 5 μg at 3 and 5 months of age). Two children received two extra doses at 7 or 8 months and at 11 months of age, and one child received an additional dose at 6 months of age at the request of their parents. These children were included in the accomplishment group. From April 1987 to May 2013, 51 children with chronic HBV infection due to mother-to-infant transmission were referred. These infants were also included in this study. These children comprised the dropout group. In this group, 30 children (59%) had received HBIG within 48 h of birth but, in most subjects, serum HBsAg testing was positive at 1 month of age. Therefore, no subsequent preventive treatment was given. For the other 21 children (41%), no precise records of immunization history were available or the dose and/or timing of HBIG treatment were inappropriate. Mothers of all these infants were HBeAg-positive HBV carriers. The study protocol conformed to the guidelines of the 1975 Declaration of Helsinki, as reflected in a priori approval by the institution’s human research committee. Serology and virology
The HBV seromarkers were measured using enzyme-linked immunoassay (ELISA) commercial kits. Serum HBV-DNA was quantitatively analyzed using branched DNA probe assay before 1998, transcription mediated amplification assay between 1999 and 2001, Roche PCR assay between 2002 and 2007 and COBAS TaqMan HBV test version 2.0 (Roche Diagnostics, Tokyo, Japan) since 2008. Results were expressed in log copies/mL in the range 1.8–9.1. HBV genotypes (A−F) were measured on ELISA using commercial kits (HBV Genotype EIA; Institutes of Immunology, Tokyo, Japan) and PCR-Invader assay with genotype-specific probes.5 Subgenotypes of B were determined on sequence analysis, restriction fragment length polymorphism,6–8 and PCRInvader assay.5 Follow-up was conducted at the outpatient clinic, and every 4–6 months HBeAg, anti-HBe, and HBV-DNA were measured. When serum HBV was 5 log copies/mL); four children (27%) had chronic hepatitis (abnormal ALT for at least 6 months); three children (20%) were anti-HBepositive inactive carriers (normal ALT and HBV-DNA
