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Hepatitis B virus infections in families in which the Takegoshi Internal Medicine Clinic, 377-7 Nomura, Takaoka, Toyama 933-0014, Japan Department of Pathology, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shaanxi 710038, China Received 11 July 2005; received in revised form 10 November 2005; accepted 8 June 2006 Abstract
We studied a total of 37 families, in which HBsAg was positive in either or both of father and mother, to assess intra-familial transmission of hepatitis B virus (HBV). The HBsAg positive rate for children with HBsAg-negative mothers was significantly lower than that with positive mothers (4 of 31, 12.9% versus 18 of 32, 56.3%, p < 0.01) of course. However, there were three families in which the infection source for children was thought to be fathers, not mothers, i.e., of eight children in these three families with HBsAg +/− father/mother pairs, 4 (50%) were positive for both HBsAg and HBV DNA of genotypes identical to those of their fathers, and another child was positive for HBcAb despite being negative for HBsAg. Interestingly, moreover, all the mothers in these three families were HBcAb-positive even though HBsAg-negative, suggesting that not only father-to-child but also inter-spouse HBV transmission might have occurred. With these findings we would suggest that all the family members with HBsAg-positive fathers should receive HBV vaccine, let alone for those with HBsAg-positive 2006 Published by Elsevier Ireland Ltd.
Keywords: Hepatitis B virus; Intra-familial transmission; Vaccine 1. Introduction
is very low However, intra-familial transmission of HBV, especially from fathers to children, was evidenced by The majority of chronic hepatitis B virus (HBV) infec- tions occur during early childhood and transmission of The aim of the present study was to assess hepatitis B HBV from an HBsAg-positive mother to her infant during or virus (HBV) infection from fathers to children in families just after birth results in the highest risk (70–90%) of persis- tent infection in countries of intermediate to high endemicity In Japan, all infants born to HBeAg-positive mothers have been receiving the HBV vaccine since 1985 As a 2. Materials and methods
result, the prevalence of chronic HBV infection at the age of 14–19 years has decreased to 0.44%, whereas chronic HBV infection at the age of 40–49 still affected as high a number as 1.46% in 1996 t is reported that the rate of HBV infec- Enrolled, in this study, were 127 individuals in 37 fam- tion for children in families with HBsAg-negative mothers ilies (15 fathers, ages 39–67; 37 mothers, ages 37–80; 75 children, ages 10–56, males/females = 38/37) who had vis- ited Takegoshi Internal Medicine Clinic during the past 14 E-mail address: (K. Takegoshi).
years. HBsAg status of the father/mother pairs in these fami- 1386-6346/$ – see front matter 2006 Published by Elsevier Ireland Ltd.
K. Takegoshi, W. Zhang / Hepatology Research xxx (2006) xxx–xxx lies was +/− in 14 families (category 1), +/− in 22 (categories 3. Results
2 and 3), and +/+ in 1 (category 4). In the father/mother +/− group, children of four families had been vaccinated (cat- 3.1. Children in the families with HBsAg-positive egory 2) while those of the other 18 families unvaccinated As depicted synoptically in the children in the families with HBsAg-positive mothers, if not protected by vaccine, were more prone to HBV infection as compared to those in the families with HBsAg-negative mothers: HBsAg All serum samples were tested for HBV and HCV serolog- positive rate was 59% (20/34) in the children of category ical markers using commercially available immunoassays, 3 + 4, whereas it was only 13% (4/31) in those of category 1 ARCHITECT® (Dinabot Co., Ltd.) and a Cobas R Core anti-HCV EIA kit (Roche Diagnostics GmbH, Mannheim, Germany), respectively. Informed consent was obtained from each individual, and the protocol of study conformed to the 3.2. Children in the families where mothers were ethical guidelines of the 1975 Declaration of Helsinki.
negative but fathers were positive for HBsAg 2.3. HBV genotyping and sequencing Among the 37 families studied, there were three fami- lies in which one or more children were HBsAg-positive HBV genotypes were determined serologically by ELISA although their mothers were HBsAg-negative. As shown in with monoclonal antibodies for type-specific epitopes in the the lower part of HBsAg tested positive in the father preS2-region (Institute of Immunology, Co., Ltd.) and two of his four children but not in his wife in the family A fragment of HBV DNA of nt positions from 1445 to A. Similarly, in the families B and C, the fathers and one of 2157 was PCR-amplified by previously reported methods their respective children were positive but their wives were PCR products were then subjected to direct sequenc- negative for HBsAg. Identical HBV genotypes were shared ing with use of ABI PRISM 377 DNA sequencer (Applied between father and child, respectively, i.e., genotype B in the Biosystems, Foster City, CA). Nucleotide data analyses were family A while genotype C in the families B and C. Sequence done with GENETYX® 6.0 (Genetyx Co., Tokyo, Japan).
analyses also supported the closeness of HBV strains within Fig. 1. Synopsis of the study results. Box and circle represent male and female, respectively. HBsAg-positive individuals were indicated by black-daubed boxesor circles, while those with HBcAb by gray ones. White characters on a black background of the boxes and circles indicate HBV genotypes.
K. Takegoshi, W. Zhang / Hepatology Research xxx (2006) xxx–xxx each pair of father and child (data not shown here). Inter- Acknowledgements
estingly, all the mothers in these three families and a child in the family C were positive for antibodies against HBV The authors thank Prof. Claus H. Schroeder (Deutsches core antigen (HBcAb) despite being negative for HBsAg, an Krebsforschungzentrum) for critical comments, Dr. Mal- evidence for cryptic HBV infection or past exposure to it colm Moore and Dr. Kevin Keane for critical reading of the manuscript, and Dr. Toshio Matsui for advice on nucleotide 4. Discussion
Franks et al. that the father-to-child HBV [1] Margolis HS, Alter MJ, Hadler SC. Hepatitis B: evolving epidemi- transmission rate was 9.4%, and our present result (13% in ology and implications for control. Semin Liver Dis 1991;11:84–92.
view of HBsAg) almost corroborates this figure. However, [2] Xu ZY, Liu CB, Francis DP, et al. Prevention of perinatal acquisition it is noteworthy that these figures may still underestimate of hepatitis B virus carriage using vaccine: preliminary report of a randomized, double-blind placebo-controlled and comparative trial.
the actual risk of father-to-child transmission, because, as exemplified by the second child of the family C in [3] Oda T. Viral hepatitis and hepatocellular carcinoma prevention strat- there might exist additional cases of infection, unnoticed egy in Japan. Jpn J Cancer Res 1999;90:1051–60.
by being negative for HBsAg although being positive for [4] Yoshizawa K. A trend of HBV carrier in Japan. In: Kanngann- Hakusho. Tokyo: Jap Soc Hepatol; 1999, 23–32, (in Japanese).
[5] Franks AL, Berg CJ, Kane MA, et al. Hepatitis B virus infection The importance of HBsAg-positive father as a possible among children born in the United States to Southeast Asian refuges.
source of HBV infection within a family was also under- scored by the finding that all the mothers in the families [6] Stevens CE, Beasley P, Tsui J, Lee WC. Vertical transmission of A–C were HBcAb-positive even though HBsAg-negative.
hepatitis B antigen in Taiwan. N Engl J Med 1975;292:771–4.
Such inter-spouse HBV transmission could easily be under- [7] Lin HJ, Lai CL, Lau JYN, et al. Evidence for intrafamilial trans- mission of hepatitis B virus from sequence analysis of mutant HBV stood because HBV is a sexually transmitted virus. Thus, DNAs in two Chinese families. Lancet 1990;336:208–12.
it could be speculated that the apparent “father-to-child” [8] Lin HJ, Lai CL, Lauder IJ, et al. Application of hepatitis B virus HBV transmission in these families might indeed have been (HBV) DNA sequence polymorphisms to the study of HBV trans- a “father-to-mother-to-child” transmission, because the con- mission. J Infect Dis 1991;164:284–8.
tact between mother and child must have been much closer [9] Usuda S, Okamoto H, Iwanari H, et al. Serological detection of hepatitis B virus genotypes by ELISA with monoclonal antibodies to type-specific epitopes in the preS2-region product. J Virol Methods In conclusion, our present results strongly support the notion that all the family members with HBsAg-positive [10] Zhang W, Hacker HJ, Tokus M, Bock T, Schroeder CH. Patterns of fathers should receive HBV vaccine, let alone for those with circulating hepatitis B virus serum nucleic acids during lamivudine therapy. J Med Virol 2003;71:24–30.


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