Infection DOI 10.1007/s15010-015-0733-6
ORIGINAL PAPER
Occult hepatitis B virus infection in children born to HBsAg‑positive mothers after neonatal passive‑active immunoprophylaxis Hanan Foaud · Sahar Maklad · Faten Mahmoud · Hanaa El‑Karaksy
Received: 2 November 2014 / Accepted: 19 January 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Background Occult hepatitis B virus infection (OBI) is a well-recognized clinical entity characterized by the detection of HBV DNA in serum and/or liver in the absence of detectable HBsAg. Diagnosis of OBI requires a sensitive HBV DNA assay. Aim We aimed at determining the frequency of OBI in infants, born to HBsAg-positive mothers, who received immunoprophylaxis at birth. Methods Sixty-four infants and children, born to HBsAgpositive mothers, who received hepatitis B immunoglobulin and HBV vaccine within 48 h after birth, were tested for HBV serological profile and HBV DNA by real-time PCR at least 1 month after last dose of HBV vaccine and not before 6 months of age. Results The median age of the studied infants and children was 8 months, ranging from 6 to 132 months; 54.7 % were females. HBV DNA was detected in 2 infants. One case had OBI; she was negative for HBsAg, anti-HBc total, H. Foaud (*) Department of Pediatrics, National Hepatology and Tropical Medicine Research Institute, 7101 El‑Kahera Buildings, El‑Mokattam, Cairo 11415, Egypt e-mail: [email protected] S. Maklad Department of Internal Medicine and Hepatology, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt F. Mahmoud Department of Clinical Chemistry, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt H. El‑Karaksy Department of Pediatrics, Kasr Alainy Medical School, Cairo University, Cairo, Egypt
HBeAg and was positive for anti-HBs (titer 267 mIU/mL) with low level of viremia (HBV DNA 1.13 x 103 IU/mL). Another infant showed immunoprophylaxis failure with positive HBsAg, anti-HBc total, HBeAg, negative anti-HBe and anti-HBs; HBV viral load was 1.7 × 108 IU/mL. Both mothers were HBsAg and HBeAg-positive. Conclusion OBI may occur in infants born to HBsAgpositive mothers despite the receipt of immunoprophylaxis. OBI was detected in a low frequency in the present study. Anti-HBs positivity does not exclude OBI. Keywords Egypt · HBsAg-positive mothers · HBV immunoprophylaxis · Occult HBV infection
Introduction Perinatal transmission of hepatitis B virus (HBV) from HBsAg-positive mothers to their infants is the most important mode of transmission in highly endemic area [1]. With no intervention, 40–90 % of these infants will acquire HBV infection [2–4]. Approximately 90 % of infected infants develop chronic HBV infection with a 15–25 % risk for premature death from cirrhosis or hepatocellular carcinoma (HCC). To prevent perinatal HBV transmission, post-exposure passive-active immunoprophylaxis using hepatitis B vaccine and hepatitis B immune globulin (HBIG) is recommended within 12 h of birth, in addition to 3-dose vaccine series at one and 6 months of age [5]. Occult hepatitis B virus infection (OBI) was defined as the presence of HBV DNA in serum and/or liver tissue without detectable HBsAg with or without anti-HBc or anti-HBs antibodies outside the pre-seroconversion window period [6]. It is classified into seropositive and seronegative infections depending on positivity for anti-HBc
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and anti-HBs antibodies [7]. Diagnosis of OBI requires a sensitive HBV DNA PCR assay because the serum level of HBV DNA in these patients is usually 106–7 IU/ml or more were candidates for lamivudine (100 mg/day) or tenofovir (300 mg/day) therapy for the last trimester of pregnancy, with further reassessment of the condition after delivery. Females who were receiving Lamivudine before pregnancy and their HBV DNA became below detection limit, were continued on lamivudine during the whole pregnancy. Females who had low viral load or below detection limit received no antiviral treatment during pregnancy [17].
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All enrolled pregnant females and their husbands were informed to contact a single researcher by cell phone at the time of delivery to administer immunoprophylaxis against HBV to their newborns. Forty-six newborns of the HBsAg-positive mothers, who contacted the researcher at the time of delivery, received HBV immunoprophylaxis in the form of 0.5 ml (100 IU) HBIG (Hepabig, Korea) and 0.5 ml of the pediatric formulation of hepatitis B vaccine (Euvax B, Korea), a recombinant vaccine containing 10 µg of HBsAg. Both were given as an intramuscular injection at 2 different sites, within 24 h after birth. Second dose of the vaccine was given 1 month later, then the infant received another 3 doses of the vaccine within the expanded program of immunization at 2, 4, 6 months of age (the corresponding vaccination schedule included quadruple vaccine containing DPT plus hepatitis B). Only one mother contacted the researcher later than 48 h after delivery, although her baby received immunoprophylaxis, still he was excluded from the study. In addition, 20 previously immunized children who received immunoprophylaxis against HBV at birth were included (Fig. 1). Blood samples were drawn from all enrolled children at least 4 weeks after the last dose of the vaccine and not before 6 months of age [5]. For all the children HBV serological profile (HBsAg, anti-HBc total, HBeAg, anti-HBe and anti-HBs titre) and HBV DNA quantification were done. Two immunized infants did not come for post-vaccination testing. Laboratory tests A 5 ml non-fasting blood sample was obtained by venipuncture and added on EDTA. Samples were centrifuged and sera were divided into 2 aliquots, one was stored at −80 °C for HBV DNA assay by PCR and the other was stored at −20 °C for HBV serology profile assay. HBV serology was done by ELISA technique (Abbott Murex was used for HBsAg, Diasorin was used for HBeAg, antiHBe, anti-HBc total, and anti-HBs titre, Clinilab). Interpretation of anti-HBs titer in infants performing postvaccination testing after few weeks of the last booster was as follows, a titer of
ORIGINAL PAPER
Occult hepatitis B virus infection in children born to HBsAg‑positive mothers after neonatal passive‑active immunoprophylaxis Hanan Foaud · Sahar Maklad · Faten Mahmoud · Hanaa El‑Karaksy
Received: 2 November 2014 / Accepted: 19 January 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Background Occult hepatitis B virus infection (OBI) is a well-recognized clinical entity characterized by the detection of HBV DNA in serum and/or liver in the absence of detectable HBsAg. Diagnosis of OBI requires a sensitive HBV DNA assay. Aim We aimed at determining the frequency of OBI in infants, born to HBsAg-positive mothers, who received immunoprophylaxis at birth. Methods Sixty-four infants and children, born to HBsAgpositive mothers, who received hepatitis B immunoglobulin and HBV vaccine within 48 h after birth, were tested for HBV serological profile and HBV DNA by real-time PCR at least 1 month after last dose of HBV vaccine and not before 6 months of age. Results The median age of the studied infants and children was 8 months, ranging from 6 to 132 months; 54.7 % were females. HBV DNA was detected in 2 infants. One case had OBI; she was negative for HBsAg, anti-HBc total, H. Foaud (*) Department of Pediatrics, National Hepatology and Tropical Medicine Research Institute, 7101 El‑Kahera Buildings, El‑Mokattam, Cairo 11415, Egypt e-mail: [email protected] S. Maklad Department of Internal Medicine and Hepatology, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt F. Mahmoud Department of Clinical Chemistry, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt H. El‑Karaksy Department of Pediatrics, Kasr Alainy Medical School, Cairo University, Cairo, Egypt
HBeAg and was positive for anti-HBs (titer 267 mIU/mL) with low level of viremia (HBV DNA 1.13 x 103 IU/mL). Another infant showed immunoprophylaxis failure with positive HBsAg, anti-HBc total, HBeAg, negative anti-HBe and anti-HBs; HBV viral load was 1.7 × 108 IU/mL. Both mothers were HBsAg and HBeAg-positive. Conclusion OBI may occur in infants born to HBsAgpositive mothers despite the receipt of immunoprophylaxis. OBI was detected in a low frequency in the present study. Anti-HBs positivity does not exclude OBI. Keywords Egypt · HBsAg-positive mothers · HBV immunoprophylaxis · Occult HBV infection
Introduction Perinatal transmission of hepatitis B virus (HBV) from HBsAg-positive mothers to their infants is the most important mode of transmission in highly endemic area [1]. With no intervention, 40–90 % of these infants will acquire HBV infection [2–4]. Approximately 90 % of infected infants develop chronic HBV infection with a 15–25 % risk for premature death from cirrhosis or hepatocellular carcinoma (HCC). To prevent perinatal HBV transmission, post-exposure passive-active immunoprophylaxis using hepatitis B vaccine and hepatitis B immune globulin (HBIG) is recommended within 12 h of birth, in addition to 3-dose vaccine series at one and 6 months of age [5]. Occult hepatitis B virus infection (OBI) was defined as the presence of HBV DNA in serum and/or liver tissue without detectable HBsAg with or without anti-HBc or anti-HBs antibodies outside the pre-seroconversion window period [6]. It is classified into seropositive and seronegative infections depending on positivity for anti-HBc
13
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and anti-HBs antibodies [7]. Diagnosis of OBI requires a sensitive HBV DNA PCR assay because the serum level of HBV DNA in these patients is usually 106–7 IU/ml or more were candidates for lamivudine (100 mg/day) or tenofovir (300 mg/day) therapy for the last trimester of pregnancy, with further reassessment of the condition after delivery. Females who were receiving Lamivudine before pregnancy and their HBV DNA became below detection limit, were continued on lamivudine during the whole pregnancy. Females who had low viral load or below detection limit received no antiviral treatment during pregnancy [17].
13
All enrolled pregnant females and their husbands were informed to contact a single researcher by cell phone at the time of delivery to administer immunoprophylaxis against HBV to their newborns. Forty-six newborns of the HBsAg-positive mothers, who contacted the researcher at the time of delivery, received HBV immunoprophylaxis in the form of 0.5 ml (100 IU) HBIG (Hepabig, Korea) and 0.5 ml of the pediatric formulation of hepatitis B vaccine (Euvax B, Korea), a recombinant vaccine containing 10 µg of HBsAg. Both were given as an intramuscular injection at 2 different sites, within 24 h after birth. Second dose of the vaccine was given 1 month later, then the infant received another 3 doses of the vaccine within the expanded program of immunization at 2, 4, 6 months of age (the corresponding vaccination schedule included quadruple vaccine containing DPT plus hepatitis B). Only one mother contacted the researcher later than 48 h after delivery, although her baby received immunoprophylaxis, still he was excluded from the study. In addition, 20 previously immunized children who received immunoprophylaxis against HBV at birth were included (Fig. 1). Blood samples were drawn from all enrolled children at least 4 weeks after the last dose of the vaccine and not before 6 months of age [5]. For all the children HBV serological profile (HBsAg, anti-HBc total, HBeAg, anti-HBe and anti-HBs titre) and HBV DNA quantification were done. Two immunized infants did not come for post-vaccination testing. Laboratory tests A 5 ml non-fasting blood sample was obtained by venipuncture and added on EDTA. Samples were centrifuged and sera were divided into 2 aliquots, one was stored at −80 °C for HBV DNA assay by PCR and the other was stored at −20 °C for HBV serology profile assay. HBV serology was done by ELISA technique (Abbott Murex was used for HBsAg, Diasorin was used for HBeAg, antiHBe, anti-HBc total, and anti-HBs titre, Clinilab). Interpretation of anti-HBs titer in infants performing postvaccination testing after few weeks of the last booster was as follows, a titer of
