Prevalence of protective antibody against hepatitis B virus in HIV-infected children with immune recovery after highly active antiretroviral therapy

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1 Vaccine 24 (2006) Prevalence of protective antibody against hepatitis B virus in HIV-infected children with immune recovery after highly active antiretroviral therapy Sudawan Siriaksorn a, Thanyawee Puthanakit a,, Thira Sirisanthana b, Virat Sirisanthana a a Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand b Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand Received 10 October 2005; received in revised form 6 December 2005; accepted 21 January 2006 Available online 6 February 2006 Abstract HIV-infected children had a lower seroconversion rate to hepatitis B immunization and a more rapid antibody decline when compared to healthy children. Whether re-immunization or additional booster dose is necessary after immune recovery remains unknown. This study was conducted to determine the prevalence of hepatitis B virus protective antibody in HIV-infected children with immune recovery after highly active antiretroviral therapy (HAART). Serum hepatitis B viral markers were measured. An antibody level of 10 miu/ml was defined as a protective antibody level. Only one out of 69 children (1%) had a protective antibody level. We concluded that despite the history of hepatitis B immunization and despite evidence of immune recovery after HAART, most HIV-infected children are still susceptible to HBV infection Elsevier Ltd. All rights reserved. Keywords: Hepatitis B virus (HBV); Human immunodeficiency virus (HIV); Protective antibody 1. Introduction Experience from studies involving hematopoietic stem cell transplantation (HSCT) recipients revealed that protective immunity to diseases preventable by routine vaccination was lost over time following transplantation. Furthermore, adoptive transfer of immunity from donors to recipients after allogeneic transplantation was not sufficient to prevent this decline. Systematic re-immunization was necessary at appropriate time intervals following transplantation to re-establish immunity [1]. Consequently, the Centers for Disease Control and Prevention (CDC), the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation have published evidence-based recommendations, including re-immunization schedules, Corresponding author at: Division of Infectious Disease, Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. Tel.: ; fax: address: tputhana@mail.med.cmu.ac.th (T. Puthanakit). for preventing of opportunistic infections among HSCT patients [2]. Human immunodeficiency virus (HIV) infection destroys CD4 cells which provide critical help to B cells in the production of antibodies against T cell-dependent antigens and in the differentiation of B cells into memory cells [3]. Previous studies had suggested that combination antiretroviral therapy can stop CD4 cell attrition and at least partially restore the immune system [4]. This restoration may include immune responses to childhood vaccines. The current World Health Organization recommendations for immunization of children with known or suspected HIV infection is based on the degree of HIV-induced immunosuppression [5]. But guidelines for HIV-infected children with immune recovery after highly active antiretroviral therapy (HAART) have not yet been established. Hepatitis B virus (HBV) infection is a major public health problem in Thailand. The estimated prevalence of HBV carriage is 8 12% in males and 4 8% in females [6]. There is also a high prevalence of 1 2% of HIV infection among X/$ see front matter 2006 Elsevier Ltd. All rights reserved. doi: /j.vaccine

2 3096 S. Siriaksorn et al. / Vaccine 24 (2006) pregnant women [7]. HBV co-infection with HIV is common because both viruses have same modes of transmission. HIVinfected homosexual men co-infected with HBV have been reported to have a higher progression rate to chronic disease, a higher degree of HBV replication with resulting increased risk of transmission, and a lower rate of serum hepatitis B e antigen (HBeAg) loss compared to healthy persons [8,9]. Immunization is an important public health measure to prevent HBV infection. Since 1992, the Thai Ministry of Public Health has included hepatitis B vaccination in its nationwide Expanded Program on Immunization [10].However, the standard immunization schedule with three doses of HBV vaccine has been associated with a lower seroconversion rate in HIV-infected children compared to non HIVinfected group (40 78% and 92 97%, respectively) [11 15]. A study in Thailand revealed the seroconversion rate at 6 months after vaccination to be 71.4% in HIV-infected infants compared to 91.9% in the non-hiv-infected group [14]. Furthermore, a more rapid serum antibody decline has also been reported. At 13 months after vaccination, protective antibody level was detected in only 42% of HIV-infected children who had seroconverted after primary series [13]. Zuin et al. had shown that the prevalence of protective antibody level in HIVinfected children declined from 77.8 to 23.1% within 2 years after vaccination, whereas that in a non-hiv-infected group remained above 90% [15]. The introduction of HAART has resulted in prolonged survival of HIV-infected children. However, information about the long-term persistence of antibody to hepatitis B surface antigen (anti-hbs Ab) after vaccination in these children is limited. Whether re-immunization or additional booster dose is necessary and effective after immune recovery remains unknown. Because of low seroconversion rate and rapid antibody decline over time, we hypothesized that most HIVinfected children have a non-protective antibody level and consequently have increased susceptibility to breakthrough HBV infection even after the commencement of HAART. Thus, we conducted this study to determine the prevalence of HBV protective antibody in HIV-infected children with immune recovery after HAART. 2. Patients and methods This cross-sectional study was conducted at Chiang Mai University hospital in March The study protocol was approved by the research ethics committee of Chiang Mai University. Written informed consent was obtained from each child s parent or guardian before enrollment. The inclusion criteria were HIV-infected children who: (1) were more than 5 years of age, (2) had been severely immunosuppressed (CD4 cell < 15%), (3) received HAART which was defined as 3 antiretroviral drugs in a regimen in which 1 of antiretroviral drugs was a protease inhibitor or a nonnucleoside reverse-transcriptase inhibitor, (4) had shown evidence of immune recovery for at least 3 months after HAART (CD4 cell 15%), and (5) had had their HBV immunization documented in the medical records or by interview with caregivers. The exclusion criteria were children who: (1) received immunosuppressive agents within 3 months, or (2) received blood component transfusion within 6 months prior to the study. Past illnesses and immunization data were collected by medical record review and caregiver interview. The clinical stage of disease was determined according to the 1994 US CDC revised classification [16]. The serial CD4 cell count and plasma HIV RNA level were routinely performed in HIV-infected children at the beginning of HAART and at every 3 6 months afterward. CD4 cell counts and percentages were assessed with the use of a FACSCount apparatus (Becton-Dickinson). Plasma HIV RNA levels were measured by the Roche Ultrasensitive Amplicor assay, version 1.5 (Roche). The most recent values of CD4 cell count and plasma HIV RNA level obtained within 3 months before or after the study were designated as current values in this report. Blood samples were collected for HBV profiles. Serum hepatitis B surface antigen (HBsAg), anti-hbs Ab, and antibody to hepatitis B core antigen (anti-hbc Ab) were measured by HBsAg (V2), AUSAB, and CORE TM, enzymelinked immunoassay diagnostic kits (Abbott Laboratories, Abbott Park, IL, USA), respectively. The amount of anti-hbs Ab was determined using the calibration curve generated by AxSYM AUSAB. An antibody level of 10 miu/ml was defined as a protective antibody level. The children who had either HBsAg or anti-hbc Ab were considered to have natural HBV infection [17]. The chronic carrier state of children with HBsAg and no anti-hbs Ab was confirmed by persisting serum HBsAg 6 months after the first test [17]. The liver function profiles of these carriers were done to determine whether active hepatitis was present. Statistical analyses were performed with Statistical Package for Social Science version 11.5 software (SPSS Inc., Chicago, IL, USA). 3. Results Seventy-five HIV-infected children were enrolled. The demographic data and immunological and viral status of the participants are shown in Table 1. There were 39 boys and 36 girls. The mean age was 9.6 years (S.D. = 2.5). Half of them (51%) were in CDC clinical category C. Means of CD4 cell percentage and plasma HIV RNA level prior to initiation of HAART were 5% (S.D. = 5) and 5.4 log 10 copies/ml (S.D. = 0.4), respectively. Means of current CD4 cell percentage and plasma HIV RNA level were 25% (S.D. = 5) and 1.8 log 10 copies/ml (S.D. = 0.5), respectively. There were only six children (8%) whose current HIV RNA levels were more than 1.7 log 10 copies/ml. The mean age at which HAART was prescribed was 7.6 years (S.D. = 2.5). They had been treated with HAART for an average of 2 years and

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Siriaksorn et al. / Vaccine 24 (2006) Table 1 Characteristics of study participants (N = 75) Characteristics Data Age (years) 9.6 ± 2.5 Male (gender) 39 (52) CDC clinical category N 7 (9) A 15 (20) B 15 (20) C 38 (51) CD4 cell percentage prior to HAART (%) 5 ± 5 Plasma HIV RNA level prior to HAART 5.4 ± 0.4 (log 10 copies/ml) HAART regimen Nevirapine-based a 35 (47) Efavirenz-based a 35 (47) Protease inhibitor-based a 5 (6) Current CD4 cell percentage (%) 25 ± 5 Current plasma HIV RNA level (log 10 copies/ml) 1.8 ± 0.5 Age at which HAART was prescribed (years) 7.6 ± 2.5 Duration of HAART (months) 24.0 ± 4.4 Duration of documented severe immune suppression 12.0 ± 7.6 (CD4 cell <15%) (months) Duration of documented immune recovery (CD ± 6.7 cell 15%) (months) Note: Data are shown in number (%) or mean ± S.D. a A combination of two nucleotide reverse transcriptase inhibitors with nevirapine, efavirenz, or a protease inhibitor. their CD4 cell percentage had been 15% for more than 1 year. The HBV immunization status was documented by medical record in 55 children (73%) and by history in 20 children (27%). There was no difference in baseline characteristics between the two groups except that the former group have received HAART slightly longer (24.6 ± 4.4 months versus 22.2 ± 4.2 months, p = 0.033). Fifty-three of 55 children whose immunization status was documented by medical record received a three-dose regimen (at birth, 2 months, and 6 months of age), while the remaining two children received a four-dose regimen (at birth, 2 months, 6 months, and 12 months of age). As Fig. 1 indicates, 69 children (92%) did not have evidence of natural HBV infection. Only one (1%) had protective level of anti-hbs Ab. Fifteen children (20%) had low levels of anti-hbs Ab and 53 children (71%) had undetectable levels of anti-hbs Ab. Among six children who had evidence of natural HBV infection, two (3%) also had persisting HBsAg and were classified as chronic HBV carriers. They had no history of clinical hepatitis. Current liver function profiles were within normal limits. They had no history of blood transfusion. There was no information on the HBV status of the mothers of these two children. Two of the remaining four (3%) developed naturally acquired immunity while another two did not. Among three children who had protective antibody levels, the one who had vaccine-induced immunity had a lower anti-hbs Ab level than the other two children who had natural infection (11.1 miu/ml versus 25.5 and 1000 miu/ml). Maternal hepatitis B status was available in only three children. Two of the mothers had positive HBsAg and the newborns were given hepatitis B vaccine and hepatitis B immune globulin (HBIG) within 12 h after birth. Neither of them acquired HBV infection through perinatal transmission. Nine children (12%) had history of blood transfusions but their most recent transfusions were more than 6 months prior to the study. None of them acquired HBV infection through blood transfusion. Of the two children who received a four-dose regimen of HBV immunization, one had an undetectable anti-hbs Ab level while the other had evidence of breakthrough infection with a low anti-hbs Ab level. 4. Discussion In the present study, we found that the prevalence of HBV protective antibody in HIV-infected children with immune recovery after HAART was as low as 1%. The result confirmed our hypothesis that most HIV-infected children with immune recovery after HAART are susceptible to HBV infection despite HBV immunization during the infancy period. Further study is required to determine whether reimmunization or additional booster dose will result in protective levels of anti-hbs Ab in this population. In our study, the percentage of children who had anti-hbs Ab 10 miu/ml was found to be 4% (three children), while two of these three children developed naturally acquired immunity. In a study in healthy Italian children who received a three-dose primary HBV immunization during infancy period, the anti-hbs Ab remained above protective level in 64% 10 years after the immunization [18]. The difference between the persistence of HBV protective antibody among HIV-infected and healthy children may be explained either by low seroconversion rate to the primary series (primary vaccine failure) [13 15] or by the more rapid rate of antibody decline (secondary vaccine failure) [13 15]. Of the 69 children in this study who did not have evidence of natural HBV infection, only one developed a protective anti-hbs Ab level from immunization. All six children who had shown evidence of natural HBV infection had no history of clinical hepatitis. Two of these six (33%) had turned into chronic carrier stage. This supported the finding from a previous study which demonstrated that HIV-infected subjects co-infected with HBV had a higher progression rate to chronic disease [8]. Factors that might affect immune responses to primary HBV immunization in HIV-infected children have been studied [11,13 15]. The CD4 cell count, clinical category, and age at first vaccination were not significantly different between children who were able to mount an immune response to HBV vaccine and those who were not. In our study, there was only one child who had vaccine-induced immunity, so

4 3098 S. Siriaksorn et al. / Vaccine 24 (2006) Fig. 1. The hepatitis B virus serological outcomes. the factors affecting immune response to HBV vaccine cannot be addressed. Findings in immunocompetent persons suggested that routine boosters were not necessary due to anamnestic antibody responses that followed exposure to HBV, even when antibodies had declined to low or undetectable levels [19,20]. This finding may not be applicable to immunocompromised persons. In HSCT recipients, the CDC recommended HBV re-immunization with the usual dosage of vaccine at 12, 14, and 24 months after transplantation, and post-vaccination anti-hbs Ab testing at 1 2 months after the third dose. Persons who do not respond to this primary vaccine series should complete a second three-dose series [2]. In studies in HIV-infected adults the majority of whom were receiving HAART, the response rates to HBV immunization were 34 47% [21,22]. Whether one should apply similar measures in HIV-infected children whose immune system had been restored by HAART should be further investigated. There were several limitations in this study. First, because of the cross-sectional study design, there was no information on the baseline primary antibody response to HBV vaccine in order to address the issue of primary versus secondary vaccine failure. Secondly, 27% of the past HBV immunization was determined by history taking. Normally in Thailand, vaccination history was documented in the medical record and in the patient s copy of the vaccination book. The medical records were kept only for 5 years after last visit. Despite efforts to contact the children s health care providers and family members, we could not obtain either medical records or vaccination books for the infancy period of these children. In conclusion, we have documented low prevalence of HBV protective antibody in HIV-infected children with immune recovery after HAART, despite HBV immunization during infancy. Further study is required to determine whether re-immunization or additional booster dose will protect these children against HBV infection. Acknowledgements This study was supported by the Faculty of Medicine, Chiang Mai University and the Thailand Research Fund of the Royal Thai Government. The authors thank John McDemed, PhD for help with the manuscript.

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