Co-infection with viruses like Hepatitis B and C is common in HIV-infected children [1]. All HIV-infected children must therefore be vaccinated against hepatitis B. Multiple factors lead to suboptimal response following vaccination in these children [2,3]. Even HIV-exposed but uninfected infants have been shown to have an altered immune response to vaccination [3,4]. This raises concern regarding the appropriate dose and schedule of vaccines to be administered to these children in order to achieve seroprotection. Numerous studies have shown a much lower level of seroprotection with Hepatitis B vaccine (HBV) in HIV-infected children and adults [5,6]. Various strategies to improve the seroconversion rates – like higher dose of the vaccine, additional doses of the standard dose or revaccination of the non-responders either by the double dose or standard dose [7,8] – have been tried. There is scarcity of data on seroconversion to HBV in HIV-infected Indian children on highly active antiretroviral therapy (HAART).

All eligible children were randomized into Standard dose or Double dose groups with an allocation ratio of 1:1 using block randomization with blocks of 6 (www.randomizer.org). Children assigned to the standard dose group were given 0.5 mL (10 µg) of recombinant HBV deep intramuscular at 0, 1, 6 months. Children assigned to the double dose group were given 1 mL (20 µg) of HBV in the same schedule. Allocation was concealed in sequentially numbered, opaque and sealed envelopes, which were opened when a child was enrolled. All the children were thoroughly assessed before enrolment and a detailed history was taken. The children were classified according to the revised World Health Organization (WHO) clinical staging and WHO immunological staging. The children received HAART according to the existing National AIDS Control Organization (NACO) guidelines. Anti-HBs antibody titres were estimated using enzyme linked immuno-sorbent assay (ELISA) (DS-EIA-ANTI-HBs) kit 12 weeks after the 3rd dose of HBV. Anti HBs titre ³10 mIU/mL were considered as seroprotection.

A total of 60 children were enrolled in the study with final analysis of 55 children (Fig. 1). The baseline characteristics were comparable in both the groups (Table I). Seroprotection was achieved by 17 (60.7%) children in standard dose against 20 (74%) in double dose group but it was not statistically significant (Table II). There was no difference in the seroprotective levels achieved when the children in both the groups were further stratified into two subgroups based on the CD4 counts at the time of enrolment; CD4 count <500 cells/mm3 and CD count ³500 cells/mm3. CD4 count <500/mm3 was independently associated with significantly lower rates of seroprotection irrespective of the dose of the vaccine (P=0.008) (Table II). The coefficient of correlation (r) between the CD4 count and the Anti HBs titers achieved was 0.31 (P<0.001) showing a weak linear positive correlation.

TABLE I Baseline Characteristics in Study Children

Fig.1 Study flow chart.

TABLE II Comparison of the Outcomes in Study Groups 

TABLE III Characteristics of Seroprotected and Unprotected Group

In this study comparing the efficacy of double dose and standard dose HBV vaccine in HIV-infected children, the seroprotection rate in the double dose group was 74% compared to 60.8% of the standard dose group, but it was not statistically significant. The CD4 count at the time of enrolment was significantly associated with seroprotection with a linear positive relationship.

The limitation of the study is the small sample size because of the limited period of the study and single center-based enrolment. Only about one-fourth of these children were receiving HAART. Long-term follow-up for duration of seroprotection or development of hepatitis B infection was also not done in the present study.

Suboptimal immunological response to HBV in HIV-infected patients has been documented by numerous studies. A search for the ideal dose and schedule for the HBV in such individuals has not lead to a final consensus. Psevdos, et al. [9] studied the efficacy of double dose of HBV in HIV-infected individuals who failed to respond to standard dose vaccination. The double dose was compared with additional standard doses in non-responders. The response rate was significantly higher in the double dose group (85%) vs. additional standard doses (61%). Cornejo Juarez, et al. [10] conducted a randomized controlled trial comparing 10 µg dose with 40 µg dose and found no significant difference. Fonseca, et al. [11] found no significant difference in response to double dose of HBV in HIV- infected adults with seroconversion rates 47% compared to 34% in standard dose. However, double dose showed significantly higher response in individuals with CD4 ³350 cells/mm3 and HIV viral load <10,000 copies/mL. A meta-analysis by Ni, et al. [7] concluded that the response rates in the patients who received high dose was higher (OR 1.96; 95% CI 1.47, 2.61) [7].

A study by Pasricha, et al. [12] in India found significantly lower HBsAb levels in HIV-infected patients, especially those with a low CD4 count (<200 cells/mm3), even with a double dose when compared to standard dose administered to healthy subjects. Bose, et al. [8] studied the immune response to 4 doses of double dose vaccine in HIV-infected children and found high (94%) seroconversion.

We found a CD4 count of <500 cells/mm3 to be associated with significantly poor immune response. Other studies also found significantly suboptimal immune response in patients with a low CD4 count [13,14]. The use of ART did not significantly affect the immunological response of children in the index study. Cornejo-Juárez, et al. [9] found no association between type and duration of HAART and seroconversion but Psevdos, et al. [10] found use of HAART to be significantly associated with seroconversion.