10 mIU/mL (measured
by ELISA) is indicative of protective response. However, vaccine
response to standard hepatitis-B vaccination is often blunted in
HIV-infected children due to depletion of CD4+ T-cells, and altered
distribution of T-cell and B-cell subsets. A decline in the total memory
B cells (CD27+) and expansion of immature B cells (CD10+) makes this
population susceptible to a high rate of reinfection and waning
vaccination-induced immunity [4]. The response rates to the ‘classic’
hepatitis-B vaccination schedule (10 µg at months 0-1-6) are much lower
in children living with HIV compared to HIV non-infected children [5-9].
To achieve higher seroprotection rates, various
vaccination strategies have been tried in these children, including the
use of double-dose hepatitis-B vaccine [10,11], additional doses of
vaccination [10], intradermal route of vaccination [12], varying
vaccination schedules (0-1-6 months, 0-1-2 months, 0-1-12 months, etc.),
and the use of combination vaccines [11]. A meta-analysis by Ni, et
al. [13] recommends the use of increased dose of hepatitis-B vaccine
for achieving adequate seroconversion after primary immunization in
HIV-infected individuals.
TABLE I Immunogenicity of Hepatitis B vaccine in HIV-infected Children
Study Group
(Year) |
Dose and route |
Number of doses (schedule) |
Proportion on ART |
Seroconversion
|
|
Siddiqui, et al. |
10 µg IM |
3 (0-1-6 mo) |
25% in 10 µg IM group |
60.8% in 10 µg IM group
|
|
(2017) [14] |
vs 20 µg IM |
|
vs 22.2% in 20 µg IM group
|
vs 74% in 20 µg IM group |
Bose, et al.
(2016) [10] |
20 µg IM |
4 (0-1-2-6 mo) |
81.8%
|
94%
|
Bunupurudah,
et al. (2011) [12] |
10 µg IM
vs 2 µg ID |
3 (0-2-6 mo) |
91.3% on ART IM: 87.2%
ID:95.1%
|
90.2% in ID vs. 92.3% in IM; 56.1% had good response (Anti HBs
>100 mIU/mL) to Hepatitis B vaccination in ID group compared to
82.1% in IM group (P=0.01)
|
Flynn, et al.
(2011) [11] |
20 µg IM vs 40 µg IM vsTwinrix (20 µg HBs antigen & 720 ELU HAV
antigen) |
3 (0-1-6 mo) |
20 µg IM: 42%
40 µg IM: 40%
Twinrix: 49% |
60% in the 20 µg IM group vs
73.2% in 40 73.2% vs 75.45%
in Twinrix group
|
|
Pippi, et al.
|
5 µg IM
|
3 (0-1-6 mo) |
52.8%
|
59.5% (70.8% in ART vs |
|
(2008) [9] |
|
|
|
44.4% in non-ART) |
Thaithumyanon,
et al. (2002) [6] |
10 µg IM |
3 (0-1-6 mo) |
- |
71.4%
|
Rutstein,
et al. (1994) [7] |
10 µg IM |
3 (0-1-6 mo) |
- |
35% |
Diamant,
et al. (1993) [8] |
10 µg IM |
3 (0-1-6 mo) |
8%
|
25% |
Zuin,
et al. (1992) [5] |
10 µg IM |
3 (0-1-6 mo) |
- |
78% |
|
ART: anti-retroviral therapy, ELU: ELISA units, HAV:
Hepatitis A virus, ID: intradermal route, IM: intramuscular
route. |
These studies of hepatitis B vaccination in
HIV-infected children are difficult to compare because of varied study
designs and heterogeneous populations, disease and treatment status of
subjects (Table I) [5-12,14]. There is no consensus, yet,
regarding the best hepatitis-B vaccine schedule for primary immunization
in HIV-infected children. Table II summarizes the
recommendations on hepatitis B vaccination in HIV-infected children as
advocated by various scientific bodies [15-18].
Table II Recommendations of Hepatitis B Vaccination in HIV-infected Children
|
Scientific Body |
Dose of Hepatitis B vaccine |
Schedule |
|
Centers For Disease Control and |
Double dose 20 µg
|
Three doses (0, 1-2, 4-6 months), IM |
|
Prevention (CDC) [15] |
|
|
|
National Institute of Health (NIH) [16] |
Standard dose 10 µg |
Three doses (0, 1-2 months, 6-18 months), IM
|
|
Children’s HIV Association (CHIVA) [17] |
Double dose 20 µg |
Three doses (0, 1-2 and 12 months), IM |
|
Indian Academy of Pediatrics (IAP) [18] |
Double dose 20 µg |
Symptomatic HIV: Four doses
|
|
|
(0,1,2,6 months), IM
|
|
|
Asymptomatic HIV: Three doses |
|
|
(0-1-6 months), IM |
|
IM: intramuscular route. |
Factors shown to be associated with improved response
to hepatitis-B vaccination include higher CD4 counts, undetectable HIV-1
viral load, younger age, increased dose and number of vaccines, and
receipt of anti-retroviral therapy (ART) [19]. The use of ART is
instrumental in viral suppression and restoration of immune functions,
especially if initiated early in life. In several developing countries,
HIV-infected children may not have access to ART until the CD4+ counts
fall below the cut-offs of severe immunodeficiency, or until they get
categorized as Stage 3 or 4 based on WHO Clinical staging of
HIV-infection. The study by Siddiqui, et al. [14], published in
the current issue of Indian Pediatrics, seems particularly
relevant in a time of introduction of universal ART for HIV-infected
children in India by National AIDS Control Organization (NACO)
irrespective of their clinical or immunological staging. In this study,
only a quarter of children (13/55) were receiving ART, which could
explain the low rate of seroprotection. The study by Bunupurudah, et
al. [12] was able to achieve 92.3% seroprotection in children (about
90% of who were receiving ART) with recombinant hepatitis-B vaccine in a
standard dose (10 µg) administered in a three-dose schedule. About 50%
of these Thai children were able to mount a good seroprotection response
(anti-HBs titers >100 mIU/mL). Siddiqui and colleagues [14] did not
compare the proportion of good responders and the long-term immunity
against hepatitis-B between the two groups. The study also has a major
drawback in terms of a small sample size. No recommendation is possible
based on the results of this study, though, it does add to the available
scant data.
There is a need for studies evaluating immune
response to hepatitis B vaccine in HIV-infected children receiving ART
(as per current guidelines) to establish optimal vaccination schedule.
It may be relevant to explore if the schedule needs to be tailored to
suit different categories based on immune status measured by CD4 counts.
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