Abstract
There is no consensus regarding a best dosing regimen of hepatitis B virus vaccine (HBVV) for non-responsive HIV-infected individuals. Double-dose of hepatitis B vaccine (DDHBVV) could enhance immunogenicity to HBVV in non-responsive HIV-infected adults. We assessed the immunogenicity of DDHBVV in HIV-infected adolescents who failed to respond to standard HBVV revaccination. HIV-infected adolescents with current CD4 ≥ 200 cells/mm3 and no protective antibody concentration of hepatitis B surface antibodies (antiHBs) after HBVV revaccination received DDHBVV, at months 0, 1, 2. The HBVV doses were 20 microgram per dose for adolescents aged < 18 years and 40 microgram per dose for adolescents aged ≥ 18 years. AntiHBs titers were measured at 1, 2, 3 months after first DDHBVV. AntiHBs ≥ 10 mIU/ml was considered protective. Seven adolescents were enrolled; mean age was 15.4 years, CD4 was 775 cells/mm3 and all had HIV-RNA < 50 copies/ml. Proportions of adolescents with protective antiHBs were 86% at months 1 and 2, and 100% at month 3. Geometric means of antiHBs were 1.1 at baseline, 101.6 at 1 month, 137.1 at 2 months, and 355.9 mIU/ml at 3 months after the first DDHBVV. No grade 3-4 adverse event was reported. DDHBVV is an option for HIV-infected adolescents who are non-responder to standard HBVV revaccination.
According to the US Centers for Disease Control recommendation, individuals who failed to develop a protective serum antibody concentration of hepatitis B surface antibody (antiHBs) >10 mIU/mL after a first course of 3 doses of hepatitis B virus vaccine (HBVV) should at least be given a second 3-dose course of HBVV. 1 However, there is no consensus regarding a best dosing regimen of HBVV for nonresponsive HIV-infected individuals. Double dose of hepatitis B vaccine (DDHBVV) could enhance the immunogenicity to HBVV in nonresponders. Response rates of 51% to 85% to 3 doses of DDHBVV have been reported in previous nonresponder, HIV-infected adults, and response rate was superior to revaccination with standard doses of HBVV. 2 –4 There are limited data on DDHBVV in HIV-infected children and adolescents. Here, we report a pilot, open-label, single-arm study to evaluate the efficacy and safety of DDHBVV in HIV-infected adolescents who were nonresponders even though they previously received the first HBVV course during infancy and second HBVV course after immune recovery.
Recombinant HBVV, manufactured by LG Life Science, Korea (Euvax B, Lot no. ULA08005 and ULA09007) and distributed by Sanofi Pasteur Ltd, Korea, was used. Each 1 mL of vaccine contained 20 μg of hepatitis B surface antigen (HBsAg) with aluminium hydroxide gel. The standard pediatric dose (recommended for individuals <15 years of age) contains 10 μg of HBsAg in a volume of 0.5 mL, while the adult dose (recommended for individuals ≥16 years of age) contains 20 μg of HBsAg in a volume of 1.0 mL. In our study, the HBVV doses were 20 μg per dose for adolescents aged <18 years and 40 μg per dose for adolescents aged ≥18 years. 3 The vaccines were administered intramuscularly at months 0, 1, and 2 at the left deltoid area 3 by experienced pediatric nurses. The antiHBs titers were measured at 1, 2, and 3 months after the first DDHBVV. The antiHBs ≥10 mIU/mL were considered protective. Good responders were defined as adolescents with antiHBs ≥100 mIU/mL. 5 All analyses were undertaken using STATA, version 10.0 (StataCorp, College Station, Texas).
Seven HIV-infected adolescents were enrolled from HIV-NAT, the Thai Red Cross AIDS Research Centre, Bangkok, Thailand. In all, 6 (85.7%) were male, mean age was 15.4 years, CD4 count was 775 cells/mm3, and all had HIV-RNA <50 copies/mL. Their characteristics at this second HBVV revaccination with DDHBVV are shown in Table 1. All were infected with HIV via mother-to-child transmission. All completed 3 doses of HBVV during their infancy and were revaccinated after immune recovery with a course of 3-dose HBVV; 4 adolescents previously received intradermal HBVV (2 μg/dose) and 3 previously received intramuscular HBVV (10 μg/dose). 5 The mean duration from last dose of HBVV revaccination to the first dose of DDHBVV was 1.2 years.
Characteristics of 7 HIV-Infected Adolescents and Response to Second Revaccination with 3 Double-Dose Hepatitis B Vaccine.
Abbreviations: antiHBs, antibody concentration of hepatitis B surface antibodies; HBVV, hepatitis B vaccine; HAART, highly active antiretroviral therapy; CDC, Centers for Disease Control and Prevention clinical classification: A (mild HIV symptoms), B (moderate HIV symptoms), C (severe HIV symptoms); SD, standard deviation.
aData are presented as mean (SD) or n (%).
Proportions of adolescents with protective antiHBs were 85.7% at months 1 and 2 and 100% at month 3. Geometric means of antiHBs were 1.1 mIU/mL at baseline, 101.6 mIU/mL at 1 month, 137.1 mIU/mL at 2 months, and 355.9 mIU/mL at 3 months after the first DDHBVV (Table 1).
There was no grade 3 or 4 adverse events related to DDHBVV. No one reported fever or swelling at the injection site. In our study, the response rate to HBVV revaccination is better than the reports of revaccination of standard dose or DDHBVV in HIV-infected adults which were reported in a range of 51% to 85%. 2 –4 This might be explained by the characteristics of our participants including young age group and high CD4 counts. 4
To our knowledge, our study is the first to report on DDHBVV in nonresponsive HIV-infected adolescents. However, the long-term immunogenicity after DDHBVV in these adolescents should be evaluated. Our study had limited number of HIV-infected adolescents. The randomized studies on DDHBVV versus standard HBVV in nonresponsive HIV-infected children and adolescents should be conducted.
In conclusion, DDHBVV at months 0, 1, and 2 is effective and safe. All 7 adolescents responded well after completing the 3 doses of DDHBVV. The DDHBVV is an option for HIV-infected adolescents who failed to respond to standard HBVV revaccination.
Footnotes
Acknowledgments
We thank the Thai National Health Security Office and the Aligning Care and Prevention of HIV/AIDS with Government Decentralization to Achieve Coverage and Impact: ACHIEVED Project (Global fund Thailand) for antiretroviral therapy, CD4, and HIV-RNA. We are grateful to the adolescents and their families for participating in this study.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: from Mr Han Nefkens and the ART AIDS Fund in the Netherlands.