HepB-CpG vs HepB-Alum Vaccine in People With HIV and Prior Vaccine Nonresponse: The BEe-HIVe Randomized Clinical Trial.

Importance: Nonresponse to hepatitis B vaccine is common among people with HIV, resulting in vulnerability to infection with hepatitis B virus (HBV).

Objective: To compare the seroprotection response achieved with a 2-dose (noninferiority, 10% margin) and a 3-dose hepatitis B vaccine with a cytosine phosphoguanine adjuvant (HepB-CpG vaccine) vs a conventional 3-dose hepatitis B vaccine with an aluminum hydroxide adjuvant (HepB-alum vaccine) in people with HIV and prior nonresponse to HepB-alum vaccine.

Design, setting, and participants: This phase 3, open-label, randomized clinical trial included people with HIV receiving antiretroviral therapy (CD4 cell count ≥100 cells/μL and HIV RNA <1000 copies/mL) without past or present serological evidence of having HBV or a response to hepatitis B vaccine. From December 2020 to February 2023, 561 adults were enrolled in the study at 41 sites in 10 countries in Africa, Asia, North America, and South America with follow-up for the primary outcome analysis through September 4, 2023.

Interventions: Participants were randomly assigned to receive 2 doses of HepB-CpG vaccine administered intramuscularly at weeks 0 and 4; 3 doses of HepB-CpG vaccine administered intramuscularly at weeks 0, 4, and 24; or 3 doses of HepB-alum vaccine administered intramuscularly at weeks 0, 4, and 24.

Main outcomes and measures: The primary outcome was a seroprotection response to hepatitis B vaccine (defined as level of antibody titer against hepatitis B surface antigen [HBsAg] ≥10 mIU/mL) at week 12 for the 2-dose regimen (8 weeks after dose 2) and at week 28 for 3-dose regimens (4 weeks after dose 3). Key secondary outcomes included seroprotection response at additional time points, antibody titer against HBsAg, and adverse events within 4 weeks of hepatitis B vaccination.

Results: Of 561 participants included in the analysis (median age, 46 years [IQR, 31-56 years]); 64% were male; 17% of participants were Asian, 42% were Black, and 35% were White), a seroprotection response was achieved in 93.1% who received 2 doses of HepB-CpG vaccine (n = 174), in 99.4% who received 3 doses of HepB-CpG vaccine (n = 169), and in 80.6% who received 3 doses of HepB-alum vaccine (n = 165). The stratified difference in seroprotection response between the 2-dose HepB-CpG vaccine group and the 3-dose HepB-alum vaccine group was 12.5% (97.5% CI, 4.1%-20.9%), achieving noninferiority and indicating superiority. The 3-dose HepB-CpG vaccine regimen was superior to the 3-dose HepB-alum vaccine regimen (stratified difference in seroprotection response, 18.4% [repeated 97.5% CI, 10.4%-26.2%]). By week 12, more than 90% of participants who received HepB-CpG vaccine achieved a seroprotection response. The 3-dose regimen of HepB-CpG vaccine achieved a higher proportion of participants with antibody titer against HBsAg greater than 1000 mIU/mL (78.1%) vs the other 2 regimen groups (26.4% for 2 doses of HepB-CpG vaccine and 35.2% for 3 doses of HepB-alum vaccine). No unexpected safety issues were observed.

Conclusions and relevance: Among people with HIV and nonresponse to prior hepatitis B vaccination, both the 2-dose and 3-dose regimens of HepB-CpG vaccine achieved a superior seroprotection response compared with 3 doses of HepB-alum vaccine.

Trial registration: ClinicalTrials.gov Identifier: NCT04193189.