A phase 3 clinical trial has demonstrated that the HepB-CpG vaccine elicits a superior seroprotection response compared to the conventional HepB-alum vaccine in people with HIV who have previously shown non-responsiveness to hepatitis B vaccination. The study, conducted across 41 sites in 10 countries, provides evidence supporting a change in practice towards using HepB-CpG vaccine for this population.
The Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG) Network 5379 B-Enhancement of HBV Vaccination in Persons with HIV (BEe-HIVe) study, a phase 3, open-label, randomized clinical trial, compared the immunogenicity of HepB-CpG vaccine in prior hepatitis B vaccine recipients with HIV who were deemed nonresponders. The trial included 561 adults 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. Participants were randomized to receive 2 doses of HepB-CpG vaccine, 3 doses of HepB-CpG vaccine, or 3 doses of HepB-alum vaccine. 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).
Superior Seroprotection with HepB-CpG
The results indicated that 93.1% of participants who received 2 doses of HepB-CpG vaccine achieved a seroprotection response, while 99.4% of those who received 3 doses of HepB-CpG vaccine achieved seroprotection. In contrast, only 80.6% of participants who received 3 doses of HepB-alum vaccine achieved seroprotection. 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%]).
Rapid Response and High Antibody Titers
Notably, by week 12, more than 90% of participants who received HepB-CpG vaccine achieved a seroprotection response. Furthermore, 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%) compared to the other two regimen groups (26.4% for 2 doses of HepB-CpG vaccine and 35.2% for 3 doses of HepB-alum vaccine).
Safety Profile
No unexpected safety issues were observed during the trial. Adverse events after vaccination (≥grade 2 within 4 weeks of vaccination) were experienced by 33.2% of participants in the 2-dose HepB-CpG vaccine group, 44.7% of participants in the 3-dose HepB-CpG vaccine group, and 43.5% of participants in the 3-dose HepB-alum vaccine group. Injection site pain, headache, fatigue, malaise, and myalgia were the most frequent adverse events related to hepatitis B vaccination.
Implications for Clinical Practice
These findings suggest that HepB-CpG vaccine should be considered for people with HIV who are vaccine-naive or have prior nonresponse to conventional hepatitis B vaccines. According to Kristen M. Marks, MD, Department of Medicine, Weill Cornell Medicine, a seroprotection response was achieved earlier in participants receiving HepB-CpG vaccine compared with HepB-alum vaccine. This was also observed in the trials among vaccine-naive adults without HIV that initially supported US Food and Drug Administration approval of the 2-dose regimen for HepB-CpG vaccine. Many people with HIV are at risk for HBV acquisition so rapid achievement of seroprotection is desirable, particularly because antiretroviral therapy regimens without tenofovir (which has antiviral activity against HBV) are increasingly used, including long-acting, injectable formulations. Other populations with increased risk for HBV acquisition related to injection drug use, sexual contact, hemodialysis, or other factors would also benefit from more rapid and complete seroprotection, particularly for those individuals who may be lost to follow-up and in whom the opportunity to repeat a vaccine series is low.
Limitations
The study had some limitations, including the heterogeneity of past vaccine experiences due to the eligibility criteria chosen to mirror real-world presentation rather than a clinical trial definition of vaccine nonresponse. However, the seroprotection response was similar when limiting the sample to those who received 3 or more prior doses. Also, there were 10 participants included who had a level of antibody titer against HBsAg that was 10 mIU/mL or greater at entry (many near the threshold), reflecting real-world practice in which antibody levels are not repeated on the day of vaccination.
Conclusion
In conclusion, the study demonstrated that both 2 and 3 doses of HepB-CpG vaccine achieved a superior seroprotection response compared with 3 doses of HepB-alum vaccine in people with HIV and prior nonresponse to hepatitis B vaccination. The results support a change in practice to use HepB-CpG vaccine for people with HIV who are vaccine-naive or have prior nonresponse to conventional hepatitis B vaccines.
