Risk of hepatitis B virus infection after vaccination
The distribution of baseline characteristics for the 972 participants in the vaccinated group is shown in Table 1(b). Followed for a total of 5445 years from the date of first vaccination (median, 4.7 years; IQR 2.4–8.1), there were 90 cases of HBV in this group resulting in an event rate of 1.65 (95% CI 1.31–1.99) per 100 person-years. In multivariate analyses male sex (hazard ratio 4.88; 95% CI 1.5–15.5) was associated with an increased risk of HBV infection, whereas HAART use (hazard ratio 0.46; 95% CI 0.2–0.9), but not mono/dual ART was associated with reduced risk [Table 3(b)]. Increasing age remained significantly associated with reduced risk of HBV among vaccine recipients (hazard ratio 0.63 per 10 year increase; 95% CI 0.4–0.9). HIV RNA was again not included in the final multivariate model, because it was unknown for a large portion of the group.
To determine the association of vaccine seroresponse and risk of HBV infection, subset analyses were performed with the 626 vaccine recipients with known vaccine response or nonresponse [vaccine response group; Table 1(c)]. There were no baseline differences between those with and without an HBsAb determination following the last dose of vaccine. During 2333 years of follow-up (median 3.0 years; IQR 1.2–5.4) there were 57 cases of HBV in this group, all of which occurred in men, resulting in a rate of 2.44 per 100 person-years (95% CI 1.81–3.08). A positive vaccine response was seen in 217 (34.7%). After adjusting for age, ethnicity, and ART use, those with a positive response had an approximately 50% reduced risk of HBV infection compared to those with nonresponse (hazard ratio 0.51; 0.3–1.0) [Table 3(c)]. Of participants with positive response, 11 (5.1%) developed HBV infection compared with 46 (11.2%) with nonresponse (P = 0.013 by log rank, Fig. 2). Proportions (95% CI) of those without HBV infection at 3, 5, and 7 years follow-up for those with a positive response were 96.6% (94.0–99.0), 95.2% (91.7–98.8), and 95.2% (91.7–98.8), respectively; for those with nonresponse proportions at the same time points were 87.6% (83.4–91.8), 85.5% (80.8–90.2), and 84.3% (79.2–89.5). Of participants with an initial positive response, risk of HBV infection was no different between those with waning or persistent vaccine responses (P = 0.26 by log rank).
Chronic hepatitis B virus infection
Overall, chronic HBV occurred in 55 (23.5%) of the 234 HBV-infected participants. Chronic infection occurred in 24% (35/144) of unvaccinated participants with HBV compared with 22% (20/90) of vaccinated participants (P = 0.75). For participants with initial nonresponse, 16 of 46 HBV infections (35%) resulted in chronic infection (P = 0.18 compared with unvaccinated participants). However, among those with a vaccine response, no chronic HBV infections were seen (P = 0.07 compared with unvaccinated participants; P = 0.02 compared with vaccinated, nonresponders). Among participants with HBV infection in the vaccine response group, there were no significant differences between those who did and did not develop chronic HBV regarding age, ethnicity, sex, HIV RNA, CD4 cell count, or use of ART at the time of HBV infection.
We found receipt of HBV vaccine after diagnosis of HIV was associated with no reduction in risk of HBV infection overall. In a previous study by Kellerman et al. , history of ever receiving one or more doses of HBV vaccine was associated with a 40% reduced risk of acute HBV infection. The reasons for the different findings are likely related to several factors including different patient populations and study endpoints, as we captured serologic and chronic infections and not only acute HBV infections. In addition, we excluded participants with known receipt of HBV vaccine prior to HIV diagnosis, whereas Kellerman, et al.  did not. Whether vaccination prior to HIV infection is associated with a reduced risk of HBV following HIV diagnosis is unknown. Other factors found to be associated with risk of HBV infection in our study were similar to previous investigations, including increased risk in those with a previous sexually transmitted infection, and reduced risk in those taking HAART [1,37,38].
From our data we are unable to determine why vaccination was not associated with reduced risk of HBV infection. One possible contributing factor to the overall lack of protection may be the high rate of exposure to HBV in this HIV-positive population. This is supported by the overall rate of HBV infection we observed (2 per 100 person-years follow-up), approximately 100-fold higher than the rate of HBV in the US military and 500-fold higher than the rate of acute HBV in the general US population [37,39]. In addition, poor initial immunogenicity of the vaccine in patients with HIV may be a second contributing factor. A vaccine response, defined as HBsAb at least 10 IU/l, was found in 35% of vaccinees, consistent with other smaller investigations where response rates have varied from 20 to 50% [11–18]. In non-HIV-infected individuals where response rates following three doses of vaccine are generally more than 90% , CD4 T-cell function is essential for development of a response [40,41]. Therefore, weakly protective vaccine responses reflected by low seroresponse rates in HIV-infected individuals may not be sufficient to protect against the high rate of HBV exposure, and possible repeated exposures seen in this population. Strategies to improve immunogenicity, such as use of adjuvants , are urgently needed.
Low vaccination coverage and low completion of the initial three dose series may also have reduced vaccine effectiveness. Of the overall group during the last two decades, 52% received at least one dose of vaccine, and of those 56% received at least three doses. The lack of coverage is partially explained by the fact that some participants in our cohort were enrolled prior to the release of universal recommendations for HBV vaccination. Although lack of vaccine coverage and completion may appear to undermine the conclusions from our study, our experience is consistent with other clinics and likely reflects clinical practice more than the idealized setting of a clinical trial. In a recent investigation from nine US metropolitan HIV clinics only 32% of those eligible for HBV vaccine received at least one dose, and of those 52% received at least three doses . In this way, our study may give a more accurate depiction of the effectiveness of HBV vaccine in HIV-infected patients. The unexpectedly low rates of HBV vaccine delivery and completion only highlight some of the challenges of using of HBV vaccine in HIV-infected individuals, especially considering our participants are relatively healthy with high CD4 cell counts, have very low rates of illicit drug use, and are seen in an optimal setting for delivery of vaccines, the open access to care military health system. Poor vaccine immunogenicity only compounds these challenges. Extrapolating the observed vaccine response rate to all vaccinated participants, only 18% of all individuals obtained a response reflecting the combination of low coverage and limited immunogenicity. Multiplying the proportion of participants, which developed a response, 18%, by the 49% reduction in HBV infection in those with a response, the expected vaccine effectiveness was approximately 9%, and well within the confidence limits we determined for overall effectiveness in any model.
Given that vaccine effectiveness may be low overall, public health officials and clinicians may speculate whether or not HBV vaccination should be routinely offered to patients with HIV. Although not definitive, our results suggest that those developing an initial response to the vaccine derived benefit from vaccination through at least 7 years of follow-up. Alternatively, development of a vaccine response may have indicated an improved ability of an individual's immune system to recognize HBV antigens associated with a reduced susceptibility to infection . However, our finding that development of HBsAb of at least 10 IU/l was associated with a reduced risk of infection, including chronic disease, is consistent with results from prospective trials of non-HIV-infected individuals [27,28,44]. Therefore, until more definitive data are known regarding vaccine effectiveness, HBV vaccination of HIV-infected patients should be continued as a portion of patients may obtain protection from receipt of vaccine. In addition, clinicians should consider checking HBsAb levels following vaccination and reimmunizing nonresponders with additional doses of vaccine , as well as informing such patients of their HBV risk.
Although a high proportion of those with incident HBV infection developed chronic disease overall, the likelihood of developing chronic HBV infection was associated with vaccine response among vaccinated participants. In HIV-uninfected individuals spontaneous recovery from HBV infection involves a strong, polyclonal CD4 cell and CD8 cell response, whereas those developing chronic HBV display weak, monoclonal or oligoclonal responses [46–49]. Similar responses in HIV-infected patients were recently reported [50,51]. Therefore, lack of functional HBsAg-specific CD4 T cells necessary for vaccine response would predict a weaker and more homogeneous response to natural HBV infection, and an increased likelihood of chronicity. An alternative hypothesis for the observed association would be that antigenic stimulation by vaccination in the setting of immune activation would result in apoptosis  of HBsAg-specific CD4 T cells with subsequent impairment of the immune response to HBV once infected. Arguing against this however, is the observation that vaccination was not associated with an increased risk of HBV infection overall.
There are limitations to our study. First, our cohort is unique compared to other large HIV cohorts in some respects, including enrollment early after infection due to routine military HIV screening, open access to care in the military health system, and virtually no intravenous drug use . However, these characteristics should only improve vaccine delivery and effectiveness. Second, HBV serologies in HIV-infected individuals may fluctuate  making diagnosis and classification for investigation difficult, but participants in our study received periodic testing of HBV serological markers, and our criteria for inclusion and definitions for infection required results of multiple serologies. Third, there may have been an indication bias for vaccination. However, the only notable difference between unvaccinated and vaccinated participants was the year of HIV diagnosis, and results were essentially identical from unadjusted and stratified models, and after utilizing propensity-scoring methods to account for potential selection bias regarding vaccination. The vaccine dose was also unknown, although providing higher doses of vaccine to patients with HIV is not clearly beneficial [18,54]. Lastly, HIV RNA levels, known to predict vaccine responses, were unknown for many participants, analyses of vaccine recipients were limited by the number of events, and analyses regarding vaccine response were further limited by HBsAb result ascertainment.
Though recommended by guidelines [7,10], the effectiveness of HBV vaccine in HIV-infected individuals had not been thoroughly investigated . Although vaccination was not associated with reduced risk of HBV infection overall, it may be beneficial for some individuals, specifically those developing an initial vaccine response of HBsAb of at least 10 IU/l. However, our data suggest overall vaccine effectiveness in this population currently appears very limited, as vaccine nonresponders typically account for one-half to two-thirds of vaccine recipients, and the risk of exposure to HBV remains high in this patient population. Continued improvements in vaccination delivery in combination with further knowledge of methods to increase initial vaccine immunogenicity would substantially improve vaccine efficacy.
The authors would like to thank Mr. William Bradley for his expertise and assistance with the United States Military HIV Natural History Study (NHS) database, and Dr Sheila Peel for her expertise in performing HBsAb testing. We would also like to express our gratitude for the current members of the IDCRP HIV Working Group and the long line of military HIV researchers who have supported the HIV NHS, and for the research coordinators and support staff for their countless hours of work. Most importantly, we would like to thank the patients for their participation, without which this research would not have been possible.
These data were presented in part at the 45th Annual Meeting of the Infectious Diseases Society of America, San Diego, California, October 4–7, 2007, Abstract #901.
Support for this work was provided by the Infectious Disease Clinical Research Program (IDCRP) of the Uniformed Services University of the Health Sciences (USUHS). The IDCRP is a DoD tri-service program executed through USUHS and the Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF), in collaboration with HHS/NIH/NIAID/DCR through Interagency Agreement HU0001-05-2-0011. The opinions or assertions contained herein are the private views of the authors, and are not to be construed as official, or as reflecting the views of the Departments of the Army, Navy, Air Force, or the Department of Defense. The authors have no commercial or other association that might pose a conflict of interest.
Authorship contribution: Conception and design: M.L.L., K.H.H. and B.K.A.
Data acquisition: M.L.L., A.G., A.C.W., N.F.C.-C., R.V.B. and R.J.O'C.
Statistical analysis: K.H.H., M.L.L. and A.F.
Data analysis and Interpretation: M.L.L., K.H.H., A.G., A.C.W., N.F.C.-C., R.V.B., R.J.O'C., A.F., H.M.C., V.C.M., M.J.D. and B.K.A.
Drafting manuscript: M.L.L. and K.H.H.
Critical revision of the manuscript: A.G., A.C.W., N.F.C.-C., R.V.B., R.J.O'C., A.F., H.M.C., V.C.M., M.J.D. and B.K.A.
Final approval of manuscript: M.L.L., K.H.H., A.G., A.C.W., N.F.C.-C., R.V.B., R.J.O'C., A.F., H.M.C., V.C.M., M.J.D. and B.K.A.
Obtaining funding: M.L.L. and B.K.A.
Technical support: R.J.O'C.
Members of the Infectious Disease Clinical Research Program HIV Working Group:
National Institute of Allergy and Infectious Diseases, Bethesda, MD: M. Polis, J. Powers, J. Metcalf, E. Tramont.
Naval Medical Center, Portsmouth, VA: J. Maguire, V. Barthel, S. Patel.
Naval Medical Center, San Diego, CA: B. Hale, N. Crum-Cianflone, M. Bavaro, H. Chun.
National Naval Medical Center, Bethesda, MD: T. Whitman, A. Ganesan.
San Antonio Military Medical Center, San Antonio, TX: V. Marconi, M. Landrum, J. Delmar, W. Bradley.
Tripler Army Medical Center: T. Ferguson, A. Johnson.
University of Minnesota, Minneapolis, MN: A. Lifson, K. Hullsiek, A. Fieberg.
Uniformed Services University of the Health Sciences, Bethesda, MD: S. Wegner, B. Agan, G. Martin.
Walter Reed Army Institute of Research, Silver Spring, MD: N. Michael, M. Milazzo, R. O'Connell, S. Peel.
Walter Reed Army Medical Center, Washington, DC: G. Wortmann, C. Hawkes, A. Weintrob, S. Fraser.
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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
hepatitis B vaccine; hepatitis B virus; human immunodeficiency virus; immunization; vaccination