Hepatitis B vaccine: a seven-year study of adherence
to the immunization guidelines and efficacy in
Christina L. Bailey, Vanessa Smith, Michael Sands*
Division of Infectious Diseases, University of Florida Health Science Center, Jacksonville, Florida 32206, USA
Received 14 February 2008; received in revised form 6 May 2008; accepted 19 May 2008
Corresponding Editor: Mark Holodniy, California, USA
Since the adoption of universal vaccination of newborns and
adolescents in 1991, overall new hepatitis B infection rates
primarily in high-risk adults. In the Centers for Disease
International Journal of Infectious Diseases (2008) 12, e77—e83
Hepatitis B vaccination;
Hepatitis B vaccination
Hepatitis B vaccine
Background: Vaccination against hepatitis B virus (HBV) has been recommended for all high-risk
adults since 1982. Since the advent of highly active antiretroviral therapy, few studies have
examined adherence to the Infectious Diseases Society of America (IDSA) and Advisory Committee
Methods: This was a seven-year retrospective, cross-sectional analysis of HBV vaccination prac-
tices in HIV-1-positive adults treated in an urban ambulatory care center. Compliance with
screening, hepatitis B vaccination recommendations, and response to vaccination were assessed.
Results: Ofthe 1601chartsreviewed, 717 persons wereeligible forvaccinationagainst hepatitisB.
Of these patients, 503 received at least one dose of vaccine, but only 356 patients completed the
three-dose series. Vaccine response was associated with CD4 count (p = 0.006) and viral load
(p = 0.001) at the time of the first dose.However, development of hepatitis B surface antibody was
seen at all CD4 counts and viral loads. The multivariate analysis showed only the HIV viral load was
predictive of immunologic response. Twenty of the vaccine-eligible patients who did not receive
vaccination were infected with HBV during the study period. No vaccinated persons contracted
Conclusion: Failure to implement these guidelines represents a missed opportunity to prevent
disease.Inour study, HIV viral load was betterthan CD4 count asa predictor ofresponse to the HBV
vaccination. However, neither low CD4 count nor high HIV viral load should be used as justification
to delay vaccination of high-risk persons.
# 2008 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
E-mail address: firstname.lastname@example.org (M. Sands).
1201-9712/$32.00 # 2008 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Control and Prevention (CDC) 2006 report, they estimate
51 000 new infections and an estimated 1.2 million people
in the USAwith chronic hepatitis B infection. Of these, 4000—
5000 people will die each year from hepatitis B virus (HBV)-
related liver disease.1,2
Both the United States Public Health Service (USPHS)/
Infectious Diseases Society of America (IDSA) and the Advi-
sory Committee on Immunization Practices (ACIP) currently
recommend screening for HBV and vaccination for all adults
at increased risk for infection due to occupational, beha-
vioral, social, or medical reasons. These risk groups include
sex with men (MSM), injection drug users, heterosexuals with
sexually transmitted diseases, household and sexual contacts
of HBV carriers, morticians, and incarcerated persons.2,3In
2005, 79% of new HBV infections were associated with either
high-risk sexual behaviors and/or intravenous drug use
For persons at risk for suboptimal response to the HBV
vaccine, such as those with HIV infection, hepatitis B surface
antibody(HBsAb) levelsshouldbecheckedwithin 6monthsof
completion of the vaccination series. Currently, it is not
recommended to vaccinate persons with isolated hepatitis
B core antibody (HBcAb) positivity.2—4
Adherence to these guidelines for HIV-infected patients
has not been well studied. One recent review of screening
and vaccination practices for hepatitis A and hepatitis B virus
in an HIV outpatient population, found low screening and
ing HIV.5Studies done to evaluate the immunogenicity of the
hepatitis B vaccine in persons infected with HIV have had
This study reviews the screening and adherence to HBV
vaccination guidelines and immunologic outcomes in a large
inner city adult HIV primary care clinic. We evaluated a
number of variables to determine their significance for
immunologic response to the HBV vaccine.
We performed a seven-year (September 1997—September
2004) retrospective, cross-sectional cohort study of all HIV-
positive adults seen in an urban, inner city, primary HIV care
clinic. Institutional review board approval was obtained prior
to review of charts. Demographic data were collected,
including age, sex, weight, income level, and race. Other
data collected included CD4 count and HIV viral load at time
of first vaccine dose, use of highly active antiretroviral
therapy (HAART), smoking history, HBsAb and hepatitis B
surface antigen (HBsAg), isolated hepatitis B core antibody
(HBcAb),hepatitis Beantigen (HBeAg) andantibody (HBeAb),
hepatitis C co-infection, number of vaccine doses received,
time from seronegative study eligibility determination to the
time the first dose of vaccine was given, and reason for not
completing the vaccine series, if available. All persons were
screened prior to administration of HBV vaccine. HAARTwas
defined as three or more antiretroviral drugs, including at
least one protease inhibitor or non-nucleoside reverse tran-
scriptase inhibitor plus two other agents.
Exclusion criteria for vaccine eligibility included persons
seropositive for isolated HBcAb were also considered ineli-
gible, as the current guidelines do not support vaccination
(Figure 1). No patient had a hepatitis B viral load performed.
Each patientwasfollowedforaminimum ofoneyear after
their initial clinic visit for screening and initiation of the HBV
vaccination series. Patients were given the standard dose of
recombinant hepatitis B vaccine, either Engerix-B (GlaxoS-
mithKline) or Recombivax-HB (Merck). Patients were consid-
ered vaccinerespondersiftheirHBsAblevels weretestedand
were greater than 10 mIU/ml.
SAS software packages (SAS institute, version 9.1) were
two-sided Fisher’s exact test, and the Wilcoxon rank sum test
were used to compare the categorical and continuous vari-
ables,respectively,between thetwo subjectgroups.p-Values
less than 0.05 were considered significant. In the multivariate
mine independent risk factors for vaccine failure. The vari-
ables tested included age, sex, race, weight, use of HAART,
hepatitis C co-infection, CD4 count, and HIV viral load.
A total of 1601 charts were reviewed, of which 25 were
excluded due to missing data or being out of the time range
of the study period. The remaining 1576 charts were included
68% were African-American, 54.7% were diagnosed with HIV,
not AIDS, and 58% lived below the level of poverty (Table 1).
Risk factors for HIV and HBV infection included homosexual
activity (23%), IVDU (10%), heterosexual activity (39%), and
Results of screening and HBV vaccination.
e78 C.L. Bailey et al.
Fifty-three patients were not screened for hepatitis B
during the study period and were therefore excluded. Eight
hundred and six patients were not eligible for vaccination for
the following reasons: prior HBV infection was identified in
510 (63.3%), 93 (11.5%) had active or chronic HBV disease, 89
(11%) had the presence of HBcAb only, and 114 (14.1%) had
already received hepatitis B vaccination (Figure 1). No
adverse events related to the vaccine or its administration
Of the 717 patients eligible to receive the hepatitis B
717 (49.7%) completed the three-dose series. Of those who
had completed the HBV vaccination series, 125 patients had
HBsAb titers tested. Fifty-nine (47.2%) patients had detect-
able HBsAb (Figure 1). For this group of seroconverters, the
median CD4 count was 502 cells/mm3(range 60—1225) and
the median HIV viral load was <400 copies/ml (range <50—
140). Fifteen patients were hepatitis C co-infected.
median CD4 count of this group was 346 cells/mm3(range 9—
1230), median HIV viral load was 5356 copies/ml (range
<50—>750 000), and thirteen were hepatitis C co-infected.
Three were not tested. Of these 66 patients who did not
series (Figure 1). Nine of these patients had detectable
HBsAbafterthesecond series,nine hadnodetectable HBsAb,
and 11 were not tested.
Response to HBV vaccination was significantly associated
with CD4 count greater than 350 cells/mm3(p = 0.006) and
undetectable HIV viral load (p = 0.001). A CD4 count of
<200 cells/mm3versus CD4 >350 cells/mm3had an odds
ratio of four times greater of non-response (point esti-
Demographic data and predictors of response to hepatitis B vaccination
Total patients screened
(N = 1601)
(N = 59)
(N = 66)
CD4+ T-cell count (cells/mm3)
p = 0.068
p = 0.006
Viral load (copies/ml)
10 000—99 999
p = 0.001
p = 0.0177
p = 0.0009
Hepatitis C-positive 1513 NS
HAART, highly active antiretroviral therapy; NS, not significant; N/A, not available for all screened patients.
aThe t-test was used for continuous variables and Fisher’s exact test or the Chi-square test was used for categorical variables.
Hepatitis B vaccine in HIV-1-positive adultse79
mate = 4.3, confidence limits 1.3—14.5). However, response
was seen even at CD4 counts <50 cells/mm3. Lack of
response to vaccine was most significantly associated with
high HIV viral load (Figure 2). No association was detected
with age, race, weight, tobacco use, use of HAART, or
hepatitis C co-infection.
During the course ofthe study,in the group of 214 patients
who were eligible but not offered vaccination, sixteen
(HBsAb-positive and HBcAb-positive). Four patients devel-
oped active hepatitis B. No patient that received full vaccine
series seroconverted or developed active HBV disease.
The documented reasons for not administering vaccina-
tion or completing the vaccination series were failure of the
provider to offer vaccination (85%), loss to follow-up (10%),
average time from serologic screening to administration of
the first vaccine dose was 21.1 months (range 0—155
months). Reasoning for delaying vaccination was not well
documented. If cited, the providers most commonly
expressed concern for poor immunogenicity of the vaccine
or not given at all during the study period, despite increased
CD4 count on follow-up visits.
Because HIVand HBV share common routes of transmission, it
is recommended that all HIV-positive adults be screened for
HBV. Any person who is HBsAb, HBsAg, and HBcAb-negative
should receive the three-dose HBV vaccination series,
regardless of CD4 count or HIV viral load.2,9,10Within 6
months after completion of the vaccination, the HBsAb
should be checked to verify adequate response. Those who
have HBsAb levels <10 mIU/ml should be given a second
Kellerman et al. looked at adults and adolescents infected
with HIV from 1998 to 2001.12The highest rates of HBV
disease were seen in black subjects, alcohol users, intrave-
nous drug users, and subjects with AIDS, with a prevalence of
7.6%. An earlier study by Goldstein et al. showed similar risk
factors.13Our cohort showed similar risk factors and a similar
prevalence of 6.1% of subjects with active or chronic HBV
disease at enrollment.
Larger studies in immunocompetent adults have shown
response rates to hepatitis B vaccination of 85—100%.
Decreased vaccine response has been seen due to obesity,
smoking,site ordose of vaccine,and gender.14Prior studiesof
had small numbers and reported response rates varying from
0% to 87%.5—8,15—19The association of seroconversion and CD4
count is not well defined. Some studies have shown higher
response rates associated with higher CD4 counts, but others
shown with suppressed HIV viral load in some studies.5,16
The response rate to initial vaccination in our cohort was
No vaccine recipient, regardless of antibody response,
acquired HBV during the study period. Higher CD4 counts
(p = 0.006) and undetectable HIV viral loads (p = 0.001) at
the time of first vaccine dose were significantly associated
with seroconversion to HBsAb-positive.
Vaccination against HBV in an HIV-positive population has
with clinical disease. HIV/HBV co-infection, especially in
persons with low CD4 counts, is associated with an increased
multivariate analysis included CD4 count, age, weight, use of HAART, sex, race, and presence of hepatitis C co-infection. Only the HIV
viral load was found to be an independent predictor of vaccine response.).
Logistic regression model demonstrating HIV viral load as a predictor of non-response to the hepatitis B vaccine. (Note: The
e80 C.L. Bailey et al.
risk for liver-related mortality, such as cirrhosis and hepato-
cellular carcinoma. Chronic or active HBV infection also
appears to increase the hepatotoxicity of HAART.20
Many eligible HIV-positive adults do not receive HBV
vaccination. At screening 7.5% of our patients had evidence
or documentation of prior HBV immunization. In a prior study
of 342 homosexual males, only 9% had received HBV vaccina-
tion.21There may be a number of reasons for missed vaccina-
tion including: (1) patient vaccination refusal, (2) loss to
follow-up, resulting in fewer than all three doses being
administered, (3) provider failure to screen or order the
administration of the full vaccination series, (4) patient
and/or provider failure to perceive the risk, (5) failure to
offer vaccination, due to the assumption it will have
decreased efficacy in patients with low CD4 counts, and
(6) financial barrier to vaccination, the vaccine may not be
reimbursed by the patient’s insurance company.
Ourstudy wasconductedina clinic specializing inthecare
of HIV-positive adults. All providers were trained in HIV care
or board-certified in infectious diseases. Despite 96.6% of
patients having HBV serologic screening at their initial visit,
49% of those patients eligible for vaccination completed the
three-dose series. Thirty percent of the vaccine eligible
patients did not receive a single vaccine dose. Other studies
have reported completion rates ranging from 29% to
50%.12,21—23The reason for missed vaccination opportunity
in our study was most often provider failure to offer vaccina-
tion or missed completion of all three doses. Similar to other
studies, the most commonly cited reason for delaying vacci-
nation wasconcern fordecreasedimmunogenicity inpatients
with lower CD4 counts. In our study no correlation was
identified between missed vaccination and the number of
clinic visits or patient demographics. Because vaccinations
were provided without charge to the patient, cost was not
considered a barrier in our cohort.
Current guidelines do not recommend HBV vaccination for
persons with isolated HBcAb positivity.3The significance of
HBcAb is unclear. Although it is seen in nearly all persons
exposed to hepatitis B, it does not appear protective against
infection. Furthermore, the presence of isolated HBcAb does
not distinguish between early acute infection, a chronic car-
with loss of HBsAb, or cross-reacting antibody (false-positive
test). Due to shared routes of transmission, patients are often
co-infected with HCV, and the presence of HCV may decrease
hepatitis B viral load.24—26Other studies have also shown only
0—10% of patients with isolated HBcAb have detectable HBV-
DNA.24,27,28HBV vaccination might benefit those patients who
have either lost HBsAb, and thus are at risk for reactivation or
re-infection, or those who have a false-positive HBcAb test.
increased reactivation or infection risk.
We were unable to assess the rate of false-positive HBcAb
in our cohort because none of the patients with this finding
Immunogenicity of hepatitis B vaccine in HIV-positive adults
HIV viral load
Collier et al. (1988)18
ND8 7 (87.5)
Hess et al. (1989)7
Rey et al. (2000)8
Wilson et al. (2001)6
<10 000 (9)
>10 000 (4)
Tedaldi et al. (2004)5
Gandhi et al. (2005)17
Overton et al. (2005)16
ND, not determined.
Significance of isolated hepatitis B core antibody
vaccine dose 1 (%)
Response to 3
Lok et al. (1988)30
Ural et al. (2001)29
Alhababi et al. (2003)27
Gandhi et al. (2005)17
Neau et al. (2005)24
1 (<1) (1/160)b
ND, not determined; VL, viral load.
aHBV-DNA <400 copies/ml.
bHBV viral DNA <200 copies ml.
Hepatitis B vaccine in HIV-1-positive adults e81
had a hepatitis B viral load performed. Nearly half of these
patients (41/89) were co-infected with HCV. Past studies of
HBV vaccination of HIV-positive persons with isolated HBcAb
positivity and negative HBeAb have shown amnestic response
rates of 16—50% after the first vaccine dose with up to a 63%
seroconversion after the third dose (Table 3).17,24,27,29,30
Given the significant prevalence of hepatitis B infection in
HIV-infected populations, failure to implement the vaccina-
morbidity and mortality associated with this disease. HBV
vaccination should be done in all HIV populations regardless
of CD4 count or viral load, although patients with a lower CD4
Current recommendations do not include vaccination of
persons seropositive for isolated HBcAb. Given the high rates
of hepatitis C co-infection in many HIV-infected patients,
that HBcAb may be falsely positive in persons co-infected
infection, vaccination should be considered.17,29,31Further
HBV-DNA screening for occult hepatitis B infection versus
vaccination in these populations.
Special thanks to Dr Peter Wludyka for his assistance with the
Conflict of interest: No conflict of interest to declare.
Financial support: None.
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Hepatitis B vaccine in HIV-1-positive adultse83