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Serologic Response to Hepatitis B Vaccination in HIV-Infected Patients with Isolated Positivity for Antibodies to Hepatitis B Core Antigen

  1. Catherine Chakvetadze1,
  2. Firouzé Bani-Sadr1,
  3. Catherine Le Pendeven2,
  4. François-Xavier Lescure1,
  5. Camille Fontaine1,
  6. Tatiana Galperine1,
  7. Laurence Slama1,
  8. Philippe Bonnard1,
  9. Philippe Mariot1,
  10. Patrick Soussan2, and
  11. Gilles Pialoux1
  1. 1Service des Maladies Infectieuses, Hôpital Tenon, Paris, France
  2. 2Laboratoire de Virologie, Hôpital Tenon, Paris, France
  1. Reprints or correspondence: Dr Firouzé Bani-Sadr, Service des Maladies Infectieuses et Tropicales, Hôpital Tenon, 4 rue de la Chine, 75 970 Paris Cedex 20, France (firouze.bani-sadr{at}tnn.ap-hop-paris.fr).
 
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Abstract

We assessed the safety and immunogenicity of hepatitis B vaccination among 40 human immunodeficiency virus-infected patients with isolated positivity for antibodies to hepatitis B core antigen. No baseline factors were found to be predictive of an anamnestic response, which occurred in 32.5% of the patients. The overall response rate among patients without an anamnestic response was 74.0% after 3–6 vaccine doses.

Isolated positivity for antibodies to hepatitis B core antigen (anti-HBc) is more frequent in patients with human immunodeficiency virus (HIV) infection and/or hepatitis C virus (HCV) infection than in the general population, with a generally reported prevalence between 20% and 40% [1–3]. The significance of isolated anti-HBc immunoglobulin G (IgG) is unclear: it may represent (1) a “window” phase that follows acute hepatitis B virus (HBV) infection, during which hepatitis B surface antigen (HBsAg) has disappeared from the bloodstream but antibody to HBsAg (anti-HBs) has not yet emerged; (2) resolved HBV infection with loss of anti-HBs antibodies; (3) occult chronic HBV infection with undetectable HBsAg; or (4) a false-positive test result [4, 5]. Whether individuals who test positive for isolated anti-HBc antibodies should be vaccinated against hepatitis B is uncertain. The European guidelines for the treatment of chronic hepatitis B and C in HIV-coinfected patients recommend hepatitis B vaccination for HIV-infected patients with isolated anti-HBc antibodies [6, 7]. However, few data on the response to hepatitis B vaccination or on the optimal vaccine schedule for this population are available [4]. Here, we evaluated the anti-HBs response to a first dose of hepatitis B vaccine among a cohort of HIV-infected patients with isolated anti-HBc antibodies as well as the response to 2–5 additional vaccine doses among those who did not respond to the initial dose. Baseline factors predictive of nonseroconversion were sought.

Methods. Patients with HIV type 1 (HIV-1) infection, no history of hepatitis B vaccination, and isolated anti-HBc positivity (negative for both HBsAg and anti-HBs antibodies) who attended our institution (Hôpital Tenon, Paris, France) were invited to receive hepatitis B vaccination. The study was approved by the Saint-Germain en Laye hospital ethics committee, and all subjects provided written informed consent.

Eligibility criteria included a CD4 T cell count of >200 cells/μL, an HIV-1 RNA level of <200 copies/mL, an HBV DNA level of <200 copies/mL (Cobas Amplicor HBV Monitor assay; Roche), and stable antiretroviral treatment during the previous 3 months. Exclusion criteria included pregnancy, cancer, asplenism, systemic steroid therapy, decompensated cirrhosis, hypersensitivity to any vaccine component, and a personal or familial history of multiple sclerosis.

Baseline tests included an assay for the presence of HBsAg as well as qualitative and quantitative assays of anti-HBs IgG, anti-HBc IgG, IgG against hepatitis B e antigen (anti-HBe) (Abbott Laboratories), and HBV DNA. The patients first received 1 intramuscular (deltoid) injection of 20 μg of hepatitis B vaccine (Engerix; SmithKline Beecham Biologicals). The anti-HBs titer was measured 2 weeks later; a value of ⩾10 IU/L was considered to be seroprotective. Initial nonresponders (those with an anti- HBs titer of <10 IU/L) to the first dose were given 2 additional doses 1 month apart, at weeks 4 and 8. Nonresponders to the first 3 doses (those with an anti-HBs titer of <10 IU/L at week 10) were then given 3 additional doses 1 month apart (weeks 12, 16, and 20). Anti-HBs titers were measured at weeks 10, 24, and 48. The response to vaccination was evaluated at week 10 so that in nonresponders it was possible to start the second series of vaccinations at week 12 (a similar seroconversion rate 2 weeks and 1 month after vaccine inoculation has been demonstrated [8, 9]). CD4 cell counts, HIV loads, and blood parameters were determined before (⩽1 month) the first vaccine injection and every 3 months thereafter.

The primary end point for immunogenicity was the frequency of seroconversion at week 2 (anamnestic responses), the frequency of seroconversion after 3 vaccine doses (week 10), and the frequency of seroconversion after 6 vaccine doses (week 24). The secondary end point was the durability of the anti-HBs titer (week 48).

The x2 test or the Fisher exact test was used to analyze qualitative variables, and the Mann-Whitney U test was used for quantitative variables. Logistic regression models were used to identify associations between vaccination success after the first 3 or 6 doses (outcome variable) and baseline characteristics (input variables). Characteristics with P < .05 in the univariate analysis were included in multivariate models on the basis of a backward-elimination procedure. All statistical tests were 2-sided, with a type I error of 5%.

Results. Baseline clinical and biological characteristics of the 40 vaccine recipients are summarized in Table 1. Most patients were of African origin (80%). Five patients (12.5%) had HCV coinfection. Ongoing antiretroviral therapy was active against HBV (lamivudine, tenofovir, and/or emricitabine) in 35 patients (87.5%). Nineteen patients (47.5%) were positive for anti-HBe antibodies.

Table 1.
View larger version:
Table 1.

Characteristics of the Study Population (n = 40)

An anamnestic response (anti-HBs titer, 110 IU/L) occurred in 13 patients (32.5%), whose median anti-HBs titer was 55 IU/L (interquartile range [IQR], 15–400 IU/L) (Table 2). No factors predictive of an anamnestic response were found in univariate analysis; these included dual anti-HBc and anti- HBe positivity (7 patients) and anti-HBc positivity with anti-HBe negativity (6 patients). One year after receiving a single vaccine dose, 7 (58.3%) of the 12 patients whose anti-HBs titers could be measured had values 110 IU/L (median, 43 IU/ L; IQR, 18–400 IU/L).

Table 2.
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Table 2.

Titers of Antibodies against Hepatitis B Surface Antigen (Anti-HBs), by Number of Hepatitis B Vaccine (Engerix) Doses Received

The remaining 27 patients received 2 or more additional vaccine doses. Seroconversion occurred after 3 doses in 11 (40.7%) of the 27 patients. The median anti-HBs titer was 56 IU/L (IQR, 22–280 IU/L). Fourteen of the 16 nonresponders to 3 vaccine doses received 3 additional doses, and 9 (64.3%) of them seroconverted. The median anti-HBs titer was 190 IU/ L (IQR, 19–400 IU/L) among these 9 patients (Table 2).

In total, 20 (74.0%) of 27 patients receiving 3–6 doses of hepatitis B vaccine became positive for anti-HBs antibodies. Of the 20 patients with protective antibody titers at week 24, 19 had available week 48 values, and anti-HBs titers persisted in 14 patients (73.7%) (median, 61 IU/L; IQR, 21–400 IU/L).

In 7 nonresponders, HBV DNA was measured again using a more sensitive test (Abbott RealTime HBV assay; detection limit, <15 IU/mL). HBV DNA was detectable (57 IU/mL) in only 1 patient.

Both the 6-dose and the 3-dose schedules were well tolerated. No statistically significant changes in the CD4 T cell count or plasma HIV-1 RNA level were reported during the 24-week follow-up period.

In univariate analysis comparing the 20 responders to the 3 or 6 vaccine doses with the 7 nonresponders, responses tended to be associated with lower age (mean ± standard deviation, 38.5±6.8 vs 44.0±6.3 years; P = .07) and nonsmoker status (10.0% vs 42.9%; P = .091). Only alcohol consumption was associated with a lack of seroconversion (20.0% vs 71.4%; P = .023).

Failure to seroconvert was not associated with sex, body mass index, ethnicity, AIDS status, baseline or nadir CD4 cell count, mean duration of antiretroviral treatment, ongoing antiretroviral treatment with activity against HBV, HCV coinfection, liver stiffness of >7.1 kPa, or anti-HBe positivity.

Discussion. This is the first study, to our knowledge, of hepatitis B vaccination of HIV-infected patients with isolated anti-HBc antibodies in which nonresponders to 3 vaccine doses received an additional 3 doses. All patients had been extensively exposed to highly active antiretroviral therapy regimens that are active against HBV and had relatively high CD4 cell counts (median, 463 cells/μL; IQR, 220–840 cells/μL). An anamnestic response to hepatitis B vaccination was observed in 32.5% of patients, a proportion similar to that observed among HIV-negative individuals with isolated anti-HBc antibodies and in another study of HIV-positive patients with isolated anti-HBc antibodies (24%) [4, 10, 11]. No baseline factors, including anti-HBe positivity, were predictive of an anamnestic response in our population. In contrast, Gandhi et al [4] observed an anamnestic response in 7% of HIV-infected patients with isolated anti-HBc antibodies (no anti-HBe) and in 43% of patients with both anti-HBc and anti-HBe antibodies. The overall response rate among patients without an anamnestic response was 40.7% after 3 vaccine doses, and another 33.3% responded after 6 vaccine doses. This rate is considerably lower than that observed elsewhere among immunocompetent recipients without markers of HBV exposure, >90% of whom generally seroconvert after the third vaccine dose. HIV infection undermines the response to hepatitis B vaccination, with reported failure rates of 44%–77% after the standard schedule. In HIV-infected adults, high-dose (40 μg/mL) and short-interval (1 month) hepatitis B vaccination was associated with a response rate of 60.0% after the first 3 doses and 89.2% after 1–3 additional doses [12]. In another study, the response rate was 55% after three 20-μg doses and 90% after 6 doses [9]. Thus, in our study the overall response rate after 6 doses was lower than that observed in HIV-infected patients negative for HBsAg, anti- HBs, and anti-HBc antibodies, but it is in line with the rate reported, regardless of HIV serostatus, in patients with isolated anti-HBc antibodies [4, 13]. Age, tobacco smoking, and alcohol consumption have been shown to affect the response to hepatitis B vaccination in immunocompetent recipients as well as to hepatitis A vaccination in HIV-infected patients [14–16]. In our study, alcohol consumption was the only factor associated with a poor hepatitis B vaccine response, although the study population was too small to detect weak effects of other baseline characteristics.

Despite our patients' good immunovirological status, anti-HBs antibodies were short lived; only 58.3% of patients with an anamnestic response and 73.6% of patients with a primary response had protective titers 1 year later. The median anti-HBs titers 1 year later were not significantly different between patients with an anamnestic response and patients with a primary response (P = .76). Other studies have also shown less durable responses to hepatitis B and A vaccination in HIVinfected patients [12, 16, 17].

Because an anamnestic response to hepatitis B vaccination is unpredictable in HIV-infected patients with isolated anti-HBc antibodies, we recommend measuring the anti-HBV titer after the first vaccine dose. If no anamnestic response occurs, a full vaccination schedule should be given (up to 6 doses, if necessary). To be adopted, this approach should be validated in a larger cohort. Other strategies, such as administration of a high dose of hepatitis B vaccine or vaccine adjuvants, should also be explored [18].

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Acknowledgments

Potential conflicts of interest. All authors: no conflicts.

  • Received September 17, 2009.
  • Accepted December 17, 2009.
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  1. Clin Infect Dis. (2010) 50 (8): 1184-1186. doi: 10.1086/651422
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