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High-Dose HBV Vaccination Rechallenge
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JID Jan 2008
"In conclusion, double-dose HBV revaccination in HIV-infected nonresponders produced a 50.7% additional success rate, justifying postvaccination anti-HBs screening. Future prospective studies are required to determine whether increasing the number of immunizations is as effective as double-dose revaccination in nonresponders to a standard initial vaccination schedule......To our knowledge, this is the first study describing the results of double-dose HBV rechallenge vaccination at monthly intervals in HIV-infected patients not responding to their initial vaccination. We revaccinated 144 patients who had failed to have an antibody response after standard vaccination and found a 50.7% response rate. Female sex was an independent predictor of an adequate response. This was not associated with a difference in BMI between men and women.....Our study shows that an undetectable HIV RNA load is associated with a better response only in patients >40 years old....Overton et al. [13] found that an undetectable HIV RNA load was the only predictor of successful HBV vaccination in a multivariate analysis....The optimal HBV vaccination schedule in HIV-infected individuals is still a matter of debate. Whether the results of revaccination in our study are due to the double dose or to the increasing number of monthly immunizations in initially nonresponding individuals remains to be elucidated. Studies comparing standard and double doses in primary vaccination schedules are not conclusive.....
.....In conclusion, a response to revaccination with a double dose of HBV vaccine was more likely in patients <40 years old irrespective of viral load. In patients >40 years old, a better response rate was observed in patients with an undetectable HIV RNA load than in patients with a detectable HIV RNA load. In the latter group, prediction of response decreased rapidly with age......
.....HIV and HBV have similar risk factors and routes of transmission. The prevalence of HIV/HBV coinfection among men who have sex with men is 6%-10%; compared with immunocompetent individuals, a large proportion of HIV-infected patients (40%-76% vs. <10%) fail to respond to standard-dose HBV vaccination [8-10]. Several groups have recently shown improved response rates when higher doses of HBV vaccine are used in the initial vaccination of HIV-infected patients. HBV vaccination is offered to all asymptomatic HIV-infected individuals as recommended by Dutch national guidelines. Approximately 50% of our HIV-infected cohort did not have an antibody response to the initial HBV vaccination with 3 doses of 10 μg of HBvaxPro. In an attempt to achieve a higher response rate, we prospectively revaccinated all nonresponders (anti-HBs titers of 0 IU/L) 3 times at monthly intervals with a double dose of HBV vaccine...."
BRIEF REPORT
A Prospective Open Study of the Efficacy of High-Dose Recombinant Hepatitis B Rechallenge Vaccination in HIV-Infected Patients
The Journal of Infectious Diseases Jan 2008;197:292-294
Theodora E. M. S. de Vries Sluijs,1
Bettina E. Hansen,2,3 Gerard J. J. van Doornum,4Tirza Springeling,1 Nicole M. Evertsz,1 Robert A. de Man,3 and Marchina E. van der Ende1
Departments of 1Internal Medicine, Infectious Diseases Section, 2Epidemiology and Biostatistics,3Gastroenterology and Hepatology, and 4Virology, Erasmus Medical Center, Rotterdam, The Netherlands
Presented in part: 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, 25-28 February 2007 (abstract 883).
Double-dose hepatitis B virus revaccination of human immunodeficiency virus (HIV)-infected patients proved to be effective in 50.7% of 144 patients who had previously failed to respond to standard doses. In the multivariate analysis, female patients were found to have a significantly better response (p=.03). The effect of age on the response depended on the viral load at the time of revaccination. For patients with a detectable HIV RNA load, the effect of age was stronger (odds ratio [OR], 0.34 per 10 years older [95% confidence interval {CI}, 0.16-0.72]; p=.005 ) than for patients with an undetectable HIV RNA load (OR, 0.74 per 10 years older [95% CI, 0.50-1.09];p=.12).
The infectious diseases outpatient clinic of the Erasmus Medical Center offers HBV vaccination to all HIV-positive patients who are >18 years old, have negative HBsAg and anti-HBc serological results, do not have an active opportunistic infection, are not pregnant, and have not been vaccinated previously. The initial vaccination schedule consists of 3 doses of 10 μg of HBvaxPro. Nonresponders, defined as having an anti-HBs titer of 0 IU/L, were offered revaccination. A double dose (20 μg of HBvaxPRO) was injected intramuscularly in the deltoid region at 0, 1, and 2 months, starting at a median of 5 weeks (25th-75th percentile, 3-10 weeks) after completing the initial vaccination. One month after the last double dose, a blood sample was taken for quantitative anti-HBs testing (Axsym; Abbott). Age, sex, route of exposure for HIV infection, nadir CD4+ cell count before and CD4+ cell count at the time of the initial vaccine administration, plasma HIV RNA load, and antiretroviral therapy received at the time of revaccination were recorded.
Hepatitis B virus (HBV) infection in patients infected with HIV is an increasing problem in the Western world. HIV and HBV have similar risk factors and routes of transmission. The prevalence of HIV/HBV coinfection among men who have sex with men is 6%-10% [1]. With the development of highly active antiretroviral therapy (HAART) and with better survival rates, liver disease has become a leading cause of mortality in patients with HIV infection [2]. Coinfection with HIV and HBV is associated with an 8-fold increase in mortality compared with HIV monoinfection and a 19-fold increase in mortality compared with HBV monoinfection [3]. In addition, HIV infection is associated with a reduced clearance of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen [4, 5] and a higher level of HBV replication, increasing its potential for transmission. Progression to cirrhosis and flare-ups of hepatitis occur more often [6,7].
Prevention of HBV infection is of great importance for HIV-infected patients. However, compared with immunocompetent individuals, a large proportion of HIV-infected patients (40%-76% vs. <10%) fail to respond to standard-dose HBV vaccination [8-10]. Several groups have recently shown improved response rates when higher doses of HBV vaccine are used in the initial vaccination of HIV-infected patients. [9, 11, 12].
HBV vaccination is offered to all asymptomatic HIV-infected individuals as recommended by Dutch national guidelines. Approximately 50% of our HIV-infected cohort did not have an antibody response to the initial HBV vaccination with 3 doses of 10 μg of HBvaxPro. In an attempt to achieve a higher response rate, we prospectively revaccinated all nonresponders (anti-HBs titers of 0 IU/L) 3 times at monthly intervals with a double dose of HBV vaccine.
Methods
The infectious diseases outpatient clinic of the Erasmus Medical Center offers HBV vaccination to all HIV-positive patients who are >18 years old, have negative HBsAg and anti-HBc serological results, do not have an active opportunistic infection, are not pregnant, and have not been vaccinated previously. The initial vaccination schedule consists of 3 doses of 10 μg of HBvaxPro. Nonresponders, defined as having an anti-HBs titer of 0 IU/L, were offered revaccination. A double dose (20 μg of HBvaxPRO) was injected intramuscularly in the deltoid region at 0, 1, and 2 months, starting at a median of 5 weeks (25th-75th percentile, 3-10 weeks) after completing the initial vaccination. One month after the last double dose, a blood sample was taken for quantitative anti-HBs testing (Axsym; Abbott). Age, sex, route of exposure for HIV infection, nadir CD4+ cell count before and CD4+ cell count at the time of the initial vaccine administration, plasma HIV RNA load, and antiretroviral therapy received at the time of revaccination were recorded.
HIV RNA was quantitated using the Cobas Amplicor (Roche Molecular Systems). The detection limit was 50 copies/mL.
Univariate and multivariate logistic regression analysis were used to determine factors that predicted success for HBV revaccination. The data analysis was performed using SPSS for Windows (release 11.0.1; SPSS).
In the multivariate logistic regression analysis, age, sex, risk group, body mass index (BMI), CD4+ cell count at the start of the initial vaccination schedule (<200, 200-500, >500 cells/mm3), HAART (yes/no), and HIV RNA load (detectable/undetectable), at the time of revaccination were included. The Medical Ethics Committee of the Erasmus Medical Center approved the study.
Results
One hundred forty-four HIV-infected patients who had an anti-HBs titer of 0 IU/L after their initial HBV vaccination schedule were offered revaccination. The study population consisted of 108 males (75%) with a mean age of 43.4 years (SD, 11.5 years). The mean BMI was 25.3 (SD, 4.6). HIV risk factors were male homosexual activity for 64 individuals (44.4%), heterosexual contacts for 72 individuals (50.0%), and miscellaneous for 8 patients (5.6%). At revaccination, 96 patients (66.7%) were receiving HAART, and 89 patients (61.8%) had an HIV RNA load <50 copies/mL. The median nadir CD4+ cell count was 205 cells/mm3 (25th-75th percentile, 90-330 cells/mm3). The median CD4+ cell count at the initial vaccination schedule was 360 cells/mm3 (25th-75th percentile, 240-540 cells/mm3); the distribution by CD4+ cell count category of <200, 200-500, and 500 cells/mm3 was, respectively, 26 (18.1%), 73 (50.7%), and 45 (31.3%). The CD4+ cell count at the time of revaccination was known in 100 of 144 patients. They were similar to those at the time of the primary vaccination (340 cells/mm3; 25th-75th percentile, 250-510 cells/mm3). No side effects were reported during revaccination. Seventy-three of 144 patients developed anti-HBs titers of >10 IU/L, giving a response rate of 50.7%. The median and mean time between when the anti-HBs titer was determined in the initial schedule and the first vaccine dose in the revaccinating schedule was, respectively, 5 and 8 weeks (25th-75th percentile, 3-10 weeks). The median anti-HBs titer of the responder group was 107.9 IU/L (25th-75th percentile, 43.7-426 IU/L).
Univariate analysis showed that only female sex (odds ratio [OR], 2.8 female/male [95% confidence interval {CI}, 1.3-6.3]; p=.009 ) and younger age (OR, 0.63 per 10 years older [95% CI, 0.46-0.86]; p=.002 ) were predictors of a successful response (figure 1). Changes in HIV RNA load or CD4+ cell count between the initial and rechallenge vaccination schedule were not found to have an influence on outcome. However, we cannot exclude an effect of changes in HIV RNA load or CD4+ cell count, given the limited numbers of patients available in this study.
In the multivariate analysis, female patients were found to have a significant better response (p=.03), whereas the effect of age depended on the viral load at the time of revaccination (i.e., viral load is an effect modifier; p=.05). For patients with a detectable HIV RNA load (not receiving HAART), the effect of age was stronger (OR, 0.34 per 10 years older [95% CI, 0.16-0.72]; p=.005) than it was for patients with an undetectable HIV RNA load, all of whom were receiving HAART except for 2 HIV-2-infected patients (OR, 0.74 per 10 years older [95% CI, 0.50-1.00]; p=.12 ) (figure 2). In conclusion, a response to revaccination with a double dose of HBV vaccine was more likely in patients <40 years old irrespective of viral load (figure 2). In patients >40 years old, a better response rate was observed in patients with an undetectable HIV RNA load than in patients with a detectable HIV RNA load. In the latter group, prediction of response decreased rapidly with age.
Discussion
To our knowledge, this is the first study describing the results of double-dose HBV rechallenge vaccination at monthly intervals in HIV-infected patients not responding to their initial vaccination. We revaccinated 144 patients who had failed to have an antibody response after standard vaccination and found a 50.7% response rate. Female sex was an independent predictor of an adequate response. This was not associated with a difference in BMI between men and women.
Our study shows that an undetectable HIV RNA load is associated with a better response only in patients 40 years old. In patients <40 years of age, the chance of a response is high, irrespective of HIV RNA load. One possible explanation for this is a shorter duration of HIV infection and a limited depletion of specific memory T cells in the younger age group. The effect of undetectable HIV RNA load on response in the older age group probably reflects long use of HAART and partial recovery of the immune system.
Overton et al. [13] found that an undetectable HIV RNA load was the only predictor of successful HBV vaccination in a multivariate analysis. Because the outcome of their study group concerned the results of initial vaccination, this may not be in conflict with our results concerning revaccination of nonresponders after initial vaccination. These patients probably are an immunological disadvantaged group.
The optimal HBV vaccination schedule in HIV-infected individuals is still a matter of debate. Whether the results of revaccination in our study are due to the double dose or to the increasing number of monthly immunizations in initially nonresponding individuals remains to be elucidated. Studies comparing standard and double doses in primary vaccination schedules are not conclusive. Cornejo-Juarez et al. [10] compared 10 and 40 μg of HBV vaccine as the initial vaccination scheme in HIV-infected patients and found no significant difference. Fonseca et al. [11] enrolled HIV-infected patients in a primary-vaccination serial study using a standard-dose and a double-dose group. The double dose improved seroconversion only in those with CD4+cell counts >350 cells/mm 3 and low HIV viremia (p=.008). In patients with predialysis chronic renal failure, McNulty et al. [14] compared 20- and 40-μg doses as the initial vaccination scheme and found 10% more seroconversions in the higher-dose group, but this difference was not statistically significant. A fourth dose increased the seroconversion rate in 4 of 31 nonresponders. The conflicting results may be due to the small numbers of included individuals and to different patient populations. According to Rey et al. [15], rechallenging of nonresponders to standard primary vaccination with HBV vaccination given at monthly intervals is very effective. In his study, 8 of 9 revaccinated patients responded. Given that the response rate of the initial standard-dose vaccination schedule at our institution is 50% and that revaccinating contributed another 50%, we achieved an overall response rate of 75% among our HIV-infected patients.
In conclusion, double-dose HBV revaccination in HIV-infected nonresponders produced a 50.7% additional success rate, justifying postvaccination anti-HBs screening. Future prospective studies are required to determine whether increasing the number of immunizations is as effective as double-dose revaccination in nonresponders to a standard initial vaccination schedule.
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