Co-infection with HIV and hepatitis B virus (HBV) is common; in the Western world, chronic HBV infection has been found in 6% to 14% among HIV-positive patients.1,2 Chronic co-infection with HBV and HIV can lead to increased rates of liver-related morbidity (cirrhosis, hepatocellular carcinoma) and mortality.3,4 Prevention of HBV infection is therefore essentially important in the setting of HIV-infection. The success rate of HBV vaccine, however, is much lower in HIV-infected patients as compared with healthy immunocompetent individuals. 90% to 95% of healthy adult individuals develop protective anti-HBV antibody, whereas only 20% to 70% of the HIV-infected patients develop protective anti-HBV antibody after a conventional standard dose of HBV vaccination at 0-1-6 monthly intervals.5 Contributing factors associated with nonresponsiveness to HBV vaccination in HIV-infected patients include ongoing HIV-viremia, impaired humoral and cellular immunity, HCV co-infection, and increasing age.6-10 The most effective strategy for maximizing HBV-vaccine response in HIV-infected patients remains unknown. Administering doubled HBV vaccine dose, i.e., from 20 to 40 µg, has been tried in several studies with improved overall success rates of 36.6% to 89.5%.11-15 In our experience, double-dose HBV rescue vaccination (40 µg HBV vaccination at 0-1-2 monthly intervals) achieved more than 80% seroconversion rates in HIV-infected patients who had failed to respond with conventional standard dose HBV vaccination (20 µg HBV vaccination at 0-1-6 monthly intervals with or without additional 20 µg HBV booster vaccination).16 Also, it is important to point out that HIV co-infection decreases hepatitis B surface antibody (anti-HBs) persistence in naturally infected and conventionally vaccinated individuals.17,18 Few data exist to assess the persistence of protective anti-HBs titers after successful double-dose HBV rescue vaccination in the setting of HIV-infection. We reviewed anti-HBs titers a year later in HIV-infected patients who had responded to double-dose HBV rescue vaccination.

A retrospective medical-chart review study was conducted in our center. HIV-infected patients who had failed to develop protective anti-HBs after three or more standard conventional dose HBV vaccine (20 µg HBV vaccination at 0-1-6 monthly intervals with or without additional 20 µg HBV booster vaccination) were identified and were given double-dose HBV rescue vaccination, (40 µg -20 µg/mL in each deltoid-) (Recombivax HB® (Merck & Co., Inc., Whitehouse Station, NJ, USA) at 0-1-2 monthly intervals. The vaccination schedule was based on a previous study, in which 0-1-2 monthly intervals of standard dose recombinant HBV vaccination resulted in a faster and also identical seroconversion rate to the standard dose recombinant HBV vaccination at 0-1-6 monthly intervals.19 Patients who developed protective anti-HBs titers of ≥10 mIU/mL after double-dose HBV rescue vaccination were classified as double-dose HBV rescue vaccination responders. These patients had anti-HBs titers assessment 12 months later.

Demographic characteristics, presence of hepatitis C virus (HCV) antibody, CD4 T-cell count, HIV RNA viral load, and use of highly active antiretroviral therapy (HAART) were reviewed at baseline -the time of first double-dose HBV rescue vaccination (at 0 month out of 0-1-2 monthly interval), and at one year follow-up, 12 months after completion of the double-dose HBV rescue vaccination series. Patients who retained anti-HBs titers of ≥10 mIU/mL at one year follow-up were classified as persistent responders (PR) while patients with decreased anti-HBs titers of <10 mIU/mL were defined as nonpersisent responders (NPR).

Statistical analysis was performed using SPSS version 15.0 for Windows (SPSS Inc., Chicago, IL, USA). Dichotomous variables were compared using Pearson χ² test or Fisher's exact test. For continuous variables, Mann-Whitney test was used. Multivariate analysis by logistic regression was used to determine factors associated with successful PR. Odds ratio (OR) and 95% confidence interval (CI) were calculated. A p-value less than 0.05 was considered to be statistically significant.

This study was approved by Institutional Review Board at St. Luke's-Roosevelt Medical Center, New York, NY, USA.

The medical records of HIV-infected patients followed in our center between January 2004 and October 2010 were reviewed. Fifty-four patients received three double-dose HBV rescue vaccine at 0-1-2 monthly intervals after failure to develop protective anti-HBs with three or more conventional standard dose HBV vaccinations. The study population consisted of 41 males (75.9%) with a median age of 45 years. Hispanics and Blacks were the predominant ethnic groups (31/54, 57.4% and 15/54, 27.8%, respectively). Homosexual men (men who have sex with men, MSM) were the major HIV-risk group, 30/54 of patients, 55.6%. Nine patients (9/54, 16.7%) had chronic HCV infection. At the start of the double-dose HBV rescue vaccination series, 49 patients (49/54, 90.7%) were on HAART. The median CD4 T-cell count was 433 cell/mm³ (interquartile range [IQR], 328 to 645 cell/mm³) and 20 patients (20/54, 35.7%) had CD4 T-cell count >500 cell/mm³. The median Log₁₀ HIV viral load was 1.699 (IQR, 1.699 to 2.358) and 30 patients (30/54, 53.6%) had HIV viral load <50 copies/mL. Forty-four patients (44/54, 81.5%) developed protective anti-HBs after completion of three double-dose HBV vaccination series (double-dose HBV rescue vaccine responders). The baseline characteristics of patients at the start of double-dose HBV rescue vaccination are shown in Table 1.

Thirty-three of 44 double-dose HBV rescue vaccine responders had follow-up evaluation at one year after the last vaccine dose. Nineteen of the 33 double-dose HBV rescue vaccine responders (19/33, 57.6%) were found to have persistent levels of protective anti-HBs ≥10 mIU/mL and they were classified as PR. Fourteen patients (14/33, 42.4%) lost their protective anti-HBs at one year follow-up were defined as NPR. These are shown in Fig. 1. We compared the PR and NPR groups and there was no significant difference in terms of median CD4 T-cell count at baseline or at follow-up. Also the proportions of patients who had CD4 T-cell count >500 cell/mm³ both at baseline and one year follow-up were not different; 4/19, 21.1% in PR group and 3/14, 21.4% in NPR group (p=1.000). Although there was no significant difference in terms of median Log₁₀ HIV viral load at baseline and follow-up between the two groups, the proportion of patients who had undetectable HIV viral load <50 copies/mL both at baseline and one year follow-up was significantly higher in PR group (11/19, 57.9%) than in NPR group (3/14, 21.4%) (p=0.036). The median of total number of overall HBV vaccinations including conventional standard dose HBV vaccine and double-dose HBV rescue vaccine was 6.0 (IQR, 6.0 to 7.0) for PR group and 6.0 (IQR, 6.0 to 6.3) for NPR group without significant difference (p=0.360) as shown in the Table 2.

A multivariate logistic regression analysis was performed using the variables of sex, HIV risk factors, presence of HCV antibody, receipt of HAART, CD4 T-cell count, and HIV viral load. Successful HIV viral load suppression defined by undetectable HIV viral load <50 copies/mL both at baseline and follow-up (OR, 12.973; 95% CI, 1.189 to 141.515; p=0.036) was found to be associated with PR among HIV-infected double-dose HBV vaccine recipients as shown in Table 3.

Our study showed an impressive response rate, 81.5%, of double-dose HBV rescue vaccination series in HIV-infected patients who had prior not responded to conventional HBV vaccination. However, levels of protective anti-HBs titer decreased over a year. 57.6% of double-dose HBV rescue vaccine responders were noted to have persistence of protective anti-HBs titer at one-year follow-up. Our findings are consistent with a previous study in which a high serologic response rate with double-dose HBV vaccination was observed, however, 63% of the responders had persistence of protective anti-HBs titer at 12 months.14 Also results of our study correspond with the results of earlier study by Cooper et al.,15 in which 89.5% of HIV-infected patients who received double-dose HBV vaccination developed protective anti-HBs titer, and persistence of seroprotective anti-HBs titer was 60% at 24 months of follow-up. Of note, Cooper et al.15 observed improved durability of the protective anti-HBs titers with the adjuvant CPG 7909 (>80% of patients at 42 to 60 months) compared to those generated by double-dose HBV vaccination without the adjuvant.

We observed that persistence of protective anti-HBs titers in HIV-infected patients at 1 year after double-dose HBV rescue vaccination was associated with HIV viral load suppression. Furthermore our logistic regression analysis supports the role of HIV suppression as an important predictor of persistent anti-HBs titers. Previous studies have also demonstrated that development of anti-HBs responses following HBV vaccination of HIV-infected patients was associated with undetectable HIV viral load.6,20 Lower hepatitis B-specific memory B-cell responses, altered B-cell and memory B-cell phenotypes, and reduced memory B-cell proliferative capacity were observed in HIV viremic patients following HBV vaccination.21 Increased regulatory T cells in HIV-infected patients were found to be associated with nonresponse to HBV vaccine.22 In addition, an expansion of regulatory T cells has been reported in HIV-infected patients with high HIV viral load.23 Our results in conjuncture with aforementioned literature further support the notion that maintaining optimal HIV load suppression after double-dose HBV rescue vaccination may play a critical role in persistence of protective anti-HBs titers.

The long-term protective effect of HBV vaccine in HIV-infected patients remains unknown. A recent multicenter observational cohort study of 11,632 person-years of follow-up demonstrated that HIV-infected patients who had achieved a response to HBV vaccine with protective anti-HBs titers ≥10 mIU/mL had a 50% reduced risk of HBV infection compared to those with nonresponse to HBV vaccine. Of the patients with an initial positive HBV vaccine response, risk of HBV infection was not different between those with waning or persistent vaccine responses. It is also interesting that of those vaccine responders who had developed acute HBV infection, none of them developed chronic HBV infection, suggesting benefit from positive response from HBV vaccination for at least 7 years of follow-up.24 Also long-term memory B cells specific for hepatitis B surface antigen were found in HIV-infected patients with serum anti-HBs titer less than 10 mIU/mL.25 Therefore, there could be still some benefit for protection against HBV infection even if protective levels of anti-HBs titers may decrease after successful response to double-dose HBV rescue vaccination in HIV-infected patients.

Our study has limitations, however, mostly stemming from its small sample size and its retrospective nature. Eleven of 44 double-dose HBV rescue vaccine responders were not available for one year follow-up evaluation, which might have affected assessment of the durability of persistent protective anti-HBs titers in double-dose HBV rescue vaccine responders. Although factors such as the level of CD4 T-cell count,26 HAART,27 and MSM28 were shown to be associated with HBV vaccine response in HIV-infected patients, our study did not show significant association between these factors and persistence of protective anti-HBs titers. This might reflect one of limitations based on the small sample size due to retrospective nature, not true absence of association. Nonetheless, our cohort of patients might well represent urban HIV-infected patients with access to HIV care in the developed world such as the United States. Therefore, this study results should be of assistance to manage HBV vaccination in urban HIV-infected patients in the developed world.

In conclusion, double-dose HBV rescue vaccination in HIV-infected patients has demonstrated a higher seroconversion rate of protective anti-HBs titers. Protective levels of anti-HBs titers may decrease over time after successful double-dose HBV rescue vaccination. Optimizing HIV viral load suppression could improve the persistence of protective anti-HBs titers. Achieving protective levels of anti-HBs titers in HIV-infected patients, even if protective levels of anti-HBs titers are decreased, might conceivably provide important protection against chronic HBV infection, and double-dose HBV rescue vaccination should be considered in HIV-infected patients who never responded to conventional or booster HBV vaccination series. Further studies involving a larger number of patients are needed to define the best strategies for improving immune response to HBV vaccination in HIV-infected patients.