Clinical Article

Double dose Hepatitis B vaccination in HIV positive patients

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Abstract

Due to the high rate of failure of the Hepatitis B vaccine in HIV positive patients, we undertook a prospective study using double the standard vaccine dose. The series was administered at 0,1,2 month in order to increase compliance and rapidity of developing antibodies.

Of 114 patients 62% developed Hepatitis B surface antibodies (HBsAb). Viral loads <1,000 copies/ml and CD4 counts >350 cells/mm3 were associated with HBsAb production. Shortening the vaccine series did not yield greater compliance or antibody response. 77% of HIV positive patient who developed antibodies had persistence of the HBsAb 21 months later.

Introduction

Prevention of hepatitis B infection in HIV patients is of great importance due to the high mortality rate associated with HIV-Hepatitis B co- infection compared with HIV mono-infection (8 fold increase). 1  In addition, HIV infection is associated with decreased clearance of hepatitis b surface antigen and increased viral replication. This can lead to progressive liver disease. 2

Due to the high rate of failure to develop immunity to the standard dose of hepatitis B series in HIV positive patients, we undertook a prospective study using double the standard vaccine dose (the same vaccine that is administered to dialysis patients) and vaccinated study subjects at 0, 1, 2 months (usual interval is 0, 1, 6 months) to increase the rapidity of developing protective antibody, and completing the vaccination series. 3 , 4

 

Method

From 2006 to 2010, HIV positive patients with negative hepatitis B surface antigen, hepatitis B core antibody, and hepatitis B surface antibody (HBsAb) were invited to participate in this study. Over 90% of those offered joined the study and signed an informed consent. Participants were offered high dose short course hepatitis B vaccination (Engerix-B, GlaxoSmithKline, two doses of the 20 micrograms/1 ml Suspension for injection, Hepatitis B recombinant vaccine). The patients were followed prospectively until the end of the study period. Vaccination was at 0, 1, 2 months. HBsAb was measured at 1 and 6 month post vaccination. HBsAb was considered present when values were greater or equal to 10 mIU/ml. Consent was obtained. The study was approved by the St. Barnabas Hospital IRB. SPSS was used for statistical analysis.

Results

Vaccine response:

During the study period from 2006 to 2009, 149 HIV positive patients were enrolled and 114 (76%) completed the study. 71 patients (62%) developed HBsAb. Patient characteristics and medical conditions were similar in responders and non responders (see table 1).

Table 1
Table 1

Although the study was designed for the participants to receive the full series of the hepatitis B vaccine in 60 days, some patients came late for their vaccine and many patients had to be recalled: 21% of participants completed their vaccines by 60 days, 65% by 90 days, and 78% by 120 days.   The average length of time between the first vaccine and the third vaccine was 94 days in the group that did not develop post vaccination antibodies, and 103 days in the responders. The difference was not statistically significant.

For similar reasons, testing for post vaccination HBsAb did not always occur at 30 days. The time between the last vaccination and HBsAb testing was 114 days for the patients who did not develop antibodies and 74 days for the responders. This difference was significant (p=0.008, 95% CI 12.4, 80.7).

In order to determine how long the HbsAb response persisted, we followed the HBsAg response in the 71 patients that developed HbsAb until the end of the study in 2010. This was possible at our HIV center, as all patients get yearly HBsAb testing. Fifty five patients (77%) had repeat HBsAb testing. The average follow up time was 21 months. Thirty nine patients (71%) remained HbsAb positive.

Immune Status:

Immune status, measured by CD4 count and viral load, influenced the ability to develop HbsAb. Patients with a viral load <1,000 copies/ml responded better to the vaccine than those with viral loads >1,000 copies/ml (p=0.01), as did patients with CD4 counts >350 cells/mm3 (p=0.019). Nadir CD4, percent CD4, or taking HIV medications did not correlate with vaccine response.

Prior hepatitis B vaccination:

Forty six patients (31%) received at least 3 doses of the standard hepatitis B vaccine prior to enrollment into this study. These patients did not develop antibodies and therefore were eligible for this study. After receiving the high dose short course hepatitis B vaccines, 61% developed antibodies. Although the mean CD4 count was higher at the time of the double dose vaccine compared to when they received the standard vaccine (460 vs 340 cells/mm3), the difference was not significant. On the other hand, the number of patients with viral loads below 1,000 at the time of the standard vaccine (13 patients) compared to when they received the double dose (34 patients) was statistically significant (p=0.0001).

 

Discussion

Historically the development of HBsAb to the standard hepatitis B vaccine in HIV positive patients varied between 35-72%. 5 , 6 , 7 , 8 A prior retrospective study at this institution showed that 31% of HIV positive patients developed HBsAb to the standard vaccine. 9 Double dose hepatitis B vaccine has been used to increase the immunogenicity of the vaccine in populations who respond poorly to the vaccine, like dialysis patients. In studies in HIV positive patients, double dose vaccine elicited an antibody response in 47-82% of patients. 10 , 11 , 12 , 13

In this prospective study, 62% of our HIV patients developed protective immunity to hepatitis B using the double dose vaccine. At 21 months, 71% remained HbsAb positive. Of note, the time between completing the hepatitis B vaccine series and the time to HBsAb measurement was much shorter in the patients who developed antibodies, suggesting that perhaps some patients would have had a positive HBsAb if tested earlier. It remains unclear if patients with a transient increase in HBsAb achieve protection against the Hepatitis B infection.

The response was significantly higher in patients with CD4 counts >350 cells/mm3 or viral loads < 1,000 copies/ml. Rey et al, 14  compared the standard Hepatitis B vaccine stratified by CD4 counts. In his study, 33.3% of patient with CD4 counts between 200 and 500 developed antibodies compared to 87.5% in patients with CD4 counts above 500. Our study using double the standard dose achieved higher rates of HBsAb: 42.9% in patients with CD4 below 200, 63.3% with CD4 200 to 500, and 72.7% in patients with CD4 counts greater than 500 cells/mm3. Although the double dose vaccine does not achieve the same protection as in healthy adults, it does protect more patients against hepatitis B than the regular vaccine even at lower CD4 counts. Other variables that have previously been shown to improve vaccine response (gender, BMI, cigarette use) were not associated with higher response to vaccination in this study.

In the subgroup of patients who were previous non responders to the standard hepatitis B vaccine, 61% developed antibodies. Comparing CD4 and viral loads at the time of previous vaccination and during this study, showed that the only statistically difference between the two groups was improvement of the viral load to less than 1,000 copies/ml.

Another aim of this study was to administer the third dose of the vaccine one month after the second dose instead of the standard six months interval in the hope of increasing compliance and obtaining earlier protection against hepatitis B. Only 21% of patients completed the series by 60 days, and 65% by 90 days. The length of time between the first vaccine and the third was longer in the group that developed antibodies. Although this difference was not statistically significant, it suggests that the shorter course may not be optimal.

In HIV positive patients, doubling the standard hepatitis B vaccine dose induces more immunity than the standard vaccine (61% compared to historical controls at our hospital or to published data by Rey). 14  This was especially true in patients with CD4 counts above 350 cells/mm3 and for patients with viral loads <1,000 copies/ml. In patients who failed prior Hepatitis B vaccination, response correlated with improvement in viral loads to <1,000 copies/ml. The strategy used in this study to decrease the time interval between the second and third dose did not yield greater compliance with vaccination, only 21% completed the vaccination by 60 days. Furthermore, the data from this study as well as other studies 15  suggests that longer intervals between the second and third vaccine dose increases response to vaccination. Seventy-seven percent of HIV positive patients who developed HBsAb had persistence of the HBsAb 21 months later. Finally future studies should further explore the relationship between single and double dose vaccine in controlled studies.

Conflict of Interest: no conflict of interest.

Funding: no source of funding was used.

Ethical Approval: This study was approved by the St. Barnabas IRB. No additional ethical approval was necessary.

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