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Safety & Immunogenicity of Hepatitis A Vaccine in HIV-Infected Patients
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The Journal of Infectious Diseases 2003;187:1327-1331; Kemper et al.
"..Patients with less immune system impairment, as reflected by higher CD4 cell counts at entry to the study, were more likely to seroconvert and to have higher antibody titers. Two-thirds of those with CD4 cell counts 200 cells/mm3 responded to 2 doses of vaccine..these results suggest that a success rate of response to HepA vaccine is somewhat lower than those found in earlier studies of HIV infection.."
A recently published study in the Journal of Infectious Diseases"Outbreak of Hepatitis A among Men Who Have Sex with Men: Implications for Hepatitis A Vaccination Strategies" says many Hep A cases in MSM communities are not related to high-risk sex practices and coverage for Hep A vaccines are low, few individuals are aware of the vaccine or had it recommended, but the vaccine is readily accessed through the doctor's office:
http://www.natap.org/2003/april/040703_3.htm
Patients in this study received 2 doses of Hep A vaccine. Authors discuss below previous study results after patients received 3 doses of Hep A vaccine. Results from previous studies showed better responses to 2 doses, discussed below.
Infection due to hepatitis A virus (HAV) remains a significant risk for homosexual men. In addition to safe sex practices, the use of an inactivated hepatitis A (HepA) vaccine provides affordable protection against HAV infection, which may be especially important in those who are infected with human immunodeficiency virus (HIV). Acute HAV infection may be more severe in HIV-infected individuals and has caused prolonged increases in HIV load.
HAVRIX (GlaxoSmithKline Beecham Biologicals), one of the inactivated Hep A vaccines currently licensed in the United States, is highly immunogenic in non HIV-infected adults, resulting in seroconversion in up to 90%-94% and 100% of persons after the first and second doses, respectively, of vaccine (1440 ELISA units [ElU]). However, antibody responses to Hep A vaccine are diminished in patients with HIV infection. In addition, several reports suggest that HIV replication may be transiently up-regulated by certain vaccines, such as influenza vaccines or others. Whether Hep A vaccine has a similar effect on HIV RNA levels has not been examined previously, to our knowledge.
Researchers determined the safety and immunogenicity of 2 doses of HepA vaccine (HAVRIX; 1440 ElU) in a group of 133 HIV-infected HAV sero-negative adults with varying levels of immunodeficiency who were seronegative for anti-HAV antibodies. Whether 2 doses of vaccine, administered 6 months apart, adversely affected CD4 cell counts, plasma HIV RNA levels, or the clinical course of HIV-infection was examined.
Patients were randomly assigned to receive, in a blinded fashion, either 2 doses of vaccine (1440 enzyme-linked immunosorbent assay units) or placebo 6 months apart.
Seroconversion at month 9 was observed in 68% of those with CD4 cell counts 200 cells/mm3 but in only 9% of those with lower CD4 cell counts (P = .004). HepA vaccine was well tolerated and had no effect on the course of HIV infection or plasma HIV RNA load.
The reasons for discontinuation from the study were similar for both groups (loss to follow-up was the most frequent reason). Baseline demographics were similar between treatment groups, although CD4 cell counts were somewhat higher at baseline in vaccine recipients, compared with placebo recipients (376 vs. 327 CD4 cells/mm3; P, not significant). Mean HIV RNA levels were also similar (3.29 vs. 3.39 log10 copies/mL). Sixty-two patients (91%) in the vaccine group were receiving antiretroviral therapy at the time of entry to the study, compared with 60 (92%) in the placebo group. Half the patients were receiving 2 agents, reflecting the pattern of antiretroviral use at the time of enrollment.
RESULTS
Sixty-two patients (91%) in the vaccine group were receiving antiretroviral therapy at the time of entry to the study, compared with 60 (92%) in the placebo group. The authors said half the patients were receiving 2 agents, reflecting the pattern of antiretroviral use at the time of enrollment.
The overall frequency of HAV seroconversion among subjects receiving vaccine was 49% at month 7 and 52% at month 9. Among patients with baseline CD4 cell counts of 200499 or 500 cells/mm3, seroconversion after two doses of vaccine was observed in 53% and 73% at month 7 and in 69% and 67% at month 9, respectively. When all 3 groups were compared, the frequency of seroconversion among patients with CD4 cell counts <200 cells/mm3 was significantly lower at month 7 (11%; P = .023) and at month 9 (9%; P = .004). After the first dose of vaccine, seroconversion at month 6 was observed in only 4 (13%) of 31 subjects with CD4 cell counts >200 cells/mm3 and in no subjects with CD4 cell counts <200 cells/mm3, and there did not appear to be a difference whether patient had 200-499 or >500 CD4 cells.
In one of the earlier studies, in which 90 HIV-infected adults received 2 doses of a HepA vaccine similar to that used in our study, seroconversion occurred in 78% and 88% of subjects after the first and second doses, respectively, of vaccine. The reason for the lower frequency of seroconversion to HepA vaccine in our study, compared with the frequencies found in the earlier studies, is not clear.
Two of these studies involved HIV-infected patients with hemophilia, who are generally younger than patients studied in other clinical trials of HIV infection; thus, their younger age may have improved their rates of response. Seroconversion in our study was defined as anti-HAV antibody titer 33 mIU/mL, whereas a lower cutoff anti-HAV antibody titer, 20 mIU/mL, was used in other studies. Using the lower cutoff value would have had only a modest effect on our overall results (only 1 patient in our study would have been reclassified as a responder at month 9, and 3 other patients, all of whom eventually responded, would have been thus classified at an earlier visit). Because patients in our study were stratified on the basis of their CD4 cell counts at entry to study and not the nadir value, the immunocompetence of our patients, which was judged on the basis of treatment-enhanced CD4 cell counts, may have been overestimated. Defects in immune responsiveness to vaccination could persist, despite improvement in CD4 cell counts due to more-potent antiretroviral therapy. This possibility is, however, inconsistent with the results of a recent study in which 94% of patients, most of whom had access to highly active antiretroviral therapy, responded to another, similar HepA vaccine. Response rates remained high (87%), even in patients with CD4 cell counts <300 cells/mm3.
Subjects with higher baseline CD4 cell counts had significantly higher GMTs (geometric mean anti-HAV titers) at both month 7 and month 9. For example, GMTs at month 9 were 23, 82, and 145 in patients with <200, 200499, and 500 CD4 cells/mm3, respectively (P = .016). Two patients in the placebo group experienced seroconversion during the study, presumably from naturally occurring HAV infection, and both events were associated with the development of very high anti-HAV titers (>75,000 mIU/mL).
No significant differences in the frequency of solicited or unsolicited reports of signs and symptoms were observed within 4 days of administration of either the first or second dose of vaccine between the vaccine and placebo groups or within the CD4 cell count subgroups. Severe vaccine-related adverse effects were uncommon.
The only statistically significant HepA vaccinerelated event was minor injection-site soreness, which was seen after 35% (39/112) of the doses administered, which was similar for each of the 2 doses, compared with 8% (9/108) of the placebo doses (P < .01).
The frequency of HIV-related events during the study was also similar between vaccine recipients and those receiving placebo. Within each of the 3 CD4 cell count groups, there was no apparent difference in the proportion of patients whose CDC category changed between the baseline and final visits.
The authors concluded HIV infection impairs the response to a variety of vaccines, including tetanus toxoid, pneumococcal polysaccharide, influenza virus, and HepA and hepatitis B virus vaccines. In addition, certain vaccines, such as influenza, have resulted in transient increases in plasma HIV loads within weeks of administration. We found no such effect of Hep A vaccine on HIV RNA levels.
Three studies of HepA vaccine in HIV infection examined the response to 3 injections of a lower dose of vaccine (HAVRIX; 720 ElU) administered at 0, 1, and 6 months. In each of these 3 studies (all of which used a seroconversion cutoff anti-HAV antibody titer 20 IU/mL), the proportion of patients who responded after a second and third dose of vaccine varied from 50% to 78% and from 76% to 85%, respectively. Of these, the best results were reported by Santagostino et al, who studied 47 HIV-infected patients with hemophilia, 19 of whom had CD4 cell counts <200 cells/mm3. After 3 doses of Hep A vaccine, 100% of subjects with CD4 cell counts >200 cells/mm3 responded, whereas only 57% of subjects with CD4 cell counts <200 cells/mm3 did.
The diminished anti-HAV antibody titer response following a single dose of HepA vaccine has implications for HIV-infected travelers. Such patients may also receive serum immunoglobulin in addition to vaccine for imminent travel, although there are some data suggesting that the coadministration of serum immunoglobulin may further blunt the antibody response to vaccination. Furthermore, clinicians may wish to counsel patients that vaccination may not provide uniform protection against HAV. Whether vaccine response can be improved by the use of adjuvants or a third dose of vaccine or by delaying vaccination until there is evidence of improvement in the immune system in response to more highly active antiretroviral therapy, deserves further study.
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