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Hep A Vaccine-High Seroconversion Rate in HIV+ <300 Cd4s
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Safety and Immunogenicity of an Inactivated Hepatitis A Vaccine among HIV-Infected Subjects
Clinical Infectious Diseases Oct 15, 2004;39:1207-1213
1Naval Medical Center San Diego, San Diego, California, and 2Merck, West Point, Pennsylvania
Background. Hepatitis A is a major health risk for many human immunodeficiency virus (HIV)--infected individuals. Vaccination is a potentially attractive measure to reduce the incidence of hepatitis A among this population, but data on its safety and immunogenicity are incomplete.
Methods. Ninety HIV-uninfected adults received an inactivated hepatitis A vaccine (VAQTA; Merck), and 90 HIV-infected subjects were randomized, in double-blind fashion, to receive either the vaccine or placebo. The HIV-infected subjects were stratified by CD4 cell count, with 45 subjects having CD4 cell counts of >300 cells/mm3 and 45 subjects having CD4 cell counts of <300 cells/mm3. Vaccine was given at weeks 0 and 24 of the study.
The 90 HIV-infected subjects in the study were stratified by CD4 cell count, with 45 subjects having CD4 cell counts of <300 cells/mm3 and 45 subjects having counts of >300 cells/mm3. In double-blind fashion and by use of a computer-generated random code, HIV-infected subjects within each CD4 cell count stratum were randomized in a 2 : 1 ratio to receive VAQTA or placebo. All 90 HIV-uninfected subjects received VAQTA; this portion of the trial was not blinded. HIV-infected subjects and HIV-uninfected subjects were matched by age (<30 years or >30 years) and weight (<77.3 kg or >77.3 kg). All subjects received 2 injections of VAQTA or placebo at weeks 0 and 24.
Results. Seroconversion rates at week 28 of the study were 94% among the HIV-infected subjects and 100% among the HIV-uninfected control subjects. HIV-infected subjects with CD4 cell counts of <300 cells/mm3 had a seroconversion rate of 87%, and HIV-infected subjects with CD4 cell counts of >300 cells/mm3 had a seroconversion rate of 100%. The vaccine was generally well tolerated, and no adverse effect on either HIV load or CD4 cell count was found.
Conclusion. Hepatitis A vaccine was both immunogenic and safe among HIV-infected subjects.
INTRODUCTION
Hepatitis A virus (HAV) infection is common among persons who are at highest risk for HIV infection. A US military study of 1502 HIV-infected service personnel that was conducted prior to availability of the hepatitis A vaccines found that 21% of the subjects had IgG antibodies to HAV. The annual incidence of hepatitis A among HIV-infected patients may be as high as 1.5%, and these cases of hepatitis A are often associated with disruptions of HIV therapy, which may, in turn, cause dramatic increases in HIV load. Data from 2 small, retrospective series suggest that acute hepatitis A is similar in severity among both HIV-infected and HIV-uninfected patients, but neither of these series included any patients with chronic viral hepatitis. Chronic hepatitis B virus infection and chronic hepatitis C virus infection are common among HIV-infected patients in the Western world, and HAV infection concurrent with preexisting chronic viral hepatitis infection may predispose patients to fulminant hepatitis.
Two inactivated hepatitis A vaccines are licensed for use in the United States: HAVRIX (Smith Kline Beecham) and VAQTA (Merck). Studies of immunocompetent hosts have shown that both vaccines are generally well tolerated, immunogenic, and effective in the prevention of HAV infection. Both vaccines are used in a 2-dose series and produce antibody levels associated with protection from HAV infection in 95%--100% of immunocompetent hosts. The potential value of hepatitis A vaccination among subjects with HIV infection was demonstrated in 5 small studies that found HAV seroconversion rates of 40%--88% after administration of 2--3 doses of HAVRIX. A larger, multicenter study of HAVRIX was recently reported by Kemper et al. The authors used a 2-dose regimen and found, 3 months after subjects had received the second dose of vaccine, a seroconversion rate of 68% among subjects with CD4 cell counts of >200 cells/mm3 and a rate of only 9% among subjects with lower CD4 cell counts. No adverse influence on HIV load was detected in their study.
We designed and conducted a double-blind trial of the use of VAQTA among HIV-infected subjects to extend characterization of hepatitis A vaccine performance in this population and to demonstrate that VAQTA is immunogenic in HIV-infected individuals, compared with HIV-uninfected individuals. A group of HIV-infected subjects who received placebo was included in the study to allow prospective evaluation of the effect of the vaccine on CD4 cell count and HIV load. We stratified the HIV-infected patients by CD4 cell count to assess the role of immunosuppression in vaccine response. A carefully matched control group of HIV-uninfected adults was included in the study to allow comparison of the immunogenicity and safety of the vaccine between HIV-infected and HIV-uninfected subjects.
The study was designed to include 180 subjects, of whom 90 were infected with HIV and 90 were not infected with HIV. The study was advertised through the display of institutional review board--approved posters in the HIV clinic at our institution (Naval Medical Center San Diego [NMCSD]) and through announcements to the hospital staff. To be enrolled in the study, subjects were required to be between 21--45 years of age, HAV seronegative (within 4 weeks before enrollment), and able to give written, informed consent. All HIV-uninfected subjects were found to be HIV negative by ELISA within 1 year before entry into the study, as determined by review of the patients' medical charts. Potential enrollees were excluded from the study if they (1) had received any immunoglobulin or blood products within 6 weeks before enrollment, (2) had known, active liver disease, (3) had received hepatitis A vaccine previously, (4) had received any other vaccine within 30 days before enrollment, (5) were febrile, or (6) were thrombocytopenic. Receipt of all other vaccines was prohibited for the period from 2 weeks prior to each injection of VAQTA through 4 weeks after each of the injections.
Study setting. This was a single-center study. All 90 HIV-infected subjects were from the HIV clinic at the NMCSD; the HIV clinic follows 450 HIV-infected patients, 〜40% of whom had CD4 cell counts of <300 cells/mm3 at the time of the present study. The 90 HIV-uninfected subjects were recruited from the medical center staff and included physicians, nurses, and corps personnel who were matched to the HIV-infected subjects by weight, age, and smoking history.
DISCUSSION
The present study demonstrates that the hepatitis A vaccine VAQTA is generally well tolerated and immunogenic among HIV-infected subjects. HAV seropositivity rates and HAV antibody production lagged among the HIV-infected subjects, compared with the rates and production noted among HIV-uninfected control subjects, but a seroconversion rate of 87% was achieved after the second injection, even among subjects who had CD4 cell counts of <300 cells/mm3 at baseline.
That the vaccine response was diminished among individuals with more-advanced HIV disease is not surprising, because a similar trend has been observed among HIV-infected patients after receipt of many other vaccines, including tetanus, diphtheria, pertussis, Haemophilus influenzae, and hepatitis B vaccines. Whether a 3-dose series might provide an additional boost to the immunogenicity among HIV-infected subjects with lower CD4 cell counts is unknown. The overall seropositivity rate (94%) after 2 doses of VAQTA among HIV-infected subjects in the present study is considerably better than that which was noted in prior studies of hepatitis A vaccination for individuals with HIV disease, which found seroconversion rates of 52%--88%. These studies all used an ELISA assay that required a final HAV antibody titer of >20--33 mIU/mL to verify seroconversion, but we used a modified HAVAB assay with a cutoff value of 10 mIU/mL as the lower threshold for seroconversion. An additional difference is that all of the prior studies used HAVRIX, but the present study used VAQTA. The largest of the trials that involved HAVRIX was conducted during 1995--1997, and the present study was conducted during 1997--1999; it is possible that the antiretroviral therapy given to the patients in the present study was more effective and contributed to better seroconversion rates.
During the planning stages of the present study, we were especially concerned about the potential adverse effects of hepatitis A vaccination on the course of HIV disease. Prior studies of vaccination had found conflicting results, with some evidence for increased HIV loads following immunization against influenza, tetanus, and pneumococcal disease. We carefully monitored viral load and CD4 cell counts and prohibited receipt of other vaccines during the periods before and after vaccination with VAQTA, and no adverse effect on viral load or CD4 cell counts was found. This result is consistent with the results of other HAART-era vaccine studies, all of which have failed to detect any deleterious effect of vaccination on HIV disease. Although speculative, these data suggest that the usually minor negative influence of vaccination on HIV load is blunted by aggressive antiretroviral therapy.
Although hepatitis A appears to be a similar clinical illness in both HIV-infected and HIV-uninfected subjects, hepatitis A viremia is prolonged in the HIV-infected host, which increases the potential for transmission and outbreaks. In addition, hepatitis A and HIV coinfection may trigger major increases in HIV load, which may not resolve with resumption of antiretroviral therapy. Our research, coupled with the results of the previously published studies, shows that hepatitis A vaccination is both generally well tolerated and immunogenic among patients with HIV infection. Given the obvious risks for hepatitis A in the HIV-infected population, vaccination should be considered as part of the preventative care of the HIV-infected patient.
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