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Routine Immunization in HIV: Helpful or Harmful?

The U.S. Public Health Service recently released Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus. Consideration of three vaccines was recommended: pneumococcal vaccine, a yearly influenza vaccine, and the hepatitis B vaccine (in susceptible patients).¹ These three vaccines are given a more formal recommendation by the CDC Advisory Committee on Immunization Practices.² In addition, these latter guidelines suggest that the Haemophilus influenzae type-B (Hib) vaccine should also be considered. Most clinical guides to management of HIV disease provide similar recommendations.

These policy statements have made the routine immunization of HIV-infected adults the standard of care. Although live vaccines (except measles-mumps-rubella) are contraindicated, it has generally been recommended that all other immunizations should be given if indicated, regardless of HIV status.

Despite these guidelines, evidence is emerging that vaccination may stimulate HIV replication, at least temporarily; this could theoretically accelerate the progression of HIV disease. Concern about this has prompted a reevaluation of routine immunization of HIV-infected people. As discussed below, few definitive data are available on the efficacy and the possible harm of vaccines.

Rationale for Routine Immunizations

Pneumococcal Vaccine: People with HIV are at high risk for invasive and recurrent pneumococcal disease, with rates of pneumococcal bacteremia 150- to 300-fold higher in HIV patients than in age-matched controls.³ Although the level of antibody correlating with clinical protection is unknown, some HIV-infected individuals do have a normal antibody response to immunization with the polyvalent pneumococcal vaccine,⁴ suggesting that the vaccine will be protective. With this vaccine, as with others, antibody response may correlate with absolute CD4 cell counts.⁵

The actual clinical efficacy of the pneumococcal vaccine in HIV infection, however, is not known. No published efficacy studies exist. A small case-control study presented in abstract form estimated an efficacy of 80% for the pneumococcal vaccine in HIV-infected persons.⁶

In a cost-effectiveness analysis of pneumococcal and influenza vaccination in HIV, the vaccine's effectiveness, the rates of infection, and the disease's morbidity and mortality were estimated.⁷ Because the pneumococcal vaccine is administered only once and at relatively low cost, this study found pneumococcal vaccination to be cost-effective, even in highly immunosuppressed individuals with low estimated vaccine-efficacy rates. This study did not take into consideration any adverse effects the vaccine would have on HIV disease progression. An efficacy trial of the pneumococcal vaccine is currently in the planning stages.

Influenza Vaccine: Several case reports have described severe influenza infections in AIDS patients. However, there is no definitive evidence demonstrating an increased incidence or severity of influenza infection in HIV-infected individuals. Although influenza vaccination has been shown to be efficacious and cost-effective in healthy immunocompetent adults,⁸ similar prospective studies have not been done in adults or children with HIV-infection.

It has been found that the antibody response to the influenza vaccine is suboptimal in HIV patients, particularly in those with absolute CD4 counts under 100.⁴ Because HIV-infected individuals experience less direct morbidity and mortality from influenza than from pneumococcal infection, and because the vaccine must be administered annually, yearly influenza vaccination was not found to be as cost-effective as the pneumococcal vaccine in the above-mentioned cost-effectiveness analysis.⁷

Hepatitis B Vaccine: Given the similar modes of transmission of hepatitis B virus (HBV) and HIV, populations at risk for HIV are also at high risk for hepatitis B. Depending on the group studied, from 35% to 80% of HIV-infected persons are already immune to or are chronic carriers of HBV and consequently are not candidates for vaccination. For those found to be HBV seronegative or not a chronic carrier, vaccination with three intramuscular doses of the hepatitis vaccine is recommended. Acute hepatitis B infection may be less severe in people infected with HIV than in HIV-negative individuals, but the risk of chronic HBV carriage is greater in those with HIV infection.⁹ From a public health standpoint, vaccination would prevent further transmission.

As with other vaccines, the antibody response to hepatitis B immunization is suboptimal in HIV-infected individuals, with less than 60% developing a protective antibody response, compared with more than 90% of HIV seronegative controls.¹⁰ There are no clinical trials of the efficacy of the hepatitis vaccine in preventing hepatitis B in people with and without concomitant HIV infection, but it is likely to be less protective in HIV-infected people, based on antibody levels. Unlike the diseases prevented by the other routinely recommended vaccines, however, behavioral interventions to prevent HIV and other disease transmission (e.g., condom use, avoidance of needle-sharing, etc.) may also prevent HBV transmission.

Haemophilus influenzae Type-B (Hib) Vaccine: The incidence and severity of H. influenza infections is higher in HIV-infected adults than in age-matched controls, but only one third of such infections are caused by type-B strains.¹¹ Although antibody response to the Hib polysaccharide vaccine in HIV-infected adults is lower than in noninfected controls, immunization with a conjugated polysaccharide vaccine results in an improved antibody response, directly correlated with the CD4 count.¹² However, whether this response protects against invasive H. influenza disease is unknown. Given the low overall incidence of invasive disease specifically secondary to H. influenza type B, efficacy trials will be difficult to conduct.

Effect of Vaccination on Viral Load

Theoretical concerns about the effect of vaccination on HIV replication were first raised when in vitro studies showed that stimulation of HIV-infected T-cells by mitogens or cytokines resulted in increased HIV replication.¹³ A number of other studies have also shown evidence for immune activation of HIV replication in vitro. A similar phenomenon can be seen in HIV-infected persons during acute infections, such as with influenza,¹⁴ HSV-1,¹⁵ HSV-2,¹⁶ and opportunistic infections.¹⁷

Several studies have evaluated the effect of influenza immunization on virologic markers in HIV-infected persons. In the most recently published study, HIV viral load, measured by quantitative PCR of peripheral blood mononuclear cell (PBMC) HIV RNA, increased an average of 11.6-fold in the first one to two weeks after immunization in 10 of 20 vaccinated patients, compared with a 2.4-fold increase in the 14 nonvaccinated controls.¹⁸ Hamilton and colleagues also demonstrated transient rises in plasma HIV RNA in 30 HIV-positive patients immunized for influenza.¹⁹

Most of the studies using modern HIV quantification techniques (quantitative PCR or bDNA) have yet to be published, and have been presented in abstract form only. In the largest study to date, a double-blind, placebo-controlled trial involving 47 HIV-infected subjects, immunization with influenza vaccine resulted in increases in HIV viral load as measured by plasma viral RNA. Preliminary analyses showed a plasma HIV RNA increase from a mean of 23,892 to 135,873 copies/ml in the vaccinated group, while in the placebo group mean plasma HIV RNA levels decreased slightly, from 25,826 to 18,470 copies/ml at one month post-vaccination. At three months post-immunization, the mean percentage of CD4 cells dropped by 1.8% in the vaccinated group and increased by 0.2% in the control group.²⁰ Viral load measurements in samples obtained at three months postvaccination are pending (S. Tasker, personal communication). Preliminary evidence has shown that immunization with the pneumococcal vaccine also results in transient increases in HIV replication.²¹

Studies with fewer participants have not shown influenza immunization to have an adverse effect on viral load. In a published study using p24 antigen measurements (a relatively insensitive marker for viral load), influenza vaccine did not boost HIV levels.²² Recent studies with newer techniques have similarly shown no change in plasma HIV RNA at one to two weeks after vaccination²³; or in HIV RNA, PBMC HIV DNA, and CD4 cell counts one month after vaccination.²⁴ An additional prospective study of the effects of influenza vaccine on viral load and CD4 cell counts is currently in progress at the Johns Hopkins University (M. Glesby, personal communication).

Conclusions

Data on clinical efficacy of immunization of the HIV-positive adult are limited. While it is established that antibody responses are lower in the HIV-infected than in noninfected controls, we do not yet know all the correlates of clinical protection, and certainly some individuals with HIV do respond adequately. However, the possibility that this preventive measure may have adverse effects on HIV viral load has necessitated a reexamination of routine immunization practices.

For the pneumococcal vaccine, the marked increase in invasive pneumococcal disease in HIV appears to outweigh the potential risks associated with immunization. Whether the modest increase in the risk of invasive haemophilus infections counters the potential risks and costs of immunization with the Hib vaccine is less clear; since most infections are not due to Haemophilus influenzae type B, the benefits of the vaccination will at most be minor. Hepatitis B vaccination is probably still warranted in HIV-infected individuals who engage in high-risk behaviors, both as a personal preventive measure and as a public health intervention, but may require monitoring of postimmunization antibody titers.¹⁰

The case for routine influenza immunization of HIV-positive adults is less convincing. Based on clinical experience thus far, the severity of influenza infection does not appear to be significantly increased in HIV. Also, most individuals with low CD4 cell counts do not form protective antibodies. Therefore, the risk of transient increases in HIV viral load, with its theoretical adverse effect on HIV disease progression, may outweigh any potential benefits of immunization. On the other hand, it is unknown whether the transient vaccine-induced increases in viral load are biologically significant, especially in comparison with potentially prolonged increases during acute infections.

Alternatives to annual influenza immunization of all HIV-positive adults would include limitation of the vaccine to those at high risk, such as health care workers, or to those most likely to mount a protective antibody response (100 or more CD4 cells/ mm³). Providing amantidine or rimantidine prophylaxis during influenza outbreaks may also be a feasible alternative.

An ACTG study currently in development plans to evaluate the effect of immune activation on HIV replication (S. Swindells, personal communication). Further studies to assess the efficacy of vaccines in HIV, and to determine the short- and long-term effects of immunization on viral load, immunologic markers, HIV disease progression, and survival, will be needed before definitive recommendations can be made. The approach we have taken is to recommend routine immunization against pneumococcus for all HIV-infected patients, and to recommend hepatitis B immunization for susceptible patients continuing high-risk behavior. With the influenza and H. influenza vaccines, we discuss potential risks and benefits with each patient before deciding what to do, especially when the patient's CD4 cell count is lower than 100. Because of the concerns discussed above and the lack of efficacy data, we seldom recommend influenza or H. influenza vaccine to those with low CD4 counts.

— Mary Singer, MD, and Paul Sax, MD

Dr. Singer is an AIDS Fellow, Brigham and Women's Hospital, and Dr. Sax is Clinical Director, HIV Program, Brigham and Women's Hospital, and ID/HIV Consultant, Harvard Community Health Plan.

Published in Journal Watch HIV/AIDS Clinical Care February 1, 1996

Citation(s):

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