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Case 4: Discussion - Immunizations for HIV-Infected Persons

General Principles

Providing appropriate immunizations is an important component of comprehensive HIV clinical care. The Advisory Committee on Immunization Practices (ACIP) provides annual recommendations for routine immunizations of adults, including specific recommendations for HIV-infected adults[1]. In addition, the US Guidelines for the Prevention and Treatment of Opportunistic Infections also provides specific vaccine recommendations for HIV-infected adults[2]. The major immunizations indicated for HIV-infected adults are summarized in Figure 1. Immunizing HIV-infected persons poses several challenges and concerns related to efficacy and safety. Unfortunately, HIV-infected persons with current or past advanced immunosuppression often have suboptimal responses to recommended vaccines[3,4,5,6,7]. In general, responses to immunization are better when the vaccine is given as early as possible in the course of HIV infection. From a safety standpoint, HIV-infected persons with advanced immunosuppression have the potential for life-threatening complications if they receive a live vaccine. Of lesser concern, early studies suggested that immune stimulation produced by vaccination resulted in a burst in HIV replication[8], but follow-up studies have shown increases in HIV RNA levels following vaccination are transient and clinically insignificant[9].

Pneumococcal Vaccine

Persons infected with HIV have an increased risk of developing invasive disease with Streptococcus pneumoniae infection[10]. Observational and placebo-controlled trials have shown conflicting results for the effectiveness of the 23-valent polysaccharide pneumococcal vaccination (PPSV23; Pneumovax 23) in HIV-infected adults[11,12]. Nevertheless, ACIP and US Guidelines for the Prevention and Treatment of Opportunistic Infections have historically recommend that all HIV-infected adults receive the 23-valent polysaccharide pneumococcal vaccine[1,2]. In June 2012, the ACIP issued a new recommendation to utilize both the conjugate 13-valent (PCV13; Prevnar 13) pneumococcal vaccine and the 23-valent polysaccharide pneumococcal vaccine in immunocompromised adults, including HIV-infected persons[13]. Pneumococcal vaccine-naïve persons should receive the PCV13 vaccine first, followed by a dose of PPSV23 at least 8 weeks later; a second dose of PPSV23 should be given 5 years later. Individuals who have previously received PPSV23 vaccination should receive PCV13, but not within 1 year of receiving a dose of the PPSV23 vaccine. In this situation, if the patient had receive only one prior dose of PPSV23, they should receive a second dose of PPSV23 at least 8 weeks after the PCV13 dose and at least 5 years after the prior PPSV23 dose. In all situations, patients who have received PPSV23 prior to age 65 should receive one additional dose of PPSV23 at age 65, or later if their last dose of PPSV23 was given within the prior 5 years. Initial vaccination should be given as early in the course of HIV infection as possible, preferably before the CD4 count decreases to less than 200 cells/mm3[5]. If a patient has a CD4 count less than 200 cells/mm3 and is not on antiretroviral therapy, many experts would recommend deferring pneumococcal immunization until the patient starts on antiretroviral therapy, suppresses HIV RNA levels, and has improvement in immune function. The widespread use of the conjugate pneumococcal vaccines in children has resulted in a significant decline in the rates of invasive pneumococcal disease in adults[14].

Tetanus, Diphtheria, and Pertussis (Tdap) Vaccine

Routine immunization with the tetanus and diphtheria toxoid vaccine (Td) is recommended for all HIV-infected adults[1]. This toxoid vaccine uses neutralized Clostridium tetani and Corynebacterium diphtheriae toxins. In addition, a one-time booster dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap). Two Tdap vaccines are approved by the FDA: Boostrix (for persons aged 10 and older) and Adacel (for persons aged 11 to 64)[15]. The recommended ACIP standard practices for primary immunization and updating immunity against tetanus and diphtheria among HIV-infected persons are the same as those for the general population. Adults who have never been vaccinated against with tetanus, diphtheria, or pertussis (or who have unknown immunization status) should receive a full series (three injections that contain the tetanus and diphtheria toxoids)[15]. Preferably, the first dose in the series should consist of Tdap, and the remaining two Td, but Tdap can substitute for any one of the Td doses in the series. The first two doses should be given at least 4 weeks apart and the third dose given 6 to 12 months after the second dose. Adults with incomplete history of completing a primary vaccination series should receive the remaining doses. The Tdap vaccine can be given regardless of the interval since the most recent tetanus or diphtheria-containing vaccine. To maintain immunity, the Td should be administered as a booster every 10 years, with the exception that adults aged 19 to 64 (and those 65 and older who anticipate contact with children aged 12 months or younger) should receive a single dose of Tdap to replace their next dose of Td if they have not previously received the Tdap vaccine[15]. Intervals less than 10 years since the prior Td may be used for giving Tdap to specifically protect against pertussis, especially in persons at increased risk for acquiring pertussis or developing pertussis-associated complications[15].

Haemophilus influenzae type b (Hib) Vaccine

Although preventing invasive Haemophilus influenzae type B infections remains an important concern for HIV-infected children, there is no evidence that invasive H. influenzae type B infections occur at a higher rate in HIV-infected adults. Administering H. influenzae type b (Hib) vaccine (HibTITER, ActHIB, and PedvaxHIB) is not recommended for HIV-infected adults because there are no efficacy data to base such a recommendation[1].

Meningococcal Vaccine

Infection with HIV is not considered a high-risk condition for developing invasive infection caused by Neisseria meningitidis. Currently available meningococcal vaccines consist of the tetravalent polysaccharide vaccine (MPSV4) (Menomune) and the tetravalent polysaccharide-protein conjugate vaccines[16,17] (MCV4) (Menactra and Menveo). Both vaccines contain the serotypes A, C, Y, and W-135[16]. The MCV4 vaccines are preferred over the polysaccharide vaccine, but the MPSV4 is considered an acceptable alternative. For HIV-infected adults, meningococcal vaccine is not routinely recommended, but it is safe to give when an indication is present. The following adult populations have a specific indication to receive meningococcal vaccine: persons with anatomical or functional asplenia, persons with terminal complement deficiency, first-year college students living in dormitories, military recruits, microbiologists routinely exposed to N. meningitidis, and persons traveling to a hyperendemic region[1,16]. In addition, the MCV4 vaccine is now recommended routinely for all children at age 11 to 12 and for unvaccinated adolescents at high school entry[16].

Influenza Vaccine

Current ACIP and DHHS guidelines recommend annual administration of inactivated trivalent influenza virus vaccine for all HIV-infected persons, regardless of CD4 count[1,2,18]. Although few data exist regarding the frequency and severity of influenza illness in HIV-infected persons, available data suggest that complications from influenza are probably higher in HIV-infected persons, particularly those patients with AIDS[18,19]. Influenza vaccination reduces respiratory symptoms and documented influenza illness among HIV-infected adults[18]. Patients with low CD4 counts often have suboptimal antibody responses to influenza vaccination[3]. The live attenuated intranasal influenza vaccine (Flumist) is contraindicated for HIV-infected persons, but not their household contacts[18].

Hepatitis A Virus Vaccine

Hepatitis A vaccination is recommended for HIV-infected persons who are seronegative for hepatitis A virus and who have medical, behavioral, or occupational indications[1,2]. Medical indications consist of clotting-factor disorders or chronic liver disease, including chronic hepatitis B or C virus infection. Behavioral indications include use of injection drugs and men who have sex with men. In addition, persons with planned travel to countries that have high or intermediate endemicity for hepatitis A virus (Figure 2) should receive hepatitis A vaccine prior to travel[1]. Occupational indications include work with hepatitis A in research laboratories or hepatitis A-infected primates. Patients should receive 2 doses of hepatitis A vaccine (Havrix or Vaqta) given at least 6 months apart (Figure 3)[20]. Several studies have shown reduced responses to hepatitis A vaccine among HIV-infected persons who have a CD4 count less than 200 to 300 cells/mm3[6,21]. Although these suboptimal vaccine responses would suggest a need for checking a post-vaccination titer, the ACIP guidelines do not recommend routinely testing for antibody to hepatitis A following vaccination[1].

Hepatitis B Virus Vaccine

Persons infected with HIV who acquire hepatitis B virus are more likely to have acute symptomatic hepatitis B virus infection and to develop chronic active hepatitis B virus infection[22,23]. Current guidelines recommend hepatitis B virus vaccination for all persons infected with HIV who do not have serologic evidence of prior infection with hepatitis B virus[1,2,24]. The 2012 ACIP vaccine guidelines[1] recommend immunocompromised adult patients receive 40 mcg of hepatitis B surface antigen with each scheduled vaccine dose for both Engerix-B and Recombivax-HB, whereas the 2009 prevention and treatment opportunistic guidelines[2] recommend 20 mcg per dose with Engerix-B and 10 mcg per dose with Recombivax-HB, but note that some experts recommend using the 40 mcg dose with either vaccine (Figure 4). In a recent randomized trial, investigators reported HIV-infected persons had better serologic responses when given 4 intramuscular 40 mcg doses of hepatitis B vaccine than 3 intramuscular 20 mcg doses[25]. Suboptimal responses to hepatitis B vaccine occur more frequently in HIV-infected persons when compared with HIV-negative controls[4]. Accordingly, the ACIP recommends testing HIV-infected persons for antibody to hepatitis B surface antigen (anti-HBs) 1 to 2 months after completing the final dose of the vaccine series, with a titer of at least 10 mIU/ml considered protective[24]. The need for booster doses in HIV-infected persons has not been determined, but existing guidelines do not recommend routinely giving booster doses[24]. Patients with an inadequate response to hepatitis B vaccine should receive three additional vaccine doses and be tested again 1 to 2 months after completing the final dose of the repeat vaccine series for serologic response to the vaccine[24]. If the HIV-infected person has not responded to a total of 6 doses of hepatitis B virus vaccine, they are unlikely to respond to further doses[24].

Measles, Mumps, and Rubella Vaccine

Although measles, mumps, and rubella (MMR) vaccine (M-M-R II) is a live attenuated vaccine, it is recommended for[1] HIV-infected adults with a CD4 of at least 200 cells/mm3 who lack evidence of immunity to measles[1,26]. The MMR vaccine is contraindicated for HIV-infected adults with a CD4 count less than 200 cells/mm3[1,26]. In order to minimize the risk of exposure of HIV-infected persons to measles, mumps, and rubella, susceptible close contacts should be vaccinated with MMR[26]. In the general adult population, the MMR vaccine is indicated for adults born after 1956 without documented evidence of immunity to measles or rubella or prior immunization. A single dose of measles vaccine results in protective immunity in 95% of persons. A second dose of MMR is recommended for adults who (1) were recently exposed to measles in an outbreak setting, (2) were previously vaccinated with killed measles virus vaccine, (3) were vaccinated with an unknown vaccine during 1963 to 1967, (4) are students in post-secondary educational institutions; (5) work in health-care facilities, and/or (6) plan to travel internationally[1]. The MMR vaccine is contraindicated during pregnancy, and pregnancy should be avoided for 28 days after vaccination to minimize the theoretical risk of congenital rubella syndrome.

Varicella Vaccine and Zoster Vaccine

Varicella vaccine (Varivax) is a live, attenuated vaccine that previously was contraindicated for all HIV-infected adults, regardless of their stage of HIV disease. More recently, however, the 2012 ACIP guidelines recommended giving varicella vaccine to HIV-infected adults who are not immune to varicella-zoster virus and who have a CD4 count of at least 200 cells/mm3[1]. If given, two doses of the varicella vaccine should be given 3 months apart[1,27]. For HIV-infected adults who have a CD4 count less than 200 cells/mm3 the varicella vaccine is contraindicated[1]. The herpes zoster vaccine (Zostavax) is also a live vaccine and it contains very high titers of varicella virus; this vaccine is contraindicated for HIV-infected adults who have a CD4 count less than 200 cells/mm3 and could be particularly dangerous if mistakenly given as the varicella vaccine to an individual without immunity to varicella-zoster virus[1]. For those patients who have a CD4 count of at least 200 cells/mm3, the 2012 ACIP recommendations do not advise for or against giving the zoster vaccine[1]. In ACTG trial 5247, HIV-infected persons with a a CD4 count of at least 200 cells/mm3 received 2 doses of herpes zoster vaccine 6 weeks apart and the vaccine appeared to be safe and immunogenic[28]

Human Papillomavirus Vaccine

In June 2006, the FDA approved the human papillomavirus (HPV-4) quadrivalent (types 6,11,16, and 18) vaccine (Gardasil)[29]. In October 2009, the HPV-2 (types 16 and 18) vaccine (Cervarix) was FDA approved[30]. These vaccine require 3 doses, given at 0, 2, and 6 months, and are recommended routinely for females at age 11 to 12 and for females aged 13 to 26 who have not previously received this vaccine or have not completed the full series. Ideally, females should receive this vaccine prior to becoming sexually active. In addition, the HPV-4 vaccine is approved for boys aged 13 to 26[31]. The HPV vaccines are considered safe for immunocompromised individuals since they are prepared from recombinant L1 capsid protein of HPV and thus are not live vaccines. Patients with low CD4 cell counts may have diminished immune responses to the HPV vaccines. There are no recommendations for the use of the HPV vaccine in men or in women older than 26. The HPV vaccine should not be given to pregnant women.

Poliovirus Vaccine

In the United States, routine use of live oral polio vaccine was discontinued in 1999[32], and the inactivated poliovirus vaccine (IPOL) is now the routinely administered vaccine. Routine vaccination of adults in the United States is not recommended, but may be indicated in travelers. For those unvaccinated HIV-infected adults who require polio vaccine, they should receive 3 doses of inactivated poliovirus vaccine, with the first 2 doses given 4-8 weeks apart and the third dose given 6 to 12 months after the second dose. Live oral poliovirus vaccine is contraindicated in HIV-infected persons and their household contacts, regardless of the HIV-infected person's immune status.

Smallpox Vaccine

The current commercially available smallpox vaccine (Dryvax) consists of live vaccinia virus (a virus similar to smallpox virus) and this vaccine is contraindicated in all HIV-infected persons if used as part of a pre-event program, mainly because of the increased risk for progressive vaccinia among persons with HIV infection[33]. There are limited data regarding the risk of smallpox vaccination for HIV-infected persons, mainly because the routine use of smallpox vaccination for the civilian population had ceased prior to the HIV epidemic. Smallpox vaccination for the military, however, has overlapped with the HIV epidemic. In 1989, a case report described an HIV-infected military recruit who received smallpox vaccination and developed disseminated vaccinia and was successfully treated with vaccinia immune globulin[34]. In the event of a bioterrorism attack involving smallpox, vaccination of potentially exposed HIV-infected individuals would be considered despite the risks of the vaccine.

Vaccines Related to Travel

Vaccines related to travel are generally not part of the initial evaluation process of HIV-infected persons. Nevertheless, many HIV-infected persons will eventually travel to regions of the world that require multiple preventive vaccinations, such as typhoid fever, cholera, yellow fever virus, Japanese encephalitis virus, and rabies virus. Recommendations for appropriate travel-related vaccines can be very complex and depend on numerous factors, including the HIV-infected person's immune status, the specific region of travel, and the types of exposure likely to occur in that region[35]. Accordingly, we recommend that HIV-infected persons who will travel undergo an evaluation by a medical provider who has expertise in travel-related issues and that this travel evaluation occur well in advance of the travel date to allow time for all appropriate immunizations to be given. The CDC provides an on-line resource for general information regarding HIV and travel[36].

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    Figure 1. Recommended Immunizations for HIV-Infected Adults

    Source: This modifed table is based on recommendations from: Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices. Recommended adult immunization schedule -United States, 2012. MMWR Morb Mortal Wkly Rep. 2012;61(04):1-7.


    Figure 1
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    Figure 2. Geographic Distribution of Hepatitis A Virus Endemicity, 2005.

    Source: Advisory Committee on Immunization Practices (ACIP), Fiore AE, Wasley A, Bell BP. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-7):1-23.


    Figure 2
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    Figure 3. Recommended Hepatitis A Virus Vaccine Dosage and Schedules for HIV-Infected Adults.

    Figure 3
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    Figure 4. Recommended Hepatitis B Virus Vaccine Dosage and Schedules for HIV-Infected Adults.

    Figure 4