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Volume 36 • ACS-7 September 2010

Updated Recommendations For The Use Of Varicella And MMR Vaccines In HIV-infected Individuals

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An Advisory Committee Statement (ACS).National Advisory Committee on Immunization (NACI).

Updated Recommendations For The Use Of Varicella And MMR Vaccines In HIV-infected Individuals

The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific and public health advice relating to immunization. The Public Health Agency of Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of the Public Health Agency of Canada’s Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

TABLE OF CONTENTS

Introduction
Previous NACI Recommendations for Varicella Vaccine in HIV-Infected Children
NACI Recommendations for Measles-Mumps-Rubella (MMR) Vaccine in HIV-Infected Children
Updated Literature Review on Varicella and MMR Vaccination in HIV-Infected Children
NACI Recommendations for HIV-Infected Children
Varicella Vaccination of HIV-Infected Adolescents and Adults
NACI Recommendations for HIV-Infected Adolescents and Adults
Combination MMRV Vaccine and HIV-Infected Individuals
HIV-Infected Individuals in Varicella Post-Exposure Situations
Varicella Vaccination of the Susceptible Contacts of HIV-Infected Individuals
Persons with Advanced HIV Infection Inadvertently Immunized with Varicella or MMR Vaccine
Research Priorities
Tables
Reference List

Introduction

This NACI statement updates the recommendations previously published in the Canadian Immunization Guide (CIG) 2006(1) for the use of varicella vaccine in individuals infected with the human immunodeficiency virus (HIV). The new varicella vaccine recommendations are now consistent with the recommendations for MMR use in HIV-infected persons, which remain unchanged.

For the purposes of this statement, NACI follows the case definitions of the immunological and clinical categories for staging HIV-infected persons as defined by the U.S. Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics (AAP). These criteria (with minor modifications) are listed in Tables 1 and 2 below.(2),(3)

Previous NACI Recommendations for Varicella Vaccine in HIV-Infected Children

NACI previously recommended that susceptible persons ≥ 12 months of age with asymptomatic or mildly symptomatic HIV infection (CDC clinical category N or A, respectively) and with age-specific CD4 percentages of ≥ 25% (CDC immunologic category 1) may be vaccinated with two doses of varicella vaccine with a three-month interval between doses (refer to CIG 2006, p. 331).(1),(4) The recommendation was based on a single study published in 2001 by Levin et al. of 41 HIV-infected children in the U.S. who received two doses of Oka/Merck vaccine (Varivax™) three months apart, after satisfying the above-stated inclusion criteria.(5) Antibody seroconversion as measured by the fluorescent antibody to membrane antigen (FAMA) test was found in 53% of children after one dose and 60% after two doses. Eight patients were evaluated for cell-mediated immunity (CMI) response post-vaccination, with 20% responding after the first dose and 63% after the second dose.(5)

NACI Recommendations for Measles-Mumps-Rubella (MMR) Vaccine in HIV-Infected Children

Since varicella vaccination is most often administered concurrently with the first dose of MMR at 12 months of age and a combination measles-mumps-rubella-varicella (MMRV) vaccine was authorized in Canada in 2007, a discussion for administering varicella vaccine to HIV-infected children has to include considerations for concurrent MMR vaccination or replacing both vaccines with the newer combination MMRV vaccine. 

In the CIG 2006, NACI recommended that asymptomatic HIV-infected infants should receive routine measles (i.e., as combination MMR) vaccination. MMR vaccination is also recommended for symptomatic HIV-infected persons without evidence of severe immunosuppression, i.e., belonging to CDC immunological categories 1 and 2 (Table 1; also refer to CIG 2006, p. 127 and p. 234).(1)

The MMR vaccine recommendations date back to the late 1980s and early 1990s, because unimmunized HIV-infected children who developed measles were observed to have a case fatality rate of up to 50%.(6)-(9) In the 1989–1991 measles outbreak in the United States, 11 of the 19 deaths reported in New York City occurred in HIV-infected persons.(9),(10) By 1999, MMR vaccine had been safely administered to more than 1,000 HIV-infected children in the U.S.(9)

However, available studies to date have shown that HIV-infected children developed suboptimal responses to measles vaccine, with antibody response rates ranging from 25% to 70% post-vaccination.(9) As measles antibody titer is known to decline more rapidly over time in HIV-infected, as compared to HIV-uninfected children, a dose of immune globulin is recommended for prophylaxis in HIV-infected children after a known exposure to confirmed wild-type measles, even if there is a history of previous MMR immunization (see CIG 2006, p. 234).(1),(9),(11),(12)

Updated Literature Review on Varicella and MMR Vaccination in HIV-Infected Children

A literature search was conducted using PubMed and EMBASE for publications on the use of varicella, MMR and MMRV vaccines in HIV-infected persons from 2001 (when Levin et al.’s first study was published) to the end of 2008. There were no publications addressing immunological and/or vaccine effectiveness data when using varicella and MMR vaccines concurrently, or administering combination MMRV vaccine in HIV-infected individuals.

Two studies regarding MMR or individual vaccine antigen use in HIV-infected children were reviewed. A small study from Brazil (15 children with HIV) showed an antibody response rate of 60% for rubella in the patients with a moderate to severe degree of immunosuppression (CDC immunological category 2 or 3), suggesting that suboptimal responses are not limited to the measles component.(13) However, the use of immune globulin is not known to be effective after exposure to wild-type rubella infection.  

The issue of waning antibody was addressed by Berkelhamer et al., who provided additional MMR vaccination to HIV-infected children previously immunized with at least two MMR doses, and whose measles antibody level had dropped below the seroprotective level.(14) They found that the HIV-infected children who were receiving highly active antiretroviral therapy (HAART) had significantly higher response rate (nine out of 14 [64%]) than the children who were not on HAART (three out of 14 [21%]), consistent with immune reconstitution while on therapy.(14) However, while antibody-boosting may occur after an MMR booster in previously immunized HIV-infected children on HAART, in the absence of disease outbreaks it is unclear whether routine booster(s) of MMR vaccine is/are needed (and at what intervals) in these children. 

With respect to varicella vaccination in HIV-infected children, there were four published studies describing a total of 139 patients who were vaccinated with univalent varicella vaccine; these papers are discussed in greater detail below. There is difficulty comparing the studies because different varicella antibody tests were used. For instance, the FAMA, immunoassay or standard ELISA tests were used in the HIV-infected children, rather than the antibody tests historically used in the pre-vaccine trials involving healthy children, e.g., the gpELISA test for studies on Varivax™ and indirect immunofluorescence antibody (IFA) test for Varilrix™. The antibody titer correlating with protection against varicella clearly differs for each test. Furthermore, while the desired protective titer has been defined for FAMA (≥1:4) and gpELISA (≥5 gpELISA units/mL) in healthy children, these titers have not as yet been determined for HIV-infected children.(15)(17) Consequently for each study below, the seroprotective titer is as specified by the authors. 

The follow-up varicella study by Levin et al.

Levin et al. conducted a follow-up study utilizing two varicella vaccine doses three months apart.(18) The follow-up study had 43 patients (including the original group of 41 children from their earlier study) who had CDC categories N1 and A1.(5),(18) Two other cohorts were also vaccinated, including 37 children with moderate symptoms and/or moderate immune suppression (CDC category B2), and 17 children who initially had severe symptoms and/or severe immune suppression (CDC category C3), but had become asymptomatic and improved on HAART to CDC immunologic category 1 for at least three months before vaccination.(18) The ages of the patients are shown in Table 3. MMR vaccine was not co-administered in this study. Antibody titers (utilizing FAMA test) and cell-mediated immunity responses (CMI, utilizing the stimulation index, or SI) were assessed up to 156 weeks after completing the vaccination series. The proportions achieving FAMA titers ≥ 1:2 and SI ≥ 3.0 are shown in Table 3. As the results were similar regardless of the baseline clinical or immunologic category, the results of all three groups were combined in the study. The combined proportion achieving adequate FAMA and/or CMI responses in these patients was 72% at eight weeks, 86% at 52 weeks, 65% at 104 weeks and 60% at 156 weeks after the second dose (see Table 3 for the individual FAMA and CMI responses).(18) In contrast, the naturally infected children (control group in Table 3) had corresponding FAMA and/or CMI responses of 100% at eight weeks, 75% at 52 weeks and 73% at 156 weeks. There were no clinically significant changes in CD4 counts or percent in any vaccinated group after each scheduled dose.(18) Level III evidence, Quality good (see Table 4 for the definition of levels of evidence and quality of evidence).

Adverse event rates were similar in all three vaccine groups, with injection-site reactions occurring in 6% to 21% of each group after the first dose, and half as common and milder after the second dose. A quarter of the reactions after the first dose were classified as grade 3 (25–50 mm of induration, erythema or crying with touch), but no children declined receiving the second dose.(18) Fever occurred in 0%–14% after the first dose and 5%–12% after the second dose. However, grade 3 temperatures (≥ 39.4°C) were uncommon, occurring in < 5% after the first dose and < 3% after the second dose.(18) Neither study by Levin et al. was powered to determine the clinical efficacy of varicella vaccine in HIV-infected children. There were 16 reported exposures to varicella, during which one child was given varicella-zoster immune globulin (VarIg). Only one child developed mild varicella-like illness with < 50 lesions (time since vaccination was not specified), and another developed zoster the year after vaccination.(18)   

The varicella study by Bekker et al.

Results similar to those discovered by Levin were reported by Bekker et al. in the Netherlands, who vaccinated 15 susceptible HIV-infected children with two doses of Oka/GSK vaccine (Varilrix™) given three to six months apart.(19) The children had a mean age of 8.3 years (range 4 to 11 years). MMR vaccine was not concurrently administered. Thirteen of the 15 patients received HAART for a median of 289 weeks before they were vaccinated, while two were not on HAART. Twelve patients had an undetectable HIV viral load; three of whom had CD4 ≥ 25% (immunologic category 1), six had CD4 at 15%–24% (category 2) and six had CD4 < 15% (category 3).(19) No patients developed any serious adverse events and their HIV viral loads and CD4 counts, or percent, did not change at six weeks after each dose. Varicella antibody was detected using the Vidas immunoassay test, and seroconversion occurred in five out of 15 (33%) after the first dose and nine out of 15 (60%) after the second dose.(19) However, the varicella IgG titers after the second dose were significantly lower in the HIV-infected children (median 0.2 IU/mL), as compared with a control group of six HIV-negative siblings who were vaccinated using the same protocol (median 4.6 IU/mL). Seven of the nine children who seroconverted were retested for varicella IgG at 24 weeks after the second dose, and IgG was not detectable in two of the children.(19) All vaccinated HIV-infected children developed significant CMI response against varicella, with levels comparable to those of their HIV-uninfected siblings. Only three vaccinated children had exposure to varicella post-vaccination, and none developed disease; this is too small a number to derive any conclusions about clinical effectiveness.(19) Level III evidence, Quality fair.

Bekker et al. also studied eight unvaccinated HIV-infected children who previously had wild-type varicella infection, and discovered that their varicella IgG titers were also low (median 0.8 IU/mL), not significantly different than that achieved after vaccination.(19) It has been postulated that functional immune restoration is still incomplete in HIV-infected children even after receiving HAART, with defective B-cell antibody responses.(19),(20) This may explain the low varicella IgG titers in the HIV-infected children who either had wild-type varicella or were vaccinated against varicella.

The varicella study by Armenian et al.

Armenian et al. immunized 10 HIV-infected children who had been on HAART for at least 4 weeks with a single dose of Oka/Merck vaccine. MMR vaccine was not concurrently administered. The patients had a mean age of 4.5 years (range 1 to 11 years) and were at varying CDC categories, N2 up to C3 before commencing HAART, but all had improved to categories N1 or N2, and with HIV viral loads of < 400 copies/mL by the time of vaccination.(21) The vaccine was well tolerated, with no serious adverse events. Vaccination did not adversely affect the patients’ CD4 cell counts and CDC clinical categories. CMI testing using a lymphoproliferative assay was positive in all vaccine recipients at four weeks after vaccination, with 90% remaining positive one year later. Varicella antibody testing using ELISA was positive in 67% of vaccinees eight weeks later, falling to 33% who remained positive one year after vaccination.(21) Vaccine clinical effectiveness was not assessed in this study. Level III evidence, Quality fair.

The varicella study by Wood et al.

A retrospective cohort study was conducted by Wood et al. to review primary varicella and herpes zoster infections among 256 perinatally HIV-infected children in Philadelphia from 1989 to 2006.(22) After the recommendation by the Advisory Committee on Immunization Practices (ACIP) for varicella vaccination of HIV-infected children was published in 1999, only 57 patients in the cohort had received at least one dose of univalent varicella vaccine (the number who received > 1 dose was not specified). Focusing only on this previously vaccinated subgroup, 13% of the patients were vaccinated before the HIV infection was diagnosed.(22) At the time of varicella immunization, 75% of the patients were receiving recommended antiretroviral therapy, the median CD4 was 34%, median HIV viral load was 200 copies/mL (range 39 to 14,000 copies/mL), and 45% of the patients had HIV-related symptoms (i.e., clinical categories B or C).(22) Only a single vaccine-related adverse event was documented, i.e., a vesicular rash that occurred at 4 weeks post-vaccination. The authors followed the subgroup of vaccinated patients for a median of 3.1 years, totalling 224 person-years of observation.(22) There was a total of five breakthrough cases of varicella, occurring at one, seven, 10, 19 and 45 months post-vaccination. The overall incidence of breakthrough varicella was 22.3/1,000 person-years, correlating with a vaccine effectiveness of 91.2%.(22) Serology for varicella IgG (test methodology not specified) was performed in 41 of the previously vaccinated patients, and was considered positive in only 17 patients (41.5%) at a median of 18.9 months post-vaccination.(22) This contrasted with a seropositive rate of 39 out of 54 (72.2%) in unvaccinated HIV-infected children who had a history of wild-type varicella (at a median of 28.7 months after the infection).

There was only a single case of zoster among the vaccinated children, which occurred 3.8 years post-vaccination; the zoster strain was not sent for typing in order to distinguish vaccine from wild-type strain. The incidence of zoster in previously vaccinated HIV-infected children was 4.5/1,000 person-years.(22) Wood et al. also reported the changing incidence of zoster (but not of primary varicella) in the whole cohort of HIV-infected patients (vaccinated and unvaccinated) in their clinic. The zoster incidence was 30.0/1,000 person-years in 1989–1996 (before the advent of highly-active or triple antiretroviral therapy), 31.9/1,000 person-years in 1979–1999 (before routine vaccination was recommended for HIV-infected children) and 6.5/1,000 person-years in 2000–2006 (with greater availability of  antiretroviral therapy and varicella vaccine).(22) Although the period of observation is shorter during the most recent observation period, the decline in zoster incidence in 2000–2006 was statistically significant when compared with the earlier periods. The authors postulated that the decline was due to the benefit from both antiretroviral therapy and vaccination.(22) Level III evidence, Quality fair.

NACI Recommendations for HIV-Infected Children

  • A pediatric infectious diseases specialist should be consulted before vaccinating HIV-infected children with varicella and MMR vaccines. The specialist can aid in staging the clinical and immunologic categories two to four weeks prior to vaccination; this interval is suggested because HIV viral load results may take this length of time to perform, depending on the reference laboratory, whereas CD4 test results are usually available in one to three days.
  • In the absence of new data, NACI’s recommendations regarding MMR vaccination of HIV-infected children published in CIG 2006 remain unchanged.
  • HIV-infected children ≥ 12 months of age who are varicella non-immune, and with CDC clinical category N, A or B, and immunologic category 1 or 2 (i.e., CD4 counts ≥ 15%) may receive two doses of univalent varicella vaccine (Oka/GSK or Oka/Merck), three to six months apart.   The same criteria apply for vaccination with MMR vaccine.  NACI Recommendation – Grade B.
  • Although the concurrent administration of varicella and MMR vaccines has not been studied, having to separate them would involve extra visits for immunization in HIV-infected children. Since the prerequisites for vaccination with both vaccines are now identical, varicella vaccine may be administered in conjunction with MMR vaccine at separate sites, if both vaccines are indicated.(1) NACI Recommendation – Grade C.
  • While published studies administered the two doses of varicella vaccine three months apart, NACI recommends that an interval of six months may be chosen in jurisdictions where MMR is routinely administered at 12 and 18 months of age, so that the two live vaccines can be administered at the same visit. For jurisdictions where the second MMR is routinely administered at preschool (4 to 6 years of age), the first varicella vaccine dose should be administered at 12 months and the second dose preferably at 15 or 18 months of age. If not administered during the same visit, MMR and varicella vaccines should be separated by at least 4 weeks. (1),(4) NACI Recommendation – Grade B.

Varicella Vaccination of HIV-Infected Adolescents and Adults

There are no published data on the use of varicella vaccine in susceptible HIV-infected adolescents and adults. In temperate countries including Canada, 95% of individuals (including HIV-infected persons) should have acquired varicella infection by 12 years of age. Therefore, Canadian-born adults with HIV are likely already immune to varicella. In contrast, studies have shown that only 40% to 70% of adults born in tropical countries have serologic evidence of previous varicella infection by their 20th birthday.(23),(24) HIV-infected susceptible adults who have come to Canada from tropical regions may be at risk for severe complications if they develop wild-type varicella infection during the adult years. Therefore, serological testing (e.g., with varicella ELISA test) is necessary to determine susceptibility in HIV-infected adolescents and adults who do not have a clear history of varicella illness or previous varicella vaccination.

NACI Recommendations for HIV-Infected Adolescents and Adults

Without published supportive data, any decision to vaccinate involves balancing the benefit of being able to prevent severe disease if a susceptible HIV-infected adolescent or adult acquires wild-type varicella, against the potential risks of vaccination. Based on expert opinion, the safety of varicella vaccine in HIV-infected adolescents and adults with CD4 cell count ≥ 200 X 106/L and percentage ≥ 15% is deemed likely to be similar to that of children 6 to 12 years old (Table 1).(25) Immunogenicity data are also lacking, and may be lower in HIV-infected adolescents and adults as compared to children.(25) NACI recommends the following:

  • HIV-infected adolescents and adults should be asked for a history of varicella illness or previous varicella vaccination, and if negative for both, a varicella antibody test (such as ELISA, latex agglutination [LA] or indirect immunofluorescent antibody [IFA]) should be requested to confirm susceptibility.
  • The susceptible HIV-infected patient’s specialist should be consulted regarding his/her clinical and immunologic categories before vaccinating with varicella (and/or MMR) vaccines.
  • Immunization with two doses of varicella vaccine administered three months apart may be considered for susceptible HIV-infected adolescents and adults with CD4 cell count ≥ 200 X 106/L and percentage ≥ 15%. NACI Recommendation – Grade I.

Combination MMRV Vaccine and HIV-Infected Individuals

A combination measles-mumps-rubella-varicella (MMRV) vaccine manufactured by GlaxoSmithKline Inc. (Priorix-Tetra™) was authorized for the vaccination of healthy children in Canada in July 2007. However, the safety and immunogenicity of this MMRV vaccine in HIV-infected individuals has not been evaluated, and MMRV currently cannot be routinely recommended until further studies are done in this patient- population.  NACI Recommendation – Grade I.

HIV-Infected Individuals in Varicella Post-Exposure Situations

Although post-exposure immunization of healthy individuals has been shown to be approximately 90% effective in preventing or attenuating varicella infection, if administered within three to five days of the exposure, this has not been studied in immunocompromised individuals (including those with HIV infection).(26),(27) NACI recommends that:

  • Varicella zoster immune globulin (VariIg) should be used (rather than varicella vaccine) for the prevention of varicella in susceptible HIV-infected children, adolescents and adults after an exposure, since it is highly unlikely that vaccine providers will know the patient’s clinical and immunologic categories in a post-exposure situation. The VarIg should be administered as soon as possible, and within 96 hours of known exposure to wild-type varicella.(1),(28) NACI Recommendation – Grade A.
  • As indicated above, previously immunized HIV-infected children may demonstrate significant waning of CMI or antibody one to two years after receiving two doses of varicella vaccine. At present, it is unknown if this implies an inability to mount an anamnestic response after exposure to wild-type disease. In the vaccine trials, most of the vaccinated HIV-infected patients with exposure during the follow-up period were not given VarIg. (18),(19) Consequently, the use of VarIg is not considered routinely necessary. However, in the event of breakthrough (vaccine-modified) varicella or zoster illness, a specialist should be contacted regarding the need for prompt antiviral therapy to reduce severity of the illness.(29) NACI Recommendation – Grade I.

Varicella Vaccination of the Susceptible Contacts of HIV-Infected Individuals

Susceptible HIV-infected individuals may be infected by household members who develop wild-type varicella infection. Although the vaccination of household contacts of HIV-infected individuals has not been specifically studied, a related study showed that varicella vaccination of 35 household members of children with cancer or leukaemia was safe, with no secondary transmission to the high-risk patients.(30)

  • The varicella vaccination of all susceptible (non-HIV-infected) household contacts of HIV-infected individuals is recommended, as a priority. NACI Recommendation – Grade A.

Persons with Advanced HIV Infection Inadvertently Immunized with Varicella or MMR Vaccine

The following published case reports highlight the danger of inadvertently immunizing persons with advanced HIV infection with live virus vaccines. In HIV-infected persons, it is essential to ascertain that they conform to the appropriate clinical and immunologic categories (Tables 1 and 2) with their specialists before making the decision to vaccinate with varicella and/or MMR vaccines.

A 16-month-old child developed disseminated infection with Oka vaccine strain three months after routine varicella and MMR vaccination.(31) He was hospitalized with fever, skin rash, lumbar radiculopathy and had multiple pulmonary opacities bilaterally on chest x-ray.(31) Skin lesions were positive for varicella and Oka strain virus confirmed by polymerase chain reaction (PCR) test on bronchoalveolar lavage and lung biopsy tissue.(31) He improved on IV acyclovir and was discharged after 39 days in hospital. His HIV test was positive, and CD4 count was 8 X 106/L, thus at CDC category B3. (31) There were no further recurrences of varicella or zoster after 2½ years of follow-up. In retrospect, he had a history of recurrent oral thrush and poor weight gain for several months before vaccination. If HIV had been diagnosed prior to vaccination and his CD4 count determined to be in immunologic category 3, varicella and MMR vaccinations would have been contraindicated.

The post-marketing adverse-event passive surveillance system at Merck Research Laboratories has received seven reports of disseminated Oka strain infection.(32) One was a 48-year-old male with Down syndrome and six involved children. Four children were subsequently diagnosed with primary immunodeficiency disorders, and one child was receiving intermittent steroid therapy around the time of vaccination.(33) The remaining case was an HIV-infected child with a history similar to the child in the preceding paragraph (not clear if it is the same case).(31),(32)

A 20-year-old man with Hemophilia A and HIV infection died after developing measles, pneumonia and other complications one year after receiving a second dose of MMR vaccine.(33) He had received the first MMR dose as a child in 1973. In the first eight months of 1992 he was asymptomatic, but although his CD4 cells were “too few to count,” he was not receiving HAART.(33) In September 1992, he received the second dose of MMR as a prematriculation requirement. Ten months later, he developed respiratory distress, and in October 1993 an open lung biopsy revealed multinucleated giant cells. Tissue culture was positive for measles virus.(33) Nucleotide sequencing confirmed that it was identical to the Moraten measles strain contained in the MMR. He died in December 1993. As the patient’s CD4 count was below the detectable level, he was in immunologic category 3, where MMR vaccination is contraindicated.

Research Priorities

Studies to address the following issues are urgently needed:

  • To determine the titers correlating with seroprotection for each individual vaccine antigen after varicella and MMR vaccines in HIV-infected persons.
  • To assess the safety and immunogenicity of concurrently administering varicella and MMR vaccines, or providing the combination MMRV vaccine (in order to minimize the number of administered doses) in HIV-infected children.
  • To assess the safety and immunogenicity of varicella vaccine in susceptible HIV-infected adolescents and adults.

The long-term immunity to varicella after vaccination of HIV-infected children is unknown. The studies by Levin et al. and Bekker et al. suggest there is a decline in the proportion of patients with protective antibody levels and CMI over time.(18),(19)

At present, it is unknown whether:

  • this decline is associated with future increased risk of vaccine-modified (breakthrough) disease, with its attendant complications and/or reactivation of zoster;
  • any sequential testing is required to confirm whether protective antibody or CMI has declined;
  • booster doses are warranted if protective antibody or CMI decline significantly over time; and
  • VariZIG administration is required in previously vaccinated patients who have lost protective antibody or CMI, upon future exposure to a wild-type varicella case. 

Long-term follow-up studies are needed to answer these questions.

Tables

Table 1. Immunonologic Categories for HIV-Infected Children (Based on Age-Specific CD4+ T-Lymphocyte Counts and Percent of Total Lymphocytes)(2-3)
Immunologic categories

HIV-infected patient’s age

< 12 months

1–5 years

≥ 6 years*

Age-specific CD4+ T-lymphocyte counts
(X 106/L)
Percent of total lymphocytes
(%)
 Age-specific CD4+ T-lymphocyte counts
(X 106/L)
 Percent of total lymphocytes
(%)
 Age-specific CD4+ T-lymphocyte counts
(X 106/L)
 Percent of total lymphocytes
(%)
1 ≥ 1,500 ≥ 25 ≥ 1,000 ≥ 25 ≥ 500 ≥ 25
2 750–1,499 15–24 500–999 15–24 200–499 15–24
3 < 750 < 15 < 500 < 15 < 200 < 15

* Previously recommended for children 6 to 12 years old, but modified in this NACI update to include adolescents and adults, based on expert opinion.

 
Table 2. Clinical Categories for HIV-Infected Children (2-3)
Clinical categories Symptoms
N: Not symptomatic Children who have no signs or symptoms considered to be the result of HIV
infection or who have only one of the conditions listed in category A.
A: Mildly symptomatic Children with two or more of the conditions listed below but none of the conditions listed in categories B and C.
  • Lymphadenopathy (≥ 0.5 cm at more than two sites; bilateral = one site)
  • Hepatomegaly
  • Splenomegaly
  • Dermatitis
  • Parotitis
  • Recurrent or persistent upper respiratory infection, sinusitis or otitis media
B: Moderately
symptomatic
Children who have symptomatic conditions, other than those listed for category
A or C, that are attributed to HIV infection. Examples of conditions in clinical category B include, but are not limited to:
  • Anemia (<8 gm/dL), neutropenia (<1,000/mm3), or thrombocytopenia (<100,000/mm3) persisting for > 30 days
  • Bacterial meningitis, pneumonia or sepsis (single episode)
  • Candidiasis, oropharyngeal (thrush), persisting (> 2 months) in children > 6 months of age
  • Cardiomyopathy
  • Cytomegalovirus infection, with onset before 4 weeks of age
  • Diarrhea, recurrent or chronic
  • Hepatitis
  • Herpes simplex virus (HSV) stomatitis, recurrent (more than two episodes within 1 year)
  • HSV bronchitis, pneumonitis or esophagitis with onset before 4 weeks of age
  • Herpes zoster (shingles) involving at least two distinct episodes or more than one dermatome
  • Leiomyosarcoma
  • Lymphoid interstitial pneumonia (LIP) or pulmonary lymphoid hyperplasia complex
  • Nephropathy
  • Nocardiosis
  • Persistent fever lasting > 4 weeks
  • Toxoplasmosis, onset before 4 weeks of age
  • Varicella, disseminated (complicated chickenpox)
  Children who have any of the conditions listed below, which fulfill the case definition for acquired immunodeficiency syndrome (AIDS):
  • Serious bacterial infections, multiple or recurrent (i.e., any combination of at least two culture-confirmed infections within a 2-year period), of the following types: septicemia, pneumonia, meningitis, bone or joint infection, or abscess of an internal organ or body cavity (excluding otitis media, superficial skin or mucosal abscesses and in-dwelling catheter-related infections)
  • Candidiasis, esophageal or pulmonary (bronchi, trachea, lungs)
  • Coccidioidomycosis, disseminated (at site other than or in addition to lungs or cervical or hilar lymph nodes)
  • Cryptococcosis, extrapulmonary
  • Cryptosporidiosis or isosporiasis with diarrhea persisting > 4 weeks
  • Cytomegalovirus disease with onset of symptoms at age > 4 weeks (at a site other than liver, spleen or lymph nodes)
  • Encephalopathy (at least one of the following progressive findings present for at least 2 months in the absence of a concurrent illness other than HIV infection that could explain the findings): a) failure to attain or loss of developmental milestones or loss of intellectual ability, verified by standard developmental scale or neuropsychological tests; b) impaired brain growth or acquired microcephaly demonstrated by head circumference measurements or brain atrophy demonstrated by computerized tomography or magnetic resonance imaging (serial imaging is required for children <2 years of age); c) acquired symmetric motor deficit manifested by two or more of the following: paresis, pathologic reflexes, ataxia or gait disturbance
  • Herpes simplex virus infection causing a mucocutaneous ulcer that persists for > 4 weeks; or bronchitis, pneumonitis or esophagitis for any duration affecting a child > 4 weeks of age
  • Histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical or hilar lymph nodes)
  • Kaposi’s sarcoma
  • Lymphoma, primary, in brain
  • Lymphoma, small, noncleaved cell (Burkitt’s), or immunoblastic or large cell lymphoma of B-cell or unknown immunologic phenotype
  • Mycobacterium tuberculosis, disseminated or extrapulmonary
  • Mycobacterium, other species or unidentified species, disseminated (at a site other than or in addition to lungs, skin, or cervical or hilar lymph nodes)
  • Mycobacterium avium complex or Mycobacterium kansasii, disseminated (at site other than or in addition to lungs, skin, or cervical or hilar lymph nodes)
  • Pneumocystis carinii pneumonia
  • Progressive multifocal leukoencephalopathy
  • Salmonella (non-typhoid) septicemia, recurrent
  • Toxoplasmosis of the brain with onset at > 4 weeks of age
  • Wasting syndrome in the absence of a concurrent illness other than HIV infection that could explain the following findings: a) persistent weight loss >10% of baseline; OR b) downward crossing of at least two of the following percentile lines on the weight-for-age chart (e.g., 95th, 75th, 50th, 25th, 5th) in a child ≥ 1 year of age; OR c) <5th percentile on weight-for-height chart on two consecutive  measurements, ≥ 30 days apart; PLUS a) chronic diarrhea (i.e., at least two loose stools per day for ≥ 30 days); OR b) documented fever (for ≥ 30 days, intermittent or constant)
 
Table 3. Immunologic Responses After Varicella Vaccination of HIV-Infected Children, Modified from Levin et al. (18)
  Control group
Past history of varicella (n=15)
Group I
CDC category N–A/1 (n=43)
Group II
CDC category B/2   (n=37)
Group III
CDC category C/3, reverted to N–A/1 on HAART (n=17)
Median age (range) 5.2 yrs  (4.6–6.9) 4.0 yrs  (3.2–5.2) 5.0 yrs  (4.2–5.8) 6.2 yrs  (3.3–6.7)
Median CD4 count (%)
Median log HIV-VL
1,072 (38%)
-
1,264 (36%)
3.9
1,022 (31%)
3.2
1,387 (38%)
3.0
Antibody level by FAMA ≥ 1:2 at # wks. post-2nd dose:
– at 20 wks.
– at 52 wks.
– at 104 wks.
– at 156 wks.

-
73%
54%
30%

59%
43%
36%
52%

72%
58%
50%
29%

71%
65%
47%
38%

CMI achieving SI ≥ 3.0 for those negative at baseline
– at 20 wks.
– at 52 wks.
– at 104 wks.
– at 156 wks.


65%
55%
70%

70%
70%
68%
55%

80%
78%
58%
43%

83%
92%
92%
33%

HAART = highly active antiretroviral therapy
SI = stimulation index
VL = viral load

 
Table 4. Quality and Strength of Evidence (34-36)
Level of evidence based on research design
I Evidence obtained from at least one properly randomized, controlled trial.
II-1 Evidence obtained from well-designed, controlled trials without randomization.
II-2 Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one centre or research group (including immunogenicity studies). 
II-3 Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments could also be included in this category. 
III Opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees.
Quality (internal validity) rating
Good A study (including meta-analyses or systematic reviews) that meets all design-specific criteria* well.
Fair A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion* but has no known “fatal flaw.”
Poor A study (including meta-analyses or systematic reviews) that has at least one design-specific* “fatal flaw,” or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations.
* General design specific criteria are outlined in Harris et al., 2001.(36)
NACI recommendation for immunization – grades
A NACI concludes that there is good evidence to recommend immunization.
B NACI concludes that there is fair evidence to recommend immunization.
C NACI concludes that the existing evidence is conflicting and does not allow making a recommendation for or against immunization; however, other factors may influence decision.
D NACI concludes that there is fair evidence to recommend against immunization.
E NACI concludes that there is good evidence to recommend against immunization.
I NACI concludes that there is insufficient evidence (in either quantity and/or quality) to make a recommendation; however, other factors may influence decision making.

Acknowledgements

† This statement was prepared by Dr. Ben Tan and Dr. Shainoor Ismail and approved by NACI.
Members: Dr. J. Langley (Chair), Dr. B. Warshawsky (Vice-Chairperson), Dr. S. Ismail (Executive Secretary), Dr. N. Crowcroft, Ms. A. Hanrahan, Dr. B. Henry  , Dr. D Kumar, Dr. S. McNeil, Dr. C. Quach-Thanh, Dr. B. Seifert, Dr. D. Skowronski, Dr. C. Cooper
Liaison Representatives: Dr. B. Bell (Center for Disease Control and Prevention), Ms. K. Pielak (Canadian Nursing Coalition for Immunization), Dr. S. Rechner (College of Family Physicians of Canada), Dr. M. Salvadori (Canadian Paediatric Society), S. Pelletier (Community Hospital Infection Control Association), Dr. N. Sicard (Canadian Public Health Association), Dr. V. Senikas (Society of Obstetricians and Gynaecologists of Canada), Dr. P. Plourde (Committee to Advise on Tropical Medicine and Travel), Dr. P.Van Buynder (Council of Chief Medical Officers of Health)
Ex-Officio Representatives: Ms. M. FarhangMehr (Centre for Immunization and Respiratory Infectious Diseases), Dr. S. Desai (Centre for Immunization and Respiratory Infectious Diseases), LCol (Dr.) James Anderson (Department of National Defence), Dr. Ezzat Farzad (First Nations and Inuit Health Branch – Office of Community Medicine), Dr. J. Xiong (Biologics and Genetic Therapies Directorate), Dr. D. Elliott (Centre for Immunization and Respiratory Infectious Diseases, Dr. P. Varughese (Centre for Immunization and Respiratory Infectious Diseases), Dr. R. Pless (Centre for Immunization and Respiratory Infectious Diseases)

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