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Persistent Humoral Immune Defect in Highly Active Antiretroviral Therapy–Treated Children With HIV-1 Infection: Loss of Specific Antibodies Against Attenuated Vaccine Strains and Natural Viral Infection

^a Emma Children's Hospital
^b Departments of Human Retrovirology
^c Medical Microbiology, Section of Clinical Virology, Academic Medical Center, Amsterdam, Netherlands

	ABSTRACT

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OBJECTIVE. In the pre–highly active antiretroviral therapy era, a loss of specific antibodies was seen. Our objective with this study was to describe the loss of specific antibodies during treatment with highly active antiretroviral therapy.

METHODS. In a prospective, single-center, cohort study of 59 children with HIV-1 infection, we investigated the long-term effect of highly active antiretroviral therapy on the titers and course of specific antibodies against measles, mumps, and rubella vaccine strains compared with wild-type varicella zoster virus, cytomegalovirus, and Epstein-Barr virus.

RESULTS. During highly active antiretroviral therapy, age-adjusted CD4⁺ T cells and B cells increased, whereas total immunoglobulin levels declined. Although these children were preimmunized before the start of highly active antiretroviral therapy, only 24 (43%) had antibodies against all 3 measles, mumps, and rubella. Antibodies against measles, mumps, and rubella were lost in 14 (40%), 11 (38%), and 5 (11%) children who were seropositive at baseline. We also observed loss of varicella zoster virus immunoglobulin G in 7 (21%) of 34, cytomegalovirus immunoglobulin G in 3 (7%) of 45, but none of 53 Epstein-Barr virus–seropositive children. During highly active antiretroviral therapy, primary vaccination in 3 patients and 15 revaccinations in those with negative serology demonstrated incomplete seroconversion.

CONCLUSIONS. Humoral reactivity in children with HIV-1 infection remains abnormal during highly active antiretroviral therapy. Despite immune reconstitution, antibodies against live-attenuated vaccine and wild-type natural virus strains disappear over time in up to 40% of children with HIV-1 infection.

Key Words: pediatric HIV • MMR vaccination • VZV serology • immunoglobulin • CD19

Abbreviations: HAART—highly active antiretroviral therapy • MMR—measles—mumps—and rubella • VZV—varicella zoster virus • CMV—cytomegalovirus • EBV—Epstein-Barr virus • RVP—Rijksvaccintieprogramma (state vaccination program) • pVL—plasma viral load • AU—arbitrary units • Ig—immunoglobulin • VCA—viral capsid antigen

HIV-1 infection causes a progressive immunodeficiency as a result of the loss of CD4⁺ T cells. Consequently, several abnormalities in the B-cell compartment occur. These include a progressive decline in total CD19⁺ B cells, with polyclonal hyperimmunoglobulinemia,^1,2 impaired reactivity to immunization,³ and loss of specific antibodies.⁴ After successful treatment with highly active antiretroviral therapy (HAART), CD4⁺ T-cell count increases and a reduction of the hyperimmunoglobulinemia is seen.^5,6 During the first 12 weeks of HAART, an increase in absolute B-cell count is found in most patients.⁷

The function of the B-cell compartment is to produce neutralizing antibodies and to maintain serologic memory after primary infection. After measles, mumps, and rubella (MMR) vaccination, lifelong immunity is maintained in healthy individuals. Before the era of HAART, it was found that in children with HIV-1 infection, the initial response to vaccination is weaker and transient compared with healthy children.^3,4 However, the long-term effect of HAART on the B-cell count and function in children is unclear.

Vaccination has led to a decline in the incidence of measles, mumps, and rubella cases in otherwise healthy children, although outbreaks still occur. MMR coverage as well as seroprevalence in the Netherlands is high at 94%, with an increase after routine booster immunization at 9 years of age.^8,9

In this study, we investigated whether the B-cell memory was restored during treatment with HAART. As a surrogate marker for B-cell memory, we determined whether the loss of specific antibodies against the components of the MMR vaccination would be influenced by the treatment with HAART. We compared the MMR serology with the humoral response against natural viral pathogens—varicella zoster virus (VZV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV)—and tested whether any loss of specific antibodies would continue despite treatment with HAART and consecutive immune reconstitution and, if so, whether this is only seen against live-attenuated viruses or against wild-type viruses as well.

	METHODS

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The Pediatric Amsterdam Cohort on HIV-1 consists of children and young adolescents who are younger than 18 years. Since 1997, patients have received HAART that consists of 2 nucleoside-analog reverse-transcriptase inhibitors and at least 1 protease inhibitor or a non–nucleoside-analog reverse-transcriptase inhibitor. For the present study, we selected all children who had started therapy between 1997 and 2005. The medical ethical committee approved the study for serotyping and (re) vaccination. Caregivers gave written informed consent.

Blood Samples
During the routine blood tests, antibody levels against MMR were checked annually, and children were (re)immunized when indicated. The Dutch national vaccination program (Rijksvaccinatieprogramma [RVP]) includes MMR vaccination at the ages of 14 months and 9 years.⁹

Lymphocytes, T-Cell Subsets, and T-Cell Proliferation
Numbers of B cells (CD19⁺), T cells (CD3⁺), and subsets (CD3⁺CD4⁺, CD3⁺CD8⁺) were determined by standard FACScan procedures, as described before in detail.⁸ Age correction for CD4⁺ and CD8⁺ T cells and CD19⁺ B cells was done by dividing the counts by the mean of an age-matched healthy control group.⁸

Plasma HIV-1 RNA Determination
Plasma HIV-1 RNA concentration was determined using either Nuclisens HIV-1 RNA QT (Biomérieux, Boxtel, the Netherlands) or Versant HIV-1 RNA 3.0 (Bayer, Tarrytown, NY). All tests were performed according to the instructions of the manufacturers. Because of a different lower limit of detection in the 2 assays, all plasma viral loads (pVLs) <400 copies per mL were considered as undetectable.

MMR, VZV, CMV, and EBV Serology
Specific antibodies to measles and mumps were determined by enzyme immunoassay (Virotech, Rüsselsheim, Germany). Serology of measles and mumps is expressed as arbitrary units (AU) per milliliter. An antibody amount of 9.0 AU/mL or more was regarded as positive. Specific antibodies to rubella were determined by Axsym (Abbott, Abbott Park, IL), expressed as IU per milliliter. An antibody amount of 10.0 IU/mL was regarded as positive. Specific antibodies to VZV were determined by Vidas tests (Biomerieux, Lyon, France). The test values of this assay were converted to IU per milliliter using the conversion factor as determined by van der Zwet et al.¹⁰ An antibody amount of 0.139 IU/mL was regarded as positive. CMV antibodies were defined by Axsym assays, expressed as AU per milliliter. An antibody amount of 15 AU/mL was regarded as positive. Specific immunoglobulin G (IgG) against the viral capsid antigen (VCA) and against nuclear antigen of EBV was determined qualitatively using respectively the anti-EBV VCA IgG enzyme-linked immunosorbent assay and the anti-EBV nuclear antigen of EBV IgG enzyme-linked immunosorbent assay (Biotest, Dreieich, Germany). All tests were performed following the instructions of the manufacturers.

Seropositivity was defined by the presence of a positive specific IgG after the age of 18 months to exclude any confounding contribution of maternal antibodies in the very young. Serologic tests within 3 months after the administration of blood products were excluded from the analyses.

Statistical Analyses
Statistical analyses were performed using SPSS 11.5 for Windows (SPSS Inc, Chicago, IL). All P values were 2-tailed. P < .05 was considered statistically significant. Continuous data were analyzed using a Mann-Whitney U test. Categorical data were compared with a Fisher's exact test. Correlation was tested using the Spearman's correlation test. The mean age-adjusted CD4⁺ T cells, CD19⁺ B cells, and total IgG were modeled using a mixed model that incorporated repeated measurements. This model handles missing data adequately by estimating the outcome using a first-order autoregressive structure. Differences in these estimates between various levels of the variable were tested for significance using t statistics.

	RESULTS

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Since 1997, 59 children started treatment with HAART at a median age of 4.3 years; 49% of the children were male, and 24 presented with a Centers for Disease Control and Prevention C classification. Median follow-up since the start of HAART at the time of analysis was 205 weeks (Table 1).

View larger version (23K): [in this window] [in a new window]   FIGURE 1 Immunologic markers during 4 years of treatment with HAART. A, Total IgG (left y-axis) and total IgM and total IgA (right y-axis). B, Age-adjusted CD4+ T-cell ratio (left y-axis) and age-adjusted CD19+ B-cell ratio (right y-axis). Shown are estimated mean and SEM.

After numeric and functional immune reconstitution as a consequence of HAART, the loss of specific antibodies was not anticipated. Several variables were tested for a correlation with the defective humoral B-cell memory response; age-adjusted CD19⁺ B-cell and CD4⁺ T-helper cell counts, HIV load at start of HAART, age at start of HAART, mode of transmission, and gender. None of these variables correlated with the loss of specific antibodies against all 3 MMR components taken together.

In contrast to the analysis for the MMR components combined, children who lost their measles antibodies were younger than children with sustained antibodies (median: 2.5 vs 6.2 years; P = .04) when these components were analyzed separately. With the surprising exception of measles antibodies, almost all children who had HIV-1 infection and showed a loss of specific antibodies during follow-up against mumps and rubella already demonstrated lower antibody titers at baseline. Only in that case of rubella did this difference in antibody titers at baseline reach significance, comparing the children who had HIV-1 infection and lost these specific antibodies with those who sustained their specific antibody titer (median: 18.1 vs 73.9 IU/mL; P = .006; Fig 2). These data suggest a weaker response on primary vaccination before the start of HAART. Looking at vertical (n = 52) and sexual (n = 7) infection separately, 1 of the sexually infected adolescents was found to lose antibodies against a single component of the MMR vaccine during follow-up, whereas 26 vertically infected children lost antibodies against at least 1 component (P = .22).

View larger version (14K): [in this window] [in a new window]   FIGURE 2 Baseline serology in children who lose specific antibodies and children with sustained antibodies. A, Measles antibodies at baseline (AU). B, Mumps antibodies (AU). C, Rubella antibodies (IU). Rubella titers at baseline were lower in children who lost these specific antibodies than in children who had sustained antibodies (P = .005). D, CMV antibodies (AU). CMV titers at baseline were lower in children who lost these specific antibodies than in children who had sustained antibodies (P < .001). E, VZV antibodies (IU) at baseline.

In contrast, 15 children received a second MMR immunization during the treatment with HAART because of the lack of specific antibodies against 1 or more components after their primary vaccination. Revaccination took place before the planned standard vaccination according to the RVP at 9 years of age. Characteristics of these children at the time of vaccination are shown in Table 3. Median age of the children was 7.3 years; median CD4⁺ T-cell count before vaccination was 1050 cells per µL (interquartile range: 830–1190). For these, the median time between the start with treatment and the date of vaccination was 119 weeks. Of the 10 children who were negative for the measles component before HAART, 6 (60%) seroconverted, 8 (89%) of 9 seroconverted for mumps, and 4 (80%) of 5 seroconverted for rubella (Fig 3). Antibodies against mumps and rubella, although detectable before revaccination, were no longer detectable after vaccination in 1 child (Table 4).

View larger version (12K): [in this window] [in a new window]   FIGURE 3 Serologic reaction before and after booster MMR vaccination during treatment with HAART.

	DISCUSSION

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In the present study, we evaluated the serologic responses against the live-attenuated viral strains of the MMR vaccine as well as naturally occurring common viral infections in children with HIV-1 infection (VZV, CMV, and EBV). We demonstrate that only 43% of the children with HIV-1 infection had specific antibodies detectable against all 3 MMR components at baseline. During treatment with HAART, 40% of the children lost specific MMR antibodies that were present at baseline despite immune reconstitution. Although less frequently, specific antibodies against naturally occurring VZV and CMV also were lost in 21% and 7% of the children, respectively.

The discordant MMR responses before HAART treatment are in line with the findings in the pre-HAART era.³ However, the low rate of seropositivity and the loss of specific antibodies are in clear contrast with our previous cross-sectional study in >200 healthy children of mixed racial background, in which we found that >90% of the children had specific antibodies against all 3 MMR components above the age of 3 years, further increasing to 100% after routine reimmunization at 9 years of age.⁸

In a longitudinal study in >350 healthy children, specific antibodies against measles and rubella, when regularly measured over a period of 12 and 15 years, respectively, remained positive in 99% to 100% of the children.^12,13 Mumps antibodies were positive in 86% of the same after 9 years of follow-up.¹⁴ These longitudinal data in pediatric control subjects support the relevance of the increased loss of specific antibodies in our cohort of HAART-treated children, irrespective of the immune reconstitution and normalized age-adjusted CD4⁺ T-cell counts on HAART.

Age was not found to correlate with the loss of specific antibodies in our cohort. Therefore, a relation between time since vaccination and start of HAART is not likely.

While on HAART, children with HIV-1 infection also showed vaccine failure on boosting. Revaccination resulted in seroconversion in only 60% to 85% of the children. Also in the pre-HAART era, it was found that children with HIV-1 infection demonstrated both primary vaccine failure and loss of antibodies after an initial response.⁴ In a recent study of 18 children who were treated with HAART and did not have evidence of measles antibodies at baseline after previous immunization, the seroconversion rate was 83% after reimmunization.¹⁵ Eleven children had antibody levels tested after 1 year of follow-up, and only 8 (73%) showed sustained antibody levels. We further extend these data, showing that this loss of antibodies is not unique to measles,^15–17 and is observed for wild-type viruses as well. In total, 27 (46%) children lost antibodies against at least 1 of the MMR, VZV, or CMV strains. Seventeen children lost antibodies against 1, 5 against 2, 4 against 3, and 1 against 4 of these viruses.

Loss of specific antibodies determines an increased risk for serious infection. In areas with a high HIV-1 prevalence, children with HIV-1 infection have high rates of mortality attributable to measles. Although the risk for waning specific antibody levels in communities with a high coverage rate of vaccination may be limited as a result of herd immunity, outbreaks still occur in the developed world.¹⁸ Waning immunity also can be a potential problem for pregnant women who have HIV-1 infection and come in contact with rubella, VZV, or CMV. Furthermore, in a study cohort of 1832 women with HIV-1 infection, an increased risk for shingles was found, irrespective of HAART.¹⁹ After primary infection, CMV and EBV persist for life and go into a stage of latency in epithelial tissue and immune cells from where they may reactivate unnoticed.²⁰ Whereas humoral immunity against EBV was not affected, CMV-specific antibodies unexpectedly were lost in 3 children.

Because the decline in total IgG during HAART and the decline in MMR-specific antibodies are not correlated, these phenomena are unrelated and the consequence of different mechanisms. Hyper-IgG before start of HAART could be produced by low-avidity polyclonal B-cell reactivity, whereas specific memory B-cells are exhausted as a result of inappropriate stimulation as well as the loss of antigen-specific CD4⁺ T-helper cells.^21,22 During HAART, an increase in total peripheral blood B-cell counts was observed without any change in the relative memory B cell (IgD^– CD27⁺) fraction (data not shown). However, B-cell memory may not recover functionally, as indicated by our specific antibody data and supported by reports on defective B-cell function in vitro.^5,23,24 Because plasma cells originate from antigen-triggered B cells, a shorter life span of plasma cells in children with HIV infection may result in the decline in specific antibody,²⁵ which is a completely uninvestigated issue.

Similar findings on vaccination responses and the loss of specific antibodies have been reported after chemotherapy and bone marrow transplantation.^26,27 The nature of the immune reconstitution is different, of course, in these settings.

Two important issues warrant additional study. First, VZV-specific cell-mediated immunity has been shown to be unresponsive to HAART.²⁸ Therefore, waning immunity against VZV may be both humoral and cellular in nature. Although beyond the scope of this study, proliferation tests against MMR and herpes viral antigens over time should give more insight in the biology of the loss of specific antibodies. Second, the order of HIV infection and previous vaccination status may be important for the induction of long-lasting B-cell memory. Studies in adults should be performed to find evidence for the impact of "time of infection."

A shortcoming of this study is the lack of a control group of healthy children who were followed prospectively. Such a control group was considered unethical for the longitudinal nature and multiple venipunctures in healthy children required for direct comparisons. Although MMR serology data in previous longitudinal cohorts of healthy children^12–14 showed that 86% to 100% of the children maintained specific antibodies during a period of 9 to 12 years when measured every 1 to 3 years, this was at the time of vaccine introduction, and the role of boosting by (subclinical) exposure to the wild-type virus disease is difficult to assess. Using the same assays, our own cross-sectional study in healthy children (admitted to the hospital for unrelated minor trauma or elective surgery) indicated good levels of seroprotection.⁸ MMR vaccination is part of the standard vaccination program in the Netherlands, covering >95% of all children since its national introduction in 1987. Only rarely, local outbreaks that are confined to small regions occur in the Netherlands, which are considered to have impact neither on the general population nor on the serology against all 3 MMR components.

The loss of specific antibodies as observed in >40% of children with HIV infection does not seem to occur to the same extent in healthy children. It still remains unclear whether the loss of specific antibodies poses a real threat to HAART-treated children.

Regular testing for the loss of specific antibodies in children with HIV infection seems mandatory. Repeated immunization may support further the antigen-specific CD4⁺ T-cell help in maintaining memory B- and plasma cell function, irrespective of HAART.

	ACKNOWLEDGMENTS

 
This research was funded by AIDS Foundation (Netherlands) grant 2002 7006.

We thank E. le Poole and A. van der Plas for support and care of the children and Drs R.A.W. van Lier and H. Schuitemaker for critically reading and commenting on the manuscript.

	FOOTNOTES

 
Accepted Feb 21, 2006.

Address correspondence to Taco W. Kuijpers, MD, PhD, Emma Children's Hospital, Academic Medical Center, Room G8-205, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands. E-mail: t.w.kuijpers{at}amc.uva.nl

The authors have indicated they have no financial relationships relevant to this article to disclose.

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