Published online December 17, 2007
PEDIATRICS Vol. 121 No. 1 January 2008, pp. e150-e156 (doi:10.1542/peds.2007-0564)
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ARTICLE

Primary Varicella and Herpes Zoster Among HIV-Infected Children From 1989 to 2006

Sarah M. Wood, BAa, Samir S. Shah, MD, MSCEb,c,d,e,f, Andrew P. Steenhoff, MDc,d,f and Richard M. Rutstein, MDa,b,d

a Special Immunology Service
b Divisions of General Pediatrics
c Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
d Departments of Pediatrics
e Epidemiology
f Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania


   ABSTRACT
TOP
 ABSTRACT
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVES. The primary objective of this study was to determine the incidence of herpes zoster in perinatally HIV-infected children. Secondary objectives included assessing the impact of highly active antiretroviral therapy and varicella zoster virus immunization on primary varicella and herpes zoster incidence and identifying risk factors for herpes zoster. We hypothesized that the incidence of herpes zoster has decreased in this population as a result of highly active antiretroviral therapy and routine varicella zoster virus immunization.

PATIENTS AND METHODS. This retrospective cohort study included HIV-infected children at a pediatric HIV clinic from 1989 to 2006. Incidence rates for 3 intervals (1989–1996, 1997–1999, and 2000–2006) were compared on the basis of introduction of highly active antiretroviral therapy (1996) and varicella zoster virus vaccination (1999). A Cox proportional-hazards regression model was developed for the time to herpes zoster among the subset of patients with primary varicella infection.

RESULTS. In 356 patients followed for 1721 person-years, the incidence of herpes zoster according to period was 30.0 per 1000 person-years in 1989–1996, 31.9 per 1000 person-years in 1997–1999, and 6.5 per 1000 person-years in 2000–2006. There was no difference in incidence-rate ratio between 1989–1996 and 1997–1999. However, there was a significant difference in herpes zoster incidence when comparing 1989–1999 with 2000–2006. The incidence of primary varicella zoster virus infection and herpes zoster in the 57 patients who received the varicella zoster virus vaccine was 22.3 per 1000 and 4.5 per 1000 person-years, respectively. Highly active antiretroviral therapy at the time of primary varicella zoster virus infection was protective against herpes zoster and increased herpes zoster-free survival.

CONCLUSIONS. The incidence of herpes zoster has decreased since 1989. The decline occurred after 2000, likely representing the combined effect of immunization and highly active antiretroviral therapy. The use of highly active antiretroviral therapy at the time of primary varicella zoster virus infection decreased the risk of herpes zoster and increased herpes zoster-free survival. Varicella zoster virus immunization was effective in preventing both primary varicella zoster virus and herpes zoster in this cohort.

Key Words: HIV • varicella • herpes zoster • pediatric

Abbreviations: VZV—varicella zoster virus • HZ—herpes zoster • HAART—highly active antiretroviral therapy • CDC—Centers for Disease Control and Prevention • IgG—immunoglobulin G • CMI—cell-mediated immunity • IVIg—intravenous immunoglobulin • VZIg—varicella zoster immunoglobulin • CI—confidence interval • PY—person-year • IQR—interquartile range

Varicella zoster virus (VZV), an {alpha} herpesvirus, is a common childhood pathogen causing chickenpox in both healthy and immunocompromised children. After primary infection, the virus becomes latent in the dorsal root ganglia and may reactivate to cause herpes zoster (HZ) in patients with compromised immune systems.1 Although HZ is often regarded as a disease of the elderly, HIV-infected children develop HZ at a rate 7 to 20 times greater than their uninfected peers.2 Immune dysfunction places all HIV-infected children at risk for HZ, but specific risk factors in this population remain to be determined.

The effect of highly active antiretroviral therapy (HAART), introduced as standard therapy in 1996, on the incidence and course of HZ remains unclear. One recent multicenter study found that the introduction of HAART was associated with a >50% decrease in the incidence of HZ.3 However, other studies have demonstrated an association between HZ and a recent initiation of HAART,4,5 which suggests that HZ may be an immune reconstitution disease resulting from a hyperactive immune response that occurs soon after the initiation of HAART in severely immunodeficient patients.4,6 Understanding the relationship between HAART and HZ may affect decisions regarding timing and implementation of antiretroviral therapy in patients with a history of HZ or primary VZV infection.

In May of 1999, the Centers for Disease Control and Prevention (CDC) and the Advisory Committee on Immunization Practices extended VZV vaccination recommendations to include HIV-infected children who were asymptomatic or had minimal evidence of immunosuppression.7 The impact of this strategy on primary VZV infection and HZ incidence rates in HIV-infected children and adolescents is not known. Because of impaired cellular and humoral immunity, HIV-infected children may not retain sufficient immunologic memory after vaccination to prevent primary VZV infection or HZ. In clinical trials of the vaccine in HIV-infected children, only 60% to 70% had detectable anti-VZV immunoglobulin G (IgG) titers 1 year after immunization despite the initiation of HAART.8 Similarly, Weinberg et al9 concluded that HAART had no effect on the duration of VZV-specific cell-mediated immunity (CMI). At present, the magnitude of VZV disease reduction in HIV-infected children is unknown, as is the duration of the vaccine's protective effect.

Studies that examined risk factors associated with HZ have yielded conflicting results. Although most studies have found that a reduced CD4+ cell count is associated with an increased risk for HZ,10–13 a recent study of HIV-infected adults indicated that increased susceptibility may occur at an intermediate level of CD4+ cell count.14 This observation has not been confirmed in children. The biological relationship between quantitative HIV viral load and HZ is also unclear.3,5

The primary aim of this study was to determine the change in incidence of HZ in children and adolescents with perinatally acquired HIV infection over 3 time periods. These periods were chosen based on the introduction of HAART in 1996 and VZV vaccination in 1999 in the study cohort. Secondary aims included determining risk factors for initial HZ episodes and assessing the impact of routine VZV immunization on HIV-infected children.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Design and Setting
A retrospective cohort study was conducted at the HIV clinic of the Children's Hospital of Philadelphia, an urban children's hospital. The clinic provides primary and specialty HIV care to perinatally infected infants, children, and adolescents. All of the patient encounters since 1990 have been entered into a clinical database. This study received approval from the hospital's institutional review board.

Selection of Participants
Patients with ≥2 outpatient visits in a calendar year between September 1, 1989, and September 1, 2006, were eligible for inclusion in the study. Patients with HIV acquired through sexual contact or blood transfusion were excluded.

Study Definitions
Primary VZV infection was defined as a multidermatomal episode diagnosed by a clinician. Laboratory confirmation was not required. HZ was defined as a unilateral vesicular rash in a dermatomal distribution without another identifiable cause. HAART was defined as receipt of ≥3 antiretroviral agents from ≥2 classes. The use of dual or monotherapy regimens was noted and analyzed as a separate category of therapy from HAART. Varicella-related complications included the following if they occurred within 30 days of onset of primary VZV infection: dissemination including pneumonia or encephalitis, ophthalmic or neurologic involvement, secondary bacterial infection, and recrudescence of vesicular rash.

Data Collection and Statistical Analysis
The medical charts of all of the eligible patients were reviewed by 1 of the authors. Data were collected from a clinical database and through directed chart review. Data abstracted included demographics, dates of primary VZV infection, HZ, VZV immunization, and anti-VZV IgG titer results. For each clinical episode (primary VZV infection, HZ, recurrent HZ, immunization, and censure point) the following data were also collected: antiretroviral therapy type, duration of regimen, CD4+ cell counts and percentages, plasma viral RNA levels, CDC clinical class, and use of intravenous immunoglobulin (IVIg) or varicella zoster immunoglobulin (VZIg) therapy.

Data were analyzed by using Stata 9.2 (Stata Corp, College Station, TX). Continuous variables were described using mean, median, and range values. Categorical variables were described using counts and percentages. Incidence rates and incidence-rate ratios were calculated for the 3 time periods: 1989–1996, 1997–1999, and 2000–2006. Of 71 cases of primary VZV infection and 29 cases of HZ, 21 (29.6%) and 5 (17%), respectively, occurred before enrolling in care at the study site. These cases did not contribute person-years (PYs) until the patients commenced care at the study site and were, therefore, not included in incidence-rate calculations.

We developed a Cox proportional-hazards regression model for the time to development of HZ among the subset of patients with documented primary VZV infection. Clinical and laboratory variables from the date of primary VZV infection, as well as treatment with HAART, VZIg, or IVIg, were considered in the model. Data on patients were censored at the time of death, the first episode of HZ, or using the censure date of September 1, 2006. The precise dates and clinical details of primary VZV infection for 8 (27%) of the 29 patients with HZ in the cohort were unknown. Therefore, these patients were excluded from the Cox model. Hazard ratios and 95% confidence intervals (CIs) were calculated to estimate the magnitude and precision of estimate of effect. A 2-tailed P value of <.05 was considered statistically significant.

HZ-free survival was described by using Kaplan-Meier survival estimates. Patients were censured at their first episode of HZ, death, or last clinic visit. HZ-free survival was compared in subgroups of patients on the basis of the presence or absence of HAART by using the log-rank test.


   RESULTS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Characteristics of the Study Population
Of the 260 patients with ≥2 outpatient visits in a calendar year, 4 were excluded because their HIV infection was acquired through either blood product transfusions (n = 2) or sexual contact (n = 2). The remaining 256 patients (99%), followed for 1761 PYs, were included in the study. The overall cohort was 59% female. The racial distribution included patients who were black (76%), white (14%), and Hispanic (8%). Characteristics of patients at their episodes of primary VZV infection and HZ are summarized in Table 1. Sixty-three subjects (17.7%) died during the study period.


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  		TABLE 1 Characteristics of Cohort Patients With Primary VZV Infection and/or HZ: 1989–2006

 
Incidence Data
The cumulative incidence of primary VZV infection was 40.9 per 1000 PYs (95% CI: 30.4–53.9). Three patients (4%) with primary VZV infection experienced recrudescence of their illness within 1 month. Fifty-seven patients received ≥1 dose of VZV vaccine and were followed for 224 PYs. The median per-person follow-up time after immunization was 3.1 years (interquartile range [IQR]: 1.7–4.9 years). The incidence of primary VZV infection in immunized patients was 22.3 per 1000 PYs (95% CI: 7.2–52.0). Five patients developed postvaccine VZV disease; in these patients, VZV infection developed 1, 7, 10, 19, and 45 months (median: 10 months) after immunization. One of these cases was severe and resulted in prolonged hospitalization. With the exception of the 1 patient who developed vesicular rash 1 month after immunization, there were no other adverse events in vaccinated patients.

HZ developed in 21 (29.6%) of the 71 patients with documented primary VZV infection. Patients with primary VZV were followed for a median of 7.3 years after primary infection (IQR: 5.5–10.2 years). The cumulative incidence of HZ was 17.4 per 1000 PYs (95% CI: 11.1–25.8). The incidence of HZ by time period is displayed in Table 2. There was no significant difference in incidence rates when comparing 1989–1996 and 1997–1999 (incidence-rate ratio: 1.06; 95% CI: 0.4–2.9). However, there was an 80% decrease in HZ incidence between 1989–1999 and 2000–2006 (incidence-rate ratio: 0.2; 95% CI: 0.1–0.6). Among the subset of immunized patients, the incidence of HZ was 4.5 per 1000 PYs (95% CI: 1.1–24.8), because 1 patient developed a single episode of HZ 3.8 years after receiving the VZV vaccine. Of patients with a documented initial episode of HZ, 50% had ≥1 recurrence (95% CI: 27%–73%) with a median of 1 recurrence (range: 1–9).


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  		TABLE 2 Incidence of HZ According to Key Time Periods

 
Clinical Characteristics
The clinical characteristics of primary VZV infections and HZ episodes are described in Table 1. The median time between primary VZV infection and HZ was 32 months. The median time from the initial episode of HZ to the first recurrence was 34.8 months. For primary VZV, 68% of episodes required inpatient hospitalization (median stay of 5 days) and 70% of patients with HZ required hospitalization (median stay of 5.5 days). Complications occurred in 15% of patients with HZ, with cellulitis occurring most commonly. CDC classification at the time of primary VZV infection was 8.5% class N, 14.3% class A, 22.8% class B, 35.7% class C, and 18.6% unknown. The CDC clinical classification of immunized patients was similarly diverse: 31% class N, 11% class A, 20% class B, and 25% class C. Of the immunized patients, 13% received the vaccine before their HIV diagnosis; therefore, clinical and immunologic data for these patients were not available.

Treatment Data
The majority of patients were not receiving HAART at the time of primary VZV, whereas approximately half of the patients were receiving HAART at the time of their initial episode of HZ (Table 1). At the time of the first HZ recurrence, 53% of patients were receiving HAART for a median duration of 35 months. When receiving their first VZV immunization, 75% of patients were on HAART for a median of 14 months.

Laboratory Features
Laboratory test results are summarized in Table 1. The median CD4+ percentage at the time of VZV immunization was 34% compared with 29% (P = .001) at the time of primary VZV infection. The median HIV-1 plasma viral RNA concentration at immunization was 200 copies per mL (IQR: 39–14000).

Anti-VZV IgG titer results for patients with a natural history of primary VZV infection or immunization are displayed in Table 3. The positive titer rate in patients with natural disease was significantly higher than the rate in patients with a history of immunization (odds ratio: 3.3; 95% CI: 1.2–8.8).


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  		TABLE 3 Summary of Anti-VZV IgG Titer Results of Patients With History of Primary Varicella or Varicella Immunization

 
Risk Factors
To identify risk factors for HZ that were present at the time of primary VZV infection, we constructed a Cox proportional-hazards model including all of the patients with documented primary VZV infection. Variables explored in the model were age, gender, race, CD4 percentage, CDC class, HAART, IVIg and VZIg therapy, and VZV immunization status. The results of the model are described in Table 4. Factors that were protective against subsequent development of HZ included receipt of HAART and age >5 years at the time of primary VZV infection. Hispanic race was significantly associated with progression to HZ. Gender, CD4 cell percentage, IVIg therapy, and a complicated course of primary VZV infection were not significantly associated with the subsequent development of HZ. We were unable to obtain a hazard ratio for VZV immunization status because of the small number of observations (n = 5). Because the majority of patients experienced primary VZV infection before routine viral load testing in 1997, this variable was not included in the model.


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  		TABLE 4 Results of the Cox Proportional-Hazards Regression Model: Risk Factors for HZ at the Time of Primary Varicella Infection

 
Kaplan-Meier survival estimates were constructed to measure HZ-free survival for patients with a documented history of primary VZV infection. Separate estimates were developed based on the presence or absence of HAART. The final analysis is displayed in Fig 1 and demonstrates increased HZ-free survival in patients receiving HAART at the time of primary VZV infection (log-rank test, P = .02).


Figure 1
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  		FIGURE 1 HZ-free survival for patients who were receiving HAART (dotted lines) versus no HAART (solid lines) at the time of primary varicella infection.

 

   DISCUSSION
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
We documented a significant decrease in the incidence of HZ since the introduction of VZV vaccination and HAART among children followed at a tertiary care pediatric HIV clinic. In secondary analysis, the VZV vaccine prevented episodes of primary VZV infection in this HIV-infected pediatric population with a breakthrough rate of 2% per year.

The 80% decline in HZ incidence occurred after 2000, likely representing the combined effect of VZV immunization and HAART in this population. Previous studies indicating a decrease in HZ in the post-HAART era have not accounted for the impact of routine VZV immunization.3,10 HZ incidence rates in the post-HAART era vary from 2 per 1000 PYs10 to 11 per 1000 PYs.3 Our HZ incidence rate of 6.5 per 1000 PYs for 2000–2006 falls within the range of these 2 studies while accounting for the impact of VZV vaccination.

Although single-center studies have found HAART not to be protective against development of HZ,5,14 the Pediatric AIDS Clinical Trials Group 219C Study found a protective role for HAART.3 However, these studies examined its use at the time of HZ rather than at the time of primary VZV infection. In contrast, we examined the effect of HAART when initiated before primary VZV and found that HAART protected against subsequent development of HZ. This suggests that the duration of HAART, rather than the simple receipt of HAART at the time of the HZ episode, may be a key factor in preventing HZ. In addition, we did not find recent initiation of HAART to be associated with HZ, suggesting that HZ did not manifest as a component of the immune reconstitution inflammatory syndrome.

Although we expected to find a reduction in HZ shortly after the introduction of HAART in 1996, our results demonstrate that the decline was delayed until after 2000. Rather than indicating that the declining incidence of HZ was related to VZV vaccination alone, this likely represents the gradual uptake of HAART within the cohort. In 1995–1996, only 2% of the cohort received HAART. This proportion increased to 74% in 1997–1998, reaching 85% by the beginning of 2000. In light of this trend, the decrease in HZ incidence seems to be temporally associated both with VZV vaccination and increased uptake of HAART within the cohort.

Our data also support the protective role of the VZV vaccine in preventing HZ in HIV-infected children. The incidence of HZ in immunized patients was substantially lower than that in patients with a history of primary VZV infection, suggesting that VZV vaccination serves a protective role. However, the independent protective effect of HAART cannot be determined. Previous data also support a decrease in HZ incidence after immunization in immunocompromised children. In the Varicella Vaccine Collaborative Study, children with leukemia who received the VZV vaccine had a lower rate of HZ (8 per 1000 PYs) compared with those with a past history of natural VZV infection (24 per 1000 PYs).15

The vaccine is currently licensed for use in minimally immunosuppressed HIV-infected children,7 although studies have validated its safe use in patients with a history of clinical immunosuppression or severe past CD4+ cell depression.8,16 Although the decrease in HZ among immunized patients could be related to their healthier immune status, we did not find this to be true in our cohort. Of the immunized patients, 45% were considered class B or C at vaccination. In addition, neither CD4+ cell percentage nor CDC classification was associated with progression to HZ in our model. Finally, although the difference between CD4+ cell percentage in patients at primary VZV infection and immunization was statistically significant, it is unlikely to be clinically relevant. Median values at both events were >25%, indicating minimal immunosuppression.

As 1 of the first long-term follow-up studies of VZV immunization in HIV-infected children, our analysis also includes novel findings regarding the effectiveness of VZV immunization against primary VZV infection. In the general population, the vaccine is 85% effective at preventing all VZV disease and 95% effective in preventing severe disease.17 Breakthrough rates of VZV infection in healthy immunized patients are 1% to 4% per year.18,19 In our cohort, there were 5 patients with VZV breakthrough, 4 of which occurred over 6 months after immunization, thereby representing true VZV disease rather than vaccine adverse reaction. This translates to a 91.2% effectiveness rate and an annual breakthrough rate of 2.2% during the study follow-up period.

Notably, the duration of humoral immunity was attenuated in this cohort. Only 41.5% of immunized patients maintained positive anti-VZV IgG titers at a median of 18.9 months after immunization, a significantly lower proportion than after natural infection.17,20 Decreased and attenuated anti-VZV IgG response is to be expected in HIV-infected children because of ongoing deficits of B-cell function.21,22 Although antiretroviral therapy bolsters CD4+ cell counts, it seems that subtle defects in B-cell and T-cell function persist during HAART leading to poor CMI and humoral immunity against VZV.9,21,22

Our data suggest that, although VZV-specific immune deficits persist in HIV-infected children even in the face of HAART, VZV vaccination may significantly lower the burden of disease in this population. The presence of only 1 adverse event in our cohort adds to current evidence regarding the safety of VZV vaccination in HIV-infected children, even in those with past immunosuppression.8,16,23 The low seroconversion rate in our cohort does not indicate a lack of protection, because immunity to VZV is multifactorial. Furthermore, the failure of IVIg to protect against HZ suggests that humoral response alone is not sufficiently protective. Finally, our median follow-up of 37 months after immunization is longer than the median 32-month period between natural primary VZV infection and HZ. It is reasonable to assume that postvaccination HZ would have emerged during our extensive follow-up time. This supports the conclusion that the risk of HZ is extremely low for HIV-infected patients receiving the live attenuated VZV vaccine. Additional studies are needed to elucidate the mechanism and duration of the VZV vaccine effect in HIV-infected children, as well as the effectiveness of vaccination after primary VZV infection in preventing HZ.

There are several limitations to this study. The routine use of antiretroviral prophylaxis to prevent vertical HIV transmission has led to a significant decrease in the number of HIV-infected children in the United States, which is reflected in the increasing age of our cohort. Because VZV infection is typically a disease of early childhood,1 one would expect incidence rates to decline as the mean patient age increases, thereby biasing data toward a falsely decreased incidence of primary VZV infection over time in a fixed cohort. However, as VZV immunization uptake increases, mathematical modeling predicts an increase in the average age of primary VZV infection, thereby delaying HZ reactivation to a later age.18

The retrospective cohort study design did not allow us to differentiate between the effects of HAART and VZV immunization on disease incidence. Therefore we are unable to assign sole causation for the decrease in HZ incidence to either HAART or immunization. Protective immunity against VZV disease involves both CMI and humoral immunity. Retrospectively we were also not able to assess VZV-specific CMI response. However, humoral immunity plays a key role in defense against recurrent VZV disease and is the most basic and cost-effective measure of vaccine response.17

In assessing the breakthrough rates of VZV disease in the cohort, we did not distinguish between vaccine Oka strain infection and wild-type infection. Finally, VZV serology was not obtained immediately after immunization or natural disease or at a uniform time point thereafter. This prevented us from determining antibody response at a specified interval from VZV exposure.


   CONCLUSIONS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
We have presented a significant decrease in the incidence of HZ in a cohort of perinatally HIV-infected children from 1989 to 2006. We believe this decrease is because of the combined effect of HAART and VZV immunization. Within our cohort, the use of HAART was protective against HZ and significantly increased HZ-free survival. VZV immunization was also largely effective in preventing both simple and complicated VZV and HZ disease, although seroconversion rates were low for immunized patients. These data support the safe and routine use of the VZV vaccine in HIV-infected children and adolescents, including those with a past history of immunosuppression.


   ACKNOWLEDGMENTS
 
This work was supported in part by the National Institutes of Health (Kirshstein T32 training grant AI 055435 [to Dr Steenhoff] and University of Pennsylvania Center for AIDS Research grant IP30AI45008-01 [to Dr Rutstein]) and the Doris Duke Charitable Foundation (Doris Duke Clinical Research Fellowship [to Ms Wood]).


   FOOTNOTES
 
Accepted Jun 12, 2007.

Address correspondence to Richard M. Rutstein, MD, Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Room 2419, Philadelphia, PA 19104. E-mail: rutstein{at}email.chop.edu

This work was presented at the annual meeting of the Pediatric Academic Societies; May 6, 2007; Toronto, Ontario, Canada.

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


   REFERENCES
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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  11. Dankner WM, Lindsey JC, Levin MJ. Correlates of opportunistic infections in children infected with the human immunodeficiency virus managed before highly active antiretroviral therapy. Pediatr Infect Dis J. 2001;20 :40 –48[CrossRef][ISI][Medline]
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