Cerebrovascular Disease in Children Perinatally Infected With Human Immunodeficiency Virus in Zambia

Abstract

Background

High rates of cerebrovascular disease (CVD) have previously been described in pediatric human immunodeficiency virus (HIV). However, little is known about pediatric CVD in the era of antiretroviral therapy or about the contribution of CVD to HIV-associated neurocognitive disorders.

Methods

We completed a neuroimaging substudy of the HIV-Associated Neurocognitive Disorders in Zambia study, a prospective cohort study of neurocognitive complications of pediatric HIV. Brain magnetic resonance imaging (1.5 T) was acquired for 34 HIV+ children on antiretroviral therapy and 17 HIV-exposed uninfected children (aged eight to 17 years). Demographics, medical history, neurological examination, and neuropsychologic testing results were collected. Two neuroradiologists, unaware of HIV status and clinical course, read the scans.

Results

CVD was identified in seven of 34 children with HIV (HIV+ CVD+) and no HIV-exposed uninfected children (21% vs 0%, P = 0.05). Three participants had white matter changes suggestive of small vessel disease, four had infarcts, and two had evidence of intracranial artery stenosis. Age of antiretroviral therapy initiation and exposure to protease inhibitors or efavirenz was not significantly different between children with and without CVD. HIV+ CVD+ children had significantly worse scores on a summary measure of cognition than the HIV+ CVD− group (NPZ8 score −0.57 vs 0.33, P = 0.04).

Conclusions

This study demonstrates high rates of CVD in children with HIV despite antiretroviral therapy, and worse cognitive performance in children with CVD. Longitudinal studies are necessary to determine the mechanisms and incidence of new-onset CVD in children with HIV.

Introduction

Symptomatic stroke affects between 0.1% and 3% of adults^1,2 with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome.^3,4 The prevalence of symptomatic stroke in children perinatally infected with HIV is unknown in the era of widespread use of antiretroviral therapy (ART), but in older studies it has been reported to be between 1.3% and 2.6%.^5,6 Neuroimaging and autopsy studies reveal an even higher incidence of stroke when clinically silent events are included. These studies report an incidence of stroke between 5% and 29% in adults with HIV^7,8 and between 1.5% and 35% in children with HIV.^9,10 When neuroimaging evidence of clinically silent cerebrovascular disease (CVD) is considered in addition to stroke, the rates of CVD in children with HIV have been reported as high as 59%.¹¹ CVD in individuals with HIV includes white matter abnormalities suggestive of small vessel ischemic disease or cerebrovascular insufficiency,^12,13 aneurysmal dilatation or stenosis of cerebral vasculature,^1,14 and moyamoya-like phenomenon,⁵ in addition to infarcts. When combination ART was first introduced, it was believed that there would be a decrease in stroke burden among individuals with HIV.¹⁵ Although ART reduces the risk of stroke caused by opportunistic infections or HIV-associated malignancies, there are data to suggest that the incidence of CVD in individuals with HIV infection has not changed in the ART era¹⁶ and may, in fact, be increasing¹⁷; this may be because HIV infection of the central nervous system (CNS) occurs early in the disease,¹⁸ before the initiation of ART, and can be a primary cause of stroke, either through vasculopathy or through inflammation.^6,19, 20, 21 In addition, some studies suggest that ART may increase the risk of stroke,^22,23 either through neurotoxicity²⁴ and the metabolic side effects of efavirenz²⁵ or through the metabolic side effects^19,26 and platelet activation²⁷ of protease inhibitors, although the data here are mixed.^28,29

Few studies have investigated the incidence of CVD among children with HIV in the ART era.⁶ To date, only five studies detail cases of CVD among children with HIV in sub-Saharan Africa.^4,18,30, 31, 32 The contribution of CVD to HIV-associated neurocognitive disorders has not been formally investigated in children. In a neuroimaging substudy of the HIV-Associated Neurocognitive Disorders in Zambia (HANDZ) study cohort, we noted that 21% children with HIV (versus 0% HIV-exposed uninfected [HEU] children) had neuroimaging evidence of CVD.³³ We evaluated the clinical associations, neurological examination findings, neuropsychologic testing results, and neuroimaging findings of these children. In addition, we compared their performance on a battery of neuropsychologic tests with those of both children with HIV who did not have imaging evidence of CVD and with HEU children. We hypothesized that CVD would be associated with poorer neurocognitive performance.