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Perinatal HIV in the brain - Editorial
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Mission incomplete despite combination antiretroviral therapy
Neurology Jan 2016
Beau M. Ances, MD, PhD, MSc, Jacqueline Hoare, MBChB, MRCPsych, MPhil From the Department of Neurology (B.M.A.), Washington University in Saint Louis, MO; and the Department of Psychiatry and Mental Health (J.H.), University of Cape Town, South Africa.
"Give a child love, laughter, and peace, not HIV.""-Nelson Mandela" HIV remains a global threat, with more than 3 million children worldwide living with this disease. Many HIV-infected (HIV+) children have neurologic complications that can lead to functional impairments and developmental delays.1 The expansion of effective combination antiretroviral therapy (cART) programs across resource-limited countries (e.g., President's Emergency Plan for AIDS Relief), has led to prolonged survival of vertically transmitted HIV+ children, with many now progressing into adolescence or adulthood. However, important differences exist between vertical and horizontal transmission.2 Challenges continue concerning how to establish the true cognitive status of the developing brain, given that neuropsychological performance (NP) is constantly changing during this period. Structural and functional neuroimaging may provide a noninvasive mechanism that helps reduce cultural and attentional confounds seen with NP testing.3
In this issue of Neurology®, Cohen et al.4 compare the brain integrity (NP and neuroimaging) of 35 perinatal HIV+ children receiving combination antiretroviral therapy (cART) to that of 37 HIV uninfected (HIV- controls). These authors demonstrate that perinatal HIV+ children, even those who have had long-term clinical and virologic control, have lower brain volumes, more white matter hyperintensities (WMHs), poorer brain structural integrity, and worse cognition compared to matched HIV- controls. In addition, neuroimaging changes correlated with HIV laboratory variables (e.g., higher viral load was associated with lower fractional anisotropy using diffusion tensor imaging). Multiple neuroimaging measures of brain structure were obtained in a difficult-to-study population in the Netherlands. The inclusion of a similar HIV- cohort is important for helping reduce overestimation of WMHs in the pediatric HIV+ population. Limitations of this study are the use of a cross-sectional design and a relatively small cohort.
Overall, these results, in conjunction with previous studies, provide us a potential timeline of pathophysiologic changes seen with this virus,5,6 especially in HIV+ children. Breakdown of the blood–brain barrier, especially within certain brain regions (e.g., subcortical), occurs soon after seroconversion. Neuronal degeneration may lead to regional atrophy. These changes collectively could associate with impairments on NP, supported by the associations between certain NP tests and neuroimaging measures. Finally, with increasing duration of infection and continued impairments in the immune system, both functional and structural connections are affected, leading to more widespread neurocognitive and neuroimaging changes typically observed with chronic HIV infection.7 Prolonged immunosuppression may lead to continued neuronal degeneration. Initiation of cART can improve but does not completely restore brain integrity.7
These current neuroimaging findings nicely complement recent CSF studies of HIV+ children.8 Compartmentalization in vertically transmitted HIV+ children evolves after birth and is related to age. Within children ages 0–6 months, an equilibrated state dominates where CSF viral populations are not genetically distinct from those in blood. By ages 7–18 months, an intermediate state is common with peripheral blood and CSF populations not uniformly equilibrated, with small CSF viral subpopulations developing. By 18 months of age, HIV+ children often have compartmentalization in the CSF.9
These results have several important implications for neurologists managing HIV+ individuals with cognitive impairment. This work adds to a growing literature that suggests that early intervention with cART may be especially beneficial. Interventions should also focus on the early identification of adherence problems or resistance to first-line cART in HIV+ children, as children on second-line cART have more white matter damage than children on first-line cART.1 Results from this study and others focusing on neuroimaging measures may provide a complementary picture of pathophysiologic changes seen with HIV. Advanced neuroimaging measures could provide an earlier window to detect changes.3
In the HIV literature, slow progressors are typically defined as children or adolescents who (1) were vertically infected with HIV, (2) received no or minimal therapy (defined as single or dual nucleoside therapy) before age 10 years, and (3) remain clinically and immunologically stable for the first decade of life (e.g., continue to maintain CD4 counts above 25%). Slow progressor HIV+ children receive limited attention from health services. Cognitive dysfunction and white matter damage occur in asymptomatic slow progressors.10
Guidelines have been developed for dividing HIV-associated neurocognitive disorders (HAND) into asymptomatic neurocognitive impairment, mild neurocognitive disorders, and HIV-associated dementia categories.11 Evaluation for HAND primarily consists of NP testing and assessment of activities of daily living. The criteria have clinical utility, as they allow for the conceptualization of a range of functional impairment, and can assist in management plans of HIV+ adults with cognitive issues. However, their applicability to HIV+ children is not well-understood. While there are clinical criteria for the diagnosis of HIV encephalopathy (HIVE), it is important to identify HIV+ children and adolescents with functional cognitive impairments who do not fit criteria for HIVE as initiation of cART could maintain brain structure.4 It may therefore be beneficial to include additional biomarkers (both neuroimaging and CSF) to future definitions of HAND. This may be especially important in HIV+ children. Earlier recognition of neurodevelopmental changes due to HIV could improve the social and educational management of HIV+ children. This may also influence health policies (especially for slow progressors) and lead to earlier initiation of cART.1,2

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