Association of Immunosuppression and Viral Load With Subcortical Brain Volume in an International Sample of People Living With HIV
Authors: Talia M. Nir, Jean-Paul Fouche, Jintanat Ananworanich, Beau M. Ances, Jasmina Boban, Bruce J. Brew, Joga R. Chaganti, Linda Chang, Christopher R. K. Ching, Lucette A. Cysique, Thomas Ernst, Joshua Faskowitz, Vikash Gupta, Jaroslaw Harezlak, Jodi M. Heaps-Woodruff, Charles H. Hinkin, Jacqueline Hoare, John A. Joska, Kalpana J. Kallianpur, Taylor Kuhn, Hei Y. Lam, Meng Law, Christine Lebrun-Frénay, Andrew J. Levine, Lydiane Mondot, Beau K. Nakamoto, Bradford A. Navia, Xavier Pennec, Eric C. Porges, Lauren E. Salminen, Cecilia M. Shikuma, Wesley Surento, April D. Thames, Victor Valcour, Matteo Vassallo, Adam J. Woods, Paul M. Thompson, Ronald A. Cohen, Robert Paul, Dan J. Stein, Neda Jahanshad
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Despite more widely accessible combination antiretroviral therapy (cART), HIV-1 infection remains a global public health challenge. Even in treated patients with chronic HIV infection, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in vivo may delineate the neuropathologic processes underlying these deficits. However, published neuroimaging findings from relatively small, heterogeneous cohorts are inconsistent, limiting the generalizability of the conclusions drawn to date. <h3>Objective</h3> To examine structural brain associations with the most commonly collected clinical assessments of HIV burden (CD4<sup>+</sup>T-cell count and viral load), which are generalizable across demographically and clinically diverse HIV-infected individuals worldwide. <h3>Design, Setting, and Participants</h3> This cross-sectional study established the HIV Working Group within the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) consortium to pool and harmonize data from existing HIV neuroimaging studies. In total, data from 1295 HIV-positive adults were contributed from 13 studies across Africa, Asia, Australia, Europe, and North America. Regional and whole brain segmentations were extracted from data sets as contributing studies joined the consortium on a rolling basis from November 1, 2014, to December 31, 2019. <h3>Main Outcomes and Measures</h3> Volume estimates for 8 subcortical brain regions were extracted from T1-weighted magnetic resonance images to identify associations with blood plasma markers of current immunosuppression (CD4<sup>+</sup>T-cell counts) or detectable plasma viral load (dVL) in HIV-positive participants. Post hoc sensitivity analyses stratified data by cART status. <h3>Results</h3> After quality assurance, data from 1203 HIV-positive individuals (mean [SD] age, 45.7 [11.5] years; 880 [73.2%] male; 897 [74.6%] taking cART) remained. Lower current CD4<sup>+</sup>cell counts were associated with smaller hippocampal (mean [SE] β = 16.66 [4.72] mm<sup>3</sup>per 100 cells/mm<sup>3</sup>;<i>P</i> &lt; .001) and thalamic (mean [SE] β = 32.24 [8.96] mm<sup>3</sup>per 100 cells/mm<sup>3</sup>;<i>P</i> &lt; .001) volumes and larger ventricles (mean [SE] β = −391.50 [122.58] mm<sup>3</sup>per 100 cells/mm<sup>3</sup>;<i>P</i> = .001); in participants not taking cART, however, lower current CD4<sup>+</sup>cell counts were associated with smaller putamen volumes (mean [SE] β = 57.34 [18.78] mm<sup>3</sup>per 100 cells/mm<sup>3</sup>;<i>P</i> = .003). A dVL was associated with smaller hippocampal volumes (<i>d</i> = −0.17;<i>P</i> = .005); in participants taking cART, dVL was also associated with smaller amygdala volumes (<i>d</i> = −0.23;<i>P</i> = .004). <h3>Conclusions and Relevance</h3> In a large-scale international population of HIV-positive individuals, volumes of structures in the limbic system were consistently associated with current plasma markers. Our findings extend beyond the classically implicated regions of the basal ganglia and may represent a generalizable brain signature of HIV infection in the cART era.