Common Brain Volume Signatures Associated with Immunosuppression and Viral Load in Over 1000 Adults Living with HIV Across 5 Continents: Findings from the ENIGMA-HIV Working Group

Background: Despite more widely accessible combination antiretroviral therapy (cART), the human immunodeficiency virus type-1 (HIV) infection remains a global public health challenge. Even in treated and chronically HIV-infected (HIV+) individuals, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in-vivo may delineate the neuropathological processes underlying these deficits. However, to date, neuroimaging findings are inconsistent. Methods: We established the ENIGMA-HIV Working Group to retrospectively pool and harmonize heterogeneous data from 12 HIV neuroimaging studies across Africa, Asia, Australia, Europe, and North America. Volume estimates for eight subcortical brain regions were extracted from T1- weighted MRI from 1,044 HIV+ adults (aged 22-81 years; 72·4% on cART; 70·3% male; 41·6% with detectable viral load; dVL), to identify associations with plasma markers reflecting current immunosuppression (CD4+ T-cell counts) or dVL. Follow-up analyses stratified data by cART status and sex. Findings: After Bonferroni correction, lower current CD4+ counts were associated with smaller hippocampal (β=20·3 mm3 per 100 cells/mm3; p=0·0001) and thalamic volumes (β=29.3; p=0·003); in participants not on cART, they were associated with smaller putamen volumes (β=65·1; p=0·0009). dVLs were associated with smaller hippocampi (Cohen's d=0·24; p=0·0003) and amygdala (d=0·18; p=0·0058). Interpretation: In a globally representative population of HIV+ individuals, volumes of structures in the limbic system were consistently associated with current plasma markers. Deficits in these regions may represent a generalizable brain signature of HIV-infection in the cART-era. Our findings support the role of viral suppression and immune restoration in maintaining brain health. Funding Statement: Funding for the ENIGMA Center for Worldwide Medicine Imaging and Genomics was provided by the NIH Big Data to Knowledge Program (BD2K; U54 EB020403). Additional funding for this work was provided by NIH grants R01AG059874 (NJ), R01MH117601 (NJ), T32AG058507 (TMN and CRKC), 5T32MH073526 (CRKC), MH083553 (CHH), MH19535 (CHH), R01HL095135 (KJK), MH095661 (TK), UL1RR033176 (TK), UL1TR000124 (TK), MH19535 (TK), NS080655 (BAN), K01AA025306 (ECP), R01HL095135 (CMS), U54MD007584 (CMS), K23MH095661 (ADT), K23AG032872 (VV), R01NS061696 (VV), K24MH098759 (VV), K01AG050707 (AJW), P01AA019072 (RAC), R01MH074368 (RAC), P30 AI042853 (RAC), and by R01MH085604 (RP). This study was also supported by the SA Medical Research Council (DJS), NHMRC APP568746 and APP1045400 (LAC), and the European Research Council Advanced Grant MedYMA 2011- 291080 (XP). Declaration of Interests: PMT, TMN, NJ, and CRKC received partial research support from Biogen, Inc., for work unrelated to the topic of this manuscript. BKN has received an honorarium from MedLink Neurology. VV has served as a consultant for Merck and ViiV Healthcare in the past 3 years, not related to this work. JA has received honoraria for participating in advisory meetings for ViiV Healthcare, Gilead, Merck, Roche and AbbVie. The remaining authors all declare no conflicts of interest. Ethics Approval Statement: Each study obtained approval from their local ethics committee or institutional review board; participants signed an informed consent form at each participating site.