Abstract
The purpose of this study was to examine the impact of early suppressive antiretroviral therapy (ART) on brain structure and neurocognitive outcomes. We conducted an observational study of subjects within 1 year of HIV infection. Ten ART-naïve and 10 ART-suppressed individuals were matched for age and infection duration and age-matched to 10 HIV-seronegative controls. Quantitative brain imaging and neurocognitive data were analyzed. Subjects on suppressive ART had diminished corpus callosum structural integrity on macromolecular and microstructural imaging, higher cerebrospinal fluid percent, higher depression scores, and lower functional performance. Early suppressive ART may alter the trajectory of neurological progression of HIV infection, particularly in the corpus callosum.
References
Ananworanich J, Vandergeeten C, Chomchey N, Phanuphak N, Ngauy V, Sekaly RP, Robb M, Michael N, Kim J, Chomont N, RV254/SEARCH 010 Study Group (2013) Early ART intervention restricts the seeding of the HIV reservoir in long-lived central memory CD4 T cells. [Abstract #47] Presented at: 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, GA
Ances BM, Ortega M, Heaps J, Paul R (2012) Independent effects of HIV, aging, and HAART on brain volumetric measures. J Acquir Immune Defic Syndr 59(5):469–477
Arnone D, Barrick TR, Chengappa S, Mackay CE, Clark CA, Abou-Saleh MT (2008) Corpus callosum damage in heavy marijuana use: preliminary evidence from diffusion tensor tractography and tract-based spatial statistics. Neuroimage 41(3):1067–1074
Benedetti F, Yeh PH, Bellani M, Radaelli D, Nicoletti MA, Poletti S, Falini A, Dallaspezia S, Colombo C, Scotti G, Smeraldi E, Soares JC, Brambilla P (2011) Disruption of white matter integrity in bipolar depression as a possible structural marker of illness. Biol Psychiatry 69(4):309–317
Brenchley JM, Douek DC (2008) HIV infection and the gastrointestinal immune system. Mucosal Immunol 1(1):23–30
Cardenas VA, Meyerhoff DJ, Studholme C, Kornak J, Rothlind J, Lampiris H, Neuhaus J, Grant RM, Chao LL, Truran D, Weiner MW (2009) Evidence for ongoing brain injury in human immunodeficiency virus-positive patients treated with antiretroviral therapy. J Neurovirol 15(4):324–333
Celano CM, Freudenreich O, Fernandez-Robles C, Stern TA, Caro MA, Huffman JC (2011) Depressogenic effects of medications: a review. Dialogues Clin Neurosci 13(1):109–125
Chang L, Andres M, Sadino J, Jiang CS, Nakama H, Miller E, Ernst T (2011) Impact of apolipoprotein E ε4 and HIV on cognition and brain atrophy: antagonistic pleiotropy and premature brain aging. Neuroimage 58(4):1017–1027
Chiang MC, Dutton RA, Hayashi KM, Lopez OL, Aizenstein HJ, Toga AW, Becker JT, Thompson PM (2007) 3D pattern of brain atrophy in HIV/AIDS visualized using tensor-based morphometry. Neuroimage 34(1):44–60
Cole J, Chaddock CA, Farmer AE, Aitchison KJ, Simmons A, McGuffin P, Fu CH (2012) White matter abnormalities and illness severity in major depressive disorder. Br J Psychiatry 201(1):33–39
Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 1998 Dec 1 (revised 2013 Feb 12). (available at http://www.guideline.gov/content.aspx?id=43783&search=dhhs+hiv. Accessed 8/1/2013)
Ellis RJ, Badiee J, Vaida F, Letendre S, Heaton RK, Clifford D, Collier AC, Gelman B, McArthur J, Morgello S, McCutchan JA, Grant I, CHARTER Group (2011) CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS 25(14):1747–1751
Eriksson S, Graf EH, Dahl V, Strain MC, Yukl SA, Lysenko ES, Bosch RJ, Lai J, Chioma S, Emad F, Abdel-Mohsen M, Hoh R, Hecht F, Hunt P, Somsouk M, Wong J, Johnston R, Siliciano RF, Richman DD, O’Doherty U, Palmer S, Deeks SG, Siliciano JD (2013) Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLoS Pathog 9(2):e1003174
Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C, van der Kouwe A, Killiany R, Kennedy D, Klaveness S, Montillo A, Makris N, Rosen B, Dale AM (2002) Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 33:341–355
Ghafouri M, Amini S, Khalili K, Sawaya BE (2006) HIV-1 associated dementia: symptoms and causes. Retrovirology 3:28
Gunning-Dixon FM, Hoptman MJ, Lim KO, Murphy CF, Klimstra S, Latoussakis V, Majcher-Tascio M, Hrabe J, Ardekani BA, Alexopoulos GS (2008) Macromolecular white matter abnormalities in geriatric depression: a magnetization transfer imaging study. Am J Geriatr Psychiatry 16(4):255–262
Guo WB, Liu F, Chen JD, Xu XJ, Wu RR, Ma CQ, Gao K, Tan CL, Sun XL, Xiao CQ, Chen HF, Zhao JP (2012) Altered white matter integrity of forebrain in treatment-resistant depression: a diffusion tensor imaging study with tract-based spatial statistics. Prog Neuropsychopharmacol Biol Psychiatry 38(2):201–206
Hammond ER, Crum RM, Treisman GJ, Mehta SH, Ellis RJ, Grant I, Letendre SL, Marra CM, Morgello S, McArthur JC (2014) Persistent CSF, but not plasma HIV RNA is associated with increased risk of new-onset depression. [Abstract #33] Presented at: 21st Conference on Retroviruses and Opportunistic Infections. Boston, MA
Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, Vaida F, Ellis RJ, Letendre SL, Marcotte TD, Atkinson JH, Rivera-Mindt M, Vigil OR, Taylor MJ, Collier AC, Marra CM, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I, CHARTER Group (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: charter study. Neurology 75(23):2087–2096
Holt JL, Kraft-Terry SD, Chang L (2012) Neuroimaging studies of the aging HIV-1-infected brain. J Neurovirol 18(4):291–302
Hunt PW (2012) HIV and inflammation: mechanisms and consequences. Curr HIV/AIDS Rep 9(2):139–147
Jahanshad N, Valcour VG, Nir TM, Kohannim O, Busovaca E, Nicolas K, Thompson PM (2012) Disrupted brain networks in the aging HIV+ population. Brain Connect 2(6):335–344
Jernigan TL, Archibald SL, Fennema-Notestine C, Taylor MJ, Theilmann RJ, Julaton MD, Notestine RJ, Wolfson T, Letendre SL, Ellis RJ, Heaton RK, Gamst AC, Franklin DR Jr, Clifford DB, Collier AC, Gelman BB, Marra C, McArthur JC, McCutchan JA, Morgello S, Simpson DM, Grant I, CHARTER Group (2011) Clinical factors related to brain structure in HIV: the CHARTER study. J Neurovirol 17(3):248–257
Keating SM, Hanson D, Lebedeva M, Laeyendecker O, Ali-Napo NL, Owen SM, Stramer SL, Moore RD, Norris PJ, Busch MP (2012) Lower-sensitivity and avidity modifications of the vitros anti-HIV 1 + 2 assay for detection of recent HIV infections and incidence estimation. J Clin Microbiol 50(12):3968–3976
Kramer-Hämmerle S, Rothenaigner I, Wolff H, Bell JE, Brack-Werner R (2005) Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus. Virus Res 111(2):194–213
Le Bihan D (2003) Looking into the functional architecture of the brain with diffusion MRI. Nat Rev Neurosci 4(6):469–480
Le T, Wright EJ, Smith DM, He W, Catano G, Okulicz JF, Young JA, Clark RA, Richman DD, Little SJ, Ahuja SK (2013) Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy. N Engl J Med 368(3):218–230
Lentz MR, Kim WK, Lee V, Bazner S, Halpern EF, Venna N, Williams K, Rosenberg ES, González RG (2009) Changes in MRS neuronal markers and T cell phenotypes observed during early HIV infection. Neurology 72(17):1465–1472
Lentz MR, Kim WK, Kim H, Soulas C, Lee V, Venna N, Halpern EF, Rosenberg ES, Williams K, González RG (2011) Alterations in brain metabolism during the first year of HIV infection. J Neurovirol 17(3):220–229
Lori F, Jessen H, Lieberman J, Finzi D, Rosenberg E, Tinelli C, Walker B, Siliciano RF, Lisziewicz J (1999) Treatment of human immunodeficiency virus infection with hydroxyurea, didanosine, and a protease inhibitor before seroconversion is associated with normalized immune parameters and limited viral reservoir. J Infect Dis 180(6):1827–1832
Muñoz-Moreno JA, Fumaz CR, Ferrer MJ, González-García M, Moltó J, Negredo E, Clotet B (2009) Neuropsychiatric symptoms associated with efavirenz: prevalence, correlates, and management. A neurobehavioral review. AIDS Rev 11(2):103–109
Mutnal MB, Schachtele SJ, Hu S, Lokensgard JR (2013) T-cell reconstitution during murine acquired immunodeficiency syndrome (MAIDS) produces neuroinflammation and mortality in animals harboring opportunistic viral brain infection. J Neuroinflammation 10(1):98
Oxenius A, Price DA, Easterbrook PJ, O’Callaghan CA, Kelleher AD, Whelan JA, Sontag G, Sewell AK, Phillips RE (2000) Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc Natl Acad Sci U S A 97(7):3382–3387
Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD, HIV Outpatient Study Investigators (1998) Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 338:853–860
Ragin AB, Du H, Ochs R, Wu Y, Sammet CL, Shoukry A, Epstein LG (2012) Structural brain alterations can be detected early in HIV infection. Neurology 79(24):2328–2334
Ragin AB, Du H, Gao Y, Li S, Sammet CL, Wu Y, Epstein L (2013) The brain in seroconversion: findings from the Chicago Early HIV Infection Study. Presented at: 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, GA
Robertson KR, Su Z, Margolis DM, Krambrink A, Havlir DV, Evans S, Skiest DJ, A5170 Study Team (2010) Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology 74(16):1260–1266
Robertson K, Liner J, Meeker RB (2012) Antiretroviral neurotoxicity. J Neurovirol 18(5):388–399
Sailasuta N, Ross W, Ananworanich J, Chalermchai T, DeGruttola V, Lerdlum S, Pothisri M, Busovaca E, Ratto-Kim S, Jagodzinski L, Spudich S, Michael N, Kim JH, Valcour V, RV254/SEARCH 010 protocol teams (2012) Change in brain magnetic resonance spectroscopy after treatment during acute HIV infection. PLoS One 7(11):e49272
Seok JH, Choi S, Lim HK, Lee SH, Kim I, Ham BJ (2013) Effect of the COMT val158met polymorphism on white matter connectivity in patients with major depressive disorder. Neurosci Lett 545:35–39
Sevigny JJ, Albert SM, McDermott MP, McArthur JC, Sacktor N, Conant K, Schifitto G, Selnes OA, Stern Y, McClernon DR, Palumbo D, Kieburtz K, Riggs G, Cohen B, Epstein LG, Marder K (2004) Evaluation of HIV RNA and markers of immune activation as predictors of HIV-associated dementia. Neurology 63(11):2084–2090
Smith SM, Zhang Y, Jenkinson M, Chen J, Matthews PM, Federico A, De Stefano N (2002) Accurate, robust, and automated longitudinal and cross-sectional brain change analysis. Neuroimage 17:479–489
Strain MC, Little SJ, Daar ES, Havlir DV, Gunthard HF, Lam RY, Daly OA, Nguyen J, Ignacio CC, Spina CA, Richman DD, Wong JK (2005) Effect of treatment, during primary infection, on establishment and clearance of cellular reservoirs of HIV-1. J Infect Dis 191(9):1410–1418
Thompson PM, Dutton RA, Hayashi KM, Lu A, Lee SE, Lee JY, Lopez OL, Aizenstein HJ, Toga AW, Becker JT (2006) 3D mapping of ventricular and corpus callosum abnormalities in HIV/AIDS. Neuroimage 31(1):12–23
Tovar-y-Romo LB, Bumpus NN, Pomerantz D, Avery LB, Sacktor N, McArthur JC, Haughey NJ (2012) Dendritic spine injury induced by the 8-hydroxy metabolite of efavirenz. J Pharmacol Exp Ther 343(3):696–703
Valcour V, Chalermchai T, Sailasuta N, Marovich M, Lerdlum S, Suttichom D, Suwanwela NC, Jagodzinski L, Michael N, Spudich S, van Griensven F, de Souza M, Kim J, Ananworanich J, RV254/SEARCH 010 Study Group (2012) Central nervous system viral invasion and inflammation during acute HIV infection. J Infect Dis 206(2):275–282
Wu Y, Du H, Storey P, Glielmi C, Malone F, Sidharthan S, Ragin A, Tofts PS, Edelman RR (2012) Comprehensive brain analysis with automated high-resolution magnetization transfer measurements. J Magn Reson Imaging 35(2):309–317
Xu K, Jiang W, Ren L, Ouyang X, Jiang Y, Wu F, Kong L, Womer F, Liu Z, Blumberg HP, Tang Y, Wang F (2013) Impaired interhemispheric connectivity in medication-naive patients with major depressive disorder. J Psychiatry Neurosci 38(1):43–48
Zalesky A, Solowij N, Yücel M, Lubman DI, Takagi M, Harding IH, Lorenzetti V, Wang R, Searle K, Pantelis C, Seal M (2012) Effect of long-term cannabis use on axonal fibre connectivity. Brain 135(7):2245–2255
Zeng M, Haase AT, Schacker TW (2012) Lymphoid tissue structure and HIV-1 infection: life or death for T cells. Trends Immunol 33(6):306–314
Acknowledgments
The Chicago Early HIV Infection Study is supported by a grant from the NIH.
Conflict of interest
B.O.T. has served as a consultant for ViiV Healthcare, Gilead Sciences, Pfizer, and GlaxoSmithKline and received research support to Northwestern University from Pfizer. For all the other authors, no conflicts of interest were declared.
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Kelly, S.G., Taiwo, B.O., Wu, Y. et al. Early suppressive antiretroviral therapy in HIV infection is associated with measurable changes in the corpus callosum. J. Neurovirol. 20, 514–520 (2014). https://doi.org/10.1007/s13365-014-0261-7
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DOI: https://doi.org/10.1007/s13365-014-0261-7