Two patterns of cerebral metabolite abnormalities are detected on proton magnetic resonance spectroscopy in HIV-infected subjects commencing antiretroviral therapy
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Cerebral function impairment remains problematic in subjects with chronic human immunodeficiency virus (HIV) infection despite effective combination antiretroviral therapy (cART). Using cerebral proton magnetic resonance spectroscopy (1H MRS), we aimed to determine if abnormalities could be detected in neurologically asymptomatic HIV-infected subjects electively commencing cART.
Therapy-naive, HIV-infected individuals and HIV-uninfected controls underwent 1H MRS in several anatomical voxels including the mid-frontal grey matter (FGM) and right basal ganglia (RBG). Differences in cerebral metabolite ratios between groups and correlations between immune and virological status were assessed.
Forty-six subjects were recruited (26 HIV-infected and 20 control subjects). In the HIV-infected group, mean CD4+ count (SD, cells per microlitre) and plasma HIV RNA (SD, log10 copies per millilitre) were 192 (86) and 4.71 (0.64), respectively. Choline (Cho)/Creatine (Cr) and myoinositol (MI)/Cr ratios were significantly lower in the FGM in HIV-infected subjects compared to controls (0.67 (0.14) versus 0.88 (0.49), p = 0.036, and 0.94 (0.28) and 1.17 (0.26), p = 0.008, for Cho/Cr and MI/Cr, respectively) and Cho/Cr ratio associated with CD4+ lymphocyte count (p = 0.041). N-Acetyl-aspartate (NAA)/Cho ratio was significantly lower in the RBG in HIV-infected subjects compared to controls (2.27 (0.54) versus 2.63 (0.68), p = 0.002), and this was associated with greater plasma HIV RNA load (p = 0.014).
Two patterns of cerebral metabolite abnormalities were observed in HIV-infected subjects electively commencing cART. Greater inflammatory metabolite ratios (Cho/Cr and MI/Cr) associated with lower markers of peripheral immune markers (CD4+ lymphocyte count) in the FGM and lower neuronal metabolite ratios (NAA/Cho) associated with greater HIV viraemia in the RBG were present in HIV-infected subjects.
KeywordsHIV MRS Antiretroviral Cerebral
AW and SDT-R are grateful for support from the NIHR Biomedical Research Centre funding scheme at Imperial College Healthcare NHS Trust, London, UK, for infrastructure funding support. The National Centre in HIV Epidemiology and Clinical Research is funded by the Australian Government Department of Health & Ageing and is affiliated with the Faculty of Medicine, The University of New South Wales. The ALTAIR study was funded with a research grant from Gilead Sciences, Foster City, CA, USA.
Conflict of interest
AW has received honoraria or research grants, or has been a consultant or investigator, in clinical trials sponsored by Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, Roche and Pfizer.
PL has been an investigator in clinical trials sponsored by Abbott, Bristol-Myers Squibb, Pfizer and Merck Sharp and Dohme, served on advisory boards of Abbott, Pfizer, Janssen-Cilag, Merck Sharp and Dohme and had been nominated by the Queen Elizabeth Hospital and local professional societies to attend conferences through grants from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp and Dohme, Roche, IDS, Bayer Schering and Merck Serono.
JG has received honoraria, consultancies and research grants from (or has been an investigator in clinical trials sponsored by) Abbott, Bristol-Myers Squibb, Thera, Pfizer, Gilead Sciences, GlaxoSmithKline and Merck Sharp and Dohme.
SE has received honoraria, consultancies and research grants from (or has been an investigator in clinical trials sponsored by) Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Chiron-Novartis, Gilead Sciences, GlaxoSmithKline, Merck Sharp and Dohme, Roche, Tibotec and Virax Immunotherapeutics.
DAC has received honoraria, consultancies and research grants from (or has been an investigator in clinical trials sponsored by) Abbott, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline and Merck Sharp and Dohme.
- 5.Garvey LJ, Yerrakalva D, Winston A (2009) Correlations between computerized battery testing and a memory questionnaire for identification of neurocognitive impairment in HIV type 1-infected subjects on stable antiretroviral therapy. AIDS Res Hum Retroviruses 25(8):765–769PubMedCrossRefGoogle Scholar
- 7.Tozzi V, Balestra P, Serraino D, Bellagamba R, Corpolongo A, Vlassi C, Piselli P, Visco-Comandini U, Quartuccio ME, Larussa D, Pucillo L, Petrosillo N, Ippolito G, Antinori A, Narciso P (2004) Neurocognitive Impairment and Survival in HIV-Positive Patients Treated with HAART: Results from an Urban Observational Cohort. In: 11th Conference on Retruviruses and Opportunistic Infections, San Fransisco, CA, February 2004Google Scholar
- 9.Valcour V, Yee P, Williams AE, Shiramizu B, Watters M, Selnes O, Paul R, Shikuma C, Sacktor N (2006) Lowest ever CD4 lymphocyte count (CD4 nadir) as a predictor of current cognitive and neurological status in human immunodeficiency virus type 1 infection–The Hawaii Aging with HIV Cohort. J Neurovirol 12(5):387–391PubMedCrossRefGoogle Scholar
- 10.Tozzi V, Balestra P, Salvatori MF, Vlassi C, Liuzzi G, Giancola ML, Giulianelli M, Narciso P, Antinori A (2009) Changes in cognition during antiretroviral therapy: comparison of 2 different ranking systems to measure antiretroviral drug efficacy on HIV-associated neurocognitive disorders. J Acquir Immune Defic Syndr 52(1):56–63PubMedCrossRefGoogle Scholar
- 16.Paul RH, Yiannoutsos CT, Miller EN, Chang L, Marra CM, Schifitto G, Ernst T, Singer E, Richards T, Jarvik GJ, Price R, Meyerhoff DJ, Kolson D, Ellis RJ, Gonzalez G, Lenkinski RE, Cohen RA, Navia BA (2007) Proton MRS and neuropsychological correlates in AIDS dementia complex: evidence of subcortical specificity. J Neuropsychiatry Clin Neurosci 19(3):283–292PubMedCrossRefGoogle Scholar
- 19.Sterne JA, May M, Costagliola D, de Wolf F, Phillips AN, Harris R, Funk MJ, Geskus RB, Gill J, Dabis F, Miro JM, Justice AC, Ledergerber B, Fatkenheuer G, Hogg RS, Monforte AD, Saag M, Smith C, Staszewski S, Egger M, Cole SR (2009) Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet 373(9672):1352–1363PubMedCrossRefGoogle Scholar
- 21.Panel on Antiretroviral Guidelines for Adults and Adolescents (2012) Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. At: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed November 9, 2009
- 23.El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, Babiker A, Burman W, Clumeck N, Cohen CJ, Cohn D, Cooper D, Darbyshire J, Emery S, Fatkenheuer G, Gazzard B, Grund B, Hoy J, Klingman K, Losso M, Markowitz N, Neuhaus J, Phillips A, Rappoport C (2006) CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 355(22):2283–2296PubMedCrossRefGoogle Scholar
- 24.Phillips AN, Gazzard B, Gilson R, Easterbrook P, Johnson M, Walsh J, Leen C, Fisher M, Orkin C, Anderson J, Pillay D, Delpech V, Sabin C, Schwenk A, Dunn D, Gompels M, Hill T, Porter K, Babiker A (2007) Rate of AIDS diseases or death in HIV-infected antiretroviral therapy-naive individuals with high CD4 cell count. AIDS 21(13):1717–1721PubMedCrossRefGoogle Scholar
- 25.Emery S, Neuhaus JA, Phillips AN, Babiker A, Cohen CJ, Gatell JM, Girard PM, Grund B, Law M, Losso MH, Palfreeman A, Wood R (2008) Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis 197(8):1133–1144PubMedCrossRefGoogle Scholar
- 26.Cooper DA, Group AS (2009) Safety and efficacy of three different combination antiretroviral regimens as initial therapy for HIV infection: week 48 data from a randomised, open-label study. In: 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, South Africa, 19–22 July 2009Google Scholar
- 27.Yiannoutsos CT, Ernst T, Chang L, Lee PL, Richards T, Marra CM, Meyerhoff DJ, Jarvik JG, Kolson D, Schifitto G, Ellis RJ, Swindells S, Simpson DM, Miller EN, Gonzalez RG, Navia BA (2004) Regional patterns of brain metabolites in AIDS dementia complex. NeuroImage 23(3):928–935PubMedCrossRefGoogle Scholar
- 30.Paul RH, Ernst T, Brickman AM, Yiannoutsos CT, Tate DF, Cohen RA, Navia BA (2008) Relative sensitivity of magnetic resonance spectroscopy and quantitative magnetic resonance imaging to cognitive function among nondemented individuals infected with HIV. J Int Neuropsychol Soc 14(5):725–733PubMedCrossRefGoogle Scholar
- 33.Corasaniti MT, Bagetta G, Rotiroti D, Nistico G (1998) The HIV envelope protein gp120 in the nervous system: interactions with nitric oxide, interleukin-1beta and nerve growth factor signalling, with pathological implications in vivo and in vitro. Biochem Pharmacol 56(2):153–156PubMedCrossRefGoogle Scholar
- 40.Taylor-Robinson SD, Oatridge A, Hajnal JV, Burroughs AK, McIntyre N, deSouza NM (1995) MR imaging of the basal ganglia in chronic liver disease: correlation of T1-weighted and magnetisation transfer contrast measurements with liver dysfunction and neuropsychiatric status. Metab Brain Dis 10(2):175–188PubMedCrossRefGoogle Scholar