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Does Antiretroviral Therapy Improve HIV-Associated Cognitive Impairment? A Quantitative Review of the Literature

Published online by Cambridge University Press:  04 August 2011

Timour Al-Khindi
Affiliation:
Department of Psychology, University of Toronto Scarborough, Toronto, Ontario
Konstantine K. Zakzanis*
Affiliation:
Department of Psychology, University of Toronto Scarborough, Toronto, Ontario
Wilfred G. van Gorp
Affiliation:
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York
*
Correspondence and reprint requests to: Konstantine K. Zakzanis, Department of Psychology, University of Toronto Scarborough, 1265 Military Trail, Toronto, Ontario, M1C 1A4, Canada. E-mail: [email protected]

Abstract

The development of antiretroviral therapy (ART) has dramatically improved survival for those living with human immunodeficiency virus (HIV), but whether ART improves cognitive functioning remains unclear. The aim of the present review was to examine systematically the extent to which ART improves cognition among individuals with HIV using meta-analytic methods. Twenty-three studies were included in the quantitative review. ART was associated with modest improvements in attention (mean d = .17; p < .001; 95% confidence interval [CI], .09/.25), executive function (mean d = .18; p < .001; 95% CI, .10/.26), and motor function (mean d = .24; p < .001; 95% CI, .16/.32). ART did not improve language, verbal memory, visual memory or visuospatial function. The extent to which cognition improved was correlated with the change in CD4 cell count following ART, suggesting a link between cognitive outcome and immune system integrity. Together, the present findings indicate that the neuropsychological test performance of most HIV patients taking ART is comparable to those not taking ART. Development of pharmaceutical treatments and rehabilitation strategies that target the cognitive effects of HIV infection is needed. (JINS, 2011, 17, 956–969)

Type
Critical Review
Copyright
Copyright © The International Neuropsychological Society 2011

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References

References preceded by an asterisk were included in the meta-analysis.Google Scholar
Adamson, C.S., Freed, E.O. (2008). Recent progress in antiretrovirals – Lessons from resistance. Drug Discovery Today, 13, 424432.CrossRefGoogle ScholarPubMed
Anthony, I.C., Ramage, S.N., Carnie, F.W., Simmonds, P., Bell, J.E. (2005). Influence of HAART on HIV-related CNS disease and neuroinflammation. Journal of Neuropathology and Experimental Neurology, 64, 529536.CrossRefGoogle ScholarPubMed
Aylward, E.H., Henderer, J.D., McArthur, J.C., Brettschneider, P.D., Harris, G.J., Barta, P.E., Pearlson, G.D. (1993). Reduced basal ganglia volume in HIV-1-associated dementia: Results from quantitative neuroimaging. Neurology, 43, 20992104.CrossRefGoogle ScholarPubMed
*Baldeweg, T., Catalan, J., Lovett, E., Gruzelier, J., Riccio, M., Hawkins, D. (1995). Long-term zidovudine reduces neurocognitive deficits in HIV-1 infection. AIDS, 9, 589596.CrossRefGoogle ScholarPubMed
Borenstein, M., Hedges, L.V., Higgins, J.P.T., Rothstein, H.R. (2009). Introduction to meta-analysis. West Sussex, UK: John Wiley & Sons, Ltd.CrossRefGoogle Scholar
*Brouwers, P., Hendricks, M., Lietzau, J.A., Pluda, J.M., Mitsuya, H., Broder, S., Yarchoan, R. (1997). Effect of combination therapy with zidovudine and didanosine on neuropsychological functioning in patients with symptomatic HIV disease: A comparison of simultaneous and alternating regimens. AIDS, 11, 5966.CrossRefGoogle ScholarPubMed
Carr, A. (2003). Toxicity of antiretroviral therapy and implications for drug development. Nature Reviews Drug Discovery, 2, 624634.CrossRefGoogle ScholarPubMed
*Carvalhal, A.S., Rourke, S.B., Belmonte-Abreu, P., Correa, J., Goldani, L.Z. (2006). Evaluation of neuropsychological performance of HIV-infected patients with minor motor cognitive dysfunction treated with highly active antiretroviral therapy. Infection, 24, 357360.CrossRefGoogle Scholar
*Chang, L., Ernst, T., Witt, M.D., Ames, N., Walot, I., Jovicich, J., Miller, E.N. (2003). Persistent brain abnormalities in antiretroviral-naïve HIV patients 3 months after HAART. Antiviral Therapy, 8, 1726.CrossRefGoogle ScholarPubMed
Chen, Y., An, H., Zhu, H., Stone, T., Smith, J.K., Hall, C., Lin, W. (2009). White matter abnormalities revealed by diffusion tensor imaging in non-demented and demented HIV+ patients. Neuroimage, 47, 11541162.CrossRefGoogle ScholarPubMed
Cohen, J. (1988). Statistical power analysis for the behavioral sciences (2nd ed.). Hillsdale, NJ: Lawrence Erlbaum Associates.Google Scholar
*Cohen, R.A., Boland, R., Paul, R., Tashima, K.T., Schoenbaum, E.E., Celentano, D.D., Carpenter, C.C. (2001). Neurocognitive performance enhanced by highly active antiretroviral therapy in HIV-infected women. AIDS, 15, 341345.Google ScholarPubMed
Cooper, H., Hedges, L.V. (1994). The handbook of research synthesis. New York: Russell Sage Foundation.Google Scholar
Cysique, L.A., Brew, B.J. (2009). Neuropsychological functioning and antiretroviral treatment in HIV/AIDS: A review. Neuropsychology Review, 19, 169185.CrossRefGoogle ScholarPubMed
Duval, S., Tweedie, R. (2000a). A nonparametric ‘trim and fill’ method of accounting for publication bias in meta-analysis. Journal of the American Statistical Association, 95, 8998.Google Scholar
Duval, S., Tweedie, R. (2000b). Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta analysis. Biometrics, 56, 455463.CrossRefGoogle ScholarPubMed
*Ferrando, S., van Gorp, W., McElhiney, M., Goggin, K., Sewell, M., Rabkin, J. (1998). Highly active antiretroviral treatment in HIV infection: Benefits for neuropsychological function. AIDS, 12, F65F70.CrossRefGoogle ScholarPubMed
Fischl, M.A., Richman, D.D., Grieco, M.H., Gottlieb, M.S., Volberding, P.A., Laskin, O.L., King, D. (1987). The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. New England Journal of Medicine, 317, 185191.CrossRefGoogle ScholarPubMed
Goldstein, G. (1984). Comprehensive neuropsychological assessment batteries. In G. Goldstein & M. Herson (Eds.), Handbook of psychological assessment (pp. 181210). New York, NY: Pergamon Press.Google Scholar
Hammer, S.M., Squires, K.E., Hughes, M.D., Grimes, J.M., Demeter, L.M., Currier, J.S., Fischl, M.A. (1997). A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS clinical trials group 320 study team. New England Journal of Medicine, 337, 725733.CrossRefGoogle ScholarPubMed
*Hayman-Abello, S.E. (2006). The effects of highly active antiretroviral therapy (HAART) on neuropsychological status in HIV-infection: A prospective study. Dissertation Abstracts International: Section B: The Sciences and Engineering, 67, 4106.Google Scholar
Heaton, R.K., Chelune, G.J., Talley, J., Kay, G.G., Curtiss, G. (1993). Wisconsin Card Sorting Test manual-revised and expanded. Odessa, FL: Psychological Assessment Resources.Google Scholar
Heaton, R.K., Clifford, D.B., Franklin, D.R. Jr., Woods, S.P., Ake, C., Vaida, F., Grant, I. (2010). HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology, 75, 20872096.CrossRefGoogle ScholarPubMed
Heaton, R.K., Franklin, D.R., Ellis, R.J., McCutchan, J.A., Letendre, S.L., Leblanc, S., Grant, I. (2011). HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: Differences in rates, nature, and predictors. Journal of Neurovirology, 17, 316.CrossRefGoogle ScholarPubMed
Hedges, L.V., Olkin, I. (1985). Statistical methods for meta-analysis. Orlando, FL: Academic Press.Google Scholar
Hunter, J.E., Schmidt, F.L. (1990). Methods of meta-analysis. Newbury Park, CA: Sage Publications.Google Scholar
Joska, J.A., Gouse, H., Paul, R.H., Stein, D.J., Flisher, A.J. (2010). Does highly active antiretroviral therapy improve neurocognitive function? A systematic review. Journal of Neurovirology, 16, 101114.CrossRefGoogle ScholarPubMed
Lezak, M.D., Howieson, D.B., Loring, D.W. (2004). Neuropsychological assessment (4th ed.). New York, NY: Oxford University Press.Google Scholar
*Lindsey, J.C., Malee, K.M., Brouwers, P., Hughes, M.D. (2007). Neurodevelopmental functioning in HIV-infected infants and young children before and after the introduction of protease inhibitor-based highly active antiretroviral therapy. Pediatrics, 119, e681e693.CrossRefGoogle ScholarPubMed
Liner, K.J. Jr., Hall, C.D., Robertson, K.R. (2008). Effects of antiretroviral therapy on cognitive impairment. Current HIV/AIDS Reports, 5, 6471.CrossRefGoogle Scholar
Liner, K.J. Jr., Ro, M.J., Robertson, K.R. (2010). HIV, antiretroviral therapies, and the brain. Current HIV/AIDS Reports, 7, 8591.CrossRefGoogle ScholarPubMed
Lipsey, M.W., Wilson, D.B. (1993). The efficacy of psychological, educational, and behavioral treatment. American Psychologist, 12, 11811209.CrossRefGoogle Scholar
*Llorente, A.M., van Gorp, W.G., Stern, M.J., George, L., Satz, P., Marcotte, T.D., Hinkin, C.H. (2001). Long-term effects of high-dose zidovudine on neuropsychological performance in mildly symptomatic HIV-positive patients: Results of a randomized, double-blind, placebo-controlled investigation. Journal of the International Neuropsychological Society, 7, 2732.CrossRefGoogle ScholarPubMed
*Martin, E.M., Pitrak, D.L., Novak, R.M., Pursell, K.J., Mullane, K.M. (1999). Reaction times are faster in HIV-seropositive patients on antiretroviral therapy: A preliminary report. Journal of Clinical and Experimental Neuropsychology, 21, 730735.CrossRefGoogle ScholarPubMed
Marzolini, C., Telenti, A., Decosterd, L.A., Greub, G., Biollaz, J., Buclin, T. (2001). Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS, 15, 7175.CrossRefGoogle ScholarPubMed
McArthur, J.C., Steiner, J., Sacktor, N., Nath, A. (2010). Human immunodeficiency virus-associated neurocognitive disorders: Mind the gap. Annals of Neurology, 67, 699714.CrossRefGoogle ScholarPubMed
*Millikin, C.P., Trépanier, L.L., Rourke, S.B. (2005). Verbal fluency component analysis in adults with HIV/AIDS. Journal of Clinical and Experimental Neuropsychology, 26, 933942.CrossRefGoogle Scholar
Mocroft, A., Phillips, A.N., Gatell, J., Ledergerber, B., Fisher, M., Clumeck, N., Lundgren, J.D. (2007). Normalization of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: An observational cohort study. Lancet, 370, 407413.CrossRefGoogle ScholarPubMed
Orenstein, J.M., Fox, C., Wahl, S.M. (1997). Macrophages as a source of HIV during opportunistic infections. Science, 276, 18571861.CrossRefGoogle ScholarPubMed
Orwin, R.G. (1983). A fail-safe N for effect size in meta-analysis. Journal of Educational Statistics, 8, 157159.Google Scholar
Reger, M., Welsh, R., Razani, J., Martin, D.J., Boone, K.B. (2002). A meta-analysis of the neuropsychological sequelae of HIV infection. Journal of the International Neuropsychological Society, 8, 410424.CrossRefGoogle ScholarPubMed
*Richardson, J.L., Martin, E.M., Jiminez, N., Danley, K., Cohen, M., Carson, V.L., Levine, A.M. (2002). Neuropsychological functioning in a cohort of HIV infected women: Importance of antiretroviral therapy. Journal of the International Neuropsychological Society, 8, 781793.CrossRefGoogle Scholar
*Robertson, K.R., Robertson, W.T., Ford, S., Watson, D., Fiscus, S., Harp, A.G., Hall, C.D. (2004). Highly active antiretroviral therapy improves neurocognitive functioning. Journal of Acquired Immune Deficiency Syndromes, 36, 562566.CrossRefGoogle ScholarPubMed
Robertson, K.R., Smurzynski, M., Parsons, T.D., Wu, K., Bosch, R.J., Wu, J., Ellis, R.J. (2007). The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS, 21, 19151921.CrossRefGoogle ScholarPubMed
Rosenthal, R. (1991). Meta-analytic procedures for social research. Beverly Hills, CA: Sage Publications.CrossRefGoogle Scholar
Rosenthal, R. (1995). Writing meta-analytic reviews. Psychological Bulletin, 118, 183192.CrossRefGoogle Scholar
Sacktor, N. (2002). The epidemiology of human immunodeficiency virus-associated neurological disease in the era of highly active antiretroviral therapy. Journal of Neurovirology, 8, 115121.CrossRefGoogle ScholarPubMed
*Sacktor, N.C., Lyles, R.H., Skolasky, R.L., Anderson, D.E., McArthur, J.C., McFarlane, G., Miller, E.N. (1999). Combination antiretroviral therapy improves psychomotor speed performance in HIV-seropositive homosexual men. Multicenter AIDS cohort study (MACS). Neurology, 52, 16401647.Google ScholarPubMed
*Sacktor, N., McDermott, M.P., Marder, K., Schitto, G., Selnes, O.A., McArthur, J.C., Epstein, L. (2002). HIV-associated cognitive impairment before and after the advent of combination therapy. Journal of Neurovirology, 8, 136142.CrossRefGoogle ScholarPubMed
*Sacktor, N., Nakasujja, N., Skolasky, R., Robertson, K., Wong, M., Musisi, S., Clifford, D.B. (2009). Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda. Neurology, 72, 165170.CrossRefGoogle ScholarPubMed
*Sacktor, N., Nakasujja, N., Skolasky, R., Robertson, K., Wong, M., Musisi, S., Katabira, E. (2006). Antiretroviral therapy improves cognitive impairment in HIV+ individuals in sub-Saharan Africa. Neurology, 67, 311314.CrossRefGoogle ScholarPubMed
Squire, L.R., Stark, C.E., Clark, R.E. (2004). The medial temporal lobe. Annual Review of Neuroscience, 27, 279306.CrossRefGoogle ScholarPubMed
Strauss, E., Sherman, E.M.S., Spreen, O. (2006). A compendium of neuropsychological tests: Administration, norms and commentary (3rd ed.). New York, NY: Oxford University Press.Google Scholar
Suarez, S., Baril, L., Stankoff, B., Khellaf, M., Dubois, B., Lubetzki, C., Hauw, J. (2001). Outcome of patients with HIV-1-related cognitive impairment on highly active antiretroviral therapy. AIDS, 15, 195200.CrossRefGoogle ScholarPubMed
Sun, B., Abadjian, L., Rempel, H., Calosing, C., Rothlind, J., Pulliam, L. (2010). Peripheral biomarkers do not correlate with cognitive impairment in highly active antiretroviral therapy-treated subjects with human immunodeficiency virus type 1 infection. Journal of Neurovirology, 16, 115124.CrossRefGoogle Scholar
Thompson, P.M., Dutton, R.A., Hayashi, K.M., Toga, A.W., Lopez, O.L., Aizenstein, H.J., Becker, J.T. (2005). Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4+ T lymphocyte decline. Proceedings of the National Academy of Sciences of the United States of America, 102, 1564715652.CrossRefGoogle ScholarPubMed
*Tozzi, V., Balestra, P., Bellagamba, R., Corpolongo, A., Salvatori, M.F., Visco-Comandini, U., Narciso, P. (2007). Persistence of neuropsychologic deficits despite long-term highly active antiretroviral therapy in patients with HIV-related neurocognitive impairment: Prevalence and risk factors. Journal of Acquired Immune Deficiency Syndromes, 45, 174182.Google ScholarPubMed
*Tozzi, V., Balestra, P., Galgani, S., Narciso, P., Ferri, F., Sebastiani, G., Benedetto, A. (1999). Positive and sustained effects of highly active antiretroviral therapy on HIV-1-associated neurocognitive impairment. AIDS, 13, 18891897.Google ScholarPubMed
*Tozzi, V., Balestra, P., Galgani, S., Pasquale, N., Sampaolesi, A., Antinori, A., Ippolito, G. (2001). Changes in neurocognitive performance in a cohort of patients treated with HAART for 3 years. Journal of Acquired Immune Deficiency Syndromes, 28, 1927.Google Scholar
*Tozzi, V., Balestra, P., Salvatori, M.F., Vlassi, C., Liuzzi, G., Giancola, M.L., 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. Journal of Acquired Immune Deficiency Syndromes, 52, 5663.Google ScholarPubMed
*Tozzi, V., Narciso, P., Galgani, S., Sette, P., Balestra, P., Gerace, C., Visco, G. (1993). Effects of zidovudine in 30 patients with mild to end-stage AIDS dementia complex. AIDS, 7, 683692.Google ScholarPubMed
*Winston, A., Duncombe, C., Li, P.C., Gill, J.M., Kerr, S.J., Puls, R., Cooper, D.A. (2010). Does choice of combination antiretroviral therapy (cART) alter changes in cerebral function testing after 48 weeks in treatment-naive, HIV-1-infected individuals commencing cART? A randomized controlled study. Clinical Infectious Diseases, 50, 920929.CrossRefGoogle ScholarPubMed
Zakzanis, K.K. (1998). Brain is related to behavior (p < .05). Journal of Clinical and Experimental Neuropsychology, 20, 419427.CrossRefGoogle ScholarPubMed
Zakzanis, K.K. (2001). Statistics to tell the truth, the whole truth, and nothing but the truth: Formulae, illustrative numerical examples, and heuristic interpretation of effect size analyses for neuropsychological researchers. Archives of Clinical Neuropsychology, 16, 653667.CrossRefGoogle ScholarPubMed