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

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)

[1]  Jacob Cohen.  Statistical Power Analysis for the Behavioral Sciences , 1969, The SAGE Encyclopedia of Research Design.

[2]  R. Orwin.  A fail-safe N for effect size in meta-analysis. , 1983 .

[3]  R. Rosenthal.  Meta-analytic procedures for social research , 1984 .

[4]  M A Fischl,et al.  The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. , 1987, The New England journal of medicine.

[5]  M. S. Patel,et al.  An introduction to meta-analysis. , 1989, Health Policy.

[6]  P. Lachenbruch.  Statistical Power Analysis for the Behavioral Sciences (2nd ed.) , 1989 .

[7]  John E. Hunter,et al.  Methods of Meta-Analysis , 1989 .

[8]  G. D. Pearlson,et al.  Reduced basal ganglia volume in HIV‐1‐associated dementia , 1993, Neurology.

[9]  P. Narciso,et al.  Effects of zidovudine in 30 patients with mild to end‐stage AIDS dementia complex , 1993, AIDS.

[10]  Robert K. Heaton,et al.  Wisconsin Card Sorting Test Manual – Revised and Expanded , 1993 .

[11]  R. Hanka.  The Handbook of Research Synthesis , 1994 .

[12]  R. Rausch.  A compendium of neuropsychological tests: administration, norms, and commentary , 1994 .

[13]  J. Catalan,et al.  Long‐term zidovudine reduces neurocognitive deficits in HIV‐1 infection , 1995, AIDS.

[14]  H. Mitsuya,et al.  Effect of combination therapy with zidovudine and didanosine on neuropsychological functioning in patients with symptomatic HIV disease: a comparison of simultaneous and alternating regimens , 1997, AIDS.

[15]  C. Fox,et al.  Macrophages as a source of HIV during opportunistic infections. , 1997, Science.

[16]  M A Fischl,et al.  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. , 1997, The New England journal of medicine.

[17]  J. Rabkin,et al.  Highly active antiretroviral treatment in HIV infection: benefits for neuropsychological function , 1998, AIDS.

[18]  K. Zakzanis.  Brain is related to behavior (p<.05). , 1998, Journal of clinical and experimental neuropsychology.

[19]  O. Selnes,et al.  Combination antiretroviral therapy improves psychomotor speed performance in HIV-seropositive homosexual men , 1999, Neurology.

[20]  P. Narciso,et al.  Positive and sustained effects of highly active antiretroviral therapy on HIV-1-associated neurocognitive impairment. , 1999, AIDS.

[21]  E. Martin,et al.  Reaction times are faster in HIV-seropositive patients on antiretroviral therapy: A preliminary report. , 1999, Journal of clinical and experimental neuropsychology.

[22]  R. Tweedie,et al.  A Nonparametric “Trim and Fill” Method of Accounting for Publication Bias in Meta-Analysis , 2000 .

[23]  S Duval,et al.  Trim and Fill: A Simple Funnel‐Plot–Based Method of Testing and Adjusting for Publication Bias in Meta‐Analysis , 2000, Biometrics.

[24]  P. Narciso,et al.  Changes in Neurocognitive Performance in a Cohort of Patients Treated With HAART for 3 Years , 2001, Journal of acquired immune deficiency syndromes.

[25]  B. Dubois,et al.  Outcome of patients with HIV-1-related cognitive impairment on highly active antiretroviral therapy , 2001, AIDS.

[26]  T. Marcotte,et al.  Long-term effects of high-dose zidovudine treatment on neuropsychological performance in mildly symptomatic HIV-positive patients: Results of a randomized, double-blind, placebo-controlled investigation , 2001, Journal of the International Neuropsychological Society.

[27]  A. Telenti,et al.  Efavirenz Plasma Levels Can Predict Treatment Failure and Central Nervous System Side Effects in Hiv-1-infected Patients , 2022 .

[28]  Ronald A. Cohen,et al.  Neurocognitive performance enhanced by highly active antiretroviral therapy in HIV-infected women , 2001, AIDS.

[29]  K. Zakzanis,et al.  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. , 2001, Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists.

[30]  K. Boone,et al.  A meta-analysis of the neuropsychological sequelae of HIV infection , 2002, Journal of the International Neuropsychological Society.

[31]  N. Sacktor.  The epidemiology of human immunodeficiency virus-associated neurological disease in the era of highly active antiretroviral therapy. , 2002, Journal of neurovirology.

[32]  Mardge H. Cohen,et al.  Neuropsychological functioning in a cohort of HIV infected women: Importance of antiretroviral therapy , 2002, Journal of the International Neuropsychological Society.

[33]  A. Carr.  Toxicity of antiretroviral therapy and implications for drug development , 2003, Nature Reviews Drug Discovery.

[34]  J. Jovicich,et al.  Persistent Brain Abnormalities in Antiretroviral-Naive HIV Patients 3 Months after Haart , 2003, Antiviral therapy.

[35]  R. Clark,et al.  The medial temporal lobe. , 2004, Annual review of neuroscience.

[36]  S. Rourke,et al.  Verbal Fluency Component Analysis in Adults with HIV/AIDS , 2004, Journal of clinical and experimental neuropsychology.

[37]  C. Hall,et al.  Highly Active Antiretroviral Therapy Improves Neurocognitive Functioning , 2004, Journal of acquired immune deficiency syndromes.

[38]  Robert Rosenthal,et al.  WRITING META-ANALYTIC REVIEWS , 1995 .

[39]  R. Jung.  Neuropsychological Assessment, 4th ed. , 2005 .

[40]  P. Simmonds,et al.  Influence of HAART on HIV-related CNS disease and neuroinflammation. , 2005, Journal of neuropathology and experimental neurology.

[41]  Kiralee M. Hayashi,et al.  Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4+ T lymphocyte decline , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[42]  N. Nakasujja,et al.  Antiretroviral therapy improves cognitive impairment in HIV+ individuals in sub-Saharan Africa , 2006, Neurology.

[43]  S. Rourke,et al.  Evaluation of Neuropsychological Performance of HIV-Infected Patients with Minor Motor Cognitive Dysfunction Treated with Highly Active Antiretroviral Therapy , 2006, Infection.

[44]  S. Hayman-Abello.  The effects of highly active antiretroviral therapy (HAART) on neuropsychological status in HIV-infection: A prospective study. , 2006 .

[45]  M. Hughes,et al.  Neurodevelopmental Functioning in HIV-Infected Infants and Young Children Before and After the Introduction of Protease Inhibitor–Based Highly Active Antiretroviral Therapy , 2007, Pediatrics.

[46]  JD Lundgren,et al.  Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study , 2007, The Lancet.

[47]  Justin C McArthur,et al.  The prevalence and incidence of neurocognitive impairment in the HAART era , 2007, AIDS.

[48]  C. Hall,et al.  Effects of antiretroviral therapy on cognitive impairment , 2008, Current HIV/AIDS reports.

[49]  E. Freed,et al.  Recent progress in antiretrovirals--lessons from resistance. , 2008, Drug discovery today.

[50]  D. Clifford,et al.  Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda , 2009, Neurology.

[51]  Dinggang Shen,et al.  White matter abnormalities revealed by diffusion tensor imaging in non-demented and demented HIV+ patients , 2009, NeuroImage.

[52]  Maria Flora Salvatori,et al.  Changes in Cognition During Antiretroviral Therapy: Comparison of 2 Different Ranking Systems to Measure Antiretroviral Drug Efficacy on HIV-Associated Neurocognitive Disorders , 2009, Journal of acquired immune deficiency syndromes.

[53]  B. Brew,et al.  Neuropsychological Functioning and Antiretroviral Treatment in HIV/AIDS: A Review , 2009, Neuropsychology Review.

[54]  Yaakov Stern,et al.  Food combination and Alzheimer disease risk: a protective diet. , 2010, Archives of neurology.

[55]  A. Winston,et al.  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. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[56]  J. McArthur,et al.  Human immunodeficiency virus‐associated neurocognitive disorders: Mind the gap , 2010, Annals of neurology.

[57]  Terry L. Jernigan,et al.  HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors , 2010, Journal of NeuroVirology.

[58]  Michael J. Taylor,et al.  HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy , 2010, Neurology.

[59]  K. Robertson,et al.  HIV, Antiretroviral Therapies, and the Brain , 2010, Current HIV/AIDS reports.

[60]  Dan J Stein,et al.  Does highly active antiretroviral therapy improve neurocognitive function? A systematic review , 2010, Journal of NeuroVirology.

[61]  L. Pulliam,et al.  Peripheral biomarkers do not correlate with cognitive impairment in highly active antiretroviral therapy—treated subjects with human immunodeficiency virus type 1 infection , 2010, Journal of NeuroVirology.

[62]  E. Daar.  Faculty Opinions recommendation of HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. , 2011 .

[63]  Yaakov Stern,et al.  HIV-associated cognitive impairment before and after the advent of combination therapy , 2011, Journal of NeuroVirology.