HIV-1-associated neurocognitive disorder: epidemiology, pathogenesis, diagnosis, and treatment

The modern antiretroviral treatment of human immunodeficiency virus (HIV-1) infection has considerably lowered the incidence of opportunistic infections. With the exception of the most severe dementia manifestations, the incidence and prevalence of HIV-associated neurocognitive disorders (HAND) have not decreased, and HAND continues to be relevant in daily clinical practice. Now, HAND occurs in earlier stages of HIV infection, and the clinical course differs from that before the widespread use of combination antiretroviral treatment (cART). The predominant clinical feature is a subcortical dementia with deficits in the domains concentration, attention, and memory. Motor signs such as gait disturbance and impaired manual dexterity have become less prominent. Prior to the advent of cART, the cerebral dysfunction could at least partially be explained by the viral load and by virus-associated histopathological findings. In subjects where cART has led to undetectable or at least very low viral load, the pathogenic virus–brain interaction is less direct, and an array of poorly understood immunological and probably toxic phenomena are discussed. This paper gives an overview of the current concepts in the field of HAND and provides suggestions for the diagnostic and therapeutic management.

[1]  I. Grant,et al.  Progression to neuropsychological impairment in human immunodeficiency virus infection predicted by elevated cerebrospinal fluid levels of human immunodeficiency virus RNA. , 2002, Archives of neurology.

[2]  Bruce J Brew,et al.  Evidence for a change in AIDS dementia complex in the era of highly active antiretroviral therapy and the possibility of new forms of AIDS dementia complex. , 2004, AIDS.

[3]  B. Clotet,et al.  Interruptions of antiretroviral therapy in human immunodeficiency virus infection: are they detrimental to neurocognitive functioning? , 2010, Journal of NeuroVirology.

[4]  H. Vinters,et al.  High levels of unintegrated HIV-1 DNA in brain tissue of AIDS dementia patients , 1990, Nature.

[5]  O. Selnes,et al.  Higher frequency of dementia in older HIV-1 individuals , 2004, Neurology.

[6]  Francesco Scaravilli,et al.  Neuropathology of Early HIV‐1 Infection , 1996, Brain pathology.

[7]  E. Masliah,et al.  Molecular and pathologic insights from latent HIV-1 infection in the human brain , 2013, Neurology.

[8]  S. Sánchez-Ramón,et al.  Low blood CD8+ T-lymphocytes and high circulating monocytes are predictors of HIV-1-associated progressive encephalopathy in children. , 2003, Pediatrics.

[9]  M. Peluso,et al.  Cerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well controlled plasma viral load , 2012, AIDS.

[10]  O. Selnes,et al.  The International HIV Dementia Scale: a new rapid screening test for HIV dementia , 2005, AIDS.

[11]  D. Clifford,et al.  Randomized trial of minocycline in the treatment of HIV-associated cognitive impairment , 2013, Neurology.

[12]  A. McMurtray Small vessel vascular disease in HIV infection , 2007 .

[13]  R. Kessels,et al.  Validity of the Montreal Cognitive Assessment and the HIV Dementia Scale in the assessment of cognitive impairment in HIV-1 infected patients , 2015, Journal of NeuroVirology.

[14]  L. Chang,et al.  Increased frontal white matter diffusion is associated with glial metabolites and psychomotor slowing in HIV , 2004, Journal of Neuroimmunology.

[15]  R. Stingele,et al.  Independent HIV replication in paired CSF and blood viral isolates during antiretroviral therapy , 2001, Neurology.

[16]  P. Vernazza,et al.  Higher CNS Penetration-Effectiveness of Long-term Combination Antiretroviral Therapy Is Associated With Better HIV-1 Viral Suppression in Cerebrospinal Fluid , 2013, Journal of acquired immune deficiency syndromes.

[17]  C. Hinkin,et al.  Reciprocal prediction of medication adherence and neurocognition in HIV/AIDS , 2010, Neurology.

[18]  B. Clotet,et al.  A Brief and Feasible Paper-Based Method to Screen for Neurocognitive Impairment in HIV-Infected Patients: The NEU Screen , 2013, Journal of acquired immune deficiency syndromes.

[19]  H. von Giesen,et al.  Therapeutic Effects of Nonnucleoside Reverse Transcriptase Inhibitors on the Central Nervous System in HIV‐1‐Infected Patients , 2002, Journal of acquired immune deficiency syndromes.

[20]  J. Glass,et al.  Immunocytochemical quantitation of human immunodeficiency virus in the brain: Correlations with dementia , 1995, Annals of neurology.

[21]  F. Vaida,et al.  Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy , 2009, Neurology.

[22]  Jianhui Zhong,et al.  Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment , 2011, AIDS.

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

[24]  D. Havlir,et al.  Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort , 2010, Neurology.

[25]  G. Arendt,et al.  Increased intrathecal release of soluble fractalkine in HIV-infected patients. , 2003, AIDS research and human retroviruses.

[26]  D. Fuchs,et al.  Immune activation of the central nervous system is still present after >4 years of effective highly active antiretroviral therapy. , 2007, The Journal of infectious diseases.

[27]  C. Sabin,et al.  Changes in the incidence and predictors of human immunodeficiency virus–associated dementia in the era of highly active antiretroviral therapy , 2008, Annals of neurology.

[28]  I. Grant,et al.  Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. , 2008, Archives of neurology.

[29]  G. Arendt,et al.  Cognitive impairment in HIV infection is associated with MRI and CSF pattern of neurodegeneration , 2013, European journal of neurology.

[30]  J. Glass,et al.  Increased frequency of the tumor necrosis factor‐α‐308 a allele in adults with human immunodeficiency virus dementia , 2001, Annals of neurology.

[31]  H. Freund,et al.  Motor dysfunction in HIV-infected patients without clinically detectable central-nervous deficit , 1990, Journal of Neurology.

[32]  B. Brew,et al.  Central nervous system antiretroviral efficacy in HIV infection: a qualitative and quantitative review and implications for future research , 2011, BMC neurology.

[33]  R. Price,et al.  Antiretroviral therapy and central nervous system HIV type 1 infection. , 2008, The Journal of infectious diseases.

[34]  P. Simmonds,et al.  Edinburgh Research Explorer Investigation of the dynamics of the spread of human immunodeficiency virus to brain and other tissues by evolutionary analysis of sequences from the p17gag and env genes , 2022 .

[35]  F. Vaida,et al.  Absence of neurocognitive effect of hepatitis C infection in HIV-coinfected people , 2015, Neurology.

[36]  P. Lantos,et al.  HIV‐Associated Disease of the Nervous System: Review of Nomenclature and Proposal for Neuropathology‐Based Terminology , 1991, Brain pathology.

[37]  L. Prockop AIDS dementia complex. , 1988, The Journal of legal medicine.

[38]  J. Becker,et al.  HIV-associated neurologic disease incidence changes: , 2001, Neurology.

[39]  P. Lantos,et al.  Circular forms of unintegrated human immunodeficiency virus type 1 DNA and high levels of viral protein expression: association with dementia and multinucleated giant cells in the brains of patients with AIDS , 1997, Journal of virology.

[40]  E. Masliah,et al.  Cortical Synaptic Density is Reduced in Mild to Moderate Human Immunodeficiency Virus Neurocognitive Disorder , 1999, Brain pathology.

[41]  B. Brew,et al.  Independent Evolution of Human Immunodeficiency Virus (HIV) Drug Resistance Mutations in Diverse Areas of the Brain in HIV-Infected Patients, with and without Dementia, on Antiretroviral Treatment , 2004, Journal of Virology.

[42]  E. Masliah,et al.  Relationship of antiretroviral treatment to postmortem brain tissue viral load in human immunodeficiency virus-infected patients , 2011, Journal of NeuroVirology.

[43]  B. Gelman Neuropathology of HAND With Suppressive Antiretroviral Therapy: Encephalitis and Neurodegeneration Reconsidered , 2015, Current HIV/AIDS Reports.

[44]  I. Elovaara,et al.  Intrathecal humoral immunologic response in neurologically symptomatic and asymptomatic patients with human immunodeficiency virus infection , 1988, Neurology.

[45]  M. Hirsch,et al.  Zidovudine treatment of the AIDS dementia complex: Results of a placebo‐controlled trial , 1993, Annals of neurology.

[46]  I. Grant,et al.  Assessment, Diagnosis, and Treatment of HIV-Associated Neurocognitive Disorder: A Consensus Report of the Mind Exchange Program , 2013 .

[47]  Andrew Levine,et al.  Prevalence of HIV-associated neurocognitive disorders in the Multicenter AIDS Cohort Study , 2016, Neurology.

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

[49]  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.

[50]  H. Hartung,et al.  Measurement of soluble inflammatory mediators in cerebrospinal fluid of human immunodeficiency virus-positive patients at distinct stages of infection by solid-phase protein array , 2009, Journal of NeuroVirology.

[51]  K. Mayer Assessment, diagnosis, and treatment of HIV-associated neurocognitive disorder: a consensus report of the mind exchange program. , 2013, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[52]  E. Masliah,et al.  Neurocognitive dysfunction predicts postmortem findings of HIV encephalitis , 2002, Neurology.

[53]  I. Grant,et al.  Predictive validity of demographically adjusted normative standards for the HIV Dementia Scale , 2008, Journal of clinical and experimental neuropsychology.

[54]  E. Masliah,et al.  Neuropathologic confirmation of definitional criteria for human immunodeficiency virus-associated neurocognitive disorders , 2011, Journal of NeuroVirology.

[55]  H. Budka Multinucleated giant cells in brain: A hallmark of the acquired immune deficiency syndrome (AIDS) , 2004, Acta Neuropathologica.

[56]  R. Heaton,et al.  Depression, Cognition, and Self-Appraisal of Functional Abilities in HIV: An Examination of Subjective Appraisal Versus Objective Performance , 2011, The Clinical neuropsychologist.

[57]  Michael J. Taylor,et al.  HIV suppression by HAART preserves cognitive function in advanced, immune-reconstituted AIDS patients , 2007, AIDS.

[58]  F. Scaravilli,et al.  The Changing Pattern of HIV Neuropathology in the HAART Era , 2003, Journal of neuropathology and experimental neurology.

[59]  J. McArthur,et al.  Relationship between human immunodeficiency virus—associated dementia and viral load in cerebrospinal fluid and brain , 1997, Annals of neurology.

[60]  Central nervous system penetration effectiveness of antiretroviral drugs and neuropsychological impairment in the Ontario HIV Treatment Network Cohort Study , 2016, Journal of NeuroVirology.

[61]  V. Valcour,et al.  Small-Vessel Vascular Disease in Human Immunodeficiency Virus Infection: The Hawaii Aging with HIV Cohort Study , 2007, Cerebrovascular Diseases.

[62]  S. Letendre Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder. , 2011, Topics in antiviral medicine.

[63]  I. Grant,et al.  Effects of HIV-1 infection and aging on neurobehavioral functioning: preliminary findings , 2004, AIDS.

[64]  W. Snider,et al.  Neurological complications of acquired immune deficiency syndrome: Analysis of 50 patients , 1983, Annals of neurology.

[65]  B. Rovin,et al.  HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[66]  K. Marder,et al.  Attenuated central nervous system infection in advanced HIV/AIDS with combination antiretroviral therapy. , 2004, Archives of neurology.

[67]  J. Margolick,et al.  Longitudinally preserved psychomotor performance in long-term asymptomatic HIV-infected individuals , 2007, Neurology.

[68]  R. Haubrich,et al.  Randomized trial of central nervous system-targeted antiretrovirals for HIV-associated neurocognitive disorder. , 2014, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[69]  J. Kaldor,et al.  Changes to AIDS dementia complex in the era of highly active antiretroviral therapy. , 1999, AIDS.

[70]  B. Clotet,et al.  Interruptions of Antiretroviral Therapy in HIV Infection : Are they Detrimental to Neurocognitive Functioning ? , 2015 .

[71]  L. Eberly,et al.  Low prevalence of neurocognitive impairment in early diagnosed and managed HIV-infected persons , 2013, Neurology.

[72]  W. Sturm,et al.  Neuropsychological assessment , 2007, Journal of Neurology.

[73]  E. Mills,et al.  Aging and HIV-related cognitive loss. , 2012, JAMA.

[74]  Genetic shift of env V3 loop viral sequences in patients with HIV-associated neurocognitive disorder during antiretroviral therapy , 2013, Journal of NeuroVirology.

[75]  G. Shaw,et al.  HTLV-III infection in brains of children and adults with AIDS encephalopathy. , 1985, Science.

[76]  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.

[77]  C A Wiley,et al.  HIV mediates a productive infection of the brain. , 1999, AIDS.

[78]  I. Grant,et al.  Symptomatic HIV seroconverting illness is associated with more rapid neurological impairment , 2001, Sexually transmitted infections.

[79]  J. Catalan,et al.  Undetectable Cerebrospinal Fluid HIV RNA and β-2 Microglobulin Do Not Indicate Inactive AIDS Dementia Complex in Highly Active Antiretroviral Therapy-Treated Patients , 2005, Journal of acquired immune deficiency syndromes.

[80]  R. Edelman,et al.  Diffusion tensor imaging of subcortical brain injury in patients infected with human immunodeficiency virus , 2005, Journal of NeuroVirology.

[81]  Maria Flora Salvatori,et al.  Persistence of Neuropsychologic Deficits Despite Long-TermHighlyActiveAntiretroviralTherapyinPatients With HIV-Related Neurocognitive Impairment: Prevalence and Risk Factors , 2007, Journal of acquired immune deficiency syndromes.

[82]  M. Roediger,et al.  Improved neurocognitive test performance in both arms of the SMART study: impact of practice effect , 2013, Journal of NeuroVirology.

[83]  Michael J. Taylor,et al.  Brain mitochondrial injury in human immunodeficiency virus-seropositive (HIV+) individuals taking nucleoside reverse transcriptase inhibitors , 2005, Journal of NeuroVirology.

[84]  I. Grant,et al.  Increased Intrathecal Immune Activation in Virally Suppressed HIV-1 Infected Patients with Neurocognitive Impairment , 2016, PloS one.

[85]  C. Marra,et al.  Interpreting cerebrospinal fluid pleocytosis in HIV in the era of potent antiretroviral therapy , 2007, BMC infectious diseases.

[86]  B. Brew,et al.  Maraviroc-intensified combined antiretroviral therapy improves cognition in virally suppressed HIV-associated neurocognitive disorder , 2016, AIDS.

[87]  Y. Persidsky,et al.  Immune privilege and HIV‐1 persistence in the CNS , 2006, Immunological reviews.

[88]  Ying Wu,et al.  Structural brain alterations can be detected early in HIV infection , 2012, Neurology.

[89]  J. Becker,et al.  Updated research nosology for HIV-associated neurocognitive disorders , 2007, Neurology.

[90]  Gregory R. Kirk,et al.  Peripheral blood HIV DNA is associated with atrophy of cerebellar and subcortical gray matter , 2013, Neurology.

[91]  D. Labar,et al.  Seizures in human immunodeficiency virus infection. , 1990, Archives of neurology.

[92]  D. Brooks,et al.  Increased microglia activation in neurologically asymptomatic HIV-infected patients receiving effective ART , 2014, AIDS.

[93]  K. Hertogs,et al.  Delayed central nervous system virus suppression during highly active antiretroviral therapy is associated with HIV encephalopathy, but not with viral drug resistance or poor central nervous system drug penetration , 2003, AIDS.

[94]  H. Budka,et al.  Prominent cortical atrophy with neuronal loss as correlate of human immunodeficiency virus encephalopathy , 2004, Acta Neuropathologica.

[95]  V. Valcour,et al.  Circulating proviral HIV DNA and HIV-associated dementia , 2005, AIDS.

[96]  H. Freund,et al.  Motor analysis predicts progression in HIV-associated brain disease , 1994, Journal of the Neurological Sciences.

[97]  D. Sharp,et al.  White matter hyperintensities in relation to cognition in HIV-infected men with sustained suppressed viral load on combination antiretroviral therapy , 2016, AIDS.

[98]  D. Simpson,et al.  Motor function and human immunodeficiency virus-associated cognitive impairment in a highly active antiretroviral therapy-era cohort. , 2008, Archives of neurology.

[99]  J. van Lunzen,et al.  HIV infection of the central nervous system is characterized by rapid turnover of viral RNA in cerebrospinal fluid. , 1999, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[100]  Alexander G. Holman,et al.  HIVBrainSeqDB: a database of annotated HIV envelope sequences from brain and other anatomical sites , 2010, AIDS research and therapy.

[101]  D. Moore,et al.  Cliniconeuropathologic correlates of human immunodeficiency virus in the era of antiretroviral therapy , 2009, Journal of NeuroVirology.

[102]  A. Fagan,et al.  CSF biomarkers of Alzheimer disease in HIV-associated neurologic disease , 2009, Neurology.

[103]  S. Evers,et al.  Impact of antiretroviral treatment on AIDS dementia: a longitudinal prospective event-related potential study. , 1998, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[104]  M. Ticchioni,et al.  Can high central nervous system penetrating antiretroviral regimens protect against the onset of HIV-associated neurocognitive disorders? , 2014, AIDS.

[105]  E. Masliah,et al.  Brain deposition of beta-amyloid is a common pathologic feature in HIV positive patients , 2005, AIDS.

[106]  R. Swanstrom,et al.  Increased Human Immunodeficiency Virus Type 1 (HIV-1) env Compartmentalization in the Presence of HIV-1-Associated Dementia , 2005, Journal of Virology.

[107]  D. Jeste,et al.  New-onset psychosis in HIV-infected patients. , 1991, The Journal of clinical psychiatry.

[108]  M. Weisbrod,et al.  HIV-Patienten mit psychiatrischen Krankheiten Behandlungsstrategien und Medikamenteninteraktionen , 2001, Der Nervenarzt.

[109]  J. Annoni,et al.  Rivastigmine for HIV-associated neurocognitive disorders , 2013, Neurology.

[110]  K. Marder,et al.  An evaluation of neurocognitive status and markers of immune activation as predictors of time to death in advanced HIV infection. , 2007, Archives of neurology.

[111]  K. Robertson,et al.  Neurocognition with maraviroc compared with tenofovir in HIV , 2016, AIDS.

[112]  B. Brew,et al.  Levels of human immunodeficiency virus type 1 RNA in cerebrospinal fluid correlate with AIDS dementia stage. , 1997, The Journal of infectious diseases.

[113]  Anthony Gamst,et al.  Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline , 2014, Neurology.

[114]  D. Reich,et al.  Immune reconstitution inflammatory syndrome in the CNS of HIV-infected patients , 2006, Neurology.

[115]  Susan Morgello,et al.  CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy , 2011, AIDS.

[116]  Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV , 2016, Journal of NeuroVirology.

[117]  I. Grant,et al.  Prediction of incident neurocognitive impairment by plasma HIV RNA and CD4 levels early after HIV seroconversion. , 2003, Archives of neurology.

[118]  M. Maschke,et al.  Structural gray and white matter changes in patients with HIV , 2011, Journal of Neurology.

[119]  J. van Lunzen,et al.  Rapid clearance of human immunodeficiency virus type 1 from ventricular cerebrospinal fluid during antiretroviral treatment , 2000, Annals of neurology.

[120]  The Alzheimer’s disease-8 and Montreal Cognitive Assessment as screening tools for neurocognitive impairment in HIV-infected persons , 2013, Journal of NeuroVirology.

[121]  P. Schulz,et al.  Cardiovascular Risk Factors Associated With Lower Baseline Cognitive Performance in HIV-Positive Persons , 2011, Neurology.

[122]  L. Fellows,et al.  A better screening tool for HIV-associated neurocognitive disorders: is it what clinicians need? , 2015, AIDS.

[123]  C. Eggers,et al.  Antibodies to myelin oligodendrocyte glycoprotein in HIV-1 associated neurocognitive disorder: a cross-sectional cohort study , 2010, Journal of Neuroinflammation.

[124]  B. Navia,et al.  The AIDS dementia complex: I. Clinical features , 1986, Annals of neurology.

[125]  Amanda M. Brown,et al.  Cortical neurons are a prominent source of the proinflammatory cytokine osteopontin in HIV-associated neurocognitive disorders , 2015, Journal of NeuroVirology.

[126]  K. Marder,et al.  Evaluation of HIV RNA and markers of immune activation as predictors of HIV-associated dementia , 2004, Neurology.

[127]  P. Sonnenberg,et al.  High human immunodeficiency virus type 1 RNA load in the cerebrospinal fluid from patients with lymphocytic meningitis. , 1998, The Journal of infectious diseases.

[128]  R. Tubiana,et al.  Discordance between cerebral spinal fluid and plasma HIV replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[129]  H. Günthard,et al.  Randomized controlled study demonstrating failure of LPV/r monotherapy in HIV: the role of compartment and CD4-nadir , 2010, AIDS.

[130]  J. Becker,et al.  Dementia in AIDS patients , 1993, Neurology.

[131]  Jean-Marie Annoni,et al.  Cognitive dysfunction in HIV patients despite long-standing suppression of viremia , 2009, AIDS.

[132]  I. Grant,et al.  Markers of Macrophage Activation and Axonal Injury are Associated With Prospective Memory in HIV-1 Disease , 2006, Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology.