Francisco González-Scarano, MD

This activity offers CE credits for:
	1. Physicians (CME)
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All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

The goal of this activity is to provide an understanding of the effects on the CNS that lead to HIV-associated neurocognitive disorders (HAND).

At the end of this CE activity, participants should be able to:

• Discuss the criteria for the three stages of HAND

• Describe the challenges associated with the diagnosis of HAND

• Communicate the role of combination antiretroviral therapy in HAND

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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Francisco GonzÃ¡lez-Scarano, MD, has no disclosures to report.

Dennis L. Kolson, MD, PhD, has no disclosures to report.

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The central nervous system (CNS) complications of human immunodeficiency virus (HIV) infection triggered directly by the virus and not by an opportunistic pathogen were recognized early in the course of this epidemic. The initial descriptions were primarily of a severe progressive illness termed the AIDS Dementia Complex. Several decades later these neurological complications persist with a different name and mostly in a milder form, which nonetheless can still be disabling.

Natural history of HIV-associated neurocognitive disorders

HIV-associated neurocognitive disorders (HAND) comprise a spectrum of conditions ranging from minor cognitive impairment to severe dementia that are felt to be a direct consequence of the infection.

 HAND generally develops over years and is classified into three categories: asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia. The criteria for these stages are outlined in

. They became generally accepted following a consensus conference held in Frascati, Italy, and they are therefore often referred to in the literature as the “Frascati” criteria.

The diagnosis of asymptomatic neurocognitive impairment by the Frascati criteria is felt by some to be a somewhat liberal interpretation of the cognitive problems of HIV, as it is strictly based upon criteria of abnormal neuropsychologic test performance without any impairment of clinical functioning. However, at least one reasonably large study indicated that individuals with asymptomatic neurocognitive impairment are more likely to progress to symptomatic HAND, making this an important classification and an entity to recognize.

Because HIV and HAND are global issues, diagnosing HAND with tests applicable to resource-limited settings is critical. A comprehensive 5-year study of neurocognitive performance in HIV-infected individuals beginning combination antiretroviral therapy (cART) in seven underdeveloped countries has established neurodiagnostic criteria and a similar worldwide prevalence of HAND.

Since the mid-1990s, HIV-associated dementia has been relatively uncommon in areas where cART is widely available, such as the US. HIV-associated dementia was described soon after the association of HIV with the syndrome of AIDS, in the 1980s. In those earlier years of the HIV epidemic when treatment was mostly ineffectual, approximately 20% to 30% of individuals had HIV-associated dementia, or AIDS Dementia Complex as it was then known.

HIV-associated dementia is a severe dementing illness that begins with disturbances of memory and cognition that affect daily living and progresses to psychomotor retardation, inability to recognize close friends or relatives, and eventual immobility. The psychomotor symptoms point to its subcortical etiology, consistent with the neuropathology of HIV-associated dementia.

 At its height (prior to cART) it was so widely recognized that it was immortalized in the second movement of 

 (1988-1989) by John Corigliano, who describes it musically in one of his friends.

Despite the dramatic decrease in the prevalence of HIV-associated dementia (to about 2% with cART) the less severe but nonetheless disabling form, mild neurocognitive disorder, affects approximately 15% of virally suppressed HIV-positive individuals today.

 Some studies suggest that up to 70% of patients with HAND who are receiving cART remain stable (at least over several years), while about 15% improve and an equal percentage further deteriorate.4 An unanswered question is how HAND prevalence will change over decades of life experienced by many individuals receiving cART.

In addition to CD4-positive lymphocytes, productive HIV infection in the CNS is principally restricted to macrophages and microglial cells, which are principally derived from mesodermal bone marrow and yolk sac precursors, respectively. HIV infection of the brain occurs within days of systemic infection, and levels of HIV RNA in the cerebrospinal fluid (CSF) correlate with the severity of HAND in individuals who are naive to antiretrovial therapy.

Studies of CSF derived from patients within days or weeks of HIV infection suggest a “Trojan horse” mechanism of entry of HIV-infected CD4-positive T lymphocytes into the brain and subsequent adaptation of the virus to infect macrophages and microglia.

This can establish viral reservoirs that are at least partially inaccessible to antiretroviral therapy. In patients who receive suppressive cART (ie, with undetectable plasma virus levels), the presence and severity of HAND correlate with certain biomarkers of inflammation and neuronal injury that are likely initiated and amplified by HIV infection of macrophages and microglia and immune activation of non-infected cells.

There is some trafficking between the systemic cellular precursors of macrophages and the brain, and they are often prominent in the perivascular spaces; less so for microglia that are parenchymal and long-lived, allowing for persistence of HIV in the CNS as well as persistence of neuroinflammation. Macrophages and microglia are the only cells in the brain that have the full complement of HIV surface receptors (ie, CD4 and CCR5); other brain cells may express CXCR4 (another HIV receptor) but not in conjunction with CD4, thereby preventing efficient entry of HIV. Brain autopsy studies have identified perivascular macrophages and parenchymal microglia as a major CNS site of productive HIV replication and inflammation, although astrocytes (up to approximately 15% infection rate) can also contain HIV genomes.

The pathological hallmark of HIV-associated dementia is the postmortem presence of multinucleated giant cells that contain viral proteins and RNA/DNA, and are thought to be derived from the fusion of infected cells.

 The presence of multinucleated giant cells in autopsy specimens probably indicates that these fused cells live for a period that is likely to be more than a few minutes or hours; specific determination of the timeframe is probably impossible with current technology.

It is thought that this long antemortem period of HIV replication within these giant cells drives the pathogenesis of HAND, primarily through elaboration of pro-inflammatory and otherwise toxic signaling cascades in infected cells. Some non-infected cells may also be activated by the presence of multinucleated giant cells. These cells are associated with severe neuronal injury and death, for which several cell death pathways, including apoptosis and necrosis, have been implicated. However, in the era of cART some individuals with HAND have no discernible neuropathological abnormalities despite having functionally significant neurocognitive impairment.

The pathophysiology of HAND in the pre- and post-cART eras is certainly multifactorial, involving effects of virus replication, residual brain injury prior to initiating cART, and variably expressed neurotoxicity cascades (

). Excluding multiple comorbid risk factors for brain injury that affect many subjects with HAND, its expression is likely to depend partly on the presence of varying degrees of, and intermittent expression of, neuroinflammation and oxidative stress, which are reduced but not eliminated by cART suppression of HIV replication.

Direct neurotoxic effects of cART on brain cells have also been implicated. In addition, early brain injury secondary to disruption of the blood-brain barrier within the first weeks after infection or residual damage from long-standing HIV infection before the initiation of cART (ie, legacy effect in some individuals) may result in an irreversible level of persistent cognitive impairment.

Inflammatory and neurotoxic cascades mediated by macrophages, microglia, and astrocytes have received the most attention. In addition to detection of HIV in macrophages and microglia in situ, virus-specific material (either DNA or proteins) has also been detected in other CNS cells, particularly astrocytes. However, in most cases the infection is not active (ie, not productive of viral progeny). This could be a sampling error given the large number of astrocytes in the human brain and the possibility that only a small proportion could be productively infected at any one time. Whether this astrocytic infection is pathophysiologically important, whether it also induces neuroinflammation, and whether these cells can serve as a long-term reservoir for infection remains a possibility, but it has never been incontrovertibly proven and has not been the focus of major treatment efforts.

Although analysis of CSF HIV levels in patients receiving cART indicates that suppression of HIV replication can be achieved within the CNS, surprisingly high rates of HIV escape from suppressive cART occur (ie, “blipping” of HIV replication). This is determined by sequential sampling of CSF and episodic detection of both HIV RNA and markers of immune activation of macrophages and microglia in individuals felt to be in a state of HIV suppression. Studies suggest transient HIV replication occurs in approximately 5% to 20% of patients.

Brain macrophages and microglia are thought to contribute to the development of brain injury and dysfunction in HAND through several mechanisms. Microglia are involved in many neurodevelopmental functions, such as synaptic/dendritic trimming, and are implicated in other neurological conditions. Perivascular macrophages, on the other hand, are not thought to be involved in neuronal trimming. Rather, they form part of the immune mechanisms of the brain.

A unifying hypothesis for the translation of a microglia/macrophage infection into a cognitive illness suggests that it is the secretion of cytokines and other immune mediators from these cells that affects neuronal function and perhaps survival. This hypothesis is consistent with the role that these cells are thought to play in other neurological conditions such as Alzheimer disease and stroke. It is also possible that infection of microglia interferes with their role in synaptic trimming or other intrinsic functions of these cells.

An alternative hypothesis is that some HIV proteins can themselves be toxic to neurons by binding at their surface and interfering with normal functions, possibly by excitatory mechanisms. In this scenario, secretion from infected macrophages or microglia is responsible for HAND abnormalities. The larger of the two viral glycoproteins (gp120) has been the subject of extensive laboratory studies that show various abnormalities in neurons exposed to it. Whether free gp120 is present in the brain at concentrations consistent with those that mediate experimental toxicity has never been formally settled, although it seems unlikely.

In view of the laboratory and pathophysiological studies that implicate viral involvement and the dramatic responses of cognitive disorders to cART, treatment has been directed at reduction of viral load, both systemically and in the brain. In either of the two proposed mechanisms discussed, reduction of the viral burden and infected macrophages/microglia is the most effective target for control and improvement of this condition.

The CNS is affected by many conditions in individuals with untreated HIV infection, particularly those with low CD4 counts. These include toxoplasmosis, progressive multifocal leukoencephalopathy, and neoplasms such as primary CNS lymphoma (

). HIV-infected patients frequently suffer from contributing or synergistic cognition-impairing comorbid conditions including depression, traumatic brain injury, developmental disability, substance abuse, cardiovascular disease, and hepatitis-C virus coinfection.

 Moreover, affected individuals can manifest behavioral features (eg, apathy, depression, delusions, hallucinations, sleep disturbances, mania) in addition to cognitive impairment, which may bring them to the attention of a psychiatrist.

Substances of abuse and methamphetamine in particular are a major contributing risk factor for cognitive dysfunction in patients with HIV with or without underlying HAND.

 The additional risks and adverse effects of methamphetamine use, including increased HIV acquisition rates, are particularly relevant for men who have sex with men, for which risk reduction strategies are being evaluated.

 Besides behavioral risk effects, methamphetamine has neuropathological effects such as damage to dopaminergic neurons and enhancement of HIV infection of macrophages; each can contribute to the worsening of HAND.

An HIV-positive patient who presents with any neurological deterioration, particularly involving cognition, must have a detailed medical history assessment and a battery of diagnostic tests, chief among these are brain imaging and CSF analysis. Because many patients on cART are well controlled virologically, free of opportunistic infection, and growing older, conditions associated with aging such as Alzheimer disease may confuse the clinical picture.

The prevalence of HAND has not decreased after the widespread institution of cART; however, the distribution by severity has changed. For example, in patients with well-controlled HIV, the prevalence of HIV-associated dementia is 2.4%, considerably lower than in the 1980s.

 Worldwide, the prevalence of HIV-associated dementia in virally suppressed HIV patients is also low.

Furthermore, the diagnosis of asymptomatic neurocognitive impairment and mild neurocognitive disorder, which are still common, can vary depending on the specific criteria used. To wit, GisslÃ©n and colleagues

 have argued for a more rigorous assessment of abnormalities by using biomarkers. In reality, it is the prevalence of two related but not identical entities that has remained constant throughout the HIV pandemic.

HIV-associated dementia, the severe form of HAND, occurs primarily in the setting of low CD4 counts (<200 cells/Î¼L), typically in individuals who are untreated. Initial abnormalities are difficulty with memory, inability to function effectively at work particularly in highly demanding professions, and eventually psychomotor retardation. The latter is characterized by slowness of movement and extrapyramidal signs.

In severe cases, T2-weighted brain MRI may demonstrate bilateral non-enhancing white matter abnormalities involving virtually both hemispheres. The CSF may have an elevated protein and detectable viral RNA, with a variable degree of lymphocytic pleocytosis. There are also several potential CSF markers such as neopterin and low molecular weight neurofilament chain (neurofilament light chain), each of whose levels correlate with dysfunction.

Neopterin, a marker of inflammation, can also be present even in asymptomatic patients with evidence of viral replication within the CNS. Neuropsychological testing is the gold standard for the diagnosis of cognitive problems. Typical testing for HAND includes analysis in six functional cognitive domains (

While neuropsychological testing is essential for individuals whose diagnosis is in doubt and for formal epidemiological or biological marker studies, this testing is generally unnecessary in individuals with HIV-associated dementia. The diagnosis can be clinically based on a history of difficulties with activities of daily living and by performance using less complex testing such as the Montreal Cognitive Assessment (MoCA).

 In the current era of cART, many clinicians believe that the symptoms of HIV-associated dementia are more commonly cortical (impairment of memory, difficulty with executive function) than the subcortical dementia with motor symptoms that characterized the initial descriptions of HIV-associated dementia. Therefore, tests that do not include motor components, such as the MoCA, are adequate for HIV-associated dementia diagnosis.

The principal goal of treatment of HAND is the systemic suppression of HIV; the number of cART drugs currently available is robust enough to preclude any detailed discussion of the components of cART in this short review. However, one area that has received a lot of attention is the importance of CNS penetration by cARTs, quantified by a CSF penetration effectiveness score.

 With the exception of HIV-associated dementia, where CNS penetration may be important for rapid reversal, most clinicians opt to treat for maximum systemic suppression of viral RNA rather than for CNS concentration.

Moreover, there is little evidence that antiretroviral drugs with enhanced CNS penetration are better as treatment for asymptomatic neurocognitive impairment or mild neurocognitive disorder, although this may be due to the difficulty in conducting accurate studies over a relatively long period of time. In general, clinicians who are concerned about neurological symptoms avoid efavirenz, which is known to have neuropsychiatric adverse effects.

The potential CNS toxicity of other antiretroviral drugs has also been proposed as a cause for persistent asymptomatic neurocognitive impairment or mild neurocognitive disorder in otherwise effectively treated individuals and such toxicity can be demonstrated in vitro. However, because of the likely subtlety of any such toxicity and the complexity of many antiretroviral regimens, it has been difficult to tease this out.

What is clearer is that in a subset of individuals (~5% to 20%), there is persistent presence of viral RNA in the CSF in spite of good control in the plasma. Typically, the threshold for consideration of discordance is a greater than 0.5 log higher concentration in the CSF than in the plasma. This CSF viremia may arise from endogenous cells such as macrophages or microglia or be the result of the individual replication of infected T cell clones within the neuraxis.

 In either case the CSF virus does not necessarily result in neurocognitive abnormalities; the CSF virus has been noted in asymptomatic individuals as well as in some with neurological worsening. Where appropriate-particularly in symptomatic patients-the usual course of action is to alter the specific cART to one that is more effective, either empirically or guided by genotypic analysis of the CSF viral genome.

A relatively rare but perplexing syndrome can also occur in some patients with low viral (plasma and CSF) RNA levels who develop signs of brain white matter damage. Brain MRI for these individuals demonstrates white matter lesions. When biopsied the brain tissue is infiltrated with CD8-positive lymphocytes. CD8 encephalitis is considered part of a spectrum of CD8 infiltrative conditions that can involve the lungs and other organs in individuals with HIV infection.

 It has also been associated with cART-resistant HIV strains. This entity responds to brief treatment with steroids sometimes coupled with modification of the cART regimen.

Candidate adjunctive neuroprotective therapies have been used only with cohorts of HIV-infected individuals with symptomatic HAND (mild neurocognitive disorder and/or HIV-associated dementia) with limited evidence of beneficial effects.

 However, because of emerging evidence of early (days to weeks) blood-brain barrier involvement and brain injury after initial HIV infection, co-administration of a neuroprotective adjunctive therapy at the time of cART initiation should be investigated.

The excellent systemic response to cART has resulted in a marked and welcome increase in lifespan for individuals living with HIV.

 Researchers have raised the possibility that asymptomatic or mildly symptomatic forms of HAND, such as asymptomatic neurocognitive impairment and mild neurocognitive disorder, will convert to more significant problems in combination with the effects of aging on the CNS. For example, given its predominantly cortical pathophysiology in the era of cART, HAND must be differentiated from other disorders of cognition that are associated with aging, particularly in patients aged older than 70 years, and in those whose treatment with cART may have been initiated later in the course of infection.

In older patients there may be some overlap with Alzheimer disease, as well as other causes of dementia such as vascular disease and Lewy body dementia.

 Indeed, several studies have shown a marked increase in minor cognitive impairment in HIV-seropositive individuals.32 In cases of viral suppression, there are no clear-cut additional therapeutic measures that can be undertaken.

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Dr GonzÃ¡lez-Scarano is Professor Emeritus of Neurology and Dr Kolson is Professor of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA.

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 Grant I, Franklin DR Jr, Deutsch R, et al, for the CHARTER Group. Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. 

 Robertson KR, Jiang H, Kumwenda J, et al. HIV Associated neurocognitive impairment in diverse resource limited settings. 

 Saylor D, Dickens AM, Sacktor N, et al. HIV-associated neurocognitive disorder: pathogenesis and prospects for treatment. 

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 Burdo TH, Lackner A, and Williams KC. Monocyte/macrophages and their role in HIV neuropathogenesis. 

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 Brew BJ. Benefit or toxicity from neurologically targeted antiretroviral therapy? 

 Peluso MJ, Meyerhoff DJ, Price RW, et al. Cerebrospinal fluid and neuroimaging biomarker abnormalities suggest early neurological injury in a subset of individuals during primary HIV infection. 

 Caniglia EC, Cain LE, Justice A, et al. Antiretroviral penetration into the CNS and incidence of AIDS-defining neurologic conditions. 

 Klasse PJ, Moore JP. Is there enough gp120 in the body fluids of HIV-1-infected individuals to have biologically significant effects? 

 Bougea A, Spantideas N, Galanis P, et al. Optimal treatment of HIV-associated neurocognitive disorders: myths and reality: a critical review. 

Articles

This CME article provides an understanding of the effects on the CNS that lead to HIV-associated neurocognitive disorders (HAND).

Francisco González-Scarano, MD

Articles

HIV-Associated Neurocognitive Disorder After the Start of Combination Antiretroviral Therapy