Continuing Education Activity

Patients with human immunodeficiency virus infection (HIV infection) have been noted to have various forms of neuropsychiatric illnesses. These include symptoms of both cognitive disorders as well as mood and anxiety symptoms. This activity reviews the epidemiology, etiology, clinical signs and symptoms, evaluation, and treatment of neurocognitive disorder secondary to HIV disease and highlights the interprofessional team's role in evaluating and treating this condition. This activity also reviews basic screening tools for the disease and evidence-based treatment guidelines. This activity also covers a section on current research studies on neurocognitive disorders secondary to HIV.

Objectives:

• Review the impact of HIV disease on major cognitive disorders or dementia.
• Identify the different stages of dementia or neurocognitive disorder secondary to HIV disease.
• Outline the management options available for dementia or neurocognitive disorder secondary to HIV disease.
• Describe the importance of improving care coordination amongst interprofessional team members to improve outcomes for patients affected by neurocognitive disorders secondary to HIV disease.

Introduction

Patients with human immunodeficiency virus (HIV) infection have been noted to have various forms of neuropsychiatric illnesses. Neuropsychiatric illnesses include symptoms of both cognitive disorders as well as mood and anxiety symptoms.[1] In the past, before the advent of antiretroviral treatment, several neuropsychiatric disorders remained untreated, resulting in significant morbidity and mortality for these patients.[2] Most of these disorders stemmed from untreated infectious diseases secondary to AIDS (acquired immunodeficiency syndrome), like toxoplasmosis and encephalitis.[3] The decline in neurocognitive disorders notably came hand in hand with the advent of HAART (highly active antiretroviral therapy). Combination treatment for HIV was developed around 1996, and since then, the incidence of HIV-related neuropsychiatric disorders has started to decline.[4] 

Frascati Classification of HIV-associated Neurocognitive Disorders

The United States National Institutes of Health published a classification scheme in 2007 to define these neuropsychiatric disorders so that there may be uniformity in clinical assessments and research for these disorders. This classification system is called the "Frascati criteria," although it has not been universally adopted.[5] This classification can only be applied when neurocognitive impairment cannot be explained by any other condition (other than HIV). Opportunistic infections, malignancy, stroke, substance use with toxicity or withdrawal syndromes, and/or acute encephalopathy must be excluded before this classification is applied or considered. 

• Asymptomatic neurocognitive impairment (ANI): When the individual scores 1 standard deviation (SD) or more below the mean in 2 or more cognitive domains on standardized neuropsychological testing. There is usually no overt functional impairment.
• Mild neurocognitive disorder (MND): When the individual scores 1  SD or more below the mean in 2 or more cognitive domains on standardized neuropsychological testing AND has evidence of overt (usually mild) functional impairment.
• HIV-associated dementia (HAD) – When the individual scores 2 SD or more below the mean in 2 or more cognitive domains on standardized neuropsychological testing AND has evidence of functional impairment affecting activities of daily living.

As is clear from the above definitions, the application of these criteria requires formalized testing and should not be applied without objective evaluation. 

Etiology

The human immunodeficiency virus (HIV) directly crosses the blood-brain barrier during the acute phase of infection. However, it is during the chronic inflammation phase that cognitive changes are seen. Monocytes, macrophages, and white matter are all affected in the brain.[6] HIV reproduces in the microglia, which are known as the brain's "immune cells." These changes are associated with clinical signs and symptoms of neurocognitive disorders seen with HIV disease. However, not all patients with HIV will develop these disorders. A number of different risk factors have been identified and are discussed below. 

• Low nadir CD4 count: Several studies have shown that the severity of HIV disease, which is extrapolated from a low nadir CD4 count, correlates with the risk of developing neurocognitive disorders.[7][8] Another study reported an increased risk for HIV-associated dementia in patients with a longer duration of HIV infection and the presence of AIDS-defining lesions with a low CD4 count (defined as less than 200 cells/mm3).[9] It is interesting to note that these studies suggested a sustained impairment with a non-reversible component of neurocognitive dysfunction in these patients.[7] The studies observed a lack of association between neurocognitive impairment and improvement in laboratory parameters following HAART therapy, suggesting that neural injury secondary to HIV does not improve despite antiretroviral therapy.[7]
• Advanced age: Although there is an increased prevalence of neurocognitive disorders in patients with HIV who are 50 years or older, it is unclear if this is due to a direct result of HIV infection versus advanced age itself.[10]
• Coexistent cardiovascular disease and obesity: There is a higher risk of dementia in patients with cardiovascular risk factors and/or underlying cardiovascular disease and HIV infection when compared to the general population.[11] These comorbidities have a higher correlation with the development of neurocognitive disorders in patients with HIV than HIV viral load or CD4 cell counts.[12]
• Coinfection with hepatitis C: There is conflicting data regarding the risk of hepatitis C coinfection in patients with HIV when determining the risk of neurocognitive disorders. Some studies identify clear risk when both infections are present,[13] but some studies report no evidence of increased neurocognitive impairment in patients coinfected with the two viruses.[14]
• History of toxoplasmosis: A prior history of toxoplasma infection has been associated with an increased risk of neurocognitive deficits, especially in patients with latent toxoplasma infections. This risk was observed independent of CD4 cell counts.[15]

Interestingly, despite multiple studies attempting to identify genetic predisposition for the development of HIV-associated neurocognitive disorder, there is no evidence to support any particular mutation. A large multicenter trial evaluating more than 1200 patients did not detect an association between any polymorphisms and HIV-associated neurocognitive disorders.[16]

Epidemiology

The initial epidemiological data on HIV-associated dementia identified this disorder as a common occurrence in patients with HIV, affecting as many as 40% of the patients infected with HIV.[17] These disorders were collectively termed "AIDS dementia complex" when they were first identified.[18] In the United States, approximately 50% of the patients with HIV were noted to have a cognitive impairment when studies were first conducted.[8]

With the advent of antiretroviral therapy, the prevalence of these disorders has declined, especially in people who are on treatment consistently.[19][20] Data from the CASCADE cohort revealed a decrease in the incidence of these disorders from 6.49 per 1000 person-years to 0.66 per 1000 person-years.[9] Despite the decline in severe neurocognitive deficits, there is a substantial prevalence of mild cognitive impairment, despite viral suppression.[21] Recent studies in the post-HAART era report asymptomatic neurocognitive impairment (ANI) as the most common neurocognitive disorder, with a prevalence of 33%. Mild neurocognitive disorder was reported to have a prevalence of 12%, and HIV-associated dementia was noted to be present in only 2% of the cases.[8]

There is recent debate regarding the cause of persistent neurocognitive deficits in the post-HAART era. While some studies continue to outline the increased risk of neurocognitive disorders in patients with HIV,[22] other studies have reported no difference in the prevalence of these disorders among patients with HIV (who were able to achieve viral suppression with adequate CD4 cell counts) and age-matched controls who did not have HIV.[23]

Pathophysiology

HIV crosses the blood-brain barrier and infiltrates the macrophages in the central nervous system. A virus-induced fusion of macrophages leads to the formation of giant cells and astrocytes activation and damage (astrocytes are cells that provide metabolic support and detoxify neurons), ultimately leading to neuronal damage in many parts of the brain. The damage is caused by verotoxins, including HIV proteins gp41, gp120, Tat, Vpr, Nef, and Rev. The subcortical structures are most affected, like the limbic structures and basal ganglia.[24] HIV infection also causes a breakdown of white matter and axonal damage.[25] Ultimately, this leads to a decline in cognition and notably a decreased volume of the brain structures like basal ganglia and caudate nucleus, causing atrophy of the brain volume.[26] Autopsy studies of patients with AIDS and HIV-associated dementia revealed white matter pallor, microglial nodules, multinucleated giant cells, and perivascular infiltrates.[27]

Histopathology

In the pre-HAART era, when the incidence of HIV-associated dementia was considerably high, brain autopsies showed meningitis with low counts of lymphocytes and perivascular lymphocytic cuffing.[28] The cells that are seen are generally CD8 T- lymphocytes and CD4 lymphocytes.[29]

HIV enters the brain via HIV-infected lymphocytes and macrophages. In addition to the passage of cell-free virus into the brain and release of the virus from the infected endothelial cells. The virus replicates in these cells and infects the microglia, astrocytes, oligodendrocytes, and neurons. HIV infection in the CNS can be detected and monitored by cerebrospinal fluid (CSF) viral load measurements. Another pathological feature in HIV-associated encephalitis is the presence of multinucleated giant cells, which was very prominent before the advent of antiretroviral drugs.[30] Multiple studies established a positive correlation between CSF viral load and the extent of cognitive dysfunction.

History and Physical

The earliest symptoms and signs are impairment in concentration, memory, and executive functioning. As the disease progresses, psychomotor retardation, depressive symptoms, irritability, and subclinical motor signs are observed. These motor signs include tremors and hyperreflexia. With time and continued progression, the clinical features evolve to include overall global dementia, myelopathy, neuropathy, and even Parkinson-like features.[31]

The severity of HIV infection and antiretroviral treatment (ART) status greatly affects the presentation of HIV-associated neurocognitive disorders (HAND). As described above, patients with severe disease (dementia) are likely to have untreated HIV infection with low CD4 cell counts. They are likely not on any ART or are on ineffective regimens. Patients on ART are likely to have a slowly progressive course of neurocognitive decline with milder deficits. 

When present, HIV-associated dementia classically presents with subcortical dysfunction. This usually constitutes attention-concentration impairment, depressive symptoms, and impaired psychomotor functions.[18][32] Cognitive deficits manifest as memory impairment, impaired executive functioning, and apathy.[33]

In mild neurocognitive decline, impaired attention and working memory are the predominant features. Higher executive functioning may also be impaired. These deficits may not necessarily be clinically evident. When symptomatic, they may reveal difficulty with reading and/or maintaining concentration in conversations or activities.[34] Motor dysfunction is usually absent in mild forms without dementia. 

CNS Viral Escape Syndrome

This is a very uncommon but clinically recognized condition. It can be seen in patients who are receiving antiretroviral therapy and present with severe new-onset neurological deficits. A "viral escape" phenomenon occurs when the patient has adequate peripheral viral suppression, but there is evidence of CNS HIV replication.[35] In most cases with this condition, there is also drug resistance in the CSF HIV viral strain. It is imperative to note that not all patients with evidence of CSF HIV viral replication will go on to develop this disease. Detectable CSF HIV RNA can be observed in patients without any evidence of neurocognitive dysfunction.[36] In patients suspected of presenting with CNS viral escape syndrome, CSF analysis for HIV RNA level and genotype testing is warranted to diagnose CNS viral escape and change the antiretroviral regimen to effective regimens if indicated based on resistance patterns. 

Immune Reconstitution Inflammatory Syndrome

Another rare cause of new-onset neurocognitive symptoms in patients with HIV is immune reconstitution inflammatory syndrome (IRIS). This is due to HIV CNS infection and presents with severe encephalitis, diffuse white and gray matter abnormalities on radiographic imaging, and CD8 cell pleocytosis in the CSF.[37]

Evaluation

The main tool for evaluation is neuropsychological testing. Some neuropsychological testing domains that have shown impairment include episodic memory (learning and recall), executive functions, attention/working memory, information processing, verbal fluency, and fine motor skills.[31][38] Some other aspects of neurocognitive testing include trail making test (to test executive functioning), use of a grooved keyboard (to test for psychomotor skills), digit span test (to determine psychomotor speed, abstraction, memory, and attention), and also use of the Stroop test (test attention and processing speed).[39]

Another form of evaluation is the use of imaging. In the pre-HIV treatment era, imaging was significant for global brain atrophy. HIV-related encephalitis can be evaluated with FLAIR imaging, which will show focal atrophy in the basal ganglia, thalamus, corpus callosum, and frontal lobes.[40] Recently, 3D imaging has studied the patterns of brain atrophy to correlate with ongoing cognitive impairment. Specific areas included sensorimotor areas, parts of the corpus callosum, and parts of the frontal lobes.[41] Many of the new imaging studies have compared infected individuals to normal same-age controls. Hence, the correlation between cognitive decline in infected individuals and relevant brain areas is now well established.

A good screening tool is the International HIV Dementia Scale, which tests memory, motor speed, and psychomotor speed. The test includes:

• Memory registration is tested by giving a patient four words and asking them to repeat them. Then the patient is requested to retain the words.
• Motor speed is tested by having the patient tap the first two fingers of their non-dominant hand as quickly as possible. The number of taps in five seconds is counted.
• The psychomotor speed is measured by having the patient use their non-dominant hand to do a series of tasks, for example, having the patient clench their fist, place the palm face down and then place it perpendicularly on the table. The speed and sequence are measured.
• The patient is asked to recall the four words practiced earlier.[42]

Another screening tool is the modified HIV scale, which tests immediate memory and delayed recall. Immediate and delayed memory is tested by asking patients to register four words and then asking them to repeat the words a few minutes later. Executive functioning is tested by copying a cube. Psychomotor speed is tested by asking the patient to write the alphabet in capital letters.[43]

One study showed that clinically three simple questions might be a good screening tool for HIV-associated Neurocognitive Disorder; these include asking whether patients experience memory loss, have difficulty paying attention, and feel slower while reasoning or doing complicated tasks.[44] However, the mainstay for evaluation is still getting a good clinical history and collaborative information around the start of cognitive decline. It is highly recommended by the Mind Exchange Program, which is established by expert clinicians around the world.[45]

Treatment / Management

Treatment with antiretroviral drugs (HAART) has shown improvement in cognitive function, including all cognitive domains. Also, the increase in CD4 count and the decrease in viral load have been correlated with cognitive improvement.[46] The treatment, therefore, revolves around the adequate treatment of HIV to achieve viral suppression and adequate CD4 counts.

Some experts believe that the drug's ability to cross the blood-brain barrier and achieve a high concentration in the cerebrovascular fluid is essential to lower the viral load. Letendre S et al. studied the CNS penetrability of ARV drugs. Individual ARV drugs were assigned a penetration rank of 0 (low), 0.5 (intermediate), or 1 (high). This ranking system was based on drug concentration in CSF, chemical properties, and CNS effectiveness in clinical studies. The CNS penetration-effectiveness (CPE) was calculated by summing the individual penetration ranks for each ARV in the regimen.[47] For example, combinations of efavirenz, lamivudine, and zidovudine have high CPE. Drugs like abacavir have a lower CPE score. Lower CPE ranks correlated with higher CSF viral load in their analysis.[48] A small study that included 37 people showed greater cognitive improvement with greater penetrability of the drug.[49] Another study looked at both HIV patients with cognitive impairment and patients with cognitive impairment without HIV, and it showed a worsening in cognitive scores. The theory is that ARV drugs with high penetrability can be neurotoxic too. So, it is suggested to suspect ARV neurotoxicity when cognitive improvement is not seen with antiretroviral treatment.[50]

Despite the above data, there is no clear evidence that certain regimens are more effective than others for neurocognitive disorders of HIV. Expert opinion suggests that antiretroviral agents with a "CNS penetration effectiveness (CPE)" score based on CSF drug kinetics might be better suited for these patients. However, clinical data to support this practice is lacking.[51] Observational studies evaluating CPE to guide regimen selection have provided conflicting data; where one study reported that ART regimens with a high CPE score were associated with greater improvements in tests of concentration and mental flexibility[52], but another study reported a small yet opposite effect.[48]

In general, however, it is important to avoid efavirenz in patients with HIV-associated neurocognitive impairment. This is not due to its CPE score but due to the risk of neuropsychiatric side effects associated with this medication.

Most research articles emphasize the use of psychiatric medications as needed for mood disorders. Many subtypes of antidepressants have been studied, including selective serotonin reuptake inhibitors, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors. All of these showed moderate symptomatic relief.[53][54] Psychostimulants may also be used for fatigue and apathy.[55] Psychotic and manic symptoms are less studied in HIV-positive patients; however, research was done on a small sample with psychosis and has shown a greater incidence of extrapyramidal symptoms.[56] Some mood stabilizers like lithium have concurrent neurotoxic effects. Some medications like carbamazepine can induce the same CYP enzyme system as many of the antiretroviral drugs and cause drug interactions.[57][58] In theory, several drugs are considered neuroprotective, such as memantine, pentoxifylline, selegiline, nimodipine, and peptide T. However, only selegiline has shown efficacy.[59]

Differential Diagnosis

Differential diagnoses include primary neurocognitive disorder and its subtypes. Given that persons with HIV have increased longevity, the primary neurocognitive disorder may also set in. It often becomes progressively more difficult to differentiate between neurocognitive disorder secondary to HIV and primary neurocognitive disorder.[60] Another differential diagnosis is major depressive disorder, which can present with signs and symptoms of pseudodementia. Some common features also include psychomotor retardation and lack of concentration. The prevalence of Major Depressive Disorder is higher in persons with HIV. Some symptoms remain in common, including apathy rather than a lack of interest in other activities. There is an increased incidence of dysphoria in both entities.[61][62]

Other differentials include substance intoxication and withdrawal, metabolic disorders, opportunistic infections (CNS toxoplasmosis, cryptococcal meningitis), brain tumors, traumatic brain injury, and even adverse effects of antiretroviral medications like efavirenz.[63]

The following conditions are important to remember in the differential diagnosis when considering possible HIV-associated dementia:

Central Nervous System Disease

• CNS lymphoma
• CNS toxoplasmosis
• CNS vasculitis
• Cryptococcal meningitis
• Cytomegalovirus encephalitis
• Metastatic disease
• Neurosyphilis
• Progressive multifocal leukoencephalopathy 
• Tuberculous meningitis

 Substance Withdrawal or Intoxication

• Alcohol
• Chronic cannabis
• Opioids

Metabolic and Endocrine Disease

• Addison disease
• B12 deficiency
• Thyroid disease 

Psychiatric Illness

• Delirium
• Mood disorders (major depression, dysthymia)

Pertinent Studies and Ongoing Trials

The longitudinal CHARTER study is one of the most prominent clinical research studies that focus on neurocognitive deficits in persons with HIV. It investigated the incidence and predictors of neurocognitive change over 16 to 72 months (mean 35) in 436 HIV-infected participants in the CNS HIV Anti-Retroviral Therapy Effects Research cohort. The conclusion was that neurocognitive changes were complex and depended on several factors, including HIV treatment and the extent of HIV infection and comorbid infections.[64]

In a study of the Use of Nonantiretroviral Medications That May Impact Neurocognition, 3300 women (71% with HIV) and data from almost 42,000 visits were studied. HIV infection was associated with neurocognitive adverse effects (NC-AE) medication use, which may influence the determinations of HIV-associated neurocognitive impairment. So it is advised that physicians consider the impact of NC-AE medications when evaluating patients with HIV and concurrent neurocognitive symptoms.[65]

Prognosis

According to the MIND exchange working group, there have been no studies that discuss the prognosis of HIV-associated neurocognitive disorder (HAND), however markers of HIV disease (low CD4 count and high viral load), ongoing poor scores on neuropsychological testing, and concurrent mood disorder all point towards a poor prognosis.[45]

Complications

Complications of HIV dementia, as mentioned above, can also include comorbid mood and anxiety disorders. Research has shown that chronic stress can lead to a weakened immune system and increase the risk of other diseases.[66] Also, given the longevity of persons living with HIV now, other forms of dementia, including primary neurocognitive illness, have become a comorbid complication.[67]

Deterrence and Patient Education

Patient education is primarily around early diagnosis and treatment of the disease. Treatment with HAART can delay and even deter the onset of dementia secondary to HIV disease. High viral loads and low CD4 cell counts are associated with a higher incidence of HIV-associated dementia; therefore, early HAART therapy is paramount in the prevention of severe neurocognitive decline in patients with HIV.

Screening asymptomatic patients with HIV for neurocognitive impairment is somewhat controversial. Arguments against this practice namely highlight cost-effectiveness and the limited resources in most settings to screen asymptomatic patients for this disease. However, some studies suggest that screening asymptomatic patients can lead to early recognition and allow a change in HAART regimens to those that optimally penetrate the central nervous system, which in turn will improve clinical outcomes.[68]

Pearls and Other Issues

Consensus Guidelines from the Mind Exchange Working Group[45]

• All patients with HIV should be assessed for neurocognitive functioning regardless of apparent symptoms or CD4/HIV viral load.
• Reassessment should occur every 6 to 12 months in high-risk patients or every 12 to 24 months in low-risk patients.
• Comprehensive neurocognitive evaluation includes the evaluation of at least 5 neurocognitive domains (verbal/language, attention/working memory, abstraction/executive function, learning/recall, speed of information processing, and motor skills).
• Any standardized and validated screening/evaluation tool is acceptable as no particular instrument has been shown to be of superior performance for the detection of this disorder.
• There is no data to support any preventive measures for this disease other than adequate treatment of HIV infection.
• Combination ART for 1 year has been shown to have modest benefits in neuropsychological functioning.
• This improved neurologic function was most apparent in attention, processing speed, and executive performance.
• Treatment regimens based on CNS penetration scores have not been consistently associated with improved neurologic functioning; therefore, changing ART to improve CNS penetration for patients whose infection is already well controlled is unwarranted.
• No therapy other than effective combination ART therapy is recommended for the treatment of this disease. Minocycline, memantine, selegiline, lithium, valproic acid, lexipafant, and nimodipine have been evaluated, but their effectiveness is not proven. 

Enhancing Healthcare Team Outcomes

The mainstay of treatment lies in early detection. All providers who encounter patients with HIV disease should be encouraged to start their patients on HAART. Patients must receive education about the onset of HIV-associated dementia, especially early signs of asymptomatic neurocognitive impairment, which may show a decrease in functioning. All providers must also be educated about the stages of dementia, especially when patients speak about the gradual loss of functioning in daily activities.

Infectious disease specialists treating these patients are encouraged to perform simple screening tests like the Mini-Mental State Exam or the Montreal Cognitive Assessments to look for neurocognitive impairment. They are also encouraged to simultaneously screen for symptoms of depression, including anhedonia, apathy, and lack of concentration. If there is any deficit seen in the screening tests, providers are highly encouraged to refer the patients for neuropsychological testing to determine areas of dysfunction.

Given that mood symptoms are prevalent in patients with HIV disease, a careful history is necessary regarding the onset of mood symptoms, and screeners such as the PHQ-9 may be used. If a patient scores in the range of moderate to severe depression, then a referral to a mental health provider should be made. Evidence has shown that treatment of concurrent mood and even psychotic symptoms has played a role in treating HIV-associated neurocognitive disorders. In case patients with HIV disease are hospitalized and show signs of cognitive dysfunction, a careful distinction must be made between delirium and cognitive decline. Longitudinal cognitive assessments and neurological exams must be made during the hospitalization.

Specialty-trained nurses can assist clinicians with early detection of this disease by conducting a cognitive screen every year and monitoring scores to recognize any sharp decline. Nurses can also help educate patients regarding the importance of compliance with HAART to prevent this disease. Clinical pharmacists can help providers identify treatment options with minimal adverse side effects and check for drug-drug interactions. A collaborative interprofessional team approach to patients with HIV can help deter neurocognitive disorders and ensure adequate management if the disease occurs.[Level 5]