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ABSTRACT

Since the introduction of combination antiretroviral therapy (cART), individuals with HIV live a fairly normal life, although some develop neurocognitive impairment. HIV-associated neurocognitive disorder (HAND) is the term used to describe these neurocognitive impairments within the HIV population, and include asymptomatic neurocognitive impairment (ANI), mild neurocognitive impairment (MND), and HIV-associated dementia (HAD). The purpose of this paper is to evaluate the diagnostic criteria for HAND used by investigators in the Multicenter AIDS Cohort Study (MACS). Two MACS studies examined the rates of HAND in the HIV+ and HIV- men and found similar prevalence rates of HAND (31.82% and 31.89%), ANI (16.23% and 15.75%), MND (12.99% and 11.81%), and HAD (2.6% and 4.33%). These rates suggest that the methods used to diagnose HAND do an inadequate job to distinguish between HIV+ and HIV- individuals. Better diagnostic criteria for HAND need to be developed to improve classification of the clinical spectrum of HAND. One way to improve the accuracy of diagnosis of HAND is to apply the Rasch analysis when analyzing the diagnostic criteria of MACS. This would help with the monitoring of disease progression, change or adjustment of cART, and identification of risk factors. By monitoring the progression of HAND, clinicians will be able to change or adjust cART as needed and help identify risk factors, which can help to alleviate public health concerns. The public health concerns associated with HAND are unemployment, social decline, lack of adherence to medications, and a poorer quality of life.

TABLE OF CONTENTS

Acknowledgements vii

1.0 Introduction 1

2.0 HIV-ASSOCIATED NEUROCOGNITIVE DISORDER (HAND) 3

2.1 THE HISTORY OF HAND 3

2.2 THE INFLUENCE OF ANTIRETROVIRAL DRUGS ON HAND 4

2.3 Stages of Hand 6

2.4 Screening and diagnosis of hand 8

2.5 Treatment of hand 11

2.6 epidemiology of hand 12

2.6.1 HAND in the Pre-cART and cART Eras 12

2.6.2 Progression of HAND 13

2.7 Risk factors FOR hand 14

2.8 Pathogensis of hand 14

3.0 Multicenter aids cohort study (macs) 16

3.1 HAND in macs 16

4.0 Discussion 19

bibliography 23

Acknowledgements

I would like to thank my academic advisor and committee chair Dr. Lawrence Kingsley for guiding me in the process of writing this essay, and everything else he has helped me with. Without him I would not be as successful as I am today. I would also like to thank Dr. James Becker who has helped shape this paper and process from the very beginning.

Introduction

In the 1980’s, the first cases of human immunodeficiency virus (HIV) were detected and since then HIV has caused about 78 million infections and killed almost 39 million people (HIV/AIDS, n.d.). With the introduction of combination antiretroviral therapy (cART) in 1996, survival rates of those infected dramatically increased to the point of nearly normal life expectancies.

Since the introduction of cART, individuals with HIV have near normal life expectancies and they are now more at risk of comorbidities associated with HIV because of this. Neurocognitive disorders associated with HIV, such as subacute encephalitis (Snider et al., 1983), AIDS dementia complex (Navia and Price, 1987), and HIV encephalopathy (Levy and Bredesen, 1988), have been researched since 1983, with the criteria for HIV-associated neurocognitive disorder (HAND) being published in 2007 by Antinorie and colleagues (Antinorie et al., 2007). HAND has three categories: asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). With the introduction of cART, the overall rates of HAND have stayed about the same, but they have shifted in which category is most prevalent, from more severe forms to milder forms. Between 2007 and 2012, the rates of HAND in those with HIV from the Multicenter AIDS Cohort Study (MACS) were: 14% ANI, 14% MND, and 5% HAD (Sacktor et al., 2016). Before the introduction of cART, the prevalence of HAD was about 10-20% (McArthur et al., 1993; Janssen et al., 1992).

The purpose of this essay is to evaluate the MACS on the diagnostic criteria for the diagnosis of HAND. Because of the shift in prevalence of HAND severity from more severe to less severe, better diagnostic criteria for identifying HAND need to be developed. Since there is no gold standard for HAND, the MACS sensitivity for HAND (a true positive rate) and specificity (a true negative rate) are not known (Lalkhen & McCluskey, 2008). Examining rates of HAND in the HIV+ and HIV- individuals within MACS will allow for further insight into the possible sensitivity and specificity of their diagnostic criteria. The evaluation of the MACS HAND diagnostic criteria will be analyzed with previously completed MACS studies, which compared HIV+ and HIV- individuals.

HIV-ASSOCIATED NEUROCOGNITIVE DISORDER (HAND)

1 THE HISTORY OF HAND

The term HIV-associated neurocognitive disorder (HAND) was developed in 2007, along with other neurocognitive disorders that were researched since 1983. At first, AIDS patients started demonstrating signs in the central or peripheral nervous system (Snider et al., 1983), which by 1983 was coined “subacute encephalitis.” It was not until 1987 that Navia and Price came up with the term “AIDS dementia complex” to describe what HIV patient’s brains were enduring (Navia and Price, 1987). In 1988, it was found that “HIV encephalopathy” was the most common complication of AIDS (Levy and Bredesen, 1988).

In 1988, Price and Brew established the first guidelines and testing criteria for HIV-associated dementia (HAD) (Price & Brew, 1988). They based their scale on 6 points; 0, .5, 1, 2, 3, and 4; where 0 is normal mental and motor functioning, .5 is subclinical, and 4 is the vegetative stage. This scale is mainly used to assess neurological and neuropsychological disorders, which is based on functional disability. Overall, Price and Brew’s scale does an adequate job of assessing HAD and is still used today by many institutions.

It was not until 1991 that an article was published to help standardize the terminology associated with HAD. The American Academy of Neurology AIDS Task Force wrote a paper to arrive at a consensus for the terminology and criteria to diagnose neurological disorders associated with HIV. Their findings were similar, but not identical to, the international classifications of diseases-10 (ICD-10) (“Nomenclature and research,” 1991).

In 1995, to make bedside testing more reliable, Power et al. developed a brief screening tool to assist in and get a better understanding of all processes associated with HAD research. The HIV dementia scale (HDS) was shown to identify HAD more consistently than the mini mental state examination, which was used frequently.

In 2003, there was a study that revised Price and Brew’s Northeast AIDS Dementia (NEAD) Consortium test criteria for HAD (Marder et al., 2003). In this study, Dana Consortium recruited participants similar to the NEAD study, with one of their primary aims being to address minor cognitive disorders. To make this change, they operationalized the definitions of each stage and used inter-rater reliability. It was found that this newly operationalized rating scale was useful for staging HAD in longitudinal studies.

To update the terminology, the US National Institute of Mental Health created a panel in 2007 to evaluate case definitions of HAD (Antinori et al., 2007). They proposed to change HAD to HIV-associated neurocognitive disorder to encompass asymptomatic neurocognitive impairment, as well as mild cognitive impairment and HIV-associated dementia.

2 THE INFLUENCE OF ANTIRETROVIRAL DRUGS ON HAND

The first therapy developed for HIV-infected individuals was Azidothymidine (AZT), also known as Zidovudine (ZDV). Studies, including a double-blinded placebo-controlled study (Schmidt et al., 1988), proved that AZT therapy decreased the mortality of HIV-infected individuals, while showing improvements in numerous cognitive areas (Yarchoan et al., 1987). As the field tried to develop more effective treatments for HIV and AIDS, they started looking at protease activity in replication of HIV. In 1995, Saquinavir, a protease inhibitor, showed efficacy in raising CD4+ cells and decreasing the viral load in plasma (Kitchen el al., 1995). These findings led to two more drugs being developed the following year, Ritonavir and Indinavir (Folkers, 1996); Saquinavir is typically used in combination with Ritonavir and Indinavir. After the development and administration of each drug individually, resistance to each drug began to occur, which led to the combination of the drugs into one. Combination antiretroviral therapy (cART), as it would become known, showed reduction in HIV disease progression. This also led to a double-blind study showing that triple combination therapy, compared to the double, preserved or improved neuropsychological performance more efficaciously (Ferrando et al., 1998).

Prior to the introduction of combination antiretroviral therapy (cART) in 1996, HAND was a progressive degenerative neurocognitive disorder that closely resembled dementia. In the HIV-infected individuals, dementia was a common source of morbidity and mortality. HAND was associated with the progression of death within months (Sacktor & Robertson, 2014). The neurocognitive disorders were usually observed in the late stages of AIDS, where the patients had CD4+ counts below 200 cells/mL (Ances and Ellis, 2007). Before cART was established as a credible treatment, the annual incidence of HAD was seven percent and had a cumulative risk of five to twenty percent (McArthur, 2004).

3 Stages of Hand

In 2007, Antinori et al. proposed to change HIV-associated dementia to HIV-associated neurocognitive disorder. This classification includes the entire spectrum of neurological disease, such as asymptomatic neurocognitive impairment (ANI), minor neurocognitive disorder (MND) and HIV-associated dementia (HAD). This paper’s scale was developed because “standardized procedures should be followed whenever possible, both to collect the needed information and to interpret that information to make three types of determination: 1) the presence and severity of neurocognitive impairment, 2) the presence and severity of functional decline, and 3) the degree to which cognitive impairment or functional decline are likely to have been influenced by comorbid conditions or confounds (including HIV-related opportunistic CNS conditions, or unrelated developmental, psychiatric, or neuromedical confounds)” (Antinorie et al., 2007).

ANI, MND and HAD are further elaborated by Antinori et al. as:

Asymptomatic neurocognitive impairment (ANI)

1. Acquired impairment in cognitive functioning involving at least two ability domains, documented by performance of at least 1.0 SD below the mean for age-education-appropriate norms on standardized neuropsychological tests†.

2. The cognitive impairment does not interfere with everyday functioning.

3. The cognitive impairment does not meet criteria for delirium or dementia.

4. There is no evidence of another pre-existing cause for the ANI.

Mild neurocognitive disorder (MND)

1. Acquired impairment in cognitive functioning involving at least two ability domains, documented by performance of at least 1.0 SD below the mean for age-education-appropriate norms on standardized neuropsychological tests†.

2. Typically, this would correspond to a Memorial Sloan Kettering scale stage of 0.5 to 1.0.

3. The cognitive impairment produces at least mild interference in daily functioning (at least one of the following):

a) Self-report of reduced mental acuity, inefficiency in work, homemaking or social functioning.

b) Observation by knowledgeable others that the individual has undergone at least mild decline in mental acuity with resultant inefficiency in work, homemaking or social functioning.

4. The cognitive impairment does not meet criteria for delirium or dementia.

5. There is no evidence of another pre-existing cause for the MND.

HIV-associated dementia (HAD)*

1. Marked acquired impairment in cognitive functioning involving at least two ability domains, typically the impairment is in multiple domains, especially in learning new information, slowed information processing and defective attention/concentration. The cognitive impairment must be ascertained by neurological testing with at least two domains 2 SD or greater than the demographically corrected means. Note that where neuropsychological testing is not available, standard neurological evaluation and simple bedside testing may be used, but this should be performed as indicated in the algorithm.

2. Typically, this would correspond to a Memorial Sloan Kettering scale stage of 2.0 or greater.

3. The cognitive impairment produces marked interference with day-to-day functioning (work, home life, social activities).

4. The pattern of cognitive impairment does not meet criteria for delirium (eg, clouding of consciousness is not a prominent feature); or, if delirium is present, criteria for dementia need to have been met on a previous examination when delirium was not present.

5. There is no evidence of another, pre-existing cause for dementia (eg, other central nervous system (CNS) infection, CNS neoplasm, cerebrovascular disease, pre-existing neurologic disease, or severe substance abuse compatible with CNS disorder)†.

*If there is a previous diagnosis of ANI, MND or HAD, but currently the individual does not meet criteria, the diagnosis of ANI, MND or HAD in remission can be made; †Neuropsychological assessment must survey at least the following abilities: verbal/language, attention/working memory, abstraction/executive, memory (learning recall), speed of information processing, sensory-perceptual, motor skills; ‡If the individual with suspected ANI, MND or HAD also satisfied criteria for a major depressive episode or substance dependence, the diagnose of HAND should be deferred to a subsequent examination conducted at a time when the major depression has remitted or at least one-month after cessation of substance use. (2007, p. 1791)

4 Screening and diagnosis of hand

In order to diagnose HAND, typically the physician will evaluate the person’s history and administer a physical exam to see if further tests are warranted. If appropriate, neuropsychological tests are given to diagnose a patient with HAND. Neuroimaging, such as a CT scan or a MRI, is given to help determine the stage of HAND and rule out other confounding factors. For rapid and bedside testing, some common screening tests may be administered. Common bedside tests are: the HIV dementia scale (Power et al., 1995), the International HIV dementia scale (Sacktor et al. 2005), and the Montreal cognitive assessment. (Nasreddine et al., 2005).

One of the first tools developed, and used frequently today, is the HIV dementia scale (HDS), which was developed in 1995 by Power et al. In this study, 152 participants were divided into five different groups: HIV-seronegative; asymptomatic HIV-seropositive; AIDS, non-demented; AIDS, mildly demented; and AIDS, severely demented. Patients were then screened with three different instruments, which are HDS, the minimental state exam (frequently used for Alzheimer’s patients), and the grooved pegboard (used to test dexterity). These tests evaluate individual motor speed, memory, constructional praxis, and executive functions. It was found that HDS is a reliable and quantitative scale for bedside testing. Based on a cut-off score of less than or equal to 10 for identifying HIV dementia, there was a sensitivity of 80% and a specificity of 91%. The specificity and sensitivity found in this study are fairly good, but is used to screen for HAD. One recommendation is to adapt the HDS to screen for ANI and MND by making it more sensitive and specific to these less sever forms.

HDS is a good screening tool for HIV-associated dementia, but can be limited in its global screening capacity. This is due to HDS using alphabet writing and cube-copying tests, which is a westernized background. Sacktor et al. (2005) saw this as limiting to the global prevalence of HIV dementia, and developed a new rapid screening test: The International HIV Dementia Scale (IHDS). IHDS eliminates the timed written alphabet and cube copy time tests with motor speed and psychomotor speed tests. Sacktor and colleagues tested 66 HIV+ individuals in the US and 81 HIV+ individuals in Uganda – all were administered the IHDS with full standardized neurological and neuropsychological assessments. Using the greater than or equal to 10 cut-off, they found the sensitivity and specificity in the United States at 80% and 57%, respectively, compared to 80% and 55% in Uganda, respectively. To calculate the sensitivity and specificity for this study, they compare their results to Price and Brew’s guidelines for HAD. Although they were able to calculate a sensitivity and specificity, it should be noted they did not compare their results to a gold standard, which make their results not as significant. Compared to HDS, IHDS has lower sensitivity and specificity score, but it’s worth noting that it can still be useful in screening for HIV dementia in the United States.

HDS and IHDS do adequate jobs at identifying HIV dementia, but lack the ability to regularly classify someone as has having MND. In 2005, Nasreddine et al. developed a brief screening tool for mild cognitive impairment, which is the Montreal cognitive assessment (MoCA). Although this was primarily developed for Alzheimer’s patients, this 10-minute cognitive screening tool can still be administered to find MND in HIV patients.

The MoCA study divided participants into three groups, which 94 had mild cognitive impairment, 93 had mild Alzheimer’s disease, and 90 were healthy elderly controls and each were given the MoCA and the minimental state examination (MMSE). The MoCA is a one-page 30-point test administered in 10 minutes and is broken up in six segments: Short-term memory recall task; Visuospatial abilities; Multiple aspects of executive function; attention, concentration, a working memory; language assessment; and, orientation to time and place. This study used a cut-off score of 26, which found the MMSE had a sensitivity and specificity of 18% and 100%, respectively, and MoCA had a sensitivity and specificity of 90% and 87% (Nasreddine et al., 2005). Since the sensitivity of MSSE was found to be 18%, which is much lower than the usual standard of 80%, this helps support the hypothesis that MoCA is a better screening tool for mild cognitive impairment. Although this study found good sensitivity and specificity, it was not applied to the HIV population.

Over recent years, there has been a push to develop new screening tools and strategies to accurately identify HAND. Recently, it was found that HDS and MoCA are not recommended as sole instruments to diagnose HAND, as they alone did not have good sensitivity or adequate specificity (Janssen et al., 2015). These findings help shape the importance of developing new tools and diagnostic strategies. One study proposed changing MoCA scoring criteria from categorical to quantifiable attributes (Brouillette et al., 2015). Brouillette stated, “quantifying performance on MoCA items through Rasch analysis improves its accuracy as a screening tool for HAND, and demonstrates that cognition can be measured as one-dimensional construct in HIV.” Based on this studies findings, Rasch analysis should be applied to the analysis of HAND studies to improve the studies accuracy of diagnostic criteria, when applicable.

5 Treatment of hand

The standard treatment for HAND is combination antiretroviral therapy (cART), or the combination of three or more drugs. There has been research documenting the reduction of HAD in the cART era (Heaton et al., 2010; Clifford & Ances, 2014; Becker et al., 2015; Sacktor et al., 2016). Although there has been a reduction of HAD rates, the overall rates of HAND are similar, which is due to milder forms of HAND (ANI and MND) becoming more prevalent (Becker et al., 2015). There is speculation that the ability of cART to penetrate the central nervous system (CNS) and prevent the viral replication of HIV in the brain contributes to these similarities in overall rates. Patients with HAND had significantly higher viral loads in their cerebrospinal fluid (CSF) compared to those without HAND (Eden et al., 2010), and by lowering the viral load of HIV in the CFS this could contribute to the reduction of HAND rates.

6 epidemiology of hand

1 HAND in the Pre-cART and cART Eras

Overall HAND prevalence is similar to that of the pre-cART era, but the most severe clinical presentation of HAND, (HAD), has declined since the introduction of cART. The reduction in the rates of HAD seem to have “transferred” to less severe stages of HAND, such as MND and ANI. The Multicenter AIDS Cohort Study (MACS) is a longitudinal study examining participants with and without HIV, which found the prevalence of HAD decreased from 10-20% (McArthur et al., 1993; Janssen et al., 1992) in the early 1990’s and to about 5% (Becker et al., 2015; Heaton et al., 2010) in the early 2000’s. In the cART era, a study conducted with the MACS data found overall rates of HAND to be 33% and are further broken down to 14% for ANI, 14% for MND, and 5% for HAD (Heaton et al., 2010). Another study, the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER), found similar rates in the cART era. CHARTER found that the prevalence of HAND was 47%, 33% for ANI, 12% for MND, and 2% for HAD (Heaton et al., 2010). Another study found the prevalence of HAND to be 59%, of which 21% had ANI, 31% had MND, and 7% had HAD (Bonnet et al., 2013).

2 Progression of HAND

It is still unclear the true impact that cART has on HAND, but it appears that HAND is not completely stable, and the individuals can fluctuate between the different stages. One study conducted in 2007-2008 and 2009-2010 found that individuals with HAND fluctuated between the different stages; 15% deteriorated (i.e., ANI to MND or HAD), while 15% showed improvement (i.e., HAD to MND) (Sacktor et al., 2016). Sacktor and Colleagues found comparable findings from 2007-2008, 2011-2012, 2009-2010, and 2011-2012. Another study found that after one year, 44% showed improvements and 21% progressed to a more severe cognitive impairment (Robertson et al., 2007).

Clinical presentation and characteristics of HAND in the cART era may differ depending on the severity of the disease. Those with ANI show no impairment in activities of daily living; however, MND show some impairment in activities of daily living; while, HAD show the most severe impairment in activities of daily living (Clifford & Ances, 2013). Although ANI does not show any clinical presentation, it should be monitored when diagnosed, as it progresses to MND or HAD 15% of the time. MND and HAD are more of a clinical concern as they may interrupt the individuals’ life by leading to unemployment, social decline, lack of adherence to medications, and a poorer quality of life (Hinkin et al., 2002; Hinkin et al., 2004; Gorman et al., 2009).

7 Risk factors FOR hand

In the cART era, there are several risk factors that have been documented to be associated with HAND. Two risk factors associated with HAND are older age (Bonnet et al., 2013; Cross et al., 2013; Fazeli et al., 2015) and older age and survival duration (McCombe et al., 2013). One study found that those older than 50 were 3.26 times more likely to develop HAD than those who were 50 or younger (Valcour et al., 2004). Other studies have shown in the cART era that lower nadir CD4+ cell counts have been correlated with HAND (Heaton et al. 2010; Ellis et al., 2011; McCombe et al., 2013). Comorbidities have been found to be independently associated with HAND: such as hepatitis C virus (HCV) (Cherner et al., 2005; Cross et al., 2013; Sun et al., 2013) obesity (McCutchan et al., 2012), and diabetes (McCutchan et al., 2012). A study found that HCV is associated with a 2.375 times greater risk of developing neurological disorder (Vivithanaporn et al., 2012); however, another study found no risk between HCV and HAND (Clifford et al., 2015). Metabolic comorbidities, such as diabetes, cardiovascular risk factors and carotid intima-media thickness, also showed strong association with HAND (Fabbiani et al., 2012).

8 Pathogensis of hand

HIV primarily affects the immune system, specifically by the infection of the CD4+ T cells. Soon after infection, HIV penetrates the blood-brain barrier (BBB) to infect the central nervous system (CNS). This occurs when infected monocytes, lymphocytes, and possibly CD4+ T cells cross the BBB. Once in the CNS, infected and activated macrophages and microglia play a role in the development of HAND, which can partly be attributed to cART not completely preventing or reversing HAND (Kaul, 2009). In the pre-cART era, it was believed that encephalitis and neurodegeneration were possible causes for HAND. Gelman (2015) stated that with the introduction of cART, the previous factors associated with HAND need replacing, as they are less prevalent today. This is supported by the rates of encephalitis decreasing from 54% in the pre-cART era to about 15% in the cART era (Vago et al. 2002), while the overall rates of HAND remain similar. Inflammation was thought to be a factor contributing to HAND in the pre-cART era, but is still acknowledged as a driving force behind HAND (Williams & Hickey, 2002; Kaul et al., 2005). When HIV enters the CNS it triggers inflammatory changes including the release of cytokines, neurotoxins, toxic viral proteins, Tat, and gp120 due to infected or activated perivascular macrophages (Griffin, 1997; Garden et al., 2005; Nacracci et al., 2005). Through this process, a cycle occurs which can contribute to neurological injury in the brain, which may increase the rates and severity of HAND. This process is one of the causes of inflammation in the brain. HIV induces this inflammatory response which is regarded as a critical component of HAND (Cartier et al., 2005).

Multicenter aids cohort study (macs)

1 HAND in macs

The Multicenter AIDS Cohort Study (MACS) is an ongoing, longitudinal study that started in 1984 to study the natural and treated histories of HIV infected men who have sex with men (MSM). Participants in the MACS study visit sites semiannually, visits include: physical examination, a neuropsychological screening and examination, and collection of blood samples.

To diagnose someone with HAND, MACS uses 1) cognitive testing, 2) an index of activities of daily living, and 3) medical history and testing to rule out alternative diagnoses:

1) Cognitive testing was used with 6 cognitive domains and cognitive functioning was derived if an individual had a high enough score in four of the six cognitive domains. Using the Antinori et al. study, an individual could fall into one of three stages: 1) normal limits if ≤ one domains were one standard deviation (SD) or more below the mean; 2) minor cognitive impairment if ≥ two domains were one or more SD below the mean, and they did not qualify for moderate to severe cognitive impairment; and 3) moderate to severe cognitive impairment if ≥ two domains were two SDs below the mean, or one domain was 2.5 SDs or more below the mean.

2) To measure actives of daily living, the MACS adapted their instrument from the Instrumental Activities of Daily Living (IADL) scale (Lawton and Brody, 1969). This scale classifies the individual as normal (did not meet criteria for major or minor impairment), mild impairment (minor decline on 2 or more questions or major or minor declines on 2 or more questions), or severe impairment (major decline on 2 or more questions or major or minor declines on 4 or more questions) based on if the completion of 14 out of the 16 questions.

3) Medical history was gathered and synthesized to rule out any confounding information, which is collected via a self-reported survey, every 6 months, and can be verified through medical charts.

Based on the diagnostic criteria and classification system used by MACS, multiple studies were conducted to identify the rates of HAND in the HIV+ population, and only a few studies compared these rates to the HIV- population. A recent study compared the rates of HAND in HIV+ and HIV- individuals in MACS. They found very similar rates of HAND, 31.82% (HIV+) and 31.89% (HIV-). For HIV+ and HIV- individuals, there are similar rates within each group of HAND: normal (68.18% vs. 68.11%), ANI (16.23% vs. 15.75%), MND (12.99% vs. 11.81%), and HAD (2.6% vs. 4.33%) (Truebig, 2016). Another study found similar rates for mild and severe cognitive outcomes for HIV+ (31.7%) and HIV- (27.17%) (Becker et al., 2015).

To find the specificity and sensitivity, a gold standard would be needed for comparison purposes. At this time there is no gold standard for the diagnostic criteria for HAND, which is why there is no sensitivity and specificity for MACS diagnostic criteria. Due to similar rates of HAND, based on the studies listed above, it appears the instruments used by MACS to diagnose and classify individuals with HAND may not be as sensitive and specific as needed to distinguish between HIV+ and HIV- individuals. By definition, HAND cannot occur in the HIV- population, and theoretically the specificity would be zero. Since HAND is being diagnosed in the HIV – population, it can be assumed that the specificity within MACS is lacking.

Discussion

HIV-associated neurocognitive disorder (HAND) was established in 2007 by Antinorie and colleagues, with other neurocognitive disorders associated with HIV being researched since 1983. With the introduction of combination antiretroviral therapy (cART), the rates of HAND shifted from HIV-associated dementia (HAD) to higher rates of minor neurocognitive disorder (MND) and asymptomatic neurocognitive impairment (ANI). With this shift, it makes the diagnosis of HAND more difficult, as it is harder to diagnosis milder forms of HAND. With that stated, current diagnostic techniques for HAND are tailored more to diagnosing the more severe HAD and not as sensitive and specific for diagnosing the less severe MND and ANI (Janssen et al., 2015).

With HAND being harder to diagnose and the tests not being adequately sensitive and specific, this clearly impacts the rates of incidence and prevalence. A public health concern arises from the lack of ability to accurately diagnose someone with HAND. With improved diagnostic criteria, clinicians are able to monitor the disease progression, while adjusting cART treatment as needed and are able to identify potential risk factors of HAND. Without proper diagnosis of ANI and MND, both have the potential to progress to HAD, which occurs in about 15% of those with ANI and MND (Sacktor et al., 2016). ANI, MND, and HAD have the potential to interrupt the individuals’ life by leading to unemployment, social decline, lack of adherence to medications, and a poorer quality of life (Hinkin et al., 2002; Hinkin et al., 2004; Gorman et al., 2009). Better diagnostic criteria for HAND will help alleviate some these public health concerns.

The Multicenter AIDS Cohort Study (MACS) has been in existence since 1984 examining HIV infection in men who have sex with men and collects information on various aspects of HIV. MACS’ criteria for diagnosing HAND has been used in various studies, but the criteria may not be sensitive or specific enough to capture the true rates. Two studies found similar rates of HAND when comparing HIV+ and HIV- individuals (Truebig, 2016; Becker et al., 2015), suggesting that either HIV does not play a role in cognitive impairment, there is another confounding factor unknown, or, more likely, the diagnostic criteria do not do an adequate job of capturing the true rates of HAND in HIV+ individuals.

By definition, sensitivity is the rate at which a disease is correctly identified with a positive result (a true positive rate) and specificity is the rate at which a non-disease is correctly identified with a negative result (a true negative rate). To find sensitivity and specificity for the diagnostic criteria for HAND in MACS is impossible because this requires a gold standard to compare to, and HAND does not have a gold standard. By definition, HIV- individuals cannot have HAND. Thus, the fact that rates of HAND are similar in the HIV+ and HIV- populations within MACS is suggestive of the lack of specificity (a true negative rate). This is because the diagnostic criteria are not able to pick up the true rates of HAND, as the instruments used are poor.

Stucky et al. (2014) stated that a test score itself does not identify “impairment”, it is the interpretation of the test scores that will define who is impaired or who is not. Impairment is defined differently depending on the study, and MACS defines their impairment based on the criteria from Antinori et al. (2007): 1) normal limits if ≤ one domains were one standard deviation (SD) or more below the mean; 2) minor cognitive impairment if ≥ two domains were one or more SD below the mean, and they did not qualify for moderate to severe cognitive impairment; and 3) moderate to severe cognitive impairment if ≥ two domains were two SDs below the mean, or one domain was 2.5 SDs or more below the mean. A reference group would be needed for comparison purposes to interpret the level of impairment, with the MACS’ reference group for HAND being the HIV- group. As stated previously, the rates of HAND, ANI, MND, and HAD are similar within the Truebig and Becker et al. studies when comparing the HIV+ and HIV- groups. There are a lot of factors that can contribute to these rates, with lack of specificity being one of them. A sample is need for comparison purposes to help identify if the MACS sample or the diagnostic criteria influence the similarities of the rates. A study was conducted in London using data from MSM who were HIV+ and HIV- between 2011-2012 (McDonnell et al., 2014). McDonnell et al. found similar rates of HAND in the HIV+ (21%) participants and the HIV- (28.9%) participants. Although these rates are lower than the MACS’ HAND rates, they are still consistent with the findings, which suggests that the diagnostic criteria influence the similarities in the MACS results.

In order to better understand the rates of HAND, further researcher needs to develop a gold standard. This will provide a standard that researchers can use to diagnose HAND, while allowing to compare the rates between studies without questioning the instruments used. With a gold standard, this will allow others to calculate their sensitivity and specificity for their diagnostic criteria. If a gold standard is found, the MACS could do just that. They could compare their criteria to know their sensitivity and specificity.

Without a gold standard being developed, HAND diagnosis can still be improved. MACS should adopt the MoCA with Rasch analysis to help screening for HAND or incorporate Rasch analysis in their own analysis. It was found that the Rasch analysis improved the accuracy of the MoCA as a screening tool for HAND (Brouillette et al., 2015).

By having better diagnostic criteria, identification of the less severe forms of HAND would be more accurate. This will allow for the monitoring of disease progression, change or adjustment of cART, and identification of risk factors. There may not be as much benefit for diagnosing ANI as MND and HAD, as the benefit of early treatment must outweigh the negative impact and stress of a positive test result (Wilson & Jungner, 1968). Since cART is the only present treatment for ANI, and those with ANI demonstrate lack of cognitive impairment, it appears that the benefits of diagnosing ANI may not outweigh the stressors of these results. Diagnosis of MND and HAD will have more benefits, as they both have clinically present cognitive impairments which can disrupt daily routines.

bibliography

Nomenclature and research case definitions for neurologic manifestations of human immunodeficiency virus-type 1 (HIV-1) infection Report of a Working Group of the American Academy of Neurology AIDS Task Force. Neurology. 1991 Jun;41(6):778-85. PubMed PMID: 2046917.

Achim CL, Adame A, Dumaop W, Everall IP, Masliah E. Increased accumulation of intraneuronal amyloid beta in HIV-infected patients. J Neuroimmune Pharmacol. 2009 Jun;4(2):190-9. PubMed PMID: 19288297; NIHMSID: NIHMS277779; PubMed Central PMCID: PMC3055557.

Ances BM, Ellis RJ. Dementia and neurocognitive disorders due to HIV-1 infection. Semin Neurol. 2007 Feb;27(1):86-92. PubMed PMID: 17226745.

Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007 Oct 30;69(18):1789-99. PubMed PMID: 17914061; NIHMSID: NIHMS278023; PubMed Central PMCID: PMC4472366.

Becker JT, Kingsley L, Mullen J, Cohen B, Martin E, et al. Vascular risk factors, HIV serostatus, and cognitive dysfunction in gay and bisexual men. Neurology. 2009 Oct 20;73(16):1292-9. PubMed PMID: 19841381; PubMed Central PMCID: PMC2764414.

Becker JT, Kingsley LA, Molsberry S, Reynolds S, Aronow A, et al. Cohort Profile: Recruitment cohorts in the neuropsychological substudy of the Multicenter AIDS Cohort Study. Int J Epidemiol. 2015 Oct;44(5):1506-16. PubMed PMID: 24771276; PubMed Central PMCID: PMC4681102.

Bonnet F, Amieva H, Marquant F, Bernard C, Bruyand M, et al. Cognitive disorders in HIV-infected patients: are they HIV-related?. AIDS. 2013 Jan 28;27(3):391-400. PubMed PMID: 23079813.

Brouillette MJ, Mayo N, Fellows LK, Lebedeva E, Higgins J, et al. A better screening tool for HIV-associated neurocognitive disorders: is it what clinicians need?. AIDS. 2015 May 15;29(8):895-902. PubMed PMID: 25291105; PubMed Central PMCID: PMC4444425.

Cartier L, Hartley O, Dubois-Dauphin M, Krause KH. Chemokine receptors in the central nervous system: role in brain inflammation and neurodegenerative diseases. Brain Res Brain Res Rev. 2005 Feb;48(1):16-42. PubMed PMID: 15708626.

Cherner M, Letendre S, Heaton RK, Durelle J, Marquie-Beck J, et al. Hepatitis C augments cognitive deficits associated with HIV infection and methamphetamine. Neurology. 2005 Apr 26;64(8):1343-7. PubMed PMID: 15851720.

Clifford DB, Ances BM. HIV-associated neurocognitive disorder. Lancet Infect Dis. 2013 Nov;13(11):976-86. PubMed PMID: 24156898; NIHMSID: NIHMS553825; PubMed Central PMCID: PMC4108270.

Clifford DB, Vaida F, Kao YT, Franklin DR, Letendre SL, et al. Absence of neurocognitive effect of hepatitis C infection in HIV-coinfected people. Neurology. 2015 Jan 20;84(3):241-50. PubMed PMID: 25503616; PubMed Central PMCID: PMC4335996.

Edén A, Fuchs D, Hagberg L, Nilsson S, Spudich S, et al. HIV-1 viral escape in cerebrospinal fluid of subjects on suppressive antiretroviral treatment. J Infect Dis. 2010 Dec 15;202(12):1819-25. PubMed PMID: 21050119; NIHMSID: NIHMS236936; PubMed Central PMCID: PMC3052942.

Ellis RJ, Badiee J, Vaida F, Letendre S, Heaton RK, et al. CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS. 2011 Sep 10;25(14):1747-51. PubMed PMID: 21750419; NIHMSID: NIHMS531762; PubMed Central PMCID: PMC3867631.

Fabbiani M, Ciccarelli N, Tana M, Farina S, Baldonero E, et al. Cardiovascular risk factors and carotid intima-media thickness are associated with lower cognitive performance in HIV-infected patients. HIV Med. 2013 Mar;14(3):136-44. PubMed PMID: 22994586.

Fazeli PL, Crowe M, Ross LA, Wadley V, Ball K, et al. Cognitive Functioning in Adults Aging with HIV: A Cross-Sectional Analysis of Cognitive Subtypes and Influential Factors. J Clin Res HIV AIDS Prev. 2014 Feb 18;1(4):155-169. PubMed PMID: 25386565; NIHMSID: NIHMS542280; PubMed Central PMCID: PMC4224145.

Ferrando S, van Gorp W, McElhiney M, Goggin K, Sewell M, et al. Highly active antiretroviral treatment in HIV infection: benefits for neuropsychological function. AIDS. 1998 May 28;12(8):F65-70. PubMed PMID: 9631133.

Folkers G. Two new protease inhibitors approved by FDA Food and Drug Administration. NIAID AIDS Agenda. 1996 Mar;PubMed PMID: 11363799.

Garden GA, Morrison RS. The multiple roles of p53 in the pathogenesis of HIV associated dementia. Biochem Biophys Res Commun. 2005 Jun 10;331(3):799-809. PubMed PMID: 15865935.

Gorman AA, Foley JM, Ettenhofer ML, Hinkin CH, van Gorp WG. Functional consequences of HIV-associated neuropsychological impairment. Neuropsychol Rev. 2009 Jun;19(2):186-203. PubMed PMID: 19472057; NIHMSID: NIHMS197466; PubMed Central PMCID: PMC2871666.

Griffin DE. Cytokines in the brain during viral infection: clues to HIV-associated dementia. J Clin Invest. 1997 Dec 15;100(12):2948-51. PubMed PMID: 9399939; PubMed Central PMCID: PMC508505.

Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology. 2010 Dec 7;75(23):2087-96. PubMed PMID: 21135382; PubMed Central PMCID: PMC2995535.

Janssen MA, Bosch M, Koopmans PP, Kessels RP. Validity of the Montreal Cognitive Assessment and the HIV Dementia Scale in the assessment of cognitive impairment in HIV-1 infected patients. J Neurovirol. 2015 Aug;21(4):383-90. PubMed PMID: 25678141; PubMed Central PMCID: PMC4510920.

Janssen RS, Nwanyanwu OC, Selik RM, Stehr-Green JK. Epidemiology of human immunodeficiency virus encephalopathy in the United States. Neurology. 1992 Aug;42(8):1472-6. PubMed PMID: 1641138.

Kaul M, Garden GA, Lipton SA. Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature. 2001 Apr 19;410(6831):988-94. PubMed PMID: 11309629.

Kaul M. HIV-1 associated dementia: update on pathological mechanisms and therapeutic approaches. Curr Opin Neurol. 2009 Jun;22(3):315-20. PubMed PMID: 19300249; NIHMSID: NIHMS136215; PubMed Central PMCID: PMC2779773.

Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist. 1969 Autumn;9(3):179-86. PubMed PMID: 5349366.

Lalkhen AG, McCluskey A. Clinical tests: Sensitivity and specificity. Continuing Education in Anaesthesia, Critical Care and Pain. 2008;8(6):221–223.

Levy RM, Bredesen DE. Central nervous system dysfunction in acquired immunodeficiency syndrome. J Acquir Immune Defic Syndr. 1988;1(1):41-64. PubMed PMID: 3063805.

Marder K, Albert SM, McDermott MP, McArthur JC, Schifitto G, et al. Inter-rater reliability of a clinical staging of HIV-associated cognitive impairment. Neurology. 2003 May 13;60(9):1467-73. PubMed PMID: 12743233.

McArthur JC. HIV dementia: an evolving disease. J Neuroimmunol. 2004 Dec;157(1-2):3-10. PubMed PMID: 15579274.

McArthur JC, Hoover DR, Bacellar H, Miller EN, Cohen BA, et al. Dementia in AIDS patients: incidence and risk factors Multicenter AIDS Cohort Study. Neurology. 1993 Nov;43(11):2245-52. PubMed PMID: 8232937.

McCombe JA, Vivithanaporn P, Gill MJ, Power C. Predictors of symptomatic HIV-associated neurocognitive disorders in universal health care. HIV Med. 2013 Feb;14(2):99-107. PubMed PMID: 22994556.

McCutchan JA, Marquie-Beck JA, Fitzsimons CA, Letendre SL, Ellis RJ, et al. Role of obesity, metabolic variables, and diabetes in HIV-associated neurocognitive disorder. Neurology. 2012 Feb 14;78(7):485-92. PubMed PMID: 22330412; PubMed Central PMCID: PMC3280051.

McDonnell J, Haddow L, Daskalopoulou M, Lampe F, Speakman A, et al. Minimal cognitive impairment in UK HIV-positive men who have sex with men: effect of case definitions and comparison with the general population and HIV-negative men. J Acquir Immune Defic Syndr. 2014 Oct 1;67(2):120-7. PubMed PMID: 24991974; PubMed Central PMCID: PMC4175121.

Nardacci R, Antinori A, Kroemer G, Piacentini M. Cell death mechanisms in HIV-associated dementia: the involvement of syncytia. Cell Death Differ. 2005 Aug;12 Suppl 1:855-8. PubMed PMID: 15846379.

Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005 Apr;53(4):695-9. PubMed PMID: 15817019.

Navia BA, Price RW. The acquired immunodeficiency syndrome dementia complex as the presenting or sole manifestation of human immunodeficiency virus infection. Arch Neurol. 1987 Jan;44(1):65-9. PubMed PMID: 3800724.

Power C, Selnes OA, Grim JA, McArthur JC. HIV Dementia Scale: a rapid screening test. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Mar 1;8(3):273-8. PubMed PMID: 7859139.

Price RW, Brew BJ. The AIDS dementia complex. J Infect Dis. 1988 Nov;158(5):1079-83. PubMed PMID: 3053922.

Robertson KR, Smurzynski M, Parsons TD, Wu K, Bosch RJ, et al. The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS. 2007 Sep 12;21(14):1915-21. PubMed PMID: 17721099.

Sacktor N, Skolasky RL, Seaberg E, Munro C, Becker JT, et al. Prevalence of HIV-associated neurocognitive disorders in the Multicenter AIDS Cohort Study. Neurology. 2016 Jan 26;86(4):334-40. PubMed PMID: 26718568; PubMed Central PMCID: PMC4776086.

Sacktor NC, Wong M, Nakasujja N, Skolasky RL, Selnes OA, et al. The International HIV Dementia Scale: a new rapid screening test for HIV dementia. AIDS. 2005 Sep 2;19(13):1367-74. PubMed PMID: 16103767.

Snider WD, Simpson DM, Nielsen S, Gold JW, Metroka CE, et al. Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. Ann Neurol. 1983 Oct;14(4):403-18. PubMed PMID: 6314874.

Stucky, K. J., Kirkwood, M. W., & Donders, J. (2014). Clinical neuropsychology study guide and board review. Oxford: Oxford University Press.

Sun B, Abadjian L, Rempel H, Monto A, Pulliam L. Differential cognitive impairment in HCV coinfected men with controlled HIV compared to HCV monoinfection. J Acquir Immune Defic Syndr. 2013 Feb 1;62(2):190-6. PubMed PMID: 23187938; NIHMSID: NIHMS424682; PubMed Central PMCID: PMC3587125.

Truebig, Janet. Prevalence of Neurocognitive Disorders and Potential Correlates in the Pitt Men’s Study Cohort. Master's Thesis, University of Pittsburgh. 2016.

Vago L, Bonetto S, Nebuloni M, Duca P, Carsana L, et al. Pathological findings in the central nervous system of AIDS patients on assumed antiretroviral therapeutic regimens: retrospective study of 1597 autopsies. AIDS. 2002 Sep 27;16(14):1925-8. PubMed PMID: 12351952.

Valcour V, Shikuma C, Shiramizu B, Watters M, Poff P, et al. Higher frequency of dementia in older HIV-1 individuals: the Hawaii Aging with HIV-1 Cohort. Neurology. 2004 Sep 14;63(5):822-7. PubMed PMID: 15365130; NIHMSID: NIHMS8501; PubMed Central PMCID: PMC1382180.

Vivithanaporn P, Nelles K, DeBlock L, Newman SC, Gill MJ, et al. Hepatitis C virus co-infection increases neurocognitive impairment severity and risk of death in treated HIV/AIDS. J Neurol Sci. 2012 Jan 15;312(1-2):45-51. PubMed PMID: 21925684.

Williams KC, Hickey WF. Central nervous system damage, monocytes and macrophages, and neurological disorders in AIDS. Annu Rev Neurosci. 2002;25:537-62. PubMed PMID: 12052920.

Wilson JM, Jungner YG. [Principles and practice of mass screening for disease]. Bol Oficina Sanit Panam. 1968 Oct;65(4):281-393. PubMed PMID: 4234760.

Yarchoan R, Berg G, Brouwers P, Fischl MA, Spitzer AR, et al. Response of human-immunodeficiency-virus-associated neurological disease to 3'-azido-3'-deoxythymidine. Lancet. 1987 Jan 17;1(8525):132-5. PubMed PMID: 2879972.

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EVALUATION OF DIAGNOSTIC CRITERIA FOR HIV-ASSOCIATED NEUROCOGNITIVE DISORDER IN THE MULTICENTER AIDS COHORT STUDY

by

Nicholas Resciniti

BS, Health Sciences Pre-Clinical, University of Central Florida, 2015

Submitted to the Graduate Faculty of

Infectious Diseases and Micr[pic][?] |

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