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Cognitive change trajectories in virally suppressed HIV-infected individuals indicate high prevalence of disease activity
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Published: March 6, 2017 - Chloe Gott1,2, Thomas Gates3, Nadene Dermody1,2, Bruce J. Brew2,3, Lucette A. Cysique2,3,4*
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171887
Despite long-term viral suppression, we found mostly subclinical levels of decline in psychomotor speed and executive functioning (mental flexibility and cognitive inhibition); well-established markers of HAND progression. Moreover, 57% of our cohort is undergoing slow evolution of their disease, challenging the notion of prevalent neurocognitive stability in virally suppressed HIV infection.
Abstract
Background
The longitudinal rate and profile of cognitive decline in persons with stable, treated, and virally suppressed HIV infection is not established. To address this question, the current study quantifies the rate of cognitive decline in a cohort of virally suppressed HIV+ persons using clinically relevant definitions of decline, and determine cognitive trajectories taking into account historical and baseline HAND status.
Methods
Ninety-six HIV+ (clinically stable and virally undetectable) and 44 demographically comparable HIV- participants underwent standard neuropsychological testing at baseline and 18-months follow-up. We described clinically relevant cognitive trajectories based on standard definitions of historical and baseline HAND status and cognitive decline. Historical, moderate to severe HAND was formally diagnosed at the start of the cART era in 15/96 participants based on clinical neurological and neuropsychological assessment. The same standard of care has been applied to all participants at St. Vincent’s Hospital Infectious Disease Department for the duration of their HIV infection (median of 20 years).
Results
Relative to HIV- controls (4.5%), 14% of HIV+ participants declined (p = .11), they also scored significantly lower on the global change score (p = .03), processing speed (p = .02), and mental flexibility/inhibition (p = .02) domains. Having HAND at baseline significantly predicted cognitive decline at follow up (p = .005). We determined seven clinically relevant cognitive trajectories taking into account whether participant has a history of HAND prior to study entry (yes/no); their results on the baseline assessment (baseline impairment: yes/no) and their results on the 18-month follow up (decline or stable) which in order of prevalence were: 1) No HAND history, no baseline impairment, 18-month follow-up stable (39%), 2) No HAND history, baseline impairment, 18-month follow-up stable (35%), 3) History of HAND; baseline impairment, 18-month follow-up stable (9%) 4) No history of HAND, baseline impairment, 18-month follow-up decline (7%), 5) History of HAND, no baseline impairment, 18-month follow-up stable (3%), 6) No HAND history, no baseline impairment, 18-month follow-up decline (3%) 7) History of HAND, baseline impairment, 18-month follow-up decline (3%). There was no relationship between cognitive decline (taking into account historical and baseline HAND) and traditional HIV disease biomarkers.
Conclusions
Despite long-term viral suppression, we found mostly subclinical levels of decline in psychomotor speed and executive functioning (mental flexibility and cognitive inhibition); well-established markers of HAND progression. Moreover, 57% of our cohort is undergoing slow evolution of their disease, challenging the notion of prevalent neurocognitive stability in virally suppressed HIV infection.
Introduction
Similar to the United Kingdom, as well as subgroups in the United States, Europe and Asia, the HIV epidemic in Australia is well controlled (with 92% of treated HIV-infected (HIV+) persons on combined anti-retroviral therapy (cART) virally undetectable)[1]. This context provides an optimal setting for the natural study of cognitive trajectories in chronic HIV infection.
The cross-sectional profile of HIV-associated neurocognitive disorder (HAND) is well established. It is described as three progressively more severe diagnoses; asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND) and HIV-associated dementia (HAD [2]. In the context of stable cART, ANI and MND are the more prevalent sub-diagnoses occurring in 50%-80% and 10–20% of HAND cases respectively [3]; while HAD is rare (2%-4% of cases). HAND is characterized by a diffuse pattern of cognitive impairment consistent with disruption to the fronto-striatal- parietal networks. The most frequent deficits are to processing speed, which typically remains prominent across all severity stages of the disorder[4]. Episodic memory impairment is also prevalent [3] as are disruptions to complex attentional processes and executive functioning [4–6]. Motor signs are relatively uncommon in the milder stages and their onset is frequently reflective of disease progression[3]. While the cross-sectional profile of cognitive impairment is well described, the rate and profile of cognitive decline in persons with stable and treated HIV infection is far from established.
Indeed, there has been a lack of research examining longitudinal neuropsychological changes in individuals with long-term viral suppression, in whom HAND is mostly characterized by ANI and MND stages. Moreover, when cognitive decline has been investigated in these samples, varying methods of defining decline have been used. Some of which have had low clinical relevance and inadequate corrections for practice effect, potentially leading to erroneous estimates of cognitive decline.
We provide a summary of the nine naturalistic longitudinal studies of cognitive change that have been conducted in samples of HIV+ participants; which the majority of the sample were on stable cART and cognitive decline in the HIV+ group was investigated as a primary outcome (S1 Table). These nine observational studies represent the total pool of research as of July 2016 to the best of our knowledge. The following main findings can be extracted from this review: 1. The definition of cognitive decline as an absorbing state (wherein once an individual is defined as having declined this status is permanent) as compared to studies with multiple follow-up points (wherein an individual’s status can fluctuate across the duration of the project) yields apparent differences in cognitive decline rates that have to be interpreted carefully. Cysique and colleagues [7] defined cognitive decline as a unique endpoint and found 30% of HIV+ participants were defined as declined at 6–12 month follow-up and 5% at 15–27 months. In contrast, the large CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study which defined cognitive decline as an absorbing state found an overall 23% cognitive decline rate over the three-year study follow-up [8]. A subsequent project also by Cysique and colleagues [9] also used an absorbing rate definition and found an overall decline over the 27 month study period of 21%. 2. Studies that used standard global change scores (standard in the sense that scores are corrected for practice effect and regression towards the mean) found fairly similar rates of cognitive decline ranging between 21%-27% across different cohorts context/nationalities [9–12]. 3. When focusing on deterioration within the HAND stages (thus not correcting for practice effect and regression towards the mean) lower rate of cognitive decline are typically observed. For example, The Multicenter AIDS Cohort Study (MACS) found that across four years of follow-up, only 10% of HIV+ individuals progressed to a worse HAND stage [13]. 4. In contrast, a study that concentrated on incident cognitive decline in 146 neurocognitively normal HIV+ participants and used a cognitively stable individuals as reference (thus correcting for both practice effect and regression towards the mean within the entire sample), detected 15% had incident cognitive decline 14.3 ± .2 months later [14]. 5. Studies that used a restricted number of tests showed inconsistent results. When focusing on verbal memory, one study found worse performance over time in HIV+ individuals compared to HIV-individuals at one year follow-up [15], while another which focused only on two tasks of psychomotor speed and mental flexibility reported stable cognitive performance across eight years [16]. 6. Finally, none of the above studies took into account the impact of individuals included in the study who may have previously been diagnosed with an HAND episode in the lifetime of their illness, especially before cART was available. Typically these individuals once put on cART have dramatically improved [17] Their long-term prognosis has however not been studied, which is important as historical HAND represents a risk for cognitive deterioration years after an initial episode [9, 18].
The aim of the current study was threefold; 1) to quantify the rate of incident neurocognitive decline in chronic treated HIV+ persons relative to healthy controls of the same age over an 18-month period, based on a test battery that assessed seven cognitive domains 2) To investigate the historical and baseline cognitive determinants of cognitive decline and to determine the profile of cognitive trajectories in functions of historical and baseline HAND status. 3). To determine whether standard HIV disease biomarkers were related to cognitive decline.
Discussion
There are three main findings in our study.
Firstly, in absolute terms, a higher portion of HIV+ participants showed clinically relevant decline over 18 months compared to HIV- participants. However, this result failed to meet statistical significance. Despite this, the HIV+ group showed statistically significant declining performance on the continuous global as well as domain change scores for psychomotor speed and mental flexibility/inhibitory control, relative to the HIV- group. Taken together, we interpret this discrepancy as indicating that gradual decline more commonly occurs at a slow sub-clinical rate, rather than at a rapid progressing rate in cART-treated individuals. While our study period was of 18 months, it is possible that these changes may be occurring over a longer period of time.
Secondly, the primary cognitive determinant of decline at the one follow-up occasion is performance prior to this assessment, rather than an historical episode of HAND. However, as baseline performance is in itself strongly related to any historical episode of HAND, we believe this result reflects a cascading effect. Wherein historical HAND has a mediating impact through baseline performance, rather than a direct effect on current cognitive decline. Interestingly, HIV+ cases who declined compared to those who were stable demonstrated already weaker performance at baseline in psychomotor speed, attention/working memory and mental flexibility. At follow-up they declined across the board, and more so in the weaker baseline tests, with relative sparing of Semantic Fluency.
Thirdly, while at first glance the level of neurocognitive stability is high (14% decline; one of the lowest rates of decline published). Our clinically relevant cognitive trajectories show a more complex picture; with the disease actually active to various degrees in a majority of participants. Namely those with stable baseline impairment (35%) + those with sustained long-term impairment since historical HAND, (9%) + those with baseline impairment and decline (7%), + those with incident decline at 18 months (3%) + those always progressing (3%) = 57% of the described sample.
Thirdly, none of the traditional HIV biomarkers were related to cognitive decline.
Our results are broadly consistent with previous reports which indicate that the majority of HIV+ persons on long-term cART are neurocognitively stable in reference to clinically meaningful cut-offs [9,11,13,16]. However, we also demonstrate that when taking into account historical HAND, the picture of mostly stable disease is much more nuanced. In fact, the majority of patients are undergoing slow evolution in their disease. Moreover, the moderate effect sizes detected for declines in the psychomotor speed and mental flexibility/inhibition domains further confirm this interpretation. This result was particularly striking for the psychomotor speed domain, on which the HIV- group improved at follow-up while the HIV+ group showed an overall decline (Fig 1). The specific domains affected are also of note, as decline in psychomotor speed and executive functioning have been robustly associated with ongoing HIV-related brain injury and progression to dementia [6,9,30]. The mostly sub-clinical levels of decline in domains of psychomotor and executive functioning suggests that brain injury in HIV in the cART era is primarily diffuse, probably affecting multiple connections within the striato-frontal and striato-parietal pathways [31]. Interestingly, and contrary to the study by Seider and colleagues [15], we did not find evidence for learning/memory decline, suggesting that major damage to enthorinal regions is unlikely at least within middle-aged persons. Our preference for using continuous changes scores over progression change in HAND stages, as well as clinically relevant definition of decline (correcting for practice effect), was key in demonstrating this more complex picture. Privileging one definition over the other, and not including practice effect corrections may yield data with poor clinical value that fails to acknowledge subtle neurocognitive change [12]. Slow progression and subclinical deficit may in fact represent key characteristics of the current HIV neuropathological processes in virally suppressed HIV+ persons consistent with common findings of chronic neuroinflammation rather than overt brain damage [31,32].
The fact that we do not detect any ongoing effect of traditional HIV biomarkers further indicates that there is an urgent need for elucidating the cause of HAND in virally suppressed patients with evidence of long-term CD4 recovery. Longer duration of infection [12] has also been reported a risk for cognitive decline and this was not found in this study. Potential reasons are that the duration of HIV infection was relatively homogeneous across our cohort and/or that the duration of follow-up may not have been long enough to detect any effect.
The HIV- and HIV+ group initially showed a small but significant difference in years of education corresponding to a 1.24 years gap between groups. However, this difference is not significant when grouping the educational achievement in the following categories: below high school, high school completed, and above high school (p = .13). This demonstrates a high proportion of overlap in the educational levels between the groups, which varies only with a year or so. Moreover, it is very unlikely that this small educational difference or any other demographic effects influenced the primary outcome of cognitive decline as the norms for change we used to quantify decline in each group were corrected for age, sex, education, Caucasian versus other ethnicity as well as baseline cognitive competence [22].
When inspecting the performance of the HIV- sample on the cognitive domain we observe relative decline in the domain of motor-coordination and verbal recall. Other domains were either stable or slightly improved. In the case of the motor-coordination domain, the relative decline lies well within the expected normal fluctuation. Indeed, using the clinically meaningful cut-off, the norms for change applied to the relevant cognitive domain [22]; 5% are expected to decline and 5% are expected to improve (90% confidence interval 2-tailed around the motor coordination change score). In the case of the HIV- group, 6.82% were classified as decliners and 2.27% were classified as improvers using this cut-off. This empirically demonstrates that while some decline is observed, the majority of performance is within the expected range. In the same domain, 11.82% of the HIV+ group was classified as decliners, and 1.05% as improvers. For verbal recall, the results are more complex. Indeed, 4.55% of the HIV- groups improved and 11.36% were classified as decliners. While the 11.36% decliner proportion was not significantly different from the expected normative 5% (Fisher’s Exact Test, one-tailed p = .22); this is a trend that was not observed in the HIV+ group (4.35% of the HIV- group were improvers and 5.43% were decliners). Possible explanations for this decline are twofold: normal amyloid burden variation in a large healthy middle-aged sample has been associated with verbal recall, with greater amyloid burden related to lower verbal recall [33]. In contrast, in the HIV+ group the normal amyloid variation is truncated because many individuals with potentially greater amyloid burden have already passed away [34].
Altogether, what this suggests is that the norms for change are very sensitive to even subclinical changes, which may or may not evolve, even in HIV- individuals.
Other limitations that should be taken into account when interpreting the findings of this study include a likely survivor bias in our cohort [7,35]. This effect may explain the lack of significant interaction between historical HAND and baseline HAND status on cognitive decline. Indeed, based on our clinical work in the hospital where this cohort was recruited, we know that the majority of persons with HAND in the pre-cART era have died. Therefore, persons from this population, who may have been more likely to decline cognitively, are now deceased. Because of this, it is possible that the observed rate of decline is an underestimate. Longer terms studies are needed both on this current population surviving from the pre-cART era as well as cohorts composed of HIV+ individuals, started on optimal cART, to reconcile how the survivor effect has impacted the current NeuroHIV longitudinal findings [18]. Finally, large collaborative international longitudinal studies are required which include large numbers of participants, reflective of the diversity of the current HIV epidemic, particularly in terms of gender and ethnicity (which the current cohort lacks).
Conclusions
Despite long-term viral suppression, immune recovery and a likely survivor bias, our study demonstrates mostly subclinical levels of decline in psychomotor speed and executive functioning, both of which are well-established markers of HAND progression. Moreover, 57% of our cohort is undergoing some evolution of their disease over the 18-month study period. This finding challenges the notion of neurocognitive stability in virally suppressed HIV+ persons and promotes an alternate hypothesis of slow progression and subclinical deficits. Confirmation in larger and more diverse HIV cohorts will be important in shifting the focus of HIV neuropathological research towards non-overt and chronic mechanisms of brain damage.
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