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Cognitive ageing is premature among a community sample of optimally treated people living with HIV
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HIV Medicine - 21 October 2020 - HL Aung 1,2,3 M Bloch ,3,4 T Vincent,4 D Quan,4 A Jayewardene ,4,5 Z Liu ,6 TM Gates ,1 B Brew ,1,3,7 L Mao 8 and LA Cysique 1,2,3
The present study sought to assess the evidence of premature cognitive ageing amongst PLHIV addressing the previous studies' limitations. For this, we tested whether there is an interaction effect of HIV and age on neurocognitive performance in a community sample of HIV-positive bisexual and gay men with low AIDS rate and high ART access and a cohort of age- and lifestyle-matched HIV-negative people. All participants were recruited from a single primary care practice in Sydney, Australia. Half of the participants were aged ≥ 50 years.
The main study finding was evidence of premature cognitive ageing. Essentially, the HIV and age interaction effect size was the largest (medium effect size) compared with all the variables that were significantly associated with neurocognitive performance. Several factors were also independently associated with neurocognitive performance, although they all had small effect sizes. In the analyses including both HIV-negative and HIV-positive samples, a higher degree of anxiety symptoms, a history of HIV-related brain involvement, and a past CDC stage C diagnosis were associated with lower neurocognitive performance, while SUD was associated with higher cognitive performance. In the analyses restricted to the HIV-positive sample, in addition to age, which has a small to medium effect size, a history of non-HIV-related neurological disorder, a past CDC stage C diagnosis and a shorter duration of ART were associated with poorer neurocognitive performance, all representing small effect sizes.
Conclusion
The current study identified premature cognitive ageing in a community sample of well-educated and well-treated HIV-positive gay and bisexual men with low AIDS rate, compared with demographically comparable HIV-negative counterparts. The study was conducted at a primary care clinic in Sydney, Australia, and included allcomers in the HIV-positive group. However, the effects of psychiatric, HIV and non-HIV neurological and other medical comorbidities were adjusted in the analyses. In terms of clinical implications, our study supports regular neurocognitive screening in treated (even if virally suppressed) PLHIV aged ≥ 50 years, particularly in those with a historical CDC stage C, or a history of HIV-related and non-HIV-related neurological conditions. Concurrent monitoring and intervention on mental health burden should also be considered for PLHIV to prevent additional risk to neurocognitive decline. In terms of research implications, it is critical that further resources and research funding be allocated to the follow-up of such cohorts.
Abstract
Objectives
Evidence of premature cognitive ageing amongst people living with HIV (PLHIV) remains controversial due to previous research limitations including underpowered studies, samples with suboptimal antiretroviral access, varying rate of virological control, high rate of AIDS, over-representation of non-community samples, and inclusion of inappropriate controls. The current study addresses these limitations, while also considering mental health and non-HIV comorbidity burden to determine whether PLHIV showed premature cognitive ageing compared with closely comparable HIV-negative controls.
Methods
This study enrolled 254 PLHIV [92% on antiretroviral therapy; 84% with HIV RNA < 50 copies/mL; 15% with AIDS) and 72 HIV-negative gay and bisexual men [mean (SD) age = 49 (10.2) years] from a single primary care clinic in Sydney, Australia. Neurocognitive function was evaluated with the Cogstate Computerized Battery (CCB) at baseline and 6 months after. Linear mixed-effects (LME) models examined main and interaction effects of HIV status and chronological age on the CCB demographically uncorrected global neurocognitive z-score (GZS), adjusting for repeated testing, and then adjusting sequentially for HIV disease markers, mental health and comorbidities.
Results
HIV status and age interacted with a lower GZS (β = -0.43, P < 0.05). Higher level of anxiety symptoms (β = -0.11, P < 0.01), historical AIDS (β = -0.12, P < 0.05) and historical HIV brain involvement (β = -0.12, P < 0.05) were associated with lower GZS.
Conclusions
We found a robust medium-sized premature ageing effect on cognition in a community sample with optimal HIV care. Our study supports routine screening of cognitive and mental health among PLHIV aged ≥ 50 years.
Introduction
Globally, people living with HIV (PLHIV) are ageing at an unprecedented rate [1] because of the accelerated decrease in AIDS-related morbidity and general mortality afforded by combination antiretroviral therapy (cART) [2, 3]. In Australia, the number of older PLHIV increased from 5564 in 2008 to 11 361 in 2017, with a dramatic increase in the proportion aged > 50 years from 5% to 46% between 1986 and 2017 [4]. Within the next 20-30 years, > 70% of the Australian PLHIV will be aged 50+ years [5].
With ageing, neurological and psychological health is becoming increasingly relevant for PLHIV. First, cognitive ageing may be premature among PLHIV because of persistent immune activation and inflammation along with an increased prevalence of other age-related comorbidities [especially cardiovascular diseases (CVD) and stroke], all of which are known risk factors for dementia in the general population [6]. Second, age is the number one risk factor for cognitive decline and dementia in the general population [7] and even mild evidence of premature cognitive ageing could have serious public health implications for the ageing HIV epidemic. Third, PLHIV carry a significant mental health burden such as anxiety and depression [8, 9], which are also known risk factors for cognitive decline and dementia [10, 11].
In our recently completed systematic review, we found that previous HIV and cognitive ageing studies have identified signals for premature neurocognitive ageing [12]. Premature cognitive ageing was defined as lower cross-sectional neurocognitive performance amongst PLHIV compared with age-matched HIV-negative people (i.e. there is significant interaction effect of HIV and age on cross-sectional continuous neurocognitive performance). However, findings of this abnormal pattern of cognitive ageing have been inconsistent across studies due to certain methodological limitations. These included small sample size, lack of age-matched HIV-negative controls, clinical heterogeneity and suboptimal representation of PLHIV aged ≥ 50 years.
Furthermore, there was an ascertainment bias towards cohorts that included a high proportion of cases with historical AIDS, and non-community samples with disparities in cART access and degree of virological control [13, 14]. Community samples are healthier and more representative of the current HIV epidemic, especially in countries where ART is subsidized [15].
Our review [12] also demonstrated that only a minority of cognitive ageing studies adjusted for the effects of age-related comorbidities and other comorbidities that may affect neurocognitive performance. Indeed, in addition to the effect of chronological age, an array of other factors such as HIV clinical characteristics (e.g. clinical stage, nadir and current CD4 counts and HIV viral load), previous HIV brain involvement [i.e. historical central nervous system (CNS) opportunistic infection (OI) and HIV-associated neurocognitive disorder (HAND)], age-related comorbidities, mental health burden and lifestyle factors will complicate the degree to which premature ageing can be ascribed [16, 17].
The present study sought to assess the evidence of premature cognitive ageing amongst PLHIV addressing the previous studies' limitations. For this, we tested whether there is an interaction effect of HIV and age on neurocognitive performance in a community sample of HIV-positive bisexual and gay men with low AIDS rate and high ART access and a cohort of age- and lifestyle-matched HIV-negative people. All participants were recruited from a single primary care practice in Sydney, Australia. Half of the participants were aged ≥ 50 years.
Discussion
Our study supports and extends previous reports of premature cognitive ageing amongst PLHIV [31, 32]. Goodkin et al. [31] identified premature cognitive ageing in a longitudinal cohort of 2278 HIV-positive and 2808 HIV-negative participants (average baseline age = 37.2 years) from the Multicenter AIDS Cohort Study (MACS) who had been followed up 6-monthly for an average duration of 7.4 years. More specifically, this study found a negative interaction effect between chronological age and CDC HIV clinical disease stage on motor function and episodic memory that were measured through standard neuropsychological testing. Another study conducted by Ding et al. [32] in China also detected premature cognitive ageing in their HIV-positive sample. The study included a community cohort of 345 HIV-positive and 345 HIV-negative participants from Taizhou prefecture of the Zhejiang province in China who were over 40 years of age (range: 40-82 years). The study detected an interaction effect of age and HIV status on lower performance in the International HIV Dementia Scale and the Chinese version of the Mini-Mental State Examination for the domains of motor speed, orientation, registration and recall.
Previous studies that did not identify a similar premature cognitive ageing effect were different from the current study in terms of demographic and clinical characteristics of the study participants. Studies that recruited unrepresentatively healthy HIV participants within their country (i.e. highly educated, stable on cART, with undetectable viral load and no neuropsychological confounds) did not observe premature cognitive ageing [33, 34]. A Polish study [33] did not observe the premature cognitive ageing effect amongst 91 HIV-positive and 95 HIV-negative participants (age range: 23-75 years) who were recruited from an infectious disease hospital and received standard neuropsychological testing. All the participants in this study were males who were highly educated (≥12 years of education), and clinically stable (no active OI, active syphilis, current hepatitis C coinfection, alcohol or substance abuse, major psychiatric illnesses, liver or renal insufficiency, and had viral load < 60 copies/mL). Towgood et al. [34] also did not identify a premature cognitive ageing effect in their study conducted in the UK in a sample of 40 HIV-positive and 42 HIV-negative participants (age range: 20-75 years) who were white/Caucasian, had CD4 count > 200 cells/μL and viral load < 50 copies/mL for 6 months, and did not have any neuropsychological confounds (i.e. history of HIV brain involvement, hepatitis B or C coinfection, any neurological disorder, history of TBI with loss of consciousness for more than 10 min, any history of alcohol or substance abuse, major psychiatric disorder, and any chronic condition related to cardiac, renal or liver). HIV-positive participants in these studies represent the well-controlled elite of the HIV epidemic. While results in similar populations may hold true, they are not representative of the typically multi-comorbid PLHIV and may be substantially biased by a survivor effect [35]. Further, we should remain critical of the conceptual circularity in pre-selecting the healthiest patients from a clinical population with a chronic disease and then determining that those people are mostly cognitively healthy. This pre-emptively removes a large number of people with age-related comorbidities, some of whom may be driven by HIV, and selects patients who are the most biologically resilient, making the detection of any age and HIV interaction effect very difficult, if not a priori undermining.
Other studies may have failed to detect an effect of premature cognitive ageing because the proportion of participants included who were aged > 50 years was low. In a study in the US [36] that included only participants under 60 (only 13% were over 45), no interaction effect of HIV and age was identified in either the composite or individual standard neuropsychological test scores. Another US study [37] where only 33% of their sample (91 HIV-positive and 184 HIV-negative participants) were older than 50 years, also did not identify the premature ageing effect in the executive function they tested.
A history of HIV brain involvement such as previous history of HAND and treated CNS OI, and previous history of non-HIV neurological disorders (e.g. mild TBI and stroke) were associated with poorer neurocognitive performance in the current study. These results bring cumulative evidence with previous studies [38, 39] that any history of neurological insult can have lasting consequences on one's cognitive health. As stated in Frascati criteria for HAND diagnosis [40], a history of HIV and non-HIV-related neurological conditions could have a profound impact on the long-term neurocognitive health in PLHIV and needs to be accounted for in the diagnostic process. Our study showed that the effect of such conditions on neurocognitive performance was small overall, but this was probably because only 13-24% of them had previous HIV or non-HIV neurological disorder.
In the current study, we found that anxiety symptoms rather than depressive symptoms were associated with poorer neurocognitive function. This result may be due to the fact that anxiety and depressive symptoms were correlated (r = 0.66, P < 0.0001), and that the iterative selection for a final best-fit model retained the stronger of the two. Nevertheless, previous studies have also identified an association between anxiety and cognitive decline and impairment in PLHIV. Malaspina et al. [41] reported that lower symptoms of depression and anxiety were associated with a higher chance of successful cognitive ageing (defined as lack of NCI) among a sample of 74 HIV-positive people. Anxiety has been less studied than depression in PLHIV [9]. It would be important to more systematically include anxiety assessment in neuro-HIV studies, as higher anxiety symptoms have been associated with lower ART adherence, as shown in a study conducted by Servellenet al. [42] among 182 PLHIV who were recruited from community-based clinics in Los Angeles, USA [43]. The clinical implication of our results is that provision of regular mental health support, including for anxiety, remains critical in ageing PLHIV [38, 44, 45]. Importantly, stress management and cognitive behavioural therapies have been reported to be effective in alleviating anxiety symptoms among PLHIV [46].
Our finding that having CDC stage C was negatively associated with neurocognitive function represents cumulative evidence that AIDS is a risk factor for NCI [47]. Heaton et al. [48] also showed, when focusing on CDC stage, that NCI rate increased with the advancing CDC stage in both the pre-cART and cART cohorts. CDC stage C implies that PLHIV may have experienced high viral load and/or low nadir CD4 and/or an AIDS-defining illness. As our analysis also included nadir and current CD4 counts, as well as viral load, it suggests that the CDC stage may be the strongest predictor for NCI.
Unexpectedly, current SUD, which was assessed with the Mini International Neuropsychiatric Interview alcohol and substance use sections, was associated with higher neurocognitive performance. This unexpected result may be explained by the significantly higher representation of younger participants among those with SUD in both HIV-positive (5% among young vs. 0% among old) and HIV-negative groups (28% among young people vs. 10% among old people) groups. Neurocognitive consequences of substance use depend on the type and dose of the drug, duration that the substance has been used, and whether it is single or polydrug use [49]. It is possible that substance users in this study, while meeting the SUD criteria, remained high-functioning individuals.
Interestingly, we found that longer duration of ART was associated with better neurocognitive performance within the HIV-positive sample when the effects of chronological age and HIV duration were controlled for. This finding supports the evidence that stability on ART is associated with better and/or stable cognitive function [50, 51]. Longer duration of ART implies longer disease stability, better viral control and greater immune reconstitution [52]. In all, this means that besides early cART initiation and low AIDS, stability on treatment is another major factor for cognitive health.
A potential explanation for premature cognitive ageing in HIV includes chronic immune activation and immune senescence [53, 54]. This mechanism is similar to what has been found in the normal ageing process, so that it has been postulated that the ageing phenomenon starts early among PLHIV [55]. Importantly, there is evidence of chronic neuroimmune activation and associated neuroinflammation despite successful cART and viral suppression [56]. Altogether, ageing and HIV may lead to brain damage via excitotoxicity, mitochondrial dysfunction and oxidative stress [53, 57].
Evidence of premature cognitive ageing in a cohort that is optimally treated and is representative of the multiple comorbidities found in a community sample has serious public health ramifications. As age is the number one factor for all-type dementia, it will be very important to follow this kind of cohort into their 70s, the age at which the dementia risk increases exponentially in the general population [6]. More worryingly, at the global level, because PLHIV who have this level of healthcare and cART access, and low AIDS proportion are in the minority [58], it can be expected that in less healthy PLHIV, the premature ageing effect may be even larger, as would be the dementia risk [13].
The implications of premature ageing are not only related to dementia risk. Poor cognitive health negatively affects physical and social functioning in ageing PLHIV [59, 60]. This, in turn, impacts quality of life [61]. Poor cognitive health may also lead to less cART adherence [62], potentially reducing the high compliance rate among older PLHIV [63]. Although there is no evidence of this in the current cohort, this is a possibility that cannot be ignored in general. Importantly, cognitive decline remains independently associated with mortality in the cART-treated cohort [64]. A higher mortality rate in people with HAND or other dementia may falsely lead the HIV research community to think that cognitive issues are less represented than they actually are due to a survivor effect [65].
Our study supports that PLHIV aged ≥ 50 years should undergo regular neurocognitive and mental health screen and further investigation when this screen is positive [66]. However, implementation research is urgently needed to enable a realistic clinical translation. For example, while the CCB is a screening option especially for repeated testing [67], we have found that involvement of neuropsychologists for the training of the non-specialist staff is needed as in the current study. This may represent a new type of work for clinical neuropsychologists in the future, but other options will need to be explored given the resource implications. Lastly, it would also be important to assess the value of cognitive remediation strategies (e.g. SmartBrain [68] and InSight [69]) as a way to prevent further deterioration [70] as pharmaceutical treatment has shown variable efficacy.
Conclusion
The current study identified premature cognitive ageing in a community sample of well-educated and well-treated HIV-positive gay and bisexual men with low AIDS rate, compared with demographically comparable HIV-negative counterparts. The study was conducted at a primary care clinic in Sydney, Australia, and included allcomers in the HIV-positive group. However, the effects of psychiatric, HIV and non-HIV neurological and other medical comorbidities were adjusted in the analyses. In terms of clinical implications, our study supports regular neurocognitive screening in treated (even if virally suppressed) PLHIV aged ≥ 50 years, particularly in those with a historical CDC stage C, or a history of HIV-related and non-HIV-related neurological conditions. Concurrent monitoring and intervention on mental health burden should also be considered for PLHIV to prevent additional risk to neurocognitive decline. In terms of research implications, it is critical that further resources and research funding be allocated to the follow-up of such cohorts.
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