Cognitive Ageing Is Premature Among a Community Sample of Optimally Treated People Living With HIV

HL Aung; M Bloch; T Vincent; D Quan; A Jayewardene; Z Liu; TM Gates; B Brew; L Mao; LA Cysique


HIV Medicine. 2021;22(3):151-164. 

In This Article

Abstract and Introduction


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.


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.