Heart disease risk factors, hepatitis C and detectable HIV emerged as key factors associated with older-appearing brain structures in people with HIV. Social factors, such as unemployment and living in a poorer neighbourhood also appear to play a central role. The study examined structural brain changes that are visible on magnetic resonance imaging (MRI) scans.
In the era of successful antiretroviral treatment, such changes are only rarely linked to dementia, but may lead to subtle forms of cognitive impairment that can diminish quality of life. It is important to understand both the contributions of HIV-related risk factors (including low CD4 counts and detectable viral loads) and other risk factors – including behavioural (such as substance use) and social determinants of health (such as education and employment). This multitude of risk factors may be key to understanding cognitive decline among those ageing with HIV, especially for those with well-controlled HIV.
Researchers led by Dr Kalen Petersen at the Washington University School of Medicine in Missouri conducted a retrospective analysis of 638 MRI brain scans of both people living with HIV and without, between 2008 and 2022, with findings published in the Lancet HIV.
Using a machine learning algorithm that compared participants’ brain scans to multiple other MRI scans that it had been trained on, researchers estimated a brain age for each participant. This was then compared to each participant’s chronological age. A brain-age gap of zero would indicate no additional brain ageing than what would be expected at a given age, whereas a positive number would indicate that the brain’s structure was more like that of an older person.
In addition, information such as heart disease risk factors (including factors such as age, sex, smoking, cholesterol, and blood pressure), lifetime substance use (alcohol, tobacco and cocaine), education, employment, early life stress events, neighbourhood deprivation (based on participants’ addresses) and a measure of reading ability were also available. For people living with HIV, additional information included their CD4 count, if they had detectable HIV levels, and whether they had hepatitis C.
The study included 379 people living with HIV, with an average age of 45. Most of these were male (78%) and Black (69%), with an average of 13 years of education, with over a quarter unemployed (27%). Most were virally suppressed (78%) with an average most recent CD4 cell count of 588. A small number had hepatitis C co-infection (7%).
The sample of 259 people without HIV were younger on average, around 38 years old. Half were male, while just over half were Black (56%), with an average of 14 years of education, with only 11% unemployed. Data on hepatitis C was not collected for this group.
People living with HIV had significantly higher heart disease risk scores, and scores for substance use. Additionally, they tended to live in more disadvantaged areas. They had significantly lower reading scores, by an average of four points.
As the authors wanted to explore within-group differences, and because the two groups were so different with respect to sociodemographic variables, a direct comparison between the groups was not carried out.
In people living with HIV, heart disease risk, detectable HIV (measured as more than 50 copies) and hepatitis C were most strongly associated with increased brain ageing as individual risk factors. Unemployment was also significant, but current and lowest ever CD4 counts were not. Hepatitis C infection was associated with approximately four additional years of brain ageing. However, heart disease risk factors exhibited an even greater impact on brain ageing: there was a gap of over ten years between those with the lowest risk and those with the highest risk.
"HIV did not emerge as an independent risk factor when people with and without HIV were combined in a single analysis."
While heart disease risk appeared to be associated with brain ageing regardless of HIV status, it was only a significant risk factor for people with HIV. Thus, this finding is especially relevant for people living with HIV, who are likely to have a greater burden of heart disease risk. Researchers emphasised the need to maintain healthy levels of blood pressure and cholesterol for people living with HIV.
For HIV-negative people, risk factors included alcohol use and early life stress, while years of education and reading ability emerged as protective factors against brain ageing, with each additional point on a reading achievement test reducing brain age by nearly half a year. This was not mirrored in people living with HIV. The researchers were unsure why this is the case, but suggested that protective educational effects may be counterbalanced by clinical and social stressors in people with HIV, such as safety, food security and meeting basic needs.
The researchers did not directly compare people living with HIV and people without. However, when they combined both groups into a single analysis, significant risk factors associated with accelerated brain ageing were: heart disease risk factors, having hepatitis C, socioeconomic disadvantage based on residential area and unemployment. The researchers caution about interpretation of the unemployment finding as cognitive decline might occur before loss of employment, possibly leading to it.
Interestingly, HIV did not emerge as an independent risk factor in this combined analysis. In the era of widely available ART, this suggests that treatment adherence, comorbidities such as hepatitis C, and social determinants of health, such as unemployment play a more important role.
“Our key findings indicate that brain ageing in people with HIV is best explained by a combination of clinical, social, and comorbid risk factors,” the researchers conclude. “Together with the reviewed literature, our findings suggest that clinical care for people with HIV should incorporate a broader view of neurological health, including management of cardiovascular disease and consideration of sociological factors such as environmental stressors, unemployment, and neighbourhood quality of life.”
Petersen K J et al. Effects of clinical, comorbid, and social determinants of health on brain ageing in people with and without HIV: a retrospective case-control study. The Lancet HIV 10(4), e244-e253.