Risk Factors for Neurocognitive Decline in HIV

HIV-associated neurocognitive disorder is a term used to describe a range of neurocognitive dysfunction issues associated with HIV infection,¹ with HIV-associated dementia being the most severe form.² Although the mechanism by which HIV infection contributes to the development of HIV-associated neurocognitive disorder is unclear, researchers now know that the virus enters the central nervous system in the early stages of infection.

Although the introduction of combination antiretroviral therapy (cART) has been associated with a marked decrease in HIV-associated dementia, from 20% to 5%,³ the incidence of milder forms of neurocognitive impairment still remains high in the HIV-infected population.⁴ Furthermore, researchers emphasize that aviremic HIV-positive individuals are not completely safe from neurocognitive decline,^5,6 for reasons that are not entirely clear. The virus may continue to have a negative impact on the brain, even when it has been suppressed in the rest of the body.¹ Therefore, identifying risk factors and finding effective treatment strategies for neurocognitive decline are vital to the everyday functioning and quality of life of HIV-infected individuals.

In an interview with Infectious Disease Advisor, Marie-Josée Brouillette, MD, associate professor of psychiatry at the Faculty of Medicine, McGill University, in Montreal, Canada, discussed the risk factors for neurocognitive decline in aviremic HIV-positive individuals.

Infectious Disease Advisor: What methods are commonly used to assess neurocognitive decline in HIV-infected individuals? 

Marie-Josée Brouillette, MD: None! Detection of decline implies repeat assessment. Access to neuropsychological testing is very limited in a clinical setting and repeat neuropsychological testing on a large number of patients is simply not an option. The cognitive screening tests that are available to detect mild cognitive impairment in the aging population, such as the MoCA [Montreal Cognitive Assessment], were designed to detect mild cognitive impairment in older, HIV-negative populations and are not suitable to detect decline in persons living with HIV for 2 main reasons: 1) they are not sensitive enough to detect the mild impairment that is more common among HIV-positive individuals, and 2) these tests were developed as screening tools — the outcome is a pass/fail — change in the total score does not provide an accurate measure and should not be used to monitor change over time.  

Infectious Disease Advisor: Can you briefly identify/explain the pattern of change in neurocognitive abilities observed in [people with] HIV in the CNS HIV Anti-Retroviral Therapy Effect Research (CHARTER) study?⁴ 

Dr Brouillette: Our group took a novel approach to look at change in performance on neuropsychological tests. We looked at the tests one at a time, as opposed to combining them into a single score. That way, improvement on one test would not mask decline on another. We also compared raw scores over time, without any transformation. We sought to identify groups of individuals with a similar trajectory of change over time by using Group Based Trajectory Analysis (GBTA). Our results are rather reassuring. Over a 3-year period, all trajectories were stable over the first 36 months in >80% of cohort participants, 15.8% declined on at least one of the 15 neuropsychological tests over 36 months, and decline on more than one test was rare. The low proportion of decliners identified is notable, because GBTA is a particularly sensitive method to detect decline: our smallest “groups” were composed of only 2 individuals with a unique trajectory. Most of the change was seen in the Grooved Pegboard test, which measures dexterity rather than cognition.

Infectious Disease Advisor: What are some of the risk factors for neurocognitive decline in HIV-infected individuals? 

Dr Brouillette: I will focus on cognitive decline among aviremic HIV-positive individuals, as this is the issue that is of concern at this point in time. It would be a shame if the gains in terms of survival and general health that come from being aviremic were underscored by the development of cognitive difficulties. Once we had identified individuals who declined cognitively using the method just described, we developed a risk index for decline. We already know that maintaining aviremia is important for protecting the brain, so we limited the analysis to the CHARTER participants who were aviremic during the 3-year follow-up.⁵ We identified 4 clinical factors that were significant predictors of neurocognitive decline. lower eGFR [estimated glomerular filtration rate] was the strongest predictor. Other factors were longer HIV duration, fewer years of education, and cerebrospinal fluid (CSF) protein concentration >45 mg/dL.

Infectious Disease Advisor: How much is known about the mechanism that governs the association between baseline eGFR and cognitive decline?

Dr Brouillette: The mechanism that underpins the correlation between lower baseline eGFR and future cognitive decline is unclear, but could reflect the presence of vascular pathology in the kidney and the brain. Vascular risk factors such as hypertension, diabetes, or smoking are more common in HIV-positive individuals than in the general population. The relationship between neurocognitive decline and estimated duration of infection ≥15 years may in part reflect the changing treatment in the pre-cART to cART. The association between increased CSF protein levels and cognitive decline may reflect a disruption in the blood-brain barrier. 

Infectious Disease Advisor: Which interventions might be beneficial to aviremic HIV-positive individuals?

Dr Brouillette: While the links between lower eGFR, vascular disease, and cognitive decline remain to be confirmed, interventions to decrease cardiovascular risk factors can be implemented now in view of their benefits on cardiovascular morbidity and mortality. These interventions are likely to be widely applicable, as smoking or obesity was present in as many as 80% of CHARTER cohort participants. Smoking cessation and management of obesity would be obvious starting points, beneficial for overall health and also to maintain brain health. 

References

1. Saylor D, Dickens AM, Sacktor N, et al. HIV-associated neurocognitive disorder – pathogenesis and prospects for treatment. Nat Rev Neurol. 2016;12:309.
2. Gisslén M, Price RW, Nilsson S. The definition of HIV-associated neurocognitive disorders: are we overestimating the real prevalence. BMC Infect Dis. 2011;11:356.
3. Nookala AR, Mitra J, Chaudhari NS, Hegde ML, Kumar A. An overview of human immunodeficiency virus type 1-associated common neurological complications: Does aging pose a challenge? J Alzheimers Dis. 2017:60:S169-S193.
4. Heaton RK, Clifford DB, Franklin DR Jr, et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology. 2010;75:2087-2096.
5. Yuen T, Brouillette MJ, Fellows LK, et al. Personalized risk index for neurocognitive decline among people with well-controlled HIV infection. J Acquir Immune Defic Syndr. 2017;76:48-54.
6. Simioni S, Cavassini M, Annoni JM, et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS. 2010;24:1243-1250.

This article originally appeared on Infectious Disease Advisor