Have HIV-associated neurological disorders declined in people with HIV due to recent antiretrovirals?

Dr Ilaria Mastrorosa (bottom left) at CROI 2022.
Dr Ilaria Mastrorosa (bottom left) at CROI 2022.

The prevalence of HIV-associated neurocognitive disorder (HAND) has decreased over the last decade among people with HIV who take antiretroviral therapy, according to an Italian study presented last week at the Conference on Retroviruses and Opportunistic Infections (CROI 2022). Lower rates of HAND were associated with various patient characteristics and HIV-related factors, including the use of dual therapies and integrase inhibitor-based regimens.

Based on the ‘Frascati criteria’, a person is said to have HAND depending on the results from tests assessing several functions such as attention and working memory, mental processing speed, memory, and fine motor skills (the co-ordination of muscles, bones and nerves to produce small, exact movements, such as picking up a small object with two fingers).

Individuals are considered to suffer from HAND if any detected impairments cannot be explained by other conditions such as head trauma, substance abuse, vascular dementia or Alzheimer’s disease. Within the criteria, there are three progressive conditions of neurocognitive decline: asymptomatic neurocognitive impairment; HIV-associated mild neurocognitive disorder; and HIV-associated dementia.


adjusted odds ratio (AOR)

Comparing one group with another, expresses differences in the odds of something happening. An odds ratio above 1 means something is more likely to happen in the group of interest; an odds ratio below 1 means it is less likely to happen. Similar to ‘relative risk’. 


Loss of the ability to process, learn, and remember information. Potential causes include alcohol or drug abuse, depression, anxiety, vascular cognitive impairment, Alzheimer’s disease and HIV-associated neurocognitive disorder (HAND). 

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.


Lowest of a series of measurements. For example, an individual’s CD4 nadir is their lowest ever measured CD4 count.

cognitive impairment

Loss of the ability to process, learn, and remember information. Potential causes include alcohol or drug abuse, depression, anxiety, vascular cognitive impairment, Alzheimer’s disease and HIV-associated neurocognitive disorder (HAND). 

Dr Ilaria Mastrorosa from the National Institute for Infectious Diseases ‘Lazzaro Spallanzani’ in Rome said that HAND continues to affect a large proportion of people with HIV. Studies from a decade ago found rates as high as 19 to 30% in people with HIV who were taking antiretroviral therapy and had a controlled HIV viral load.

Mastrorosa and colleagues looked for potential changes: their primary aim was to observe the evolution of the prevalence of HAND in people taking antiretroviral therapy in recent years. Additionally, they wanted to assess the relationships between HAND and several socio-demographic, clinical, laboratory and therapeutic variables, in order to identify predictive factors for HAND.

The team analysed the neurocognitive profiles of 1365 HIV-positive people receiving antiretroviral therapy, who were enrolled in the Institute’s HIV cohort between 2009 and 2020. The profiles were derived from neuropsychological assessment through 13 tests of functions covered by the Frascati criteria.

In addition, depending on whether or not they presented with a deficit of memory, attention or concentration, participants were defined as “complaining” or “not complaining”. While a person who is “complaining” has symptoms, this is a slightly different definition to that of the Frascati criteria, in which people with HIV-associated mild neurocognitive disorder or HIV-associated dementia have symptoms that interfere with their ability to carry out daily tasks or activities.

A total of 2383 neuropsychological test results collected from the 1365 participants were analysed. Overall, 791 (33%) participants were identified as “complaining” and 1592 (69%) as “not complaining” patients.


Most participants were male and in their forties and fifties, while the median time since HIV diagnosis was ten years. Between the “complaining” and the “not complaining”, numerous characteristics were different. In the “complaining” group, there were fewer men (78% vs 84%), fewer gay and bisexual men (40% vs 48%), fewer people with a viral load below 40 (78% vs 89%), and more with a CD4 nadir of below 200 (51% vs 26%) than in the “not complaining” group.

Dr Mastrorosa highlighted that 18% and 8% received an integrase inhibitor-based or a dual (rather than triple) antiretroviral regimen, respectively. 

Overall in the study, the HAND prevalence was 22%. Unsurprisingly, it was much higher among “complaining” participants (40%) than in their “not complaining” counterparts (13%). Over time, the investigators found a remarkable decreasing trend in the prevalence of HAND, both in the entire cohort and in the two groups:

  • All study population: from 38% in 2009-2011 to 16% in 2018-2020.
  • “Complaining”: from 52% in 2009-2011 to 29% in 2018-2020.
  • “Not complaining”: from 23% in 2009-2011 to 11% in 2018-2020.

This trend was confirmed after stratifying for age, mode of HIV transmission, CD4 nadir, current CD4 count and HIV viral load.

A higher risk of presenting with HAND was found to be associated with having hepatitis C antibodies (Adjusted Odds Ratio 1.44), reporting a cognitive complaint (AOR 3.83) and being an extra ten years older (AOR 1.16). Meanwhile, a lower risk was found with:

  • An extra year of education (AOR 0.84).
  • A higher CD4 cell count (AOR 0.66 for 351-500 vs 1.00 for <350).
  • Being on an integrase inhibitor-based regimen or a dual regimen (AOR 0.67 and 0.59 vs ≥ 1.00 with other regimens).
  • Neuropsychological assessment in recent years (AOR 0.48 in 2015-2017 and 0.43 in 2018-2020 vs 1.00 in 2009-2011).

Dr Mastrorosa concluded that these results reflect the multifactorial pathogenesis of HAND, even with successfully treated HIV. She also said that the results “suggest a potential role, in the HAND prevalence decline, of the most recent treatment strategies, which have shown a greater virological efficacy and a better tolerability.”

Dr Mastroroso did not address the potential overestimation of the cognitive impairment in people with HIV, which has been debated for years. According to some researchers, relying on the use of the Frascati criteria rather than on the actual presence of clinical symptoms, leads to this overestimation.

As highlighted by a question from a conference delegate, it would have been interesting to see if there were similar results when only looking at participants with symptomatic cognitive impairment.


Mastrorosa I et al. Is there a role of novel ART regimens in the declining prevalence of HAND? Conference on Retroviruses and Opportunistic Infections, abstract 132, 2022.

View the abstract on the conference website.

Update: Following the conference presentation, this study was published in a peer-reviewed journal:

Mastrorosa I et al. Declining Prevalence of Human Immunodeficiency Virus (HIV)–Associated Neurocognitive Disorders in Recent Years and Associated Factors in a Large Cohort of Antiretroviral Therapy–Treated Individuals With HIV. Clinical Infectious Diseases, 76: e629–e637, February 2023.