An Overview of HIV-Associated Neurocognitive Disorder

Brain complexity. Conceptual computer artwork of a brain represented as a complex maze. This could represent the complexity of the human brain, and the difficulty of researching brain conditions such as Alzheimer’s disease.
Rates of HIV-associated dementia have decreased from approximately 50% in the pre-cART era to 2% currently. However, roughly 50% of patients treated with cART have the milder forms of HIV-associated neurocognitive disorder (HAND).

Since the introduction of combined antiretroviral therapy (cART), the most severe form of neurocognitive impairment in people living with HIV (PLWHIV) has become increasingly rare. Rates of HIV-associated dementia have decreased from approximately 50% in the pre-cART era to 2% currently.1,2 However, roughly 50% of patients treated with cART have milder forms of HIV-associated neurocognitive disorder (HAND), such as asymptomatic neurocognitive impairment and mild neurocognitive disorder.3 Although neurocognitive impairment in the pre-cART era commonly involved deficits in information processing, verbal fluency, and motor dexterity, cART-era deficits more often involve learning and executive function.3

Potential mechanisms

“[E]arly HIV infection of the [central nervous system (CNS)] is believed to contribute to the development of HAND, and evidence suggests that the CNS can subsequently serve as a reservoir for ongoing HIV replication, thereby limiting the opportunity for a sterilizing cure or eradication,” according to a 2016 review published in Nature Reviews Neurology.4 Mechanisms that perpetuate the high prevalence of HAND are likely multifactorial and may include suboptimal efficacy of antiretroviral therapy in the CNS and consequent deficient viral suppression; the presence of drug-resistant viruses in the CNS; neuronal damage caused by continual viral replication in the CNS; and neurotoxic cART exposure, according to the results of a 2019 critical review.5

Some experts propose a fundamental role for vascular cognitive impairment in the pathogenesis of HAND in cART-treated patients, including the authors of a 2019 review published in the Journal of NeuroVirology.6 They noted that there is significant overlap in the neuropsychological and neuroimaging phenotypes of patients with vascular cognitive impairment and those with HAND, thus suggesting that they may be on the same spectrum of illness, rather than disparate diagnoses. Conversely, emerging research investigating the role of genetics in the pathogenesis of HAND has demonstrated that specific gene variants may influence the risk of developing HAND.7

Asymptomatic neurocognitive impairment and risk for progression

Asymptomatic neurocognitive impairment now accounts for roughly 70% of cases of HAND and is characterized by impairment on neurocognitive testing with no obvious associated deficits in daily functioning.2 Even with optimal viral suppression, many patients with HIV who have asymptomatic neurocognitive impairment transition to more severe HAND, increasing the risk for poor treatment adherence, and thus impaired day-to-day functionality and higher mortality.5 In a longitudinal study reported in 2014 in Neurology (n=347), researchers from several US universities linked asymptomatic neurocognitive impairment at baseline to a 2- to 6-fold increase in the risk for earlier transition to symptomatic HAND compared with patients who did not have baseline cognitive impairment.2

Women were more likely to experience symptomatic progression, as were patients with substance abuse disorders, major depressive disorder, and hepatitis C virus coinfection.2 In addition, low nadir CD4 count, older age, and cardiovascular risk factors have been linked with an increased risk for HAND in patients receiving cART.8,4 These data support the importance of diagnosing asymptomatic neurocognitive impairment in clinical settings, specifically in cases of patient at highest risk for symptomatic decline, as it may offer an opportunity to modify treatment to delay progression.2

Screening and differential diagnosis

There is currently no consensus on adjuvant treatment approaches for HAND in patients with optimal viral suppression, and there are no established biomarkers to distinguish between patients with and without neurocognitive impairment or to predict the progression of HAND. “The identification of biomarkers with the potential for predicting or stratifying the risk for [neurocognitive impairment] could be pivotal for the early diagnosis of HAND and long-term management of chronically infected [PLWHIV],” according to a 2019 review published in Frontiers in Aging Neuroscience.9

The authors of this review also highlighted that because effective cART commonly achieves viral suppression in the PLWHIV, and thus the role of this infection as a mechanism of CNS injury, more investigation is needed on inflammation-linked biomarkers or neuronal damage markers that may be influenced by different individual patient characteristics, such as the genetic likelihood of Alzheimer’s, age, and comorbidities.

Among promising findings thus far, recent study results suggest that a combination of fluid neuronal biomarkers (elevated high mobility group box 1 [HMGB1], neurofilament light protein [NF-L], and Aβ proteins) may help to differentiate stages of HAND and predict positive cART outcomes.5 Further studies are needed to investigate these and other potential cerebrospinal fluid (CSF) and neuroimaging biomarkers for use in research and clinical practice, as well as to inform the development of effective therapies targeting HAND in virally suppressed patients.

Related Articles

For patients with HIV who exhibit new-onset neurologic or neurocognitive signs or symptoms despite virologic control, clinicians “should have a low threshold for performing a lumbar puncture to measure CSF HIV RNA” to rule out the possibility of CNS viral escape, as advised in a guide for healthcare providers by the Memory and Aging Center at the University of California at San Francisco Weill Institute for Neurosciences.8 “Simultaneous plasma HIV RNA should also be ordered, and genotyping for drug resistance patterns should be performed if there are detectable levels of HIV RNA,” with subsequent alterations in the ART regimen as indicated by any observed drug resistance patterns.

In addition to considering these factors and the possibility of non-HIV-associated neurodegenerative disease, it is recommended that physicians screen for reversible causes of cognitive dysfunction, including obstructive sleep apnea, low vitamin B12 levels, abnormal thyroid-stimulating hormone, and a positive rapid plasma regain.

Although the differential diagnosis of the various types of HAND requires comprehensive neuropsychological testing and functional assessment, brief validated screening tools can help to determine the need for more formal evaluation.4,10 Results of a 2019 study support the use of the Montreal Cognitive Assessment in detecting early neurocognitive impairment in HIV, and it is generally unaffected by coexisting depression and anxiety, unlike other instruments.10

The Montreal Cognitive Assessment can be administered along with the Depression Anxiety Stress Scales to “discriminate impaired neurocognitive functioning from mood disorders and identify patients who may require further psychological assessment and/or specialist referral,” the authors concluded.10 “These screening tools are simple and quick to administer in a practice setting, and the immediacy of the feedback may serve to either validate or alleviate patient concerns.”


1. Alford K, Banerjee S, Nixon E, et al. Assessment and management of HIV-associated cognitive impairment: Experience from a multidisciplinary memory service for people living with HIV. Brain Sci. 2019;9(2):37.

2. Grant I, Franklin DR Jr, Deutsch R, et al. Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. Neurology. 2014;82(23):2055-2062.

3. Clifford DB, Ances BM. HIV-associated neurocognitive disorder.. Lancet Infect Dis. 2013;13(11):976-986.

4. Saylor D, Dickens AM, Sacktor N, et al. HIV-associated neurocognitive disorder–pathogenesis and prospects for treatment. Nat Rev Neurol. 2016;12(4):234-248.

5. Bougea A, Spantideas N, Galanis P, Gkekas G, Thomaides T. Optimal treatment of HIV-associated neurocognitive disorders: myths and reality. A critical review [Published online April 4, 2019]. Ther Adv Infect Dis. doi:10.1177/2049936119838228

6. Cysique LA, Brew BJ. Vascular cognitive impairment and HIV-associated neurocognitive disorder: a new paradigm [Published online January 11, 2019]. J Neurovirol. doi:10.1007/s13365-018-0706-5.

7. Olivier IS, Cacabelos R, Naidoo V. Risk factors and pathogenesis of HIV-associated neurocognitive disorder: The role of host genetics. Int J Mol Sci. 2018;19(11):3594.

8. UCSF Weill Institute for Neurosciences—Memory and Aging Center. A healthcare provider’s guide to HIV-associated neurocognitive disorder (HAND): Diagnosis, pharmacologic management, non-pharmacologic management, and other considerations. Accessed September 30, 2019.

9. Bandera A, Taramasso L, Bozzi G, et al. HIV-associated neurocognitive impairment in the modern ART era: Are we close to discovering reliable biomarkers in the setting of virological suppression? Front Aging Neurosci. 2019;11:187.

10. Herrmann S, McKinnon E, Skinner M, et al. Screening for HIV-associated neurocognitive impairment: Relevance of psychological factors and era of commencement of antiretroviral therapy. J Assoc Nurses AIDS Care. 2019;30(1):42-50.