Beyond the barrier: Navigating the challenges of HIV-associated neurocognitive disorders

In 2003, Persidsky and Gendelman first highlighted the pivotal role of HIV in the disruption of the blood-brain barrier — the biological defense that prevents most foreign substances from entering the brain — and its contribution to AIDS-related neuropathogenesis. (1) HIV can infect the host immune cells that traverse this protective barrier, allowing the virus to bypass it. This lapse can create latent viral reservoirs within the central nervous system, which can lead to HIV-associated neuropathology.

This is fascinating due to a central paradox: While HIV hides within the host’s own cells and easily crosses the blood-brain barrier, antiretroviral therapy drugs may struggle to do so.

While ART can suppress HIV replication in peripheral blood, its limited ability to penetrate the blood-brain barrier may diminish its effectiveness in reversing cognitive damage caused by HIV. (2) This limitation contributes further to the development of HIV-associated neurocognitive disorders, or HAND, which can present in various ways, including advanced cognitive decline, vegetative states, personality changes, social withdrawal and mutism. While these severe symptoms were more common in the pre-ART era, they can still occasionally be seen today, even with the availability of highly effective ART and in individuals with normal CD4 counts. (3)

A challenging diagnosis

Low CD4 counts are a strong predictor of HAND, underscoring the importance of starting ART as early as possible in individuals with HIV to minimize the risk. (4) Due to easy availability of ART, diagnosing HAND has been challenging because of its subtle presentation. (5) In 1991, the AIDS Task Force of the American Academy of Neurology first described two levels of neurological manifestations of HIV infection in the brain: HIV-associated dementia and minor cognitive motor disorder.

These were based on the presence of abnormal cognitive functioning that affects daily activities, combined with abnormal motor functioning, behavior, attention and concentration, provided that other possible causes were ruled out. In 2007, the U.S. National Institute of Mental Health introduced updated criteria, known as the Frascati criteria, which are considered the current gold standard for diagnosing HAND.

According to the Frascati criteria, HAND is classified into three categories: asymptomatic neurocognitive impairment, mild neurocognitive disorder and HIV-associated dementia. A key distinction between these HAND subtypes is the level and severity of functional decline, which is classified into three levels: functionally intact (no decline, as seen with asymptomatic neurocognitive impairment), mild decline (as in mild neurocognitive disorder) and major decline (which can occur in individuals with mild neurocognitive disorder or HIV-associated dementia, depending on the level of neurocognitive impairment). (6)

Diagnosing HAND requires a multifaceted approach that combines clinical assessments, neurocognitive testing and advanced neuroimaging techniques. To facilitate early detection, a range of screening tools have been recommended. Neuroimaging plays a crucial role in providing objective insights into HIV-related brain damage. (7)

Variable presentations, mild cases and remaining questions

Recently, we encountered two cases that underscore the critical role of ART in managing neurocognitive and psychiatric symptoms in individuals with HIV. The first involved an 81-year-old patient with multiple comorbidities, including HIV and baseline dementia. After accidentally skipping their ART, the patient experienced a sharp decline in cognitive function and suffered multiple falls. Despite thorough testing, including evaluations for stroke, no organic causes were found. It was then discovered that the patient’s HIV was no longer suppressed. Once ART was resumed, their cognitive abilities returned to baseline.

In another case, a 34-year-old patient with a history of nonadherence to ART was admitted to a psychiatric facility for acute delusions and psychosis. Extensive testing, including drug screening, showed no underlying cause. The patient’s condition improved significantly once the HIV infection was brought under control after resuming ART. These cases illustrate that HAND can present in highly variable ways, affecting both young and older individuals without limitation.

The widespread use of combination ART has led to a significant decline in severe neurocognitive issues among people with HIV. (7) However, despite this success, milder cognitive impairments remain surprisingly common, even among patients with well-controlled viral loads. Various studies have shown that these milder deficits affect anywhere from 20% to 69% of these individuals, suggesting that while ART has reduced the more severe complications, it hasn’t fully eliminated the risk of cognitive issues. (3)

The main key question that remains is whether these cognitive impairments in virally suppressed patients are lingering effects from earlier brain injury that occurred before treatment or if ongoing brain damage can still occur despite effective viral suppression. Can measuring the HIV viral load in cerebrospinal fluid be an effective indicator for identifying this phenomenon of viral escape in the central nervous system? Can this impairment be directly attributed to HIV itself? The research remains insufficient to fully comprehend the extensive effects of HIV on the brain, highlighting a significant gap that needs to be addressed in future studies.

It is intriguing to see how long-acting injectable medications, such as cabotegravir-rilpivirine and lenacapavir, are emerging as a promising strategy for HIV management. Only time will tell regarding their potential impact on managing HAND. Additionally, there is growing excitement around the use of nanotechnology to modify the blood-brain barrier, potentially enhancing the penetration of medications into cerebrospinal fluid. This innovative approach could also herald a new era in the fight against the diverse spectrum of HIV-related complications. (8)

References

1. Persidsky Y, Gendelman HE. Mononuclear phagocyte immunity and the neuropathogenesis of HIV-1 infection. J Leukoc Biol. 2003;74(5):691-701. doi:10.1189/jlb.0503205
2. Osborne O, Peyravian N, Nair M, Daunert S, Toborek M. The Paradox of HIV Blood-Brain Barrier Penetrance and Antiretroviral Drug Delivery Deficiencies. Trends Neurosci. 2020;43(9):695-708. doi:10.1016/j.tins.2020.06.007
3. 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(23):2087-2096. doi:10.1212/WNL.0b013e318200d727
4. Ellis RJ, Badiee J, Vaida F, et al. CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS. 2011;25(14):1747-1751. doi:10.1097/QAD.0b013e32834a40cd
5. D'Arminio Monforte A, Cinque P, Mocroft A, et al. Changing incidence of central nervous system diseases in the EuroSIDA cohort. Ann Neurol. 2004;55(3):320-328. doi:10.1002/ana.10827
6. Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69(18):1789-1799. doi:10.1212/01.WNL.0000287431.88658.8b
7. Elendu C, Aguocha CM, Okeke CV, Okoro CB, Peterson JC. HIV-related neurocognitive disorders: Diagnosis, Treatment, and Mental Health Implications: A Review. Medicine (Baltimore). 2023;102(43):e35652. doi:10.1097/MD.0000000000035652
8. Surve DH, Jindal AB. Recent advances in long-acting nanoformulations for delivery of antiretroviral drugs. J Control Release. 2020;324:379-404. doi:10.1016/j.jconrel.2020.05.022