Interrogating the Impact of Combination Antiretroviral Therapies on HIV-Associated Neurocognitive Disorders

Ishta Sharma


HIV Medicine. 2021;22(9):783-790. 

In This Article

Abstract and Introduction


Objectives: Although the advent of Combination Antiretroviral Therapy (cART) has greatly reduced the prevalence of HIV-Associated Dementia, the most severe form of HIV-Associated Neurocognitive Disorder (HAND), the incidence of the milder forms of HAND have risen. The explanations proposed include persistent central nervous system (CNS) viraemia and the neurotoxicity of chronic cART regimens. Nonetheless, controversies in HAND prevalence estimates, alongside a lack of consensus on the significance of CNS Penetration Effectiveness (CPE) have added to the complexity of elucidating the role of cART in HAND. The present review will evaluate the evidence underlying these explanations, as well as highlighting the need for improved trial designs and the incorporation of emerging biomarkers and neuroimaging tools.

Methods: A review of the current literature investigating cART neurotoxicity, controversies in HAND prevalence estimates, CNS Penetration Effectiveness, and neuroprotective adjuvant therapies.

Conclusions: Ultimately, the inadequacy of cART in achieving complete preservation of the CNS underscores the imminent need for neuroprotective adjuvant therapies, where the efficacy of combining multiple adjuvant classes presents a potential therapeutic frontier which must be interrogated.


Affecting 38 million individuals worldwide, with 1.7 million newly infected patients in 2019, the global burden imposed by HIV cannot be overstated. Although HIV is notorious for its devastating impact on the cellular immune system, it also instigates direct pathology in the central nervous system (CNS), culminating in a group of syndromes of impaired cognition and functionality, known collectively as HIV-associated neurocognitive disorders (HAND). The implementation of combination antiretroviral therapy (cART) since 1996 has greatly revolutionized HIV prognosis, transforming it to a chronic disease where patient life expectancy resembles that of uninfected cohorts. The combination of multiple antiretroviral agents from different classes targeting the viral life cycle at distinct points reduces the risk of developing resistance to a single agent, as well as potently suppressing viral replication. In addition to decreasing mortality attributed to opportunistic infections, cART has more than halved the incidence of HIV-associated dementia (HAD), the most severe form of HAND, from around 20% in the pre-cART era to below 5%.[1] Nevertheless, the milder forms of HAND, asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND), not only persist in the cART era but also numerous studies have observed higher rates and severity of ANI following the introduction of cART.[1,2] In addition to the devastating repercussions on the quality of life, the endurance of cognitive disorders also perturbs cART adherence which has serious implications for increased mortality and the development of cART resistance.[3] The explanations proposed for this phenomenon range from persistent CNS HIV replication, ineffective CNS penetration of cART, to the long-term neurotoxicity of cART regimens. Despite a plethora of preclinical and clinical studies, these conflicting hypotheses have proved challenging to reconcile. This review will examine the role of cART in the endurance of HAND by evaluating several of the factors implicated in persistent HAND pathogenesis.