HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment

Abstract

In the past two decades, several advancements have improved the care of HIV-infected individuals. Most importantly, the development and deployment of combination antiretroviral therapy (CART) has resulted in a dramatic decline in the rate of deaths from AIDS, so that people living with HIV today have nearly normal life expectancies if treated with CART. The term HIV-associated neurocognitive disorder (HAND) has been used to describe the spectrum of neurocognitive dysfunction associated with HIV infection. HIV can enter the CNS during early stages of infection, and persistent CNS HIV infection and inflammation probably contribute to the development of HAND. The brain can subsequently serve as a sanctuary for ongoing HIV replication, even when systemic viral suppression has been achieved. HAND can remain in patients treated with CART, and its effects on survival, quality of life and everyday functioning make it an important unresolved issue. In this Review, we describe the epidemiology of HAND, the evolving concepts of its neuropathogenesis, novel insights from animal models, and new approaches to treatment. We also discuss how inflammation is sustained in chronic HIV infection. Moreover, we suggest that adjunctive therapies -treatments targeting CNS inflammation and other metabolic processes, including glutamate homeostasis, lipid and energy metabolism -are needed to reverse or improve HAND-related neurological dysfunction. Competing interests statementThe authors declare no competing interests. HHS Public AccessAuthor manuscript Nat Rev Neurol. Author manuscript; available in PMC 2016 July 08. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript chronic infection that can be managed, is associated with a near-normal lifespan and in which opportunistic infections are rare 1 .The first major advancement was an understanding of the direct relationship between HIV replication and subsequent immunological and clinical progression. This finding emphasized the need to completely suppress HIV replication in order to control disease progression.The second major advancement was the development and deployment of combination antiretroviral therapy (CART), which can provide effective systemic suppression of HIV replication. The introduction of CART in the mid-1990s resulted in a 50% decline in the rate of death from AIDS, substantial decreases in rates of maternal-infant transmission, reduced incidence of opportunistic infections, and a 40-50% decrease in the incidence of HIVassociated dementia (HAD), which was previously common and is the most severe form of cognitive impairment associated with the infection 2 .The third major change in the care of HIV+ patients was the ability to monitor the efficacy of CART through the reliable and widespread measurement of CD4 + helper T cells, plasma HIV RNA levels and antiretroviral resistance profiles, all of which are now fully integrated into routine clinical care in the developed world and used to optimize treatment for individual patients. Plasma viral l...

Risk Factors Leading to Most Severe Forms of HAND in Adults on cART who Present Suppressed Plasma HIV-1 viral load

“…Although antiretrovirals contribute to complete suppression of HIV replication, in order to control disease progression, development and deployment of combination antiretroviral therapy (cART), the ability to monitor the efficacy of cART through the measurement of CD4+ helper T cells in plasma does not always ensure healthy living for adults living with HIV+ (2) , since there have been changes in the pattern of neurocognitive impairments, as well as shift in the severity of deficits, because cognitive impairment can be present in HIV+ subjects, even in the cART era International Annals of Medicine Vol1;1 (8) dementia) was the most common form of HAND and had a negative impact of the patients' quality of life. However, the prevalence of HAD has substantially declined with the advent of cART, making the HAND reduction, although the adults HIV+ longevity can led to an overall increased of the prevalence of more severe forms of HAND, ie, mild neurocognitive disorder form (MND) and HAD (4) .…”

“…But, the era difference (pre and cART) in degree of immunosuppression (nadir CD4, especially) is much larger for the drug-asymptomatic-phase than for the other disease stages, and low nadir CD4+ was a robust predictor for neurocognitive impairment (NCI) in both treatment eras (6) . Of all cognitive impairments, problems with learning and memory are reported to a greater extent in the cART era (1,2,6) . Clinical characteristics and risk factors for HAND have also changed with cART.…”

“…Although antiretroviral drugs can control infection, there are few studies examining low CD4+ count and HAND in patients who present undetectable viral loads, in the cART era (6) . Additionally, depression is a common condition experienced by people living with chronic diseases that cause disability, which interferes in the recovery of the patient and is considered a potential risk for increased morbidity and mortality, including HIV/AIDS (2,7) . This neuropsychiatric disease is associated with higher sexual risk behaviors, less adherence to antiretroviral medication and worse clinical outcomes (7) .…”

“…Depression and cognitive deficits in individuals with HAND, are still an issue that requires further elucidation for the understanding of this psychopathology. Generally, some risk factors are involved in the development of HAND in HIV+ adults, the main factors being: cardiovascular factors (obesity and diabetes) (2,8) and advanced age (>50 years) (9) . However, some social-behavioral factors may also be involved in HAND.…”

A Modified P1 Moiety Enhances In Vitro Antiviral Activity against Various Multidrug-Resistant HIV-1 Variants and In Vitro Central Nervous System Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413

“…These include (i) drug-related toxicities, (ii) an inability to fully restore normal immunologic functions once individuals develop full-blown AIDS, (iii) the development of various cancers as a consequence of survival prolongation, (iv) flaring up of inflammation in individuals receiving cART or the occurrence of immune reconstruction syndrome (IRS), (v) development of HIV-1-associated neurocognitive disorders (HAND) as a result of prolonged patient survival and poor antiretroviral drug penetration into the central nervous system (CNS), and (vi) the increased cost of antiviral therapy. Although recent first-line cART with boosted protease inhibitor (PI)-based and integrase inhibitorbased regimens has made the development of HIV-1 resistance relatively less likely over an extended period (9,10), the various limitations and flaws of cART listed above are still exacerbated by persisting HIV-1 drug resistance (11)(12)(13)(14)(15)(16).…”