Defining and Evaluating HIV-Related Neurodegenerative Disease and Its Treatment Targets: A Combinatorial Approach to Use of Cerebrospinal Fluid Molecular Biomarkers

Abstract

There are a number of reasons that the accomplishments of clinical trials related to HIV-related neurodegenerative disease (HRND) and the AIDS dementia complex (ADC) have had such limited impact on clinical practice. These include: rapid evolution and progress in the treatment of systemic HIV infection that has quickly outpaced neurological efforts and has markedly reduced disease incidence; ethical constraints that (rightly) demand neurologically compromised patients receive the best available treatment before experimental therapeutics; complicated backgrounds and comorbidities of patients now most susceptible to HRND; and reluctance of general AIDS clinicians and drug companies to look beyond systemic or pivotal outcomes. However, the field has also been slow to adopt methods that better exploit advances in understanding of the pathogenesis of central nervous system (CNS) infection and brain injury, and that might circumvent some of these constraints. Using a simple model of pathogenesis, we propose an approach to characterizing patients, selecting treatment targets, and evaluating outcomes that emphasize a combination of cerebrospinal fluid (CSF) markers. This model begins by using three markers related to cardinal components of HRND: CNS HIV infection (measurement of CSF HIV RNA), intrathecal immunoactivation (CSF neopterin), and brain injury [CSF light chain neurofilament (NFL)]. Careful analysis of this and other marker combinations promises more rational trial design and more rapid progress in managing CNS HIV infection and HRND using both antiviral and adjuvant treatment approaches.

Compartmentalization and Clonal Amplification of HIV-1 Variants in the Cerebrospinal Fluid during Primary Infection

“…The CSF/plasma albumin ratios were calculated as a measure of blood-brain barrier (BBB) disruption, while CSF WBC levels were measured as a simple marker of inflammation and inflammatory-cell migration into the CNS. Additionally, the level of CSF neopterin, a pteridine produced by activated macrophages and associated with intrathecal immunoactivation, is elevated in HIV-infected subjects and is characteristically particularly high (Ͼ22 nmol/ liter) in those with HIV-1-associated dementia (3,17). All 17 subjects were enrolled within the first year of infection, with a median at baseline of 143 days p.i.…”

Prevalence and Correlates of Persistent HIV-1 RNA in Cerebrospinal Fluid During Antiretroviral Therapy

“…Autopsy and neuroimaging studies have identified that HIV-1 can localize in the basal ganglia and hippocampus [13,14], even during the first weeks of infection [15]. Potent ART can reduce the HIV-1 level in blood and cerebrospinal fluid (CSF) below the quantification limit of commercially available assays, but HIV-1 might continue to replicate at low levels, increasing the risk for viral compartmentalization in the CNS [16]. Persistent low-level HIV-1 replication could also lead to glial activation and neuronal injury.…”

A guide to interpretation of neuroimmunological biomarkers in the combined antiretroviral therapy-era of HIV central nervous system disease

“…It has been proposed that a combination of markers be used in ongoing trials. 1,2 This approach would combine indicators of neuronal damage (eg, NFL), HIV activity (eg, HIV-RNA), and neuroinflammation (eg, MCP-1) to create a combined picture of ongoing CNS activity and disease risk.…”

“…Combinations of markers may be useful in caring for patients with HIV, 1 but much work remains to validate these biomarkers with their clinical correlates. 2 The translation of this work into day-to-day patient care is an ongoing endeavor. A particular challenge is to develop biomarkers that can be used in resource-poor settings, where the majority of disease burden lies.…”