Defining and evaluating HIV-related neurodegenerative disease and its treatment targets: a combinatorial approach to use of cerebrospinal fluid molecular biomarkers.
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.
Gisslen
Magnus
M
Department of Infectious Diseases, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
Hagberg
Lars
L
Rosengren
Lars
L
Brew
Bruce J
BJ
Cinque
Paola
P
Spudich
Serena
S
Price
Richard W
RW
D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage; D015415:Biomarkers / Q000134:cerebrospinal fluid; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D016503:Drug Delivery Systems / Q000379:methods*; D015658:HIV Infections / Q000134:cerebrospinal fluid* / Q000188:drug therapy; D006801:Humans; D019636:Neurodegenerative Diseases / Q000134:cerebrospinal fluid* / Q000188:drug therapy
D019380:Anti-HIV Agents; D015415:Biomarkers