Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort

Abstract

Objective-Differences in antiretroviral (ARV) distribution into the central nervous system (CNS) may impact neurocognitive status. We assessed the relationship between estimates of ARV therapy penetration into the CNS, using a published ranking system, and neurocognitive status in HIV-positive subjects with plasma HIV-1 RNA (vRNA) suppression.Design-Subjects with ≥6 weeks ongoing ARV use and vRNA<50 copies/mL (N=2,636; 83% male, median baseline CD4 T-cells: 244 cells/uL) had ≥1 neuroscreen assessment (Trailmaking A,B, WAIS-R Digit Symbol) at 10,413 neurovisits. Neuroscreen test scores were demographically adjusted and converted to Z-scores (NPZ3: lower scores imply more impairment). CNS penetration-effectiveness (CPE) ranks of 0.0(low), 0.5(medium) or 1.0(high) were assigned to ARVs and summed per regimen, per neurovisit. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Role of author:Marlene Smurzynski: study and conceptual design, assisted with data analysis, interpretation of findings, wrote and edited manuscript, finalized manuscript for publication Kunling Wu: data analysis, created figures and tables, interpretation of findings, reviewed manuscript Scott Letendre: study and conceptual design, interpretation of findings, contributed to manuscript development, edited manuscript Kevin Robertson: study and conceptual design, interpretation of findings, edited manuscript Ronald J. Bosch: assisted with data analysis, interpretation of findings, edited manuscript David B. Clifford: interpretation of findings, edited manuscript Scott Evans: assisted with data analysis, interpretation of findings, reviewed manuscript Ann C. Collier: interpretation of findings, edited manuscript Michael Taylor: completed the normalized neurocognitive test scores (NPZ3 scores), reviewed manuscript Ronald Ellis: study and conceptual design, interpretation of findings, contributed to manuscript development, edited manuscript NIH Public Access Methods-Multivariate linear regression models using generalized estimating equations assessed NPZ3 scores with respect to ARV regimen. Covariates were retained if p≤0.1.Results-A final model demonstrated that better NPZ3 scores were associated with higher CPE among subjects taking >3 ARVs (+0.07 per one unit increase in CPE score; p=0.004) but not among subjects with ≤3 ARVs in the regimen (+0.01; p=0.5). Results were adjusted for demographics, injection drug use, HCV serostatus, CD4 count (current and nadir), baseline vRNA, ARV experience and years since first ARV use.Conclusions-Use of ARVs with better estimated CNS penetration may be associated wi...

Pharmacokinetics and Pharmacodynamics of Antiretrovirals in the Central Nervous System

“…Most of the studies found a lower CSF HIV RNA with higher CPE score while the effect on immune-activation, MRI cerebral metabolites concentrations and neurocognitive testing were less concordant among studies: the results are summed up in table 2. [160][161][162][163][164][165][166][167][168][169][170][171][172] Furthermore while several retrospective studies found an association between higher CPE scores and lower CSF viral loads [153,154,[173][174][175] only one study (out of three) found a correlation with CSF escape. [21,143,176] Some reports tried to define a CPE cut off: respectively a value of 6 or 7 were found to be associated with heterogeneous CSF outcomes.…”

Raltegravir Permeability across Blood-Tissue Barriers and the Potential Role of Drug Efflux Transporters

“…Furthermore, the raltegravir cerebrospinal fluid-to-plasma concentration ratio varies significantly between individuals (16-18), suggesting that its permeability across the blood-brain barrier may be dependent on the expression/activity of drug efflux transporters, such as P-gp or BCRP, at this blood-tissue barrier. Poor drug penetration into the CNS, a known sanctuary site for HIV-1 replication, has been linked to a suboptimal clinical response to ARV therapy and a decline in neurocognitive function (43,44). Although a recent study by Johnson et al (18) did not demonstrate a link between raltegravir cerebrospinal fluid concentrations and ABCB1 (P-gp) polymorphisms in healthy volunteers, this observation might be due to compensatory efflux mechanisms at the blood-brain barrier (e.g., BCRP-mediated efflux) or other interindividual differences that were not accounted for in this sample population (18).…”

Neuropsychiatric effects of tenofovir in comparison with other antiretroviral drugs

“…This relationship, however, was not reported in patients using ART with three or less ARV drugs. 62 Better CNS-penetrating ART provides better control of viral replication within the CNS; however, HIV suppression below the levels of detection does not guarantee full cognitive recovery. 46 Interestingly, a study by Marra et al suggested that ARV drugs with good CNS penetration were associated with worse neurocognitive performance.…”