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Validation of the CNS Penetration-Effectiveness Rank for Quantifying Antiretroviral Penetration Into the Central Nervous System
Scott Letendre, MD;
Jennifer Marquie-Beck, BS;
Edmund Capparelli, PharmD;
Brookie Best, PharmD;
David Clifford, MD;
Ann C. Collier, MD;
Benjamin B. Gelman, MD, PhD;
Justin C. McArthur, MPH, MBBS;
J. Allen McCutchan, MD;
Susan Morgello, MD;
David Simpson, MD;
Igor Grant, MD;
Ronald J. Ellis, MD, PhD; for the CHARTER Group
Arch Neurol. 2008;65(1):65-70.
Objective To evaluate whether penetration of a combination regimen into the central nervous system (CNS), as estimated by the CNS Penetration-Effectiveness (CPE) rank, is associated with lower cerebrospinal fluid (CSF) viral load.
Design Data were analyzed from 467 participants who were human immunodeficiency virus (HIV) seropositive and who reported antiretroviral (ARV) drug use. Individual ARV drugs were assigned a penetration rank of 0 (low), 0.5 (intermediate), or 1 (high) based on their chemical properties, concentrations in CSF, and/or effectiveness in the CNS in clinical studies. The CPE rank was calculated by summing the individual penetration ranks for each ARV in the regimen.
Results The median CPE rank was 1.5 (interquartile range, 1-2). Lower CPE ranks correlated with higher CSF viral loads. Ranks less than 2 were associated with an 88% increase in the odds of detectable CSF viral load. In multivariate regression, lower CPE ranks were associated with detectable CSF viral loads even after adjusting for total number of ARV drugs, ARV drug adherence, plasma viral load, duration and type of the current regimen, and CD4 count.
Conclusions Poorer penetration of ARV drugs into the CNS appears to allow continued HIV replication in the CNS as indicated by higher CSF HIV viral loads. Because inhibition of HIV replication in the CNS is probably critical in treating patients who have HIV-associated neurocognitive disorders, ARV treatment strategies that account for CNS penetration should be considered in consensus treatment guidelines and validated in clinical studies.
Author Affiliations: University of California, San Diego (Drs Letendre, Capparelli, Best, McCutchan, Grant, and Ellis and Ms Marquie-Beck); Washington University, St Louis, Missouri (Dr Clifford); University of Washington, Seattle (Dr Collier); University of Texas Medical Branch, Galveston (Dr Gelman); Johns Hopkins University, Baltimore, Maryland (Dr McArthur); and Mt Sinai School of Medicine, New York, New York (Drs Morgello and Simpson).
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