BACKGROUND: Cerebrospinal fluid (CSF) concentrations of multiple drugs in a large human immunodeficiency virus (HIV)-infected patient population, the virtual phenotype profiles for HIV in the plasma and CSF compartments, and the correlation of these profiles with exposure to antiretroviral therapy need to be further investigated. METHODS: Drug concentrations in CSF and plasma were concomitantly determined for a large group of HIV-infected individuals receiving highly active antiretroviral therapy (HAART). Samples were analyzed using a validated method consisting of liquid chromatography with mass spectrometry. For patients with detectable levels of virus, genotypic analysis was performed, followed by a virtual phenotype study. RESULTS: Sixty-three HIV-infected patients were included in the study, 78% of whom were affected by neurological disease. Drug concentrations in CSF specimens were undetectable for didanosine, efavirenz, nelfinavir, and concomitantly administered ritonavir and saquinavir. CSF concentrations were higher for nevirapine, with a median CSF-to-plasma concentration ratio of 0.63, followed by lamivudine (0.23), stavudine (0.20), and indinavir (0.11). In 18 of the 40 patients with virtual phenotype data available for virus recovered from CSF samples and from plasma samples, differences in fold-change of resistance between the CSF virus and the plasma virus were noted for at least 1 drug. Factors associated with having differences in fold-change of resistance were number of drugs to which the patient had been exposed (P=.02) and presence of neurological disease (P=.05). A significant association was found between duration of therapy and fold-change of resistance in CSF and plasma isolates. CONCLUSIONS: Antiretrovirals have different levels of penetration in the CSF, with several drugs achieving only low CSF concentrations. CSF isolates have different resistance profiles than do plasma isolates. Effective treatment decisions for CSF manifestations of disease may require better knowledge of drug penetration and the drug susceptibility of HIV in the CSF.
BACKGROUND: Cerebrospinal fluid (CSF) concentrations of multiple drugs in a large human immunodeficiency virus (HIV)-infectedpatient population, the virtual phenotype profiles for HIV in the plasma and CSF compartments, and the correlation of these profiles with exposure to antiretroviral therapy need to be further investigated. METHODS: Drug concentrations in CSF and plasma were concomitantly determined for a large group of HIV-infected individuals receiving highly active antiretroviral therapy (HAART). Samples were analyzed using a validated method consisting of liquid chromatography with mass spectrometry. For patients with detectable levels of virus, genotypic analysis was performed, followed by a virtual phenotype study. RESULTS: Sixty-three HIV-infectedpatients were included in the study, 78% of whom were affected by neurological disease. Drug concentrations in CSF specimens were undetectable for didanosine, efavirenz, nelfinavir, and concomitantly administered ritonavir and saquinavir. CSF concentrations were higher for nevirapine, with a median CSF-to-plasma concentration ratio of 0.63, followed by lamivudine (0.23), stavudine (0.20), and indinavir (0.11). In 18 of the 40 patients with virtual phenotype data available for virus recovered from CSF samples and from plasma samples, differences in fold-change of resistance between the CSF virus and the plasma virus were noted for at least 1 drug. Factors associated with having differences in fold-change of resistance were number of drugs to which the patient had been exposed (P=.02) and presence of neurological disease (P=.05). A significant association was found between duration of therapy and fold-change of resistance in CSF and plasma isolates. CONCLUSIONS: Antiretrovirals have different levels of penetration in the CSF, with several drugs achieving only low CSF concentrations. CSF isolates have different resistance profiles than do plasma isolates. Effective treatment decisions for CSF manifestations of disease may require better knowledge of drug penetration and the drug susceptibility of HIV in the CSF.
Authors: Brookie M Best; Peter P Koopmans; Scott L Letendre; Edmund V Capparelli; Steven S Rossi; David B Clifford; Ann C Collier; Benjamin B Gelman; Gilbert Mbeo; J Allen McCutchan; David M Simpson; Richard Haubrich; Ronald Ellis; Igor Grant Journal: J Antimicrob Chemother Date: 2010-11-23 Impact factor: 5.790
Authors: Paul Shapshak; Pandjassarame Kangueane; Robert K Fujimura; Deborah Commins; Francesco Chiappelli; Elyse Singer; Andrew J Levine; Alireza Minagar; Francis J Novembre; Charurut Somboonwit; Avindra Nath; John T Sinnott Journal: AIDS Date: 2011-01-14 Impact factor: 4.177
Authors: Álvaro H Borges; Jemma L O'Connor; Andrew N Phillips; Frederikke F Rönsholt; Sarah Pett; Michael J Vjecha; Martyn A French; Jens D Lundgren Journal: J Infect Dis Date: 2015-02-26 Impact factor: 5.226
Authors: Stefany Moreno-Gamez; Alison L Hill; Daniel I S Rosenbloom; Dmitri A Petrov; Martin A Nowak; Pleuni S Pennings Journal: Proc Natl Acad Sci U S A Date: 2015-05-18 Impact factor: 11.205