Cerebrospinal Fluid and Brain Tissue Penetration of Tenofovir, Lamivudine, and Efavirenz in Postmortem Tissues with Cryptococcal Meningitis
The central nervous system (CNS) is a known HIV reservoir, yet little is known about drug exposure in the brain. Our primary objective was to quantify exposure of three common antiretrovirals in brain tissue and compare exposures to plasma and cerebrospinal fluid (CSF). We also sought to identify po...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-09-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.12661 |
| _version_ | 1811262986520625152 |
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| author | Melanie R. Nicol Katelyn A. Pastick Joneé Taylor Olivie C. Namuju Joshua Rhein Darlisha A. Williams David B. Meya David R. Boulware Robert Lukande |
| author_facet | Melanie R. Nicol Katelyn A. Pastick Joneé Taylor Olivie C. Namuju Joshua Rhein Darlisha A. Williams David B. Meya David R. Boulware Robert Lukande |
| author_sort | Melanie R. Nicol |
| collection | DOAJ |
| description | The central nervous system (CNS) is a known HIV reservoir, yet little is known about drug exposure in the brain. Our primary objective was to quantify exposure of three common antiretrovirals in brain tissue and compare exposures to plasma and cerebrospinal fluid (CSF). We also sought to identify pockets of brain most vulnerable to inadequate drug exposures and examine the role of meningitis in drug penetration into the CNS. Tenofovir, lamivudine, and efavirenz concentrations were measured using liquid chromatography and tandem mass spectrometry in plasma and CSF from 14 individuals with HIV, 7 with cryptococcal meningitis. In four individuals (three with meningitis) drug concentrations were also measured in 13 distinct brain tissue regions. In subjects with meningitis, geometric mean ratio (95% confidence interval) of tenofovir CSF to plasma was 66% (7–598%) and 14% (6–31%) in subjects without meningitis. Lamivudine CSF penetration was 100% (25–409%) in subjects with meningitis and 30% (24–37%) in subjects without meningitis. Tenofovir brain tissue concentrations were 36% (14–124%) of plasma and 49% (1–572%) of CSF. Lamivudine brain concentrations were 37% (23–64%) of plasma and 27% (1–104%) of CSF. Efavirenz brain tissue concentrations were 128% (108–179%) of plasma. Tissues collected postmortem provide a unique opportunity to assess drug distribution in tissues difficult to sample in living subjects. CSF is a poor surrogate for drug exposure throughout the CNS. Antiretrovirals differentially penetrate into the CNS and penetration may be enhanced by meningitis. |
| first_indexed | 2024-04-12T19:36:51Z |
| format | Article |
| id | doaj.art-cbd298f727f44e8daf595e5dd01ae1aa |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-04-12T19:36:51Z |
| publishDate | 2019-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-cbd298f727f44e8daf595e5dd01ae1aa2022-12-22T03:19:12ZengWileyClinical and Translational Science1752-80541752-80622019-09-0112544544910.1111/cts.12661Cerebrospinal Fluid and Brain Tissue Penetration of Tenofovir, Lamivudine, and Efavirenz in Postmortem Tissues with Cryptococcal MeningitisMelanie R. Nicol0Katelyn A. Pastick1Joneé Taylor2Olivie C. Namuju3Joshua Rhein4Darlisha A. Williams5David B. Meya6David R. Boulware7Robert Lukande8Department of Experimental and Clinical Pharmacology College of Pharmacy University of Minnesota Minneapolis Minnesota USADepartment of Medicine Medical School University of Minnesota Minneapolis Minnesota USANew York City Office of the Chief Medical Examiner and New York University New York City New York USAInfectious Disease Institute of Makerere University Kampala UgandaDepartment of Medicine Medical School University of Minnesota Minneapolis Minnesota USADepartment of Medicine Medical School University of Minnesota Minneapolis Minnesota USADepartment of Medicine Medical School University of Minnesota Minneapolis Minnesota USADepartment of Medicine Medical School University of Minnesota Minneapolis Minnesota USADepartment of Pathology Makerere University Kampala UgandaThe central nervous system (CNS) is a known HIV reservoir, yet little is known about drug exposure in the brain. Our primary objective was to quantify exposure of three common antiretrovirals in brain tissue and compare exposures to plasma and cerebrospinal fluid (CSF). We also sought to identify pockets of brain most vulnerable to inadequate drug exposures and examine the role of meningitis in drug penetration into the CNS. Tenofovir, lamivudine, and efavirenz concentrations were measured using liquid chromatography and tandem mass spectrometry in plasma and CSF from 14 individuals with HIV, 7 with cryptococcal meningitis. In four individuals (three with meningitis) drug concentrations were also measured in 13 distinct brain tissue regions. In subjects with meningitis, geometric mean ratio (95% confidence interval) of tenofovir CSF to plasma was 66% (7–598%) and 14% (6–31%) in subjects without meningitis. Lamivudine CSF penetration was 100% (25–409%) in subjects with meningitis and 30% (24–37%) in subjects without meningitis. Tenofovir brain tissue concentrations were 36% (14–124%) of plasma and 49% (1–572%) of CSF. Lamivudine brain concentrations were 37% (23–64%) of plasma and 27% (1–104%) of CSF. Efavirenz brain tissue concentrations were 128% (108–179%) of plasma. Tissues collected postmortem provide a unique opportunity to assess drug distribution in tissues difficult to sample in living subjects. CSF is a poor surrogate for drug exposure throughout the CNS. Antiretrovirals differentially penetrate into the CNS and penetration may be enhanced by meningitis.https://doi.org/10.1111/cts.12661 |
| spellingShingle | Melanie R. Nicol Katelyn A. Pastick Joneé Taylor Olivie C. Namuju Joshua Rhein Darlisha A. Williams David B. Meya David R. Boulware Robert Lukande Cerebrospinal Fluid and Brain Tissue Penetration of Tenofovir, Lamivudine, and Efavirenz in Postmortem Tissues with Cryptococcal Meningitis Clinical and Translational Science |
| title | Cerebrospinal Fluid and Brain Tissue Penetration of Tenofovir, Lamivudine, and Efavirenz in Postmortem Tissues with Cryptococcal Meningitis |
| title_full | Cerebrospinal Fluid and Brain Tissue Penetration of Tenofovir, Lamivudine, and Efavirenz in Postmortem Tissues with Cryptococcal Meningitis |
| title_fullStr | Cerebrospinal Fluid and Brain Tissue Penetration of Tenofovir, Lamivudine, and Efavirenz in Postmortem Tissues with Cryptococcal Meningitis |
| title_full_unstemmed | Cerebrospinal Fluid and Brain Tissue Penetration of Tenofovir, Lamivudine, and Efavirenz in Postmortem Tissues with Cryptococcal Meningitis |
| title_short | Cerebrospinal Fluid and Brain Tissue Penetration of Tenofovir, Lamivudine, and Efavirenz in Postmortem Tissues with Cryptococcal Meningitis |
| title_sort | cerebrospinal fluid and brain tissue penetration of tenofovir lamivudine and efavirenz in postmortem tissues with cryptococcal meningitis |
| url | https://doi.org/10.1111/cts.12661 |
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