The role of cohort studies in drug development: Clinical evidence of antiviral activity of serotonin reuptake inhibitors and HMG-CoA reductase inhibitors in the central nervous system

Scott L. Letendre, Jennifer Marquie-Beck, Ronald J. Ellis, Steven Paul Woods, Brookie Best, David B. Clifford, Ann C. Collier, Benjamin Gelman, Christina Marra, Justin C. McArthur, J. Allen McCutchan, Susan Morgello, David Simpson, Terry J. Alexander, Janis Durelle, Robert Heaton, Igor Grant, Thomas D. Marcotte, Shondra Neumayer, Edmund CapparelliJ. Hampton Atkinson, Donald Franklin, Joseph K. Wong, Caroline Ignacio, Terry Jernigan, Michael J. Taylor, Rebecca Theilmann, Anthony C. Gamst, Clint Cushman, Michelle Frybarger, Ian Abramson, Deborah Lazzaretto, Rodney Von Jaeger, Muhammad Al-Lozi

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Background: Effective antiretroviral therapy (ART) has reduced the incidence of HIV-associated neurocognitive impairment (HNCI) but its prevalence remains high. Clinical trials have yet to identify a consistently effective treatment for HNCI, other than ART, but in vitro data support that some drugs approved by the Food and Drug Administration (FDA) for other indications might benefit individuals with HNCI. Some of these drugs, such as serotonin reuptake inhibitors (SRIs) and HMG-CoA reductase inhibitors (statins), may do so by reducing HIV replication in the CNS and are already widely used by HIV-infected individuals. Methods: Six-hundred fifty-eight HIV-infected participants of the CHARTER cohort had a baseline assessment, which included comprehensive neuropsychological (NP) testing and HIV RNA measurements in plasma and cerebrospinal fluid (CSF). Four-hundred sixty-seven (71%) subjects used ART, 195 (30%) used SRIs, and 63 (10%) used statins. Results: SRI users were less likely to have HIV RNA levels in CSF above 50 copies (c)/mL (29 vs. 37% in non-SRI users, OR 0.69, p=0.05). This association was most evident for three of the seven SRIs (citalopram, sertraline, and trazodone, or "antiviral" SRIs, combined 25 vs. 38% in non-SRI users, OR 0.56, p=0.01) and was strongest in those not taking concomitant ART (61 vs. 83%, OR 0.31, p=0.01). "Antiviral" SRI users also performed better on NP tests (median global deficit score 0.37 vs. 0.47, p=0.04). Statin users were also less likely to have HIV RNA levels in CSF above 50 c/mL (16 vs. 37%, p<0.001) but, in contrast to SRIs, the association was strongest in those taking ART (2 vs. 18%, p<0.001). Statin use was not associated with better NP performance. Multivariate analyses indicated that the use of "antiviral" SRIs-but not statins-was associated with undetectable HIV RNA levels in CSF and better NP performance. Conclusions: SRIs may reduce HIV replication in CSF and improve NP performance. This was particularly true for three SRIs-supporting differences in antiviral efficacy between drugs-in individuals who were not taking ART. In contrast, statins were not associated with lower HIV replication in CSF in multivariate analyses and were not associated with better NP performance. These analyses support the value of large observational cohort studies in identifying FDA-approved drugs that may be worth further investigation.

Original languageEnglish (US)
Pages (from-to)120-127
Number of pages8
JournalJournal of NeuroImmune Pharmacology
Volume2
Issue number1
DOIs
StatePublished - Mar 2007

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Serotonin Uptake Inhibitors
Antiviral Agents
Cohort Studies
Central Nervous System
HIV
Pharmaceutical Preparations
Cerebrospinal Fluid
RNA
United States Food and Drug Administration
Therapeutics
Multivariate Analysis
Trazodone
Sertraline
Citalopram
Neuropsychological Tests
Observational Studies

Keywords

  • Cerebrospinal fluid
  • HIV
  • Serotonin reuptake inhibitors
  • Statins

ASJC Scopus subject areas

  • Pharmacology
  • Immunology and Allergy
  • Immunology
  • Neuroscience (miscellaneous)

Cite this

The role of cohort studies in drug development : Clinical evidence of antiviral activity of serotonin reuptake inhibitors and HMG-CoA reductase inhibitors in the central nervous system. / Letendre, Scott L.; Marquie-Beck, Jennifer; Ellis, Ronald J.; Woods, Steven Paul; Best, Brookie; Clifford, David B.; Collier, Ann C.; Gelman, Benjamin; Marra, Christina; McArthur, Justin C.; McCutchan, J. Allen; Morgello, Susan; Simpson, David; Alexander, Terry J.; Durelle, Janis; Heaton, Robert; Grant, Igor; Marcotte, Thomas D.; Neumayer, Shondra; Capparelli, Edmund; Atkinson, J. Hampton; Franklin, Donald; Wong, Joseph K.; Ignacio, Caroline; Jernigan, Terry; Taylor, Michael J.; Theilmann, Rebecca; Gamst, Anthony C.; Cushman, Clint; Frybarger, Michelle; Abramson, Ian; Lazzaretto, Deborah; Von Jaeger, Rodney; Al-Lozi, Muhammad.

In: Journal of NeuroImmune Pharmacology, Vol. 2, No. 1, 03.2007, p. 120-127.

Research output: Contribution to journalArticle

Letendre, SL, Marquie-Beck, J, Ellis, RJ, Woods, SP, Best, B, Clifford, DB, Collier, AC, Gelman, B, Marra, C, McArthur, JC, McCutchan, JA, Morgello, S, Simpson, D, Alexander, TJ, Durelle, J, Heaton, R, Grant, I, Marcotte, TD, Neumayer, S, Capparelli, E, Atkinson, JH, Franklin, D, Wong, JK, Ignacio, C, Jernigan, T, Taylor, MJ, Theilmann, R, Gamst, AC, Cushman, C, Frybarger, M, Abramson, I, Lazzaretto, D, Von Jaeger, R & Al-Lozi, M 2007, 'The role of cohort studies in drug development: Clinical evidence of antiviral activity of serotonin reuptake inhibitors and HMG-CoA reductase inhibitors in the central nervous system', Journal of NeuroImmune Pharmacology, vol. 2, no. 1, pp. 120-127. https://doi.org/10.1007/s11481-006-9054-y
Letendre, Scott L. ; Marquie-Beck, Jennifer ; Ellis, Ronald J. ; Woods, Steven Paul ; Best, Brookie ; Clifford, David B. ; Collier, Ann C. ; Gelman, Benjamin ; Marra, Christina ; McArthur, Justin C. ; McCutchan, J. Allen ; Morgello, Susan ; Simpson, David ; Alexander, Terry J. ; Durelle, Janis ; Heaton, Robert ; Grant, Igor ; Marcotte, Thomas D. ; Neumayer, Shondra ; Capparelli, Edmund ; Atkinson, J. Hampton ; Franklin, Donald ; Wong, Joseph K. ; Ignacio, Caroline ; Jernigan, Terry ; Taylor, Michael J. ; Theilmann, Rebecca ; Gamst, Anthony C. ; Cushman, Clint ; Frybarger, Michelle ; Abramson, Ian ; Lazzaretto, Deborah ; Von Jaeger, Rodney ; Al-Lozi, Muhammad. / The role of cohort studies in drug development : Clinical evidence of antiviral activity of serotonin reuptake inhibitors and HMG-CoA reductase inhibitors in the central nervous system. In: Journal of NeuroImmune Pharmacology. 2007 ; Vol. 2, No. 1. pp. 120-127.
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title = "The role of cohort studies in drug development: Clinical evidence of antiviral activity of serotonin reuptake inhibitors and HMG-CoA reductase inhibitors in the central nervous system",
abstract = "Background: Effective antiretroviral therapy (ART) has reduced the incidence of HIV-associated neurocognitive impairment (HNCI) but its prevalence remains high. Clinical trials have yet to identify a consistently effective treatment for HNCI, other than ART, but in vitro data support that some drugs approved by the Food and Drug Administration (FDA) for other indications might benefit individuals with HNCI. Some of these drugs, such as serotonin reuptake inhibitors (SRIs) and HMG-CoA reductase inhibitors (statins), may do so by reducing HIV replication in the CNS and are already widely used by HIV-infected individuals. Methods: Six-hundred fifty-eight HIV-infected participants of the CHARTER cohort had a baseline assessment, which included comprehensive neuropsychological (NP) testing and HIV RNA measurements in plasma and cerebrospinal fluid (CSF). Four-hundred sixty-seven (71{\%}) subjects used ART, 195 (30{\%}) used SRIs, and 63 (10{\%}) used statins. Results: SRI users were less likely to have HIV RNA levels in CSF above 50 copies (c)/mL (29 vs. 37{\%} in non-SRI users, OR 0.69, p=0.05). This association was most evident for three of the seven SRIs (citalopram, sertraline, and trazodone, or {"}antiviral{"} SRIs, combined 25 vs. 38{\%} in non-SRI users, OR 0.56, p=0.01) and was strongest in those not taking concomitant ART (61 vs. 83{\%}, OR 0.31, p=0.01). {"}Antiviral{"} SRI users also performed better on NP tests (median global deficit score 0.37 vs. 0.47, p=0.04). Statin users were also less likely to have HIV RNA levels in CSF above 50 c/mL (16 vs. 37{\%}, p<0.001) but, in contrast to SRIs, the association was strongest in those taking ART (2 vs. 18{\%}, p<0.001). Statin use was not associated with better NP performance. Multivariate analyses indicated that the use of {"}antiviral{"} SRIs-but not statins-was associated with undetectable HIV RNA levels in CSF and better NP performance. Conclusions: SRIs may reduce HIV replication in CSF and improve NP performance. This was particularly true for three SRIs-supporting differences in antiviral efficacy between drugs-in individuals who were not taking ART. In contrast, statins were not associated with lower HIV replication in CSF in multivariate analyses and were not associated with better NP performance. These analyses support the value of large observational cohort studies in identifying FDA-approved drugs that may be worth further investigation.",
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TY - JOUR

T1 - The role of cohort studies in drug development

T2 - Clinical evidence of antiviral activity of serotonin reuptake inhibitors and HMG-CoA reductase inhibitors in the central nervous system

AU - Letendre, Scott L.

AU - Marquie-Beck, Jennifer

AU - Ellis, Ronald J.

AU - Woods, Steven Paul

AU - Best, Brookie

AU - Clifford, David B.

AU - Collier, Ann C.

AU - Gelman, Benjamin

AU - Marra, Christina

AU - McArthur, Justin C.

AU - McCutchan, J. Allen

AU - Morgello, Susan

AU - Simpson, David

AU - Alexander, Terry J.

AU - Durelle, Janis

AU - Heaton, Robert

AU - Grant, Igor

AU - Marcotte, Thomas D.

AU - Neumayer, Shondra

AU - Capparelli, Edmund

AU - Atkinson, J. Hampton

AU - Franklin, Donald

AU - Wong, Joseph K.

AU - Ignacio, Caroline

AU - Jernigan, Terry

AU - Taylor, Michael J.

AU - Theilmann, Rebecca

AU - Gamst, Anthony C.

AU - Cushman, Clint

AU - Frybarger, Michelle

AU - Abramson, Ian

AU - Lazzaretto, Deborah

AU - Von Jaeger, Rodney

AU - Al-Lozi, Muhammad

PY - 2007/3

Y1 - 2007/3

N2 - Background: Effective antiretroviral therapy (ART) has reduced the incidence of HIV-associated neurocognitive impairment (HNCI) but its prevalence remains high. Clinical trials have yet to identify a consistently effective treatment for HNCI, other than ART, but in vitro data support that some drugs approved by the Food and Drug Administration (FDA) for other indications might benefit individuals with HNCI. Some of these drugs, such as serotonin reuptake inhibitors (SRIs) and HMG-CoA reductase inhibitors (statins), may do so by reducing HIV replication in the CNS and are already widely used by HIV-infected individuals. Methods: Six-hundred fifty-eight HIV-infected participants of the CHARTER cohort had a baseline assessment, which included comprehensive neuropsychological (NP) testing and HIV RNA measurements in plasma and cerebrospinal fluid (CSF). Four-hundred sixty-seven (71%) subjects used ART, 195 (30%) used SRIs, and 63 (10%) used statins. Results: SRI users were less likely to have HIV RNA levels in CSF above 50 copies (c)/mL (29 vs. 37% in non-SRI users, OR 0.69, p=0.05). This association was most evident for three of the seven SRIs (citalopram, sertraline, and trazodone, or "antiviral" SRIs, combined 25 vs. 38% in non-SRI users, OR 0.56, p=0.01) and was strongest in those not taking concomitant ART (61 vs. 83%, OR 0.31, p=0.01). "Antiviral" SRI users also performed better on NP tests (median global deficit score 0.37 vs. 0.47, p=0.04). Statin users were also less likely to have HIV RNA levels in CSF above 50 c/mL (16 vs. 37%, p<0.001) but, in contrast to SRIs, the association was strongest in those taking ART (2 vs. 18%, p<0.001). Statin use was not associated with better NP performance. Multivariate analyses indicated that the use of "antiviral" SRIs-but not statins-was associated with undetectable HIV RNA levels in CSF and better NP performance. Conclusions: SRIs may reduce HIV replication in CSF and improve NP performance. This was particularly true for three SRIs-supporting differences in antiviral efficacy between drugs-in individuals who were not taking ART. In contrast, statins were not associated with lower HIV replication in CSF in multivariate analyses and were not associated with better NP performance. These analyses support the value of large observational cohort studies in identifying FDA-approved drugs that may be worth further investigation.

AB - Background: Effective antiretroviral therapy (ART) has reduced the incidence of HIV-associated neurocognitive impairment (HNCI) but its prevalence remains high. Clinical trials have yet to identify a consistently effective treatment for HNCI, other than ART, but in vitro data support that some drugs approved by the Food and Drug Administration (FDA) for other indications might benefit individuals with HNCI. Some of these drugs, such as serotonin reuptake inhibitors (SRIs) and HMG-CoA reductase inhibitors (statins), may do so by reducing HIV replication in the CNS and are already widely used by HIV-infected individuals. Methods: Six-hundred fifty-eight HIV-infected participants of the CHARTER cohort had a baseline assessment, which included comprehensive neuropsychological (NP) testing and HIV RNA measurements in plasma and cerebrospinal fluid (CSF). Four-hundred sixty-seven (71%) subjects used ART, 195 (30%) used SRIs, and 63 (10%) used statins. Results: SRI users were less likely to have HIV RNA levels in CSF above 50 copies (c)/mL (29 vs. 37% in non-SRI users, OR 0.69, p=0.05). This association was most evident for three of the seven SRIs (citalopram, sertraline, and trazodone, or "antiviral" SRIs, combined 25 vs. 38% in non-SRI users, OR 0.56, p=0.01) and was strongest in those not taking concomitant ART (61 vs. 83%, OR 0.31, p=0.01). "Antiviral" SRI users also performed better on NP tests (median global deficit score 0.37 vs. 0.47, p=0.04). Statin users were also less likely to have HIV RNA levels in CSF above 50 c/mL (16 vs. 37%, p<0.001) but, in contrast to SRIs, the association was strongest in those taking ART (2 vs. 18%, p<0.001). Statin use was not associated with better NP performance. Multivariate analyses indicated that the use of "antiviral" SRIs-but not statins-was associated with undetectable HIV RNA levels in CSF and better NP performance. Conclusions: SRIs may reduce HIV replication in CSF and improve NP performance. This was particularly true for three SRIs-supporting differences in antiviral efficacy between drugs-in individuals who were not taking ART. In contrast, statins were not associated with lower HIV replication in CSF in multivariate analyses and were not associated with better NP performance. These analyses support the value of large observational cohort studies in identifying FDA-approved drugs that may be worth further investigation.

KW - Cerebrospinal fluid

KW - HIV

KW - Serotonin reuptake inhibitors

KW - Statins

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