Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy

Ronald J. Ellis, Jennifer Marquie-Beck, Patrick Delaney, Terry Alexander, David B. Clifford, Justin C. McArthur, David M. Simpson, Christopher Ake, Ann C. Collier, Benjamin Gelman, J. Allen McCutchan, Susan Morgello, Igor Grant, Thomas D. Marcotte, Donald Franklin, Scott Letendre, Edmund Capparelli, Janis Durelle, Robert K. Heaton, J. Hampton Atkinson & 24 others Steven Paul Woods, Matthew Dawson, Joseph K. Wong, Terry Jernigan, Michael J. Taylor, Rebecca Theilmann, Anthony C. Gamst, Clint Cushman, Ian Abramson, Florin Vaida, Rodney Von Jaeger, Justin McArthur, Gilbert Mbeo, David Simpson, Letty Mintz, Susan Ueland, Ann Collier, Christina Marra, Trudy Jones, Benjamin Gelman, Eleanor Heckendorn, David Clifford, Muhammad Al-Lozi, Mengesha Teshome

Research output: Contribution to journalArticle

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Abstract

Objective: Two recent analyses found that exposure to protease inhibitors (PIs) in the context of antiretroviral (ARV) therapy increased the risk for distal sensory polyneuropathy (DSPN) in subjects with human immunodeficiency virus (HIV) infection. These findings were supported by an in vitro model in which PI exposure produced neurite retraction and process loss in dorsal root ganglion sensory neurons. Confirmation of peripheral nerve toxicity with PIs could substantially limit their long-term use in highly active ARV therapy. Methods: We evaluated current and past exposure to PIs as a risk factor for DSPN in 1,159 HIV-infected individuals enrolled in a large, prospective, observational, multicenter study. Signs of DSPN were ascertained by neurological examination. Subjects were grouped into categories according to past and current exposure to any ARV and to PIs. We included disease indicators such as nadir CD4, plasma viral load, and duration of HIV infection, as well as advancing age and exposure to dideoxynucleoside ARVs in multivariate models. Results: In univariate analyses, both past and current PI exposure significantly increased the risk for DSPN. However, after adjusting for previously validated concomitant risk factors in multivariate models, none of the PI exposure groups was more likely to have DSPN than ARV naive subjects. A secondary evaluation of duration of PI use and exposure to individual PI drugs was similarly nonsignificant in multivariate models, except for small effects of amprenavir and lopinavir. Interpretation: Evaluation of concomitant risks for HIV DSPN suggests that the independent risk attributable to PIs, if any, is small. This risk must be weighed against the important role of PIs in modern ARV therapy regimens.

Original languageEnglish (US)
Pages (from-to)566-572
Number of pages7
JournalAnnals of Neurology
Volume64
Issue number5
DOIs
StatePublished - Nov 2008

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Peripheral Nervous System Diseases
Protease Inhibitors
HIV
Polyneuropathies
Virus Diseases
Dideoxynucleosides
Lopinavir
Highly Active Antiretroviral Therapy
Neurologic Examination
Spinal Ganglia
Sensory Receptor Cells
Neurites
Viral Load
Peripheral Nerves
Multicenter Studies
Observational Studies
HIV-1

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Ellis, R. J., Marquie-Beck, J., Delaney, P., Alexander, T., Clifford, D. B., McArthur, J. C., ... Teshome, M. (2008). Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy. Annals of Neurology, 64(5), 566-572. https://doi.org/10.1002/ana.21484

Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy. / Ellis, Ronald J.; Marquie-Beck, Jennifer; Delaney, Patrick; Alexander, Terry; Clifford, David B.; McArthur, Justin C.; Simpson, David M.; Ake, Christopher; Collier, Ann C.; Gelman, Benjamin; McCutchan, J. Allen; Morgello, Susan; Grant, Igor; Marcotte, Thomas D.; Franklin, Donald; Letendre, Scott; Capparelli, Edmund; Durelle, Janis; Heaton, Robert K.; Atkinson, J. Hampton; Woods, Steven Paul; Dawson, Matthew; Wong, Joseph K.; Jernigan, Terry; Taylor, Michael J.; Theilmann, Rebecca; Gamst, Anthony C.; Cushman, Clint; Abramson, Ian; Vaida, Florin; Von Jaeger, Rodney; McArthur, Justin; Mbeo, Gilbert; Simpson, David; Mintz, Letty; Ueland, Susan; Collier, Ann; Marra, Christina; Jones, Trudy; Gelman, Benjamin; Heckendorn, Eleanor; Clifford, David; Al-Lozi, Muhammad; Teshome, Mengesha.

In: Annals of Neurology, Vol. 64, No. 5, 11.2008, p. 566-572.

Research output: Contribution to journalArticle

Ellis, RJ, Marquie-Beck, J, Delaney, P, Alexander, T, Clifford, DB, McArthur, JC, Simpson, DM, Ake, C, Collier, AC, Gelman, B, McCutchan, JA, Morgello, S, Grant, I, Marcotte, TD, Franklin, D, Letendre, S, Capparelli, E, Durelle, J, Heaton, RK, Atkinson, JH, Woods, SP, Dawson, M, Wong, JK, Jernigan, T, Taylor, MJ, Theilmann, R, Gamst, AC, Cushman, C, Abramson, I, Vaida, F, Von Jaeger, R, McArthur, J, Mbeo, G, Simpson, D, Mintz, L, Ueland, S, Collier, A, Marra, C, Jones, T, Gelman, B, Heckendorn, E, Clifford, D, Al-Lozi, M & Teshome, M 2008, 'Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy', Annals of Neurology, vol. 64, no. 5, pp. 566-572. https://doi.org/10.1002/ana.21484
Ellis RJ, Marquie-Beck J, Delaney P, Alexander T, Clifford DB, McArthur JC et al. Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy. Annals of Neurology. 2008 Nov;64(5):566-572. https://doi.org/10.1002/ana.21484
Ellis, Ronald J. ; Marquie-Beck, Jennifer ; Delaney, Patrick ; Alexander, Terry ; Clifford, David B. ; McArthur, Justin C. ; Simpson, David M. ; Ake, Christopher ; Collier, Ann C. ; Gelman, Benjamin ; McCutchan, J. Allen ; Morgello, Susan ; Grant, Igor ; Marcotte, Thomas D. ; Franklin, Donald ; Letendre, Scott ; Capparelli, Edmund ; Durelle, Janis ; Heaton, Robert K. ; Atkinson, J. Hampton ; Woods, Steven Paul ; Dawson, Matthew ; Wong, Joseph K. ; Jernigan, Terry ; Taylor, Michael J. ; Theilmann, Rebecca ; Gamst, Anthony C. ; Cushman, Clint ; Abramson, Ian ; Vaida, Florin ; Von Jaeger, Rodney ; McArthur, Justin ; Mbeo, Gilbert ; Simpson, David ; Mintz, Letty ; Ueland, Susan ; Collier, Ann ; Marra, Christina ; Jones, Trudy ; Gelman, Benjamin ; Heckendorn, Eleanor ; Clifford, David ; Al-Lozi, Muhammad ; Teshome, Mengesha. / Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy. In: Annals of Neurology. 2008 ; Vol. 64, No. 5. pp. 566-572.
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abstract = "Objective: Two recent analyses found that exposure to protease inhibitors (PIs) in the context of antiretroviral (ARV) therapy increased the risk for distal sensory polyneuropathy (DSPN) in subjects with human immunodeficiency virus (HIV) infection. These findings were supported by an in vitro model in which PI exposure produced neurite retraction and process loss in dorsal root ganglion sensory neurons. Confirmation of peripheral nerve toxicity with PIs could substantially limit their long-term use in highly active ARV therapy. Methods: We evaluated current and past exposure to PIs as a risk factor for DSPN in 1,159 HIV-infected individuals enrolled in a large, prospective, observational, multicenter study. Signs of DSPN were ascertained by neurological examination. Subjects were grouped into categories according to past and current exposure to any ARV and to PIs. We included disease indicators such as nadir CD4, plasma viral load, and duration of HIV infection, as well as advancing age and exposure to dideoxynucleoside ARVs in multivariate models. Results: In univariate analyses, both past and current PI exposure significantly increased the risk for DSPN. However, after adjusting for previously validated concomitant risk factors in multivariate models, none of the PI exposure groups was more likely to have DSPN than ARV naive subjects. A secondary evaluation of duration of PI use and exposure to individual PI drugs was similarly nonsignificant in multivariate models, except for small effects of amprenavir and lopinavir. Interpretation: Evaluation of concomitant risks for HIV DSPN suggests that the independent risk attributable to PIs, if any, is small. This risk must be weighed against the important role of PIs in modern ARV therapy regimens.",
author = "Ellis, {Ronald J.} and Jennifer Marquie-Beck and Patrick Delaney and Terry Alexander and Clifford, {David B.} and McArthur, {Justin C.} and Simpson, {David M.} and Christopher Ake and Collier, {Ann C.} and Benjamin Gelman and McCutchan, {J. Allen} and Susan Morgello and Igor Grant and Marcotte, {Thomas D.} and Donald Franklin and Scott Letendre and Edmund Capparelli and Janis Durelle and Heaton, {Robert K.} and Atkinson, {J. Hampton} and Woods, {Steven Paul} and Matthew Dawson and Wong, {Joseph K.} and Terry Jernigan and Taylor, {Michael J.} and Rebecca Theilmann and Gamst, {Anthony C.} and Clint Cushman and Ian Abramson and Florin Vaida and {Von Jaeger}, Rodney and Justin McArthur and Gilbert Mbeo and David Simpson and Letty Mintz and Susan Ueland and Ann Collier and Christina Marra and Trudy Jones and Benjamin Gelman and Eleanor Heckendorn and David Clifford and Muhammad Al-Lozi and Mengesha Teshome",
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T1 - Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy

AU - Ellis, Ronald J.

AU - Marquie-Beck, Jennifer

AU - Delaney, Patrick

AU - Alexander, Terry

AU - Clifford, David B.

AU - McArthur, Justin C.

AU - Simpson, David M.

AU - Ake, Christopher

AU - Collier, Ann C.

AU - Gelman, Benjamin

AU - McCutchan, J. Allen

AU - Morgello, Susan

AU - Grant, Igor

AU - Marcotte, Thomas D.

AU - Franklin, Donald

AU - Letendre, Scott

AU - Capparelli, Edmund

AU - Durelle, Janis

AU - Heaton, Robert K.

AU - Atkinson, J. Hampton

AU - Woods, Steven Paul

AU - Dawson, Matthew

AU - Wong, Joseph K.

AU - Jernigan, Terry

AU - Taylor, Michael J.

AU - Theilmann, Rebecca

AU - Gamst, Anthony C.

AU - Cushman, Clint

AU - Abramson, Ian

AU - Vaida, Florin

AU - Von Jaeger, Rodney

AU - McArthur, Justin

AU - Mbeo, Gilbert

AU - Simpson, David

AU - Mintz, Letty

AU - Ueland, Susan

AU - Collier, Ann

AU - Marra, Christina

AU - Jones, Trudy

AU - Gelman, Benjamin

AU - Heckendorn, Eleanor

AU - Clifford, David

AU - Al-Lozi, Muhammad

AU - Teshome, Mengesha

PY - 2008/11

Y1 - 2008/11

N2 - Objective: Two recent analyses found that exposure to protease inhibitors (PIs) in the context of antiretroviral (ARV) therapy increased the risk for distal sensory polyneuropathy (DSPN) in subjects with human immunodeficiency virus (HIV) infection. These findings were supported by an in vitro model in which PI exposure produced neurite retraction and process loss in dorsal root ganglion sensory neurons. Confirmation of peripheral nerve toxicity with PIs could substantially limit their long-term use in highly active ARV therapy. Methods: We evaluated current and past exposure to PIs as a risk factor for DSPN in 1,159 HIV-infected individuals enrolled in a large, prospective, observational, multicenter study. Signs of DSPN were ascertained by neurological examination. Subjects were grouped into categories according to past and current exposure to any ARV and to PIs. We included disease indicators such as nadir CD4, plasma viral load, and duration of HIV infection, as well as advancing age and exposure to dideoxynucleoside ARVs in multivariate models. Results: In univariate analyses, both past and current PI exposure significantly increased the risk for DSPN. However, after adjusting for previously validated concomitant risk factors in multivariate models, none of the PI exposure groups was more likely to have DSPN than ARV naive subjects. A secondary evaluation of duration of PI use and exposure to individual PI drugs was similarly nonsignificant in multivariate models, except for small effects of amprenavir and lopinavir. Interpretation: Evaluation of concomitant risks for HIV DSPN suggests that the independent risk attributable to PIs, if any, is small. This risk must be weighed against the important role of PIs in modern ARV therapy regimens.

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