Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy.
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.


CONCLUSIONS
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.
Ellis
Ronald J
RJ
University of California, San Diego, San Diego, CA, USA. roellis@ucsd.edu
Marquie-Beck
Jennifer
J
Delaney
Patrick
P
Alexander
Terry
T
Clifford
David B
DB
McArthur
Justin C
JC
Simpson
David M
DM
Ake
Christopher
C
Collier
Ann C
AC
Gelman
Benjamin B
BB
McCutchan
J Allen
JA
Morgello
Susan
S
Grant
Igor
I
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000201:enzymology / Q000821:virology; D000328:Adult; D000367:Age Factors; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D018791:CD4 Lymphocyte Count; D003430:Cross-Sectional Studies; D005260:Female; D017320:HIV Protease Inhibitors / Q000009:adverse effects*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010525:Peripheral Nerves / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000453:epidemiology*; D011446:Prospective Studies; D012307:Risk Factors; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000473:pathology; D019562:Viral Load
D017320:HIV Protease Inhibitors