title: Distal leg epidermal nerve fiber density as a surrogate marker of HIV-associated sensory neuropathy risk: risk factors and change following initial antiretroviral therapy.
abstract: Distal leg epidermal nerve fiber density (ENFD) is a validated predictor of HIV sensory neuropathy (SN) risk. We assessed how ENFD is impacted by initiation of first-time antiretroviral therapy (ART) in subjects free of neuropathy and how it is altered when mitochondrial toxic nucleoside medications are used as part of ART. Serial changes in proximal thigh and distal leg ENFD were examined over 72 weeks in 150 Thai subjects randomized to a regimen of stavudine (d4T) switching to zidovudine (ZDV) at 24 weeks vs ZDV vs tenofovir (TDF) for the entire duration of study, all given in combination with nevirapine. We found individual variations in ENFD change, with almost equal number of subjects who decreased or increased their distal leg ENFD over 72 weeks and no relationship to nucleoside backbone or to development of neuropathic signs or symptoms. Lower baseline distal leg ENFD and greater increases in mitochondrial oxidative phosphorylation complex I (CI) activity were associated with larger increases in distal leg ENFD over 72 weeks. Distal leg ENFD correlated with body composition parameters (body surface area, body mass index, height) as well as with blood pressure measurements. Assessed together with a companion cross-sectional study, we found that mean distal leg ENFD in all HIV+ subjects was lower than in HIV- subjects but similar among HIV+ groups whether ART-naïve or on d4T with/without neuropathy/neuropathic symptoms. The utility of ENFD as a useful predictor of small unmyelinated nerve fiber damage and neuropathy risk in HIV may be limited in certain populations.
authors.affiliation: University of Hawaii, Honolulu, HI, USA. shikuma@hawaii.edu.|South East Asia Research Collaboration with Hawaii, Bangkok, Thailand. shikuma@hawaii.edu.|Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii at Manoa, 651 Ilalo St. BSB Suite 231, Honolulu, HI, 96813, USA. shikuma@hawaii.edu.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Shikuma
authors.affiliation: Bennett Statistical Consulting, Inc, Ballston Lake, NY, USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Bennett
authors.affiliation: South East Asia Research Collaboration with Hawaii, Bangkok, Thailand.|US Military HIV Research Program, Walter Reed Army Institute of Research and Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
authors.forename: Jintanat
authors.initials: J
authors.lastname: Ananworanich
authors.affiliation: University of Hawaii, Honolulu, HI, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Gerschenson
authors.affiliation: The Thai Red Cross AIDS Research Center, Bangkok, Thailand.
authors.forename: Nipat
authors.initials: N
authors.lastname: Teeratakulpisarn
authors.affiliation: Queen Savang Vadhana Memorial Hospital, Chonburi, Thailand.
authors.forename: Tanate
authors.initials: T
authors.lastname: Jadwattanakul
authors.affiliation: Harvard School of Public Health, Boston, MA, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: DeGruttola
authors.affiliation: Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Justin C
authors.initials: JC
authors.lastname: McArthur
authors.affiliation: Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Gigi
authors.initials: G
authors.lastname: Ebenezer
authors.affiliation: South East Asia Research Collaboration with Hawaii, Bangkok, Thailand.
authors.forename: Nitiya
authors.initials: N
authors.lastname: Chomchey
authors.affiliation: South East Asia Research Collaboration with Hawaii, Bangkok, Thailand.
authors.forename: Pairoa
authors.initials: P
authors.lastname: Praihirunkit
authors.affiliation: The Thai Red Cross AIDS Research Center, Bangkok, Thailand.
authors.forename: Piranun
authors.initials: P
authors.lastname: Hongchookiat
authors.affiliation: Queen Savang Vadhana Memorial Hospital, Chonburi, Thailand.
authors.forename: Pornpen
authors.initials: P
authors.lastname: Mathajittiphun
authors.affiliation: University of Hawaii, Honolulu, HI, USA.|Straub Medical Center, Honolulu, HI, USA.
authors.forename: Beau
authors.initials: B
authors.lastname: Nakamoto
authors.affiliation: Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Hauer
authors.affiliation: South East Asia Research Collaboration with Hawaii, Bangkok, Thailand.|The Thai Red Cross AIDS Research Center, Bangkok, Thailand.
authors.forename: Praphan
authors.initials: P
authors.lastname: Phanuphak
authors.affiliation: South East Asia Research Collaboration with Hawaii, Bangkok, Thailand.|The Thai Red Cross AIDS Research Center, Bangkok, Thailand.
authors.forename: Nittaya
authors.initials: N
authors.lastname: Phanuphak
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000009:adverse effects*; D003430:Cross-Sectional Studies; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D007866:Leg; D008297:Male; D010523:Peripheral Nervous System Diseases / Q000209:etiology* / Q000473:pathology*; D012307:Risk Factors; D011984:Sensory Receptor Cells / Q000473:pathology*; D012867:Skin / Q000294:innervation; D018119:Stavudine / Q000009:adverse effects; D000068698:Tenofovir / Q000009:adverse effects; D013785:Thailand; D015215:Zidovudine / Q000009:adverse effects
chemical_list: D044966:Anti-Retroviral Agents; D015215:Zidovudine; D000068698:Tenofovir; D018119:Stavudine
keywords: Epidermal nerve fiber density; HIV; Neuropathy; Stavudine