Epidermal nerve fiber density, oxidative stress, and mitochondrial haplogroups in HIV-infected Thais initiating therapy.
OBJECTIVE
We explored associations between mitochondrial DNA (mtDNA) haplogroups, epidermal nerve fiber density (ENFD), and HIV-associated sensory neuropathy (HIV-SN) in a randomized trial of Thai patients initiating antiretroviral therapy (ART).


METHODS
The South East Asia Research Collaboration with Hawaii 003 study evaluated toxicity of nucleoside reverse transcriptase inhibitors (stavudine vs. zidovudine vs. tenofovir). We present secondary analyses of mtDNA haplogroups and ENFD changes.


METHODS
ENFD, peripheral blood mononuclear cell mitochondrial complex I and IV, and 8-oxo-deoxyguanine (8-oxo-dG) were quantified. Peripheral blood mononuclear cell mtDNA sequences were obtained for haplogroup determination. Multivariate regression of ENFD change was performed.


RESULTS
Paired ENFD was available from 118 patients. Median age, CD4 cell count, and height at entry were 34 years, 172 cells/μl, and 162 cm, respectively. Major haplogroups included M (42%), F (21%), and B (16%). Baseline ENFD, CD4 cell count, randomized ART, and biomarkers did not differ by haplogroup. Haplogroup B patients were older (P=0.02) at baseline, and had an increase in median ENFD (+1.5 vs. -2.9 fibers/mm; P=0.03) and 8-oxo-dG break frequency (+0.05 vs. 0.00; P=0.05) compared to other haplogroups. In a multivariate model, haplogroup B was associated with increased ENFD (β=3.5, P=0.009) at week 24, whereas older age (P=0.02), higher baseline CD4 cell count, (P=0.03), higher complex I level (P=0.03), and higher ENFD (P<0.001) at baseline were all associated with decreased ENFD. Three of the six HIV-SN cases were haplogroup B (P=0.05).


CONCLUSIONS
Thai persons belonging to mtDNA haplogroup B had increased ENFD and 8-oxo-dG on ART, and were more likely to develop HIV-SN. These results suggest that mtDNA variation influences early oxidative damage and ENFD changes.
aVanderbilt University, Nashville, Tennessee bUniversity of Hawaii, Honolulu, Hawaii, USA cSouth East Asia Research Collaboration with Hawaii dThai Red Cross AIDS Research Centre eHIV-NAT, Bangkok fQueen Savang Vadhana Memorial Hospital, Chonburi, Thailand gThe Johns Hopkins University, Baltimore, Maryland, USA.
Todd
T
Hulgan
Rebecca T
RT
Levinson
Mariana
M
Gerschenson
Nittaya
N
Phanuphak
Jintanat
J
Ananworanich
Nipat
N
Teeratakulpisarm
Tanate
T
Jadwattanakul
Daniel E
DE
LiButti
Heidi
H
Fink
Justin C
JC
McArthur
Gigi J
GJ
Ebenezer
Peter
P
Hauer
Deborah
D
Murdock
Cecilia M
CM
Shikuma
David C
DC
Samuels
D000328:Adult; D000818:Animals; D044466:Asian People; D004817:Epidermis / Q000473:pathology*; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics*; D009412:Nerve Fibers / Q000473:pathology*; D009422:Nervous System Diseases / Q000453:epidemiology* / Q000473:pathology; D018384:Oxidative Stress