Rates of HIV-associated sensory neuropathies (HIV-SN) remain high despite the introduction of highly active antiretroviral therapy (HAART). While both HIV and its inflammatory responses as well as toxic effects of antiretroviral therapy are believed to be important etiologic factors, how these two factors affect the pathogenic mechanisms underlying HIV-SN in individuals initiating HAART;how the pathogenesis and interactions may be altered by stavudine (d4T), a neuropathic anitretroviral (ARV) medication;and whether irreparable damage to the nerves can occur with even short-term use of d4T is not well defined. The issue of d4T-induced neuropathy is of particular concern in developing countries where d4T is heavily used. Our program, through our collaborative coordinating center SEARCH (South East Asia Research Collaboration with Hawaii), intends to launch a 150 n, 72 week, clinical trial (SEARCH 003) to assess the relative toxicities of short-term d4T + lamivudine [3TC] (24 week) followed by zidovudine [ZDV] + 3TC (n=50) compared to continuous ZDV + 3TC (n=50) or tenofovir (TDF) + emtricitabine (FTC) (n=50), all given with nevirapine (NVP) in ARV-naive subjects in Bangkok, Thailand. Within the framework of this trial, we propose to evaluate the impact of HAART on serial (baseline, week 24 and week 72) measurements of epidermal nerve fiber density (ENFD), a likely pathologic correlate of HIV-SN. We will assess whether improvement in ENFD typically occurs with the expected HAART-induced improvement in immuno-virologic parameters, how this is altered by the use of d4T, and whether low baseline or differential changes in ENFD predict the development of HIV-SN in individuals initiated on HAART. To assess the pathogenesis involved in its development, we will assess the relationship of neuropathy/ENFD to fat and PBMC mitochondrial (mt) /mt-specific oxidative stress parameters (mtDNA, oxidative phosphorylation Complex I and IV, mt-specific 8-oxodeoxyguanine) and to intracellular levels of d4T triphosphates. We will also assess its relationship to levels of HIV DNA within the CD14+ sub-fraction of PBMCs which we hypothesize represent HIV-infected M/M7s responsible for the inflammation surrounding peripheral nerves. Finally, we will assess how individual mitochondrial genomic variations influence the development of HIV-SN. This research will help to increase our understanding of how HIV-SN develops and potentially lead to effective preventive/ therapeutic modalities.

Public Health Relevance

This proposal will study whether low baseline peripheral nerve fiber density (the nerves responsible for pain in the extremities) will predict the development of neuropathy (pain in the extremities) and whether HIV-infected subjects on antiretroviral therapy will have different effects on their nerve fiber densities. We will also study the role of mitochondria (a source of energy for the cell) and HIV in the development of neuropathy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-AARR-G (03))
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Wong, May
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University of Hawaii
Internal Medicine/Medicine
Schools of Medicine
United States
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Shikuma, Cecilia M; Bennett, Kara; Ananworanich, Jintanat et al. (2015) Distal leg epidermal nerve fiber density as a surrogate marker of HIV-associated sensory neuropathy risk: risk factors and change following initial antiretroviral therapy. J Neurovirol 21:525-34
Hulgan, Todd; Levinson, Rebecca T; Gerschenson, Mariana et al. (2014) Epidermal nerve fiber density, oxidative stress, and mitochondrial haplogroups in HIV-infected Thais initiating therapy. AIDS 28:1625-33
Shikuma, Cecilia M; McArthur, Justin C; Ebenezer, Gigi J et al. (2013) Ethnic differences in epidermal nerve fiber density. Muscle Nerve 48:462-4
Phanuphak, Nittaya; Ananworanich, Jintanat; Teeratakulpisarn, Nipat et al. (2012) A 72-week randomized study of the safety and efficacy of a stavudine to zidovudine switch at 24 weeks compared to zidovudine or tenofovir disoproxil fumarate when given with lamivudine and nevirapine. Antivir Ther 17:1521-31
Shikuma, Cm; Gerschenson, M; Ananworanich, J et al. (2012) Determinants of epidermal nerve fibre density in antiretroviral-naïve HIV-infected individuals. HIV Med 13:602-8
Nakamoto, Beau K; McMurtray, Aaron; Davis, James et al. (2010) Incident neuropathy in HIV-infected patients on HAART. AIDS Res Hum Retroviruses 26:759-65