Abstract

To define the direct toxicities of antiretroviral drugs (ARV) and separate those changes from their effects on HIV infection, we gave single ARV to healthy volunteers and compared results to studies in HIV infected patients on those ARV. We now propose to resolve controversies with currently used ARV. 1) The mechanism(s) by which ritonavir increases triglycerides is unknown, but have significant implications for atherosclerosis. Hypothesis 1: Ritonavir-based regimens increase triglycerides and VLDL by both increasing VLDL production and decreasing VLDL clearance.
Specific Aim 1 A: To quantify the effect of ritonavir on VLDL production and clearance using stable isotope turnover and other clearance methods.
Specific Aim 2 B: To determine the composition of the triglyceride rich particles 2) NNRTI increase HDL cholesterol, but the mechanism is unknown and NNRTI may not generate HDL particles that have strong anti-atherogenic effects. Hypothesis 2: NNRTI drugs do not increase HDL by increasing apo AI production, but by decreasing apo AI clearance, prolonging time in circulation and producing particles with limited anti-atherogenic properties.
Specific Aim 2 A: To determine the composition of HDL before and after NNRTI and assess its function.
Specific Aim 2 B: To quantify the effect of NNRTI on apo AI production & clearance using stable isotopes.
Specific Aim 2 C: To determine if the efavirenz induced increase in HDL is accompanied by improvement in flow mediated vasodilation and circulating markers of endothelial function 3) The effects of PI on glucose metabolism cannot be solely explained by their effects on insulin resistance. PIs may impair insulin secretion, which has important implications for design of safer PI. Hypothesis 3: Ritonavir-based PIs impair insulin secretion.
Specific Aim 3 : To determine which ritonavir-based PI regimens alter insulin secretion. The results from these studies will define the direct toxicities of ARV, which provide essential information for rationally evaluating treatment strategies and counseling patients.Carl Grunfeld, MD, PhD. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK066999-05
Application #
7419141
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Pawlyk, Aaron
Project Start
2004-03-01
Project End
2012-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
5
Fiscal Year
2008
Total Cost
$362,480
Indirect Cost

  Institution

Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121

  Publications

Rao, Madhu N; Mulligan, Kathleen; Tai, Viva et al. (2010) Effects of insulin-like growth factor (IGF)-I/IGF-binding protein-3 treatment on glucose metabolism and fat distribution in human immunodeficiency virus-infected patients with abdominal obesity and insulin resistance. J Clin Endocrinol Metab 95:4361-6
Grunfeld, Carl (2010) Dyslipidemia and its Treatment in HIV Infection. Top HIV Med 18:112-8
Pao, Vivian Y; Lee, Grace A; Taylor, Steven et al. (2010) The protease inhibitor combination lopinavir/ritonavir does not decrease insulin secretion in healthy, HIV-seronegative volunteers. AIDS 24:265-70
Delaney, Joseph A C; Scherzer, Rebecca; Biggs, Mary L et al. (2010) Associations of antiretroviral drug use and HIV-specific risk factors with carotid intima-media thickness. AIDS 24:2201-9
Taylor, Steven A; Lee, Grace A; Pao, Vivian Y et al. (2010) Boosting dose ritonavir does not alter peripheral insulin sensitivity in healthy HIV-seronegative volunteers. J Acquir Immune Defic Syndr 55:361-4
Lee, Grace A; Schwarz, Jean-Marc; Patzek, Sophie et al. (2009) The acute effects of HIV protease inhibitors on insulin suppression of glucose production in healthy HIV-negative men. J Acquir Immune Defic Syndr 52:246-8
Mulligan, Kathleen; Khatami, Hootan; Schwarz, Jean-Marc et al. (2009) The effects of recombinant human leptin on visceral fat, dyslipidemia, and insulin resistance in patients with human immunodeficiency virus-associated lipoatrophy and hypoleptinemia. J Clin Endocrinol Metab 94:1137-44
Pao, Vivian; Lee, Grace A; Grunfeld, Carl (2008) HIV therapy, metabolic syndrome, and cardiovascular risk. Curr Atheroscler Rep 10:61-70
Lee, Grace A; Rao, Madhu; Mulligan, Kathleen et al. (2007) Effects of ritonavir and amprenavir on insulin sensitivity in healthy volunteers. AIDS 21:2183-90
Lee, Grace A; Lo, Joan C; Aweeka, Francesca et al. (2006) Single-dose lopinavir-ritonavir acutely inhibits insulin-mediated glucose disposal in healthy volunteers. Clin Infect Dis 43:658-60

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