Effect of Valganciclovir on Endothelial Function in HIV Pts

Priscilla Y. Hsue, UC San Francisco
2006

Cardiovascular disease remains the underlying cause of death in 1 of every 2.7 people in the
U.S. and California; the HIV-infected population in California continues to increase and live longer, making atherosclerosis an important health concern for patients with HIV. In addition, recent studies suggest that HIV-infected patients are at increased risk for cardiovascular events.
The mechanism accounting for this increased risk remains unclear. In patients without HIV, inflammation and T cell activation are important components in the development of atherosclerotic lesions. Preliminary studies from our group have shown that CMV-specific T cell responses in patients with HIV infection are independently associated with a carotid IMT, which is a marker for atherosclerosis.

We propose to conduct a pilot study in HIV-infected individuals to determine if anti-CMV therapy, valganciclovir, is associated with changes in endothelial function and levels of circulating endothelial progenitor cells, both of which are noninvasive assays highly predictive of cardiovascular outcomes. These assays were chosen because prior studies show that they can change rapidly with treatment. This study will be performed in conjunction with an already IRB-approved randomized, placebo-controlled trial at UCSF. The purpose of the parent study is to assess whether treatment with valganciclovir will reduce T cell activation levels among HIV and CMV-infected patients treated with HAART with sub-optimal responses to antiretroviral therapy. Thirty patients will be randomized in a 1:1 ratio to receive either valganciclovir or placebo for 8 weeks. The parent study will measure T cell activation, HIV viral load, CD4 count, and CMV-specific flow cytometry for 12 weeks (8 weeks on treatment, followed by 4 weeks off treatment).

Our proposal has 2 specific aims:

  • Aim 1: To determine whether treatment with valganciclovir results in improved endothelial function.
  • Aim 2: To determine whether treatment with valganciclovir will result in higher levels of circulating endothelial progenitor cells.

Endothelial function will be determined by using high-resolution ultrasound to measure flow-mediated dilation (FMD) of the brachial artery before and after administration of nitroglycerin. Endothelial progenitor cells will be measured using flow cytometry on whole blood using fluorescent conjugated antibody CD34-fluorescein isothiocyanate, KDR, and CD133-phycoerthrin. The primary outcome will be change in FMD from baseline to week 8 between treatment groups for Aim 1, and for Aim 2, change in levels of circulating endothelial progenitor cells from baseline to week 8 between treatment groups. We hypothesize that valganciclovir therapy will be associated with improved endothelial function as assessed by measuring FMD and higher levels of circulating endothelial progenitor cells. If this pilot study shows improvement in endothelial function and increased levels of endothelial progenitor cells, these findings would support the earlier use of antiretroviral treatment, since HIV therapy in general reduces HIV-associated inflammation. In addition, this pilot study would prompt future studies aimed at determining if anti-CMV treatment would be a useful adjunct for HIV-infected patients at high risk for atherosclerosis.