Pentoxifylline May Improve Endothelial Dysfunction in People with HIV

		SUMMARY: The anti-inflammatory dug pentoxifylline improved blood flow and reduced levels of 2 blood biomarkers associated with inflammation and endothelial dysfunction in untreated people with HIV in a small pilot study described in a research letter in the June 1, 2010 issue of AIDS. These findings suggest that reducing inflammation may help lower the risk of atherosclerosis, which can lead to heart attacks.

By Liz Highleyman

pentoxifylline (Trental)

Observational studies have found that people with HIV have a higher risk of cardiovascular disease compared with the general population. The reason for this is not fully understood, but inflammation and metabolic changes related to antiretroviral drugs appear to play a role.

Inflammation is a key feature of atherosclerosis, or "hardening of the arteries," a progressive condition in which arteries lose their elasticity and become filled with plaques made up of lipids, immune cells, and other material. Eventually this blockage can impair blood flow and pieces of plaque or blood clots can break away and become lodged in vessels supplying the heart (causing a heart attack) or the brain (causing a stroke). Many signaling molecules are involved in this process, some of which can be measured in the blood as biomarkers of inflammation, coagulation (clotting), and endothelial (blood vessel lining) dysfunction.

Samir Gupta from Indiana University School of Medicine and colleagues conducted a small pilot study to assess whether the anti-inflammatory drug pentoxifylline (Trental) could reduce systemic inflammation and improve endothelial function in HIV positive people who did not require antiretroviral therapy (ART).

The SMART study showed that CD4-guided ART interruption was associated with elevated levels of certain inflammation biomarkers and increased risk of heart disease, the study authors noted as background, but this link has not been extensively studied in individuals who have a CD4 cell count high enough that they have not yet started treatment.

The researchers previously found that another anti-inflammatory drug, salsalate, improved endothelial function in untreated HIV positive patients, but caused liver toxicity. Here, they tested pentoxifylline, a drug approved for treatment of impaired peripheral blood flow, that works by blocking tumor necrosis factor-alpha (TNF-alpha) production.

This open-label study included 9 participants (6 men, 3 women) who had CD4 counts above 350 cells/mm3 (median 552 cells/mm3) and were either treatment-naive or had not taken ART for at least 6 months. People with pre-existing cardiovascular disease, diabetes, high blood pressure, use of cholesterol-lowering dugs, or signs of impaired liver or kidney function were excluded. Four were smokers and 2 were coinfected with hepatitis C.

All participants received 400 mg oral pentoxifylline 3 times daily for 8 weeks. Endothelial function was determined by flow-mediated dilation of the brachial artery in the upper arm (a measure of how well blood vessels expand in response to changes in blood flow) and nitroglycerin-mediated dilation.

The researchers also measured levels of several biomarkers of inflammation and endothelial function including soluble vascular cell adhesion molecule-1 (VCAM-1), soluble intercellular adhesion molecule-1 (ICAM-1), and E-selectin -- molecules that enable leukocytes, or immune system white blood cells, to adhere to and move along blood vessel walls -- high sensitivity C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein 1-beta (MIP-1-beta), TNF-alpha, soluble TNF receptor 1 and 2, and interferon-gamma induced protein (IP-10).

Results

	At baseline, flow-mediated dilation was impaired (at 2.1%) compared with healthy HIV negative control subjects.
	7 participants completed the study (the other 2 discontinued because they started ART or steroid treatment for bronchitis).
	Over 8 weeks of treatment, pentoxifylline significantly improved endothelial function:
	Week 4: 1.5% increase; Week 8: 4.4% increase.
	Nitroglycerin-mediated dilation did not change significantly.
	Pentoxifylline significantly reduced circulating levels of soluble VCAM-1 and IP-10, but there were no significant changes in other biomarkers.
	6 patients experienced mild diarrhea that was not treatment-limiting.
	No notable clinical or laboratory or toxicities, including liver abnormalities, were observed.

"Eight weeks of treatment with pentoxifylline safely and significantly improved endothelial function in HIV-infected patients not receiving combination ART," the investigators concluded. "Pentoxifylline may reverse HIV-related endothelial dysfunction by directly inhibiting the endothelial leukocyte adhesion pathway."

Two randomized, placebo-controlled trials are now underway and recruiting participants to investigate the effects of pentoxifylline on endothelial function in HIV patients not requiring ART (ClinicalTrials.gov identifier NCT00796822) and those starting ART (NCT00864916).

Investigator affiliations: Department of Cellular and Integrative Physiology, Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, IN; Section of Cardiology, University of Chicago Medical Center, Chicago, IL; Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN; Division of Infectious Diseases, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA.

7/9/10

Reference
SK Gupta, RM Johnson, KL Mather, and others. Anti-inflammatory treatment with pentoxifylline improves HIV-related endothelial dysfunction: a pilot study. AIDS 4(9): 1377-1380 (Abstract). June 1, 2010.