The Inflammatory Debate: Is it the Virus, the Drugs or the Host?  WEAB01

Oral Abstract Session Back
Venue: SR 11 (1400)
Interpretation: None
Time: 11:00 - 12:30, 06.08.2008
Code: WEAB01
Co-Chairs: Judith Currier, United States
Mauro Schechter, Brazil

Presentations in this session:

Mauro Schechter, Brazil

Whole genome transcriptomic analysis of adipose tissue from patients at distinct stages of progression of HIV-1/HAART-associated lipodystrophy reveals alterations in inflammation and metabolism due to HIV-1 infection before antiretroviral treatment
Presented by Francesc Villarroya, Spain
F. Villarroya1, J.P. Guallar1, P. Domingo2, J.C. Domingo1, M. Alegre3, M. Giralt1
1University of Barcelona. Institut de Biomedicina (IBUB), Biochemistry and Molecular Biology, Barcelona, Spain, 2Hospital de la Santa Creu i Sant Pau, Internal Medicine, Barcelona, Spain, 3Hospital de la Santa Creu i Sant Pau, Dermatology, Barcelona, Spain

Clinical predictors of Tenofovir-associated nephrotoxicity in HIV-1-infected patients
Presented by Chelsea Castellano, United States
C. Castellano1, W. Williams2, T.B. Kepler1, S. Kim1, L. Szczech1, C. Hicks1
1Duke University Medical Center, Durham, United States, 2Ryan White Clinic, Hickory, United Kingdom

A pilot study of urinary markers of endothelial function and oxidant stress for the prediction of cardiovascular disease (CVD) risk with antiretroviral therapy (ART)
Presented by Michael Boger, United States
M. Boger1, G. Milne2, J. Morrow2, H. Erdem3, V. Mitchell3, D. Haas1, T. Hulgan1
1Vanderbilt University School of Medicine, Division of Infectious Diseases, Nashville, United States, 2Vanderbilt University School of Medicine, Clinical Pharmacology, Nashville, United States, 3Vanderbilt-Meharry Center for AIDS Research, Nashville, United States

Is abacavir (ABC)-containing combination antiretroviral therapy (CART) associated with myocardial infarction (MI)? No association identified in pooled summary of 54 clinical trials
Presented by John Pottage, United States
A. Cutrell1, J. Hernandez1, J. Yeo2, C. Brothers1, W. Burkle1, W. Spreen1
1GlaxoSmithKline Research & Development, HIV Medicine Development Center, Research Triangle Park, United States, 2GlaxoSmithKline Research & Development, HIV Medicine Development Center, Greenford, United Kingdom
Jaime Hernandez, United States

The inflammatory debate: is it the drug, the virus or the host?
Judith Currier, United States

Rapporteur report

Track B report by Francois Venter

The inflammatory debate continues, and today very interesting presentations showed that virus, the host or also the drugs are involved in the immunoactivation. We need to understand deeply these phenomena in order to design clinical interventions translatable to the general practice.


In the first presentation Dr Villarroya, from Spain, provided evidence that both, alterations in inflammation and lipid metabolism (expected to see in patient lipodystrophy) are present in naïve patients and treated individuals without this syndrome. Analysis of adipose tissue RNA whit whole-genome expression from revelled that the adipose tissue from HIV-1-infected naïve patients has alterations in the gene expression evidenced by induction of a pro-inflammatory status and signs of impaired adipogenesis such as the alterations of carbohydrate and fatty acid metabolism (which was attributed to the HIV infection, and termed as the “first wave”). These alterations were also seen in patients receiving treatment and without lipodystrophy. Patients with lipodystrophy showed higher alterations and increased apoptosis. They proposed that the introduction of HAART induces a “second wave” of inflammation that affects mitochondrial function, enhancing activation of catabolism genes and impairing adipocyte differentiation. However, the contribution of the first and the second wave in the developing of lypodistrophy syndrome is yet unknown.



In the second presentation, Dr. Castellano from Duke University presented the results of a retrospective evaluation of TDF-associated renal toxicity. This study included all patients exposed >3 months to TDF that presented a 50% decrease in GRF, or an absolute decrement in CrCl > or = 25 mL/m from a cohort of 1574 patients. Renal toxicity was present in 35 of 744 patients exposed to TDF (7.5%). The comparison with 191 unexposed controls allowed the identification of associated factors such as the use of nephrotoxic medications (OR 6.2), hypertension (OR 4.43), suspected NSAID use (OR 4.58), concurrent PI use (OR 3.79), previous IP use (OR 2.8) and prior OIs (OR 2.4); while the use of NNRTI has a protective effect. Most cases of nephrotoxicity reversed when TDF was discontinued. A 55% of Afro-American individuals in the cohort, and a 4.2% of nephrotoxicity in the unexposed patients could help to explain the high percentage of renal toxicity in this cohort.


Dr Boger, from Vanderbilt University, proposed eicosanoids as a marker of oxidant stress and endothelial damage related to ARV therapy. He compared these markers with traditional cardiovascular (CVD) risk factors and hsCRP in 33 HIV-infected patients on stable ART (45% PIs) without CVD, diabetes, and no current aspirin or tobacco use.  Urine metabolites of F2-isoprostane (PGF2 alfa), and prostaglandin-E (PGE-M) correlated with hsCRP, and were higher than published values detected in HIV negative individuals. PGI-M and TxB2, in normal levels, correlated with increased non-HDL cholesterol. Classical CVD factors (sex, PI use, and lipoatrophy) influenced these measures, suggesting that urinary eicosanoids may be promising non invasive markers of CVD risk in HIV-infected patients on ART. Further studies with higher number of individuals with adequate follow-up and including patients with diagnosis of CVD are warranted to characterize these new potential non invasive markers of CVD.


Dr Cutrell, from GSK, summarized the safety information on abacavir (ABC) and cardiovascular risk using data from 14683 patients who participated in 54 clinical trials sponsored by GSK, where all AE were captured systematically whit MeDRA. There were 9639 patients receiving ABC (7845 person years) and 5044 (4653) controls. No significant differences were observed regarding baseline characteristics, including lipids and glucose values. The incidence of myocardial infarction was low and comparable between the two groups (11 cases, 2.039 /1000 patient-years in ABC group vs. 7 cases, 2.363 in non-ABC group, pNS).  These data could not confirm the increased risk of myocardial ischemic events with ABC reported by DAD study. Although this study has some strengths (prospective data, well monitorized, standardized definitions for AE), has also some limitations (short follow-up, not designated to evaluate CV risk, high proportion of young patients meeting the selection criteria of those studies) that prevent to take definite conclusion regarding the role of ABC in the development of CVD.


Finally, Dr Currier from UCLA, made a comprehensive review of the current evidence of potential factors involved in the development of atherosclerosis. She summarized the genetics that could be implicated in the development of CVD, some of them implicated also in the risk of acquisition of HIV (MCP-1 and its receptor CCR-2), the potential direct effect of HIV (trough the impairment of lipid metabolism, and direct muscle cell infection) and through the induction of immunoactivation. She also summarize the effects of ARV drugs in several parameters (lipid alterations, insulin resistance, inflammation) showing that the development of CV events can be multi-factorial warranting the need of explore inflammatory markers, genetics, metabolic patterns and ARV drugs in the genesis of atherosclerosis in HIV patients.




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