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  5th IAS Conference on HIV Pathogenesis, Treatment and Prevention
July 19th-22nd 2009
Capetown, South Africa
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Abacavir Not Associated with MIs, 2 Studies Report at IAS
  IAS Capetown, July 19-22 2009
From Jules: At this IAS conference on Monday afternoon, in an oral panel session chaired by Judy Currier on cardiovascular disease there was a continuation of the discussion about MIs and abacavir with 3 studies reporting on this ongoing 2-year saga. Two studies did not find an associstion between abacavir & MIs, and the the third study did not find an association between abacavir and inflammation and several additional biomarkers.
Roger Bedimo looked in the VA's clinical case registry where 19,424 patients were analyzed. Mean age of 46, follow-up 76, 376 patient-years, mean: 3.93 years per patient for MIs and CVAs (cerebrovascular disease). He found abacavir was not associated with MIs for both abacavir cumulative use and as well he looked at the most recent regimen patients used. I have attached all his slides. He summarized: "In the univariate analysis we observed a marginal association between cumulative abacavir use and AMIs. No association with ABC use in last regimen. Chronic kidney disease was associated with a significant increase in AMIs Abacavir use was more common among patients with eGFR <60. Association between both cumulative abacavir use and abacavir use in last regimen with new AMI are attenuated by
-- traditional risk factors (diabetes, hypertension, hypercholesterolemia, HCV)
-- renal dysfunction prior to regimen initiation
Similar trends observed for abacavir use and CVA."
Bedimo discussed in his talk, and there was discussion at the meeting regarding that a main driver of the use of abacavir vs tenofovir is chronic kidney disease. Bedimo also found that HCV played a role regarding the development of MI & CVA (see his slides) and mentioned that HCV has been found to be associated with MIs in both HIV-negs and HIV-positives.
Of note was the opening presentation by Dominique Costagliola, who reported at CROI from a large French database that abacavir was associated with MIs, and has reversed her position. She now says that upon further analysis of her cohort current cocaine use and IVDU is associated with MIs, and if you eliminate patients from the study with current use of cocaine & IVDU there is no association between abacavir & MIs. I spoke with her after her talk and she said, as well as others at the session were saying, that is the problem with observational cohorts. She said to me you can have confounders that you had not thought of including in the analysis, and that is just what happened here with these 2 studies and that is the problem with observational studies. When these 2 studies separately consider abnormal kidney function and cocaine & IVDU abacavir was not associated with MIs. She showed a summary slide of 7 studies on the association between exposure to abacavir & the risk for MI. In 3 of the 7 studies where there was no risk found all or the majority of patients were ART naives while in the other 4 where an association was found all or majority of patients were ART-experienced at ABC initiation and she added the impact of CVD risk factors on the likelihood of receiving TDF and ABC is important (see her slides).
In addition Esteban Martinez presented results from a substudy of the BICOMBO study. He reported "in otherwise healthy, virologically suppressed HIV+ patients from the BICOMBO study, the initiation of ABC/3TC did not lead to significant changes after 48 weeks in markers of inflammation, endothelial dysfunction, insulin resistance or hypercoagulability as compared with the initiation of TDF/FTC. These results argue against the involvement of ABC in any of these mechanisms and therefore do ot explain the higher risk of MI associated with recent ABC use in some cohorts." (see his slides attached).

Jules Levin
Cardiovascular Disease: to HAART or not to HAART: abacavir & MIs
Oral Abstract Session
Monday July 19 2009
Rapporteur report
Track B report by Pablo Tebas
Not surprisingly the session started with presentations related to the presumed role of abacavir in increasing the risk of cardiovascular events in patients with HIV infection, a topic that has been in the mind of clinicians, patients, and researchers since the original presentation of this data by the DAD group in 2007. Bedimo et al. presented a large epidemiological study of the VA cohort that included more than 19000 participants. In this cohort the use of abacavir was marginally associated with an increased cardiovascular risk, and the association disappeared after adjusting for traditional risk factors, renal function (the main reason ABC is used instead of tenofovir) and HCV. Importantly, renal dysfunction was an additional strong predictor of cardiovascular risk.
Esteban Martinez et al. asked the question: if abacavir is associated with an increased cardiovascular risk, then what is the biological mechanism? The Spanish group looked at 80 patients of the BICOMBO study in which fully supressed individuals were randomized to receive abacavir/3TC or TFV/3TC. The authors did not see any difference between the two groups in markers of inflammation, endothelial function, coagulation, cytokines and insulin resistence, which increased cardiovascular risk in other studies.
Seaberg of the MACS cohort compared the carotid stiffness, a surrogate of the subsequent risk of atherosclerosis, of individuals with known duration of HIV infection with seronegative controls. The longer the duration of HIV infection, after controling for traditional risk factors, the higher the carotid stifness, suggesting that HIV itself, increases the cardiovascular risk of HIV infected patients.
In the small study of Kristofersen (N=11) the initiation of ART was associated with decrease in the vasomotor function, linking the use of ART with a proatherogenic effect in the heart. This study and the BICOMBO study are limited by the small numbers of patients in each cohort
Finally, in the study of Witvrouw et al. the use of a 14 days of a COX-2 inhibitor in antiretroviral naive individuals decreased the inflammation of the lymph nodes.

Abacavir & MIs: 3 slide presentations at IAS
Capetown July 19-22 2009