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Abacavir Heart Attack Controversy: Kidney Disease Appears to Matter
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5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2009, Cape Town
Mark Mascolini
Failure to account for chronic kidney disease as a myocardial infarction (MI) risk factor in the D:A:D cohort may contribute to the correlation between abacavir use and MI in that analysis [1], results of a Veterans Administration (VA) study suggest [2]. The findings are compelling for two reasons: kidney ailments themselves raise the MI risk, and physicians are more likely to prescribe abacavir, rather than tenofovir, for people with kidney problems. However, accounting for chronic kidney disease only slightly diminished the (already nonsignificant) MI risk with abacavir in VA patients.
In the same 5th IAS Conference session, Dominique Costagliola offered a second suggestion of why three studies found no link between abacavir and MIs and four studies--including D:A:D--did [3].
VA investigators calculated patient-days of antiretroviral use before acute MIs in four groups from 1996 through 2004: (1) people on combination antiretroviral therapy (CART) including abacavir, (2) people on CART with nucleotide/nucleosides (NRTIs) other than abacavir, (3) people on suboptimal one- or two-drug antiretroviral regimens, and (4) people not taking antiretrovirals. The researchers assessed the impact of cumulative abacavir use as a time-dependent variable; they analyzed the predictive value of abacavir, tenofovir, or both in each patient's last regimen; and they calculated the impact of chronic kidney disease before the last regimen began.
The study involved 19,424 people with an average 3.9 years of follow-up. Average antiretroviral duration was 1.93 years. During follow-up, 278 people had an acute MI for an incidence of 3.69 per 1000 person-years. There were 868 cerebrovascular accidents (strokes) for an incidence of 11.68 per 1000 person-years. Several traditional risk factors correlated significantly with acute MI: older age (P < 0.0001), chronic kidney disease (P < 0.0001), diabetes (P < 0.0001), hypertension (P < 0.0001), hypercholesterolemia (P < 0.0001), and HCV coinfection (P = 0.013).
In an analysis that did not consider other risk factors, chronic kidney disease, defined as a glomerular filtration rate (GFR) below 60, almost quadrupled the risk of acute MI, while boosting the risk of cerebrovascular accident 30 times. Abacavir nonsignificantly raised the MI risk 17% in an unadjusted analysis (hazard ratio [HR] 1.17, 95% confidence interval [CI] 0.98 to 1.39, P = 0.081), while CART with other NRTIs had no impact on MI risk in this analysis.
In comparison with the unadjusted analysis, a statistical model adjusting for chronic kidney disease (most recent estimated GFR) found a fractionally lower MI risk with abacavir (HR 1.16, 95% CI 0.97 to 1.38, P = 0.098). Finally, a statistical model considering five other heart risk factors (age, high cholesterol, hypertension, type 2 diabetes, and smoking) trimmed the abacavir-associated MI risk even more (HR 1.15, 95% CI 0.97 to 1.37, P = 0.103). GFR-defined chronic kidney disease had a similar attenuating impact on abacavir-associated risk of cerebrovascular accident (HR 1.04, 95% CI 0.83 to 1.29, P = 0.094 in unadjusted analysis; HR 0.97, 95% CI 0.77 to 1.22, P = 0.813 in analysis adjusted for chronic kidney disease at regimen initiation).
To no one's surprise, significantly more people with an estimated GFR below 60 got abacavir prescribed (12.3% of abacavir starters) than got tenofovir prescribed (7.2% of tenofovir starters) (P < 0.0001).
The VA team noted several differences between their study and the D:A:D analysis: Their cohort study is retrospective, while D:A:D is prospective. D:A:D is bigger. The VA study did not have confirmed MI or stroke diagnoses, relying instead of ICD9 codes. But the VA team counted MIs for the whole study period (1996-2004), while D:A:D counted MIs only after enrollment in the cohort in 1999.
Before the VA analysis, seven cohort studies or trial analyses evaluated the impact of abacavir on MI. Four of them found a correlation, and three did not. Three of the four studies that did see a link involved people with or without impaired kidney function. All three studies that found no link were trials that excluded people with chronic kidney disease.
· D:A:D: Abacavir linked to MI: no exclusion based on kidney function
· French Hospital Database on HIV: Abacavir linked to MI: no exclusion based on kidney function
· SMART trial: Abacavir linked to MI: no exclusion based on kidney function
· STEAL study: Abacavir linked to MI: excluded patients with kidney disease
· Glaxo trial analysis: Abacavir not linked to MI: excluded patients with kidney disease
· ACTG A5001 analysis: Abacavir not linked to MI: excluded patients with kidney disease
· HEAT trial analysis: Abacavir not linked to MI: excluded patients with kidney disease
Thus the STEAL study is the only abacavir analysis that ruled out people with chronic kidney disease yet found that abacavir makes MIs more likely. Dominique Costagliola, who headed the French Hospital study, noted another correlation between the studies that implicated abacavir in MIs and those that did not [3]. In the four studies that did implicate abacavir, all or most of the patients had antiretroviral experience when starting abacavir. In the three studies that did not implicate abacavir, all or most of the patients started abacavir in their first regimen. If the question is whether to use abacavir in first-line therapy, Costagliola suggested, that discrimination may be critical.
From Jules: as I mentioned in my earlier email I spoke with Dominique Costagliola presented the French study data at CROI 2009 that found abacavir associated with MI. but she told me here that upon further analysis that use of cocaine and IVDs by patuents are associated with MIs, and analysis excluding these patients found no association between abacavir & MI. As well, I spoke with Roger Bedimo and asked about patients with abnormal kidney function but not as bad as with eGFR <60. He has not performed analysis with these patients but I suggested that this might also be associated with abacavir & MI, he agreed and said he would look at that.
References
1. Lundgren J, Reiss P, Worm S, et al. Risk of myocardial infarction with exposure to specific ARV from the PI, NNRTI, and NRTI drug classes: the DAD study. 16th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2009. Montreal. Abstract 44LB.
2. Bedimo R, Westfall A, Drechsler H, Tebas P. Abacavir use and risk of acute myocardial infarction and cerebrovascular disease in the HAART era. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract MOAB202.
3. Costagliola D. The current debate on abacavir; risks and relationship between HIV viremia and cardiovascular events. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Invited lecture MOAB201.
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