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Abacavir & MIs - IAS Summary
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from Jules: I've tried here to provide here a final IAS summary on what went on at the meeting related to abacavir & MIs. There are links to 6 separate reports below and correspondence reported in The Lancet in 2008 related the D.A.D and the same issue raised at IAS, that of accounting for patients who received abacavir because they had kidney disorders. The correspondence from the Lancet is also controversial. The poster on channeling bias below discusses this and similar issues in interpreting cohort studies. Two cohort studies at IAS - the Quebec cohort and the LATINA cohort reported associations between abacavir & MIs, while as I have reported in the report below "Abacavir Not Associated with MIs, 2 Studies Report at IAS" Dominique Costagliola, who reported the French database at CROI finding ABC & MIs associated, recants this, and Roger Bedimo reports the VA Study finding association between abacavir & MIs disappears after accounting for CVD patients demographics & patients who received abacavir due to kidney disorder.
At IAS there was more controversy including this correspondence and response by Caroline Sabin from the D.A.D group published in the Lancet in 2008 which in and of itself is controversial.
MIs & ARTs: Nested Control Study in Quebec Cohort - (07/30/09)
Predictive factors of serious vascular events in HIV patients in LATINA (LATInamerican Network on AIDS) - (07/30/09)
Influence of patient baseline clinical and demographic characteristics on choice of initial antiretroviral therapy regimen: evidence of channeling bias in HIV clinical care - (07/30/09)
Abacavir Not Associated with MIs, 2 Studies Report at IAS - (07/23/09)
5th IAS: New Drugs, New strategies - (08/12/09) Joe Eron MD
Abacavir Heart Attack Controversy: Kidney Disease Appears to Matter - written by Mark Mascolini - (07/20/09)
The Lancet, Volume 372, Issue 9641, Page 803, 6 September 2008
Abacavir and increased risk of myocardial infarction
Frank A Post aEmail Address, Lucy J Campbell a
King's College London, London SE5 9RJ, UK
The D:A:D study (April 26, p 1417)1 suggests that patients with current or recent exposure to abacavir are at increased risk of myocardial infarction that is not explained by established cardiovascular risk factors. Unfortunately, markers for chronic kidney disease (CKD) such as reduced estimated glomerular filtration rate (eGFR) or proteinuria, both of which are risk factors for cardiovascular morbidity in the general population,2, 3 were not included in the analysis.
About 15% of HIV-infected patients have evidence of CKD.4, 5 Given that abacavir is generally safe and does not require dose adjustment in patients with advanced renal failure, patients might have been preferentially prescribed abacavir if CKD was present. To test this hypothesis, we examined the association between abacavir exposure and CKD among HIV-infected patients who attended the King's College Hospital HIV service, London, UK, between 1998 and 2005. Of the 2033 attendees, 42 (2·1%) were diagnosed with CKD as defined by an eGFR of less than 60 mL/min for more than 3 months. Among 1491 patients who had received antiretroviral drugs, 23 of 40 (58%) patients with CKD versus 314 of 1451 (22%) without CKD had received abacavir-containing therapy (p<0·0001). Furthermore, of the 22 patients who developed end-stage kidney disease between 1998 and 2007, 17 (77%) had received abacavir-containing therapy.
CKD can affect cardiovascular risk even after adjusting for hypertension, diabetes, and dyslipidaemia. The presence of CKD could affect the choice of antiretroviral therapy and might confound the observed association between abacavir and coronary events in the D:A:D study.
FAP has received honoraria, research grants, or both from Gilead Sciences and GlaxoSmithKline. LJC has no conflict of interest.
References
1 D:A:D Study Group. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet 2008; 371: 1417-1426. Summary | Full Text | PDF(158KB) | CrossRef | PubMed
2 Di Angelantonio E, Danesh J, Eiriksdottir G, Gudnason V. Renal function and risk of coronary heart disease in general populations: new prospective study and systematic review. PLoS Med 2007; 4: e270. CrossRef | PubMed
3 Hillege HL, Fidler V, Diercks GF, et al. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation 2002; 106: 1777-1782. CrossRef | PubMed
4 Wyatt CM, Winston JA, Malvestutto CD, et al. Chronic kidney disease in HIV infection: an urban epidemic. AIDS 2007; 21: 2101-2103. CrossRef | PubMed
5 Cheung CY, Wong KM, Lee MP, et al. Prevalence of chronic kidney disease in Chinese HIV-infected patients. Nephrol Dial Transplant 2007; 22: 3186-3190. CrossRef | PubMed
Abacavir and increased risk of myocardial infarction - Authors' reply
Caroline A Sabin a, Signe Worm b, Andrew N Phillips a, Jens D Lundgren bEmail Address, on behalf of the authors
a Royal Free & University College Medical School, London, UK
b Rigshospitalet & University of Copenhagen, 2200 Copenhagen, Denmark
We share Frank Post and colleagues' interest in whether impaired renal function affects the risk of cardiovascular disease in HIV infection, as it does in the general population. Within D:A:D, we started the collection of S-creatinine measurements in 2006 (including some retrospective collection of measurements where available) to estimate glomerular filtration rate (eGFR).1, 2 Our preliminary analyses (unpublished data) suggest that, among those with eGFR measurements available (73% of the cohort with 43% of follow-up after an eGFR measurement), the proportion of follow-up time spent with an eGFR of less than 60 mL/min/1·73 m2 is low (3·7%), as also seen in Post's cohort and in other studies of HIV-infected individuals.3 The myocardial infarction rate is, as expected, higher in those with an eGFR of less than 60 mL/min/1·73 m2 (8·0/1000 person-years) than in those with higher eGFR values (2·6/1000 person-years).
Furthermore, as suggested by Post, a slightly higher proportion of follow-up time among patients who were currently receiving or who had recently received abacavir was spent with a low eGFR measurement than was among those who had not recently received this drug (4·9% vs 3·4%). However, adjustment for a low eGFR value did not modify our findings relating to recent abacavir exposure, which remained strongly associated with the development of myocardial infarction (adjusted rate ratio 1·89; 95% CI 1·46-2·44; p=0·0001).
Thus, although we must interpret our findings cautiously given the lack of eGFR values for a large proportion of our cohort, we do not believe that the selection bias proposed by Post is the explanation for our findings.
We thank Miguel Goicoechea and Allen McCutchan for suggesting a possible biological explanation for our finding of an increased risk of myocardial infarction in HIV-infected individuals treated with abacavir or didanosine. The increased risk for those exposed to abacavir and didanosine in our study was evident while patients were actually receiving the drugs as well as shortly after stopping them, but appeared reversible within a few months after their cessation. This finding is compatible with the suggestion that these drugs might, by some mechanism, lead to instability of existing plaques in the coronary artery walls. This hypothesis is further supported by recent evidence.4
We need direct evidence to support this adenosine hypothesis, as well as the results from other ongoing biomarker studies that will assess whether these drugs could be proinflammatory. Any inflammatory reaction in the coronary arterial wall could lead to instability of plaques, resulting in a similar net effect to that of perturbations of intracellular adenosine concentrations, as suggested by Goicoechea and McCutchan.
We declare that we have no conflict of interest.
References
1 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41. PubMed
2 Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999; 130: 461-470. PubMed
3 Mocroft A, Kirk O, Gatell J, et al. Chronic renal failure among HIV-1-infected patients. AIDS 2007; 21: 1119-1127. PubMed
4 SMART/INSIGHT and D:A:D Study Groups. Use of NRTIs and risk of myocardial infarction in HIV-infected patients. AIDS 2008; 22: 1-8. CrossRef | PubMed
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