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Cardiovascular complications 16th CROI
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Pablo Tebas, MD
University of Pennsylvania
Whether we like it or not, the agenda for the cardiovascular complications discussions at CROI was set by the DAD study. Abacavir cardiovascular risk dominated several sessions, and was passionately discussed between groups that agree or disagree with the conclusions of the original DAD study 1. Dr. Peter Reiss, a member of the DAD cohort study, summarized the state o the topic in a very nice presentation worth seeing in the available webcast at the CROI site.
For the few that have not been paying attention to this: the DAD cohort study reported last year in the Retrovirus Conference , and published subsequently in Lancet 1, that current or recent exposure to Abacavir and DDI was associated with increased cardiovascular risk. The magnitude of the association was significant -close to a relative risk of 2-. Since then, the discussions about cardiovascular risk have revolved around that study. It is interesting to put this increased risk in the context of the increased cardiovascular risk associated with the use of other medications that have been presented over the last few years. For example, the increased cardiovascular risk of rosiglitazone, that created havoc in 2007 was smaller (odds ratio, 1.43; 95% confidence interval [CI], 1.03 to 1.98; P=0.03) 2; the relative risk of increased thrombotic cardiovascular events (myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke, and transient ischemic attacks) in the infamous rofecoxib (Vioxx) fiasco 3 was 2.38 (95% confidence interval, 1.39-4.00; P=.002). Both of them similar in magnitude to the abacavir risk... so why the FDA is not running to take abacavir out of the market?
The difference is the dramatic disparity in the design of the studies. In the case of rosiglitazone and Vioxx, the increases in cardiovascular risk were apparent after only a few thousand patient years of follow up and they did not require 30,000 patients years of follow up to reach statistical significance as it seems to be the trend in the DAD study. The other critical difference between those two studies and DAD is that individuals that received rosiglitazone or Vioxx were randomized to receive them, as opposed to the DAD study, where the physicians decided to give the patients whatever antiretroviral they wanted, so no randomization to receive abacavir was involved. Abacavir has always been perceived as a lipid friendly, simple drug, and has been (or was) a popular drug to substitute for other nucleoside or antiretrovirals when the patient had metabolic complications associated with antiretroviral treatment. It is possible that abacavir was prescribed more frequently to individuals with higher cardiovascular risk, and that because of that those patients were more likely to have cardiovascular events. The DAD study tried to control for that, but it is very difficult to control for this type of systematic bias in an observational study, no matter how many statistical tricks are used. Observational studies are not the same level of evidence than randomized trials, and should always be seen with a lot of caution and skepticism. However, there was some evidence that seemed to corroborate the DAD findings: during the Mexico International AIDS conference in 2008, an analysis of the SMART study 4 seemed to confirm the association of recent abacavir use and myocardial infarctions. To makes things more confusing, Glaxo (the maker of abacavir) reviewed their own database and looked at the HEAT study, a study that randomized naïve individuals to receive abacavir and lamivudine vs tenofovir and FTC with lopinavir ritonavir and did not confirm the association of abacavir and cardiovascular events5.
During the retrovirus meeting in Montreal the saga continued and evidence was presented both confirming the DAD observations and refuting it. The DAD cohort presented an updated version of their previous study showing that the association of myocardial infarction with recent use of ABC and DDI persisted, and this time, there was also a smaller, barely significant, association with the continuous use of abacavir. This year the DAD also showed evidence of a statistically significant increase of MIs with the use of lopinavir and fosamprenavir but not with other antiretrovirals like tenofovir6.
Part of the corroborating group, the French ANRS group presented a study confirming that the recent use of abacavir (for less than a year) increased the cardiovascular risk. This was a matched case control study of 268 cases of MI and 865 controls, matched for age, sex and place of treatment. The investigators found an association with <1 year or recent ABC use and MI risk of approximately 2, similar to the one in the original study7.
On the other hand, the ACTG presented data from the ALRT study8, a study that collects information from multiple randomized trials. The main difference with DAD and the French cohort is that in this study individuals did not start abacavir because their physician wanted them to do so, they did because they were randomized to start abacavir as opposed to other nucleoside analog. In this very large study (10000 patients' years of follow up) there were 27 MI and 63 cardiovascular events, there was no evidence of an increased cardiovascular risk in patients started on abacavir, what suggest that the observation of DAD is due to some confounder that cannot be completely adjusted for. Obviously the DAD investigators say that the ACTG study is too small, and that they do not have the power to refute their conclusions.
What can the clinician do with all this confusing data? I think the data from ALRT is stronger, because it comes from a series of randomized trials, but the relative small size (compared to the DAD) does not completely rule out that abacavir may increase slightly the CVD risk. If abacavir increases the risk of cardiovascular events, that increase in the risk is small, specially for patients with a small cardiovascular risk to begin with (more than 80% of the HIV infected population), and this increased risk should not weigh too much in the decision of starting abacavir or not. On the other hand, if the cardiovascular risk of the individual patient is high it seems prudent to consider other alternatives to this drug.
In my opinion, the problem of abacavir is not the DAD study. The main abacavir problem is the relative lack of potency at high viral loads when compared with the other most popular nucleoside backbone tenofovir/emtricitavine9. This data was presented last fall, and will be presented again when the final results of ACTG 5202 will become available next winter. This relatively lack of potency and the uncertainty about the increased incidence of cardiovascular events are the two main reasons why abacavir/lamivudine is not anymore a "preferred initial nucleoside backbone" in the DHHS guidelines and has become an "alternative" regimen. These DHHS recommendations match what most clinicians taking care of HIV patients do nowadays in their daily practices.
There were also presentations trying to explain the potential mechanisms of the increased cardiovascular risk associated with abacavir use. I find these studies very confusing, small and not conclusive enough to provide a final answer.
Some of this studies evaluated changes in inflammatory markers associated with the use of abacavir. Frank Palela and the WAIS and MACs study did not find increased levels of hsCRP, IL-6 or D dimer in patients receiving abacavir10, the HEAT study (a comparison between ABC/3TC and TFV/FTC, discussed briefly at the beginning of this article, did not show differences in hs CRP, IL-6 and sVCAM-1 between the two arms of the study5. However, other studies did found platelet hyper-reactivity in ABC recipients 11or worsening endothelial function among patients receiving abacavir containing combinations.
In summary, little clarification came from mechanistic studies trying to understand the presumed association between abacavir and increased cardiovascular risk.
There were other interesting studies in the cardiovascular section of the CROI meeting that were diluted in the abacavir controversy.
A few studies suggest that HIV infection per se is associated with an increased risk of cardiovascular disease. These studies used surrogate markers of atherosclerosis, like coronary artery calcium (OR = 2.7 for worse calcium scores among HIV positive individuals, after adjusting for traditional risk factors)13, and arterial elasticity (individuals with untreated HIV infection had lower levels of eleasticity than HIV negative individuals after adjusting for traditional risk factors)14
The ACTG study presented a small study (17 patients, ACTG study # A5206) showing that tenofovir (TFV) has lipid lowering properties independent of its anti HIV properties, maybe explaining some of the results seen in studies like Gilead 903 and switch studies that have showed improvements in lipids when individuals start tenofovir compared to other nucleoside analogs. In this ACTG study, the addition of TDF to existing virologically-suppressed ART regimens improved lipid parameters -LDL-C (-12%), TC (-16%), non-HDL-C (-16%). The intervention had little effect on triglycerides. The mechanism/s by which tenofovir has these lipid lowering effects is not clear15.
The results of ACTG protocol A5209 were also presented, showing that Ezetimibe (Zetia) was well tolerated as an add on drug to 44 patients receiving a statin for managing their cholesterol, with a clinical safety profile similar to that of placebo, and that adding ezetimibe to ongoing statin therapy resulted in significant reductions in LDL-C (-14%), TC (-19%), non-HDL-C (-23%), and Apo B (-9%)16.
I liked a study form the Kaiser permanent group that looked at the frequency of MIs between the years 1996 and 2008 among Californians with and without HIV infection. Although initially HIV infected patients were more likely to have MIs than HIV negatives, the rates of MI among HIV+ and HIV-patients converged during the last two years of the observation period (2006 to 2008) to the point that the difference in rates between the two groups became non significant. The convergence was due to a decline in the rate of MIs among HIV+ patients , as the rate in HIV-patients was stable. If true and confirmed, this means that something that we are doing (paying attention to traditional cardiovascular risk factors in this population, or using drugs with less toxic profiles) is working. A study with good news in an ocean of concerning studies17. Another important study trying to control the most serious cardiovascular risk factor: smoking, showed how difficult is to control traditional risk factors in the HIV infected population18.
To me one of the most important developments regarding cardiovascular risk in patients receiving antiretroviral therapy was presented in a different section of the meeting. I am referring to the two presentations about the new "ritonavir like" analogs that inhibit CYP3A4, but do not have the antiviral activity or the secondary lipid profile changes associated with ritonavir. This new drug family could dramatically change the antiretroviral therapy field as would allow the use of drugs like elvitegravir or maraviroc in once a day regimens, maybe as fixed dose combinations, without the adverse lipid profile associated with the use of ritonavir. These new drugs may also improve the lipid profile of "older" protease inhibitors, potentially reducing the cardiovascular risk associated with their use.
Gilead presented data with the most promising of these new agents (GS-9350)19. This compound does not have any antiretroviral activity, so when used in combination with other drugs there will be no risk for the development of protease inhibitor associated mutations, and does not have the lipid effects of ritonavir. Apparently Gilead is planning to develop this compound in a fixed dose combination with elvitegravir, and also as a stand alone drug. One of the most interesting pieces of information was asked during the questions and answer section of the presentation: somebody form the audience asked Dr. Struble from the FDA (who was one of the season moderators), what would it take to get this compound approved and her answer was: a 500 patient study for 6 months demonstrating the tolerability and the potency of this compound. This answer basically sets the stage for what is going to be a race to develop these products. Another similar product developed by a company named Sequia (SPI-452)20 has a similar profile, potent inhibition of CYP3A4 and the ability to increase the levels of concomitantly administered protease inhibitors. This second compound seems to have more side effects (headache nausea and vomiting) and apparently it is more difficult to formulate (less water soluble). These compounds have the potential to change the antiretroviral field, and during the next two years, they are going to be the most important development in antiretroviral therapy.
Bibliography
1. Sabin CA, Worm SW, Weber R, et al. 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;371:1417-26.
2. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. The New England journal of medicine 2007;356:2457-71.
3. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. Jama 2001;286:954-9.
4.Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. Aids 2008;22:F17-24.
5. KY Smith, D Fine, P Patel, and others. Similarity in efficacy and safety of abacavir/lamivudine (ABC/3TC) compared to tenofovir/emtricitabine (TENOFOVIR/FTC) in combination with QD lopinavir/ritonavir (LPV/r) over 96 weeks in the HEAT study. XVII International AIDS Conference (AIDS 2008). Mexico City. August 3-8, 2008. Abstract LBPE1138.
6. Jens Lundgren, P Reiss, S Worm, R Weber, W El-Sadr, S De Wit, M Law, A d'Arminio Monforte, C Pradier, C Sabin, and Aquataine, AHOD, ATHENA, INSIGHT, EuroSIDA, ICONA, Nice, SHCS, St Pierre Cohorts & D:A:D Study Group. Risk of Myocardial Infarction with Exposure to Specific ARV from the PI, NNRTI, and NRTI Drug Classes: The D:A:D Study. Abstract 44LB
7. S Lang, M Mary-Krause, L Cotte, J Gilquin, M Partisani, A Simon, F Boccara, Dominique Costagliola*, and the Clinical Epi Group of the French Hosp Database on HIV. Impact of Specific NRTI and PI Exposure on the Risk of Myocardial Infarction: A Case-Control Study Nested within FHDH ANRS CO4. Abstract 43LB
8. Constance Benson, H Ribaudo, E Zheng, S Koletar, M Smurzynski, R Bosch, B Bastow, A Collier, J Schouten, and the ACTG A5001/ALLRT Protocol Team. No Association of Abacavir Use with Risk of Myocardial Infarction or Severe Cardiovascular Disease Events: Results from ACTG A5001. 16th Conference on Retrovirus and Opportunistic Infections, Montreal, Canada, February 2009. Abstract 721
9. P Sax, C Tierney, A Collier, and others. ACTG 5202: shorter time to virologic failure with ABC/3TC than TENOFOVIR/FTC in treatment-naive subjects with HIV RNA >100,000. XVII International AIDS Conference (AIDS 2008). Mexico City. August 3-8, 2008. Abstract THAB0303.
10. Frank Palella, S Gange, R Elion, L Benning, R Kaplan, C WIllliams, A Landay, L Jacobson, and R Tracy Title: Inflammatory Markers among Abacavir and non-Abacavir Recipients in the Womens' Interagency HIV Study and the Multicenter AIDS Cohort Study . 16th Conference on Retrovirus and Opportunistic Infections, Montreal, Canada, February 2009. Abstract 150LB
11. Claudette Satchell, E O'Connor, A Peace, A Cotter, G Sheehan, T Tedesco, P Doran, W Powderly, D Kenny, and P Mallon. Platelet Hyper-Reactivity in HIV-1-infected Patients on Abacavir-containing ART. 16th Conference on Retrovirus and Opportunistic Infections, Montreal, Canada, February 2009. Abstract 151LB
12. P Hsue, Y Wu, A Schnell, P Ganz, P Hunt, H Hatano, J Martin, and Steven Deeks. Association of Abacavir and HIV Disease Factors with Endothelial Function in Patients on Long-term Suppressive ART. 16th Conference on Retrovirus and Opportunistic Infections, Montreal, Canada, February 2009. Abstract 723.
13. Priscilla Hsue*, S Deeks, A Schnell, M Krone, Y Xie, T Lee, K Ordovas, G Reddy, P Ganz, and J Martin. HIV Infection Is Independently Associated with Detectable Coronary Artery Calcium. 16th Conference on Retrovirus and Opportunistic Infections, Montreal, Canada, February 2009. Abstract 724
14. Jason Baker, D Duprez, J Rapkin, R Grimm, J Neaton, and K Henry. Untreated HIV Infection Is Associated with Imparied Arterial Elasticity. 16th Conference on Retrovirus and Opportunistic Infections, Montreal, Canada, February 2009. Abstract 725
15. Marisa Tungsiripat, D Kitch, M Glesby, S Gupta, J Mellors, L Moran, L Jones, B Alston-Smith, J Rooney, and J Aberg . A Pilot Study to Determine the Effect on Dyslipidemia of the Addition of Tenofovir to Stable Background ART in HIV-infected Subjects: Results from the A5206 Study Team. 16th Conference on Retrovirus and Opportunistic Infections, Montreal, Canada, February 2009. Abstract 714
16. Dominic Chow, H Chen, M Glesby, A Busti, S Souza, S Kohrs, J Wu, J Andersen, S Koletar, and ACTG Protocol A5209. Ezetimibe Is Safe and Effective in Combination with Statin Therapy for the Treatment of Elevated Low-density Lipoprotein Cholesterol in HIV-infected Subjects: Results of ACTG Protocol A5209. 16th Conference on Retrovirus and Opportunistic Infections, Montreal, Canada, February 2009. Abstract 712.
17. L Hurley, W Leyden, L Xu, M Silverberg, C Chao, B Tang, W Towner, M Horberg, and Daniel Klein. Updated Surveillance of Cardiovascular Event Rates among HIV-infected and HIV-uninfected Californians, 1996 to 2008. 16th Conference on Retrovirus and Opportunistic Infections, Montreal, Canada, February 2009. Abstract 982.
18. Karen Tashima, R Niaura, E Richardson, C Stanton, M De Dios, and M Kojic. A Motivational Intervention for Smoking Cessation among HIV+ Smokers. 16th Conference on Retrovirus and Opportunistic Infections, Montreal, Canada, February 2009. Abstract 148.
19. A Mathias, M Lee, C Callebaut, L Xu, L Tsai, B Murray, H Liu, K Yale, D Warren, and Brian Kearney.GS-9350: A Pharmaco-enhancer without Anti-HIV Activity. 16th Conference on Retrovirus and Opportunistic Infections, Montreal, Canada, February 2009. Abstract 40
20. S Gulnik, M Eissenstat, E Afonina, D Ludtke, J Erickson, R Dagger, B Wynne, and Robert Guttendorf Preclinical and Early Clinical Evaluation of SPI-452, a New Pharmacokinetic Enhancer. 16th Conference on Retrovirus and Opportunistic Infections, Montreal, Canada, February 2009. Abstract 41
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