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Cardiovascular Risks of Antiretroviral Therapy: traditional risk factors more worrisome than ART EDITORIAL
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NEJM, April 26, 2007
James H. Stein, M.D.
This week Steve Grinspoon published a study finding HIV associated with almost double the risk of heart attack compared to HIV-negative control group. At CROI in Feb 2007, the second cut of data from ACTG 5142, the metabolics substudy found Kaletra was associated with less risk for body changes and similar risk for lipids abnormalities compared to efavirenz. In this context James Stein who has been an active thought leader in HIV but works in the field of cardiology questions the perceptions regarding the results of the D.A.D. study:
--"the long-term effects of such therapy on cardiovascular disease are unclear"
-- in D.A.D. "the trend is unclear....After adjustment for cardiovascular risk factors (excluding lipids), patients receiving protease inhibitors had an increase in the risk of myocardial infarction of 16% per year (P<0.001), as compared with an increase of only 5% per year (P=0.17) among patients receiving nonnucleoside reverse-transcriptase inhibitors. Adjusting for lipid levels, hypertension, and diabetes mellitus reduced the relative risk for use of protease inhibitors to 10% (P=0.002) and for nonnucleoside reverse-transcriptase inhibitors to 0% (P=0.92).... cardiovascular risk observed with protease inhibitors is not high, especially as compared with the effect of other cardiovascular risk factors. The relative risk per year of exposure to protease inhibitors was 1.16, which is considerably smaller than the relative risk of increasing age (1.39), male sex (1.91), current smoking (2.83), and history of cardiovascular disease (4.3) (all P<0.001). Whether the use of nonnucleoside reverse-transcriptase inhibitors is associated with a lower risk of myocardial infarction than the use of protease inhibitors is less certain. The incidence rates of myocardial infarction according to years of exposure to protease inhibitors and nonnucleoside reverse-transcriptase inhibitors overlap, and the relative risks appear to be quite unstable, with significant overlap noted through year 4, followed by a sudden decrease in risk in the group receiving nonnucleoside reverse-transcriptase inhibitors by year 5.....
....regarding the results from D.A.D. where PIs were reported to be associated with an increased risk for there does not appear to be an epidemic on the horizon - simply a risk that needs to managed. Given the much greater cardiovascular risks associated with diabetes mellitus and with smoking (and the high prevalence of smoking among HIV-infected patients), perhaps more effort should be spent assisting our patients with smoking cessation and the prevention of diabetes, rather than our focusing so intently on the dyslipidemic effects of antiretroviral therapy, especially since uncontrolled viremia is a greater risk factor for death from cardiovascular causes than are the metabolic changes associated with such therapy...."
Treatment with potent antiretroviral therapy has transformed human immunodeficiency virus (HIV) infection from a rapidly fatal disease into a chronic illness that some patients can live with for more than two decades. However, shortly after antiretroviral therapy was introduced, there were several reports of acute myocardial infarction and premature atherosclerotic vascular disease among young patients receiving such treatment.1 Attention quickly focused on the protease inhibitors, with speculation that lipodystrophy and its associated metabolic disorders, including hyperlipidemia and insulin resistance, were increasing the cardiovascular risk.
These findings were alarming, and a flurry of research reports and editorials created a sense of an impending "epidemic" of cardiovascular disease, described by one writer as a "clockwork bomb" that might explode.2 Adding to the fire were reports from observational studies suggesting that the risk of myocardial infarction was higher among patients receiving antiretroviral therapy and particularly that the use of protease inhibitors might increase cardiovascular risk.3 However, the data were not consistent, and the largest study, the Veterans Affairs Quality Enhancement Research Initiative for HIV, reported that rates of hospital admission for cardiovascular disease declined after the introduction of antiretroviral therapy, that the number of deaths from cardiovascular causes did not increase, and that specific classes of antiretroviral drugs were not related to cardiovascular risk during a mean follow-up of 15 months.4 Unfortunately, the association between antiretroviral therapy and cardiovascular disease remained uncertain because several of these studies had methodologic limitations, including incomplete case ascertainment, incomplete data regarding exposure to antiretroviral therapy, and a low number of cardiovascular events.3,4
Recently, several well-designed prospective studies have shed some light on the complex interactions among the use of antiretroviral therapy, HIV infection, and cardiovascular risk. The Strategies for Management of Antiretroviral Therapy (SMART) study demonstrated that interruption of antiretroviral therapy was associated with an increased risk of opportunistic disease or death.5 Furthermore, the drug-conservation strategy in the SMART trial was associated with a 60% increase in the risk of cardiovascular disease during a mean follow-up of only 16 months, indicating that effective viral suppression actually may reduce short-term cardiovascular risk. These findings mirror those of AIDS Clinical Trials Group Study 5152S, which assigned HIV-positive patients who had not previously received antiretroviral therapy to one of three drug regimens, each omitting one aspect of the therapy (one omitting a protease inhibitor, another omitting a nucleoside reverse-transcriptase inhibitor, and a third omitting a nonnucleoside reverse-transcriptase inhibitor). The study showed that after 24 weeks of therapy, endothelial dysfunction improved to a similar degree in all groups, despite significant differences in lipoprotein levels.6 The implication of these studies is that short-term use of antiretroviral therapy reduces cardiovascular risk.
However, the long-term effects of such therapy on cardiovascular disease are unclear, and the report by the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study group in this issue of the Journal is informative.7 Among the 23,437 patients who were followed for a median of 4.5 years, there were 345 myocardial infarctions. After adjustment for cardiovascular risk factors (excluding lipids), patients receiving protease inhibitors had an increase in the risk of myocardial infarction of 16% per year (P<0.001), as compared with an increase of only 5% per year (P=0.17) among patients receiving nonnucleoside reverse-transcriptase inhibitors. Adjusting for lipid levels, hypertension, and diabetes mellitus reduced the relative risk for use of protease inhibitors to 10% (P=0.002) and for nonnucleoside reverse-transcriptase inhibitors to 0% (P=0.92). The authors concluded that increased exposure to protease inhibitors was associated with an increased risk of myocardial infarction, a finding that was partly explained by dyslipidemia, and that "no evidence of such an association" was seen for nonnucleoside reverse-transcriptase inhibitors. The conclusions regarding protease inhibitors are sound and are supported by the results of the AIDS Clinical Trials Group Study 5078, which showed that the use of the protease inhibitor ritonavir had a small but statistically significant effect on the progression of carotid-wall thickness among patients with HIV infection.8 Collectively, these studies indicate that the short-term and long-term risks of antiretroviral therapy may differ.
How should physicians interpret these data? First, it is critically important to recognize that the magnitude of increased cardiovascular risk observed with protease inhibitors is not high, especially as compared with the effect of other cardiovascular risk factors. The relative risk per year of exposure to protease inhibitors was 1.16, which is considerably smaller than the relative risk of increasing age (1.39), male sex (1.91), current smoking (2.83), and history of cardiovascular disease (4.3) (all P<0.001). Whether the use of nonnucleoside reverse-transcriptase inhibitors is associated with a lower risk of myocardial infarction than the use of protease inhibitors is less certain. The incidence rates of myocardial infarction according to years of exposure to protease inhibitors and nonnucleoside reverse-transcriptase inhibitors overlap, and the relative risks appear to be quite unstable, with significant overlap noted through year 4, followed by a sudden decrease in risk in the group receiving nonnucleoside reverse-transcriptase inhibitors by year 5. Because of the low number of myocardial infarctions and the short duration of follow-up of patients receiving nonnucleoside reverse-transcriptase inhibitors, the trend is unclear. In the analysis restricted to patients who had not previously received treatment with the other drug class, the confidence intervals were so wide that strong conclusions cannot be drawn.
A second important point is that the incidence of myocardial infarction among patients exposed to protease inhibitors for more than 6 years was only 0.6% per year, a rate similar to that of cardiovascular events in the viral-suppression group of the SMART study (0.8%).5 This level of cardiovascular risk would be considered low or at most moderate, depending on a patient's risk-factor burden.9 Thus, there does not appear to be an epidemic on the horizon - simply a risk that needs to managed. Given the much greater cardiovascular risks associated with diabetes mellitus and with smoking (and the high prevalence of smoking among HIV-infected patients), perhaps more effort should be spent assisting our patients with smoking cessation and the prevention of diabetes, rather than our focusing so intently on the dyslipidemic effects of antiretroviral therapy, especially since uncontrolled viremia is a greater risk factor for death from cardiovascular causes than are the metabolic changes associated with such therapy.
Aggressive treatment of HIV clearly is the main clinical priority, and such therapy appears to reduce cardiovascular risk, at least in the short term. With increased exposure to antiretroviral therapy, there is increased exposure to cardiovascular risk factors. Being treated with a protease inhibitor may increase cardiovascular risk modestly; however, longer-term studies are needed to understand the significance of this observation and to determine which drugs within the classes of protease inhibitors and nonnucleoside reverse-transcriptase inhibitors may contribute to the problem. Patients with HIV infection are living longer - that's the good news. But the longer you live, the more likely it is that heart disease will develop, so the treatment of modifiable risk factors is prudent.
Dr. Stein reports receiving consulting fees from Abbott and Bristol-Myers Squibb and grant support from Bristol-Myers Squibb. No other potential conflict of interest relevant to this article was reported.
Source Information
From the University of Wisconsin School of Medicine and Public Health, Madison.
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