Correspondence

Trends in Rates of Myocardial Infarction among Patients with HIV

N Engl J Med 2004; 350:730-732February 12, 2004

Article

To the Editor:

The use of protease-inhibitor drugs is associated with increased levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol and with diabetic diathesis in patients infected with the human immunodeficiency virus (HIV).1 Because these metabolic problems can lead to cardiovascular disease, we examined data from the HIV Outpatient Study (HOPS), which involved a large cohort of HIV-infected outpatients followed at nine HIV clinics in seven U.S. cities: 3247 patients who had taken protease inhibitors for more than six months, and 2425 patients who had not taken protease inhibitors. These patients were followed for a total of 17,712 person-years of observation.

As previously reported, the use of protease inhibitors was strongly correlated with hyperlipidemia and with diabetes mellitus.2 There were 19 documented myocardial infarctions in the group of patients who had taken protease inhibitors but only 2 in the group of patients who had not taken these drugs (Cox proportional-hazards model; hazard ratio, 8.1; 95 percent confidence interval, 1.1 to 56.8; P=0.036). An analysis that controlled for age, sex, cigarette-smoking status, and the presence or absence of hypertension, diabetes, and hyperlipidemia reduced but did not eliminate this association (Cox model; adjusted hazard ratio, 6.5; 95 percent confidence interval, 0.9 to 47.8; P=0.065). The results of a European study, Data Collection on Adverse Events of Anti-HIV Drugs (DAD) (Nov. 20 issue),3 accord with our findings in the United States.

We have now followed our cohort for another year, and reanalysis of the data shows three trends. First, the rate of myocardial infarction has decreased somewhat (Figure 1AFigure 1Rate of Myocardial Infarction (Panel A) and Percentages of Patients Taking Protease Inhibitors and Statins or Other Lipid-Lowering Therapy (LLT) (Panel B) in the HIV Outpatient Study, 1993 through 2002.), from 3.10 cases per 1000 person-years in 2000 to 1.91 per 1000 person-years in 2002. This decrease appears to have been preceded by declining use of protease inhibitors, from a rate of 75.7 percent among patients in HOPS in 1998 to 58.0 percent in 2002 (chi-square for trend, 283.6; P<0.001), and by increasing use of statins and other lipid-lowering therapy, from a rate of 4.2 percent in 1998 to more than 15 percent in 2002 (chi-square for trend, 285.7; P<0.001) (Figure 1B). Therapy with statins accounted for two thirds or more of all lipid-lowering therapy in recent years.

Several lines of evidence suggest that the use of protease inhibitors may lead to myocardial infarction and other forms of cardiovascular disease: biologic plausibility,1 a temporal association,2 a statistical association,2-4 and dose–response data.3,4 Cardiovascular disease in HIV-infected patients is still uncommon, and to our knowledge, no one has suggested that it seriously compromises the use of this valuable class of antiretroviral drugs. However, partly in recognition of this potentially adverse effect of protease inhibitors in patients with cardiovascular risk factors, U.S. clinicians are now using protease inhibitors less — and statins and other lipid-lowering therapy more5 — in the care of their HIV-infected patients.

Scott D. Holmberg, M.D., M.P.H.
Ann C. Moorman, M.P.H.
Alan E. Greenberg, M.D., M.P.H.
Centers for Disease Control and Prevention, Atlanta, GA 30333
sdh1@cdc.gov

5 References

1. 1

   Rhew DC, Bernal M, Aguilar D, Iloeje U, Goetz MB. Association between protease inhibitor use and increased cardiovascular risk in patients infected with human immunodeficiency virus: a systematic review. Clin Infect Dis 2003;37:959-972
   CrossRef | Web of Science | Medline

2. 2

   Holmberg SD, Moorman AC, Williamson JM, et al. Protease inhibitors and cardiovascular outcome in patients with HIV-1. Lancet 2002;360:1747-1748
   CrossRef | Web of Science | Medline

3. 3

   The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003;349:1993-2003
   Full Text | Web of Science | Medline

4. 4

   Mary-Krause M, Cotte L, Simon A, Partisani M, Costagliola D, Clinical Epidemiology Group from the French Hospital Database. Increased risk of myocardial infarction with duration of protease inhibitor therapy in HIV-infected men. AIDS 2003;17:2479-2486
   CrossRef | Web of Science | Medline

5. 5

   Stein JH, Wu Y, Kawabata H, Iloeje UH. Increased use of lipid-lowering therapy in patients receiving human immunodeficiency virus protease inhibitors. Am J Cardiol 2003;92:270-274
   CrossRef | Web of Science | Medline

Author/Editor Response

The finding of a decrease in the incidence of myocardial infarction that is temporally associated with a reduction in the use of protease-inhibitor–containing regimens and a simultaneous increase in statin use is intriguing. However, although the results cited by Holmberg and colleagues are based on a very large number of patients,1 the number of events remains small, making the annual rates of myocardial infarction prone to random fluctuation. Larger cohorts are required to determine whether these trends are genuine.

Although reported associations favor a causal link between the use of protease inhibitors and the risk of cardiovascular disease,1,2 it is unclear whether this effect is limited to this class of drugs. The longest experience is with protease inhibitors relative to other types of drugs. Moreover, dyslipidemia and diabetes are not restricted to the class of protease-inhibitor drugs, and within-class differences exist.3-5

We believe that it is premature to release guidelines recommending changes in the use of anti-HIV drugs or the introduction of statins for abnormal lipid profiles except in patients with an immediate, high absolute risk of cardiovascular disease. However, current knowledge does support recommendations to modify lifestyle risk factors in patients who are receiving antiretroviral therapy.

Nina Friis-Møller, M.D.
Hvidovre University Hospital, 2650 Hvidovre, Denmark

Caroline Sabin, Ph.D.
Royal Free and University College Medical Schools, London NW3 2PF, United Kingdom

Jens D. Lundgren, M.D., D.M.Sc.
Hvidovre University Hospital, 2650 Hvidovre, Denmark
jdl@cphiv.dk

for the DAD Steering Committee

5 References

1. 1

   Holmberg SD, Moorman AC, Williamson JM, et al. Protease inhibitors and cardiovascular outcome in patients with HIV-1. Lancet 2002;360:1747-1748
   CrossRef | Web of Science | Medline

2. 2

   The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003;349:1993-2003
   Full Text | Web of Science | Medline

3. 3

   Dragsted UB, Gerstoft J, Pedersen C, et al. Randomized trial to evaluate indinavir/ritonavir versus saquinavir/ritonavir in human immunodeficiency virus type 1-infected patients: the MaxCmin1 Trial. J Infect Dis 2003;188:635-642
   CrossRef | Web of Science | Medline

4. 4

   Fontas E, van Leth F, Sabin C, et al. Lipid profiles in HIV-1-infected individuals receiving combination antiretroviral therapy: are different protease inhibitors or non-nucleoside reverse transcriptase inhibitors associated with different lipid profiles? J Infect Dis (in press).
   

5. 5

   Carr A, Miller J, Law M, Cooper DA. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS 2000;14:F25-F32
   CrossRef | Web of Science | Medline

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8. 8

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9. 9

   R. C. Kaplan, L. A. Kingsley, A. R. Sharrett, X. Li, J. Lazar, P. C. Tien, W. J. Mack, M. H. Cohen, L. Jacobson, S. J. Gange. (2007) Ten-Year Predicted Coronary Heart Disease Risk in HIV-Infected Men and Women. Clinical Infectious Diseases 45:8, 1074-1081
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12. 12

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13. 13

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14. 14

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16. 16

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17. 17

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18. 18

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