Correspondence

Absence of Cardiac Toxicity of Zidovudine in Infants

N Engl J Med 2001; 344:458February 8, 2001

Article

To the Editor:

In their article, Lipshultz and colleagues (Sept. 14 issue)1 conclude that perinatal exposure to zidovudine does not result in echocardiographic evidence of acute or chronic cardiac abnormalities. The importance of perinatal treatment with antiretroviral agents in pregnant women who are infected with human immunodeficiency virus type 1 (HIV-1) is clear. Despite the importance of this study, the long-term effects of zidovudine on the heart in children and adults may require further exploration.

My group and others demonstrated that high-dose zidovudine caused mitochondrial cardiomyopathy in rats2 and worsened cardiac dysfunction in adult transgenic mice with AIDS.3 This resulted in alterations in the steady-state abundance of mitochondrial DNA, mitochondrial RNA, and mitochondrially encoded polypeptides in affected tissues and correlated with molecular evidence of cardiac remodeling.4 Clinical data suggest that treatment with zidovudine is a risk factor for the development of cardiomyopathy in adults with AIDS.5 Taken together, clinical and experimental data indicate that potential mechanisms for zidovudine toxicity relate to cumulative exposure to zidovudine, its resultant effects on mitochondrial biogenesis, and subsequent alterations in the energetics of the adult heart.

If zidovudine cardiac toxicity does occur in children, the mechanisms may be somewhat different from those in adults, owing to intrinsic biologic differences. The growth and differentiation of cardiac myocytes are ongoing, extensive, and rapid in children, whereas in adults these events are substantially attenuated. In the present study, the duration of exposure to zidovudine was relatively short. The median duration of postnatal zidovudine exposure was 42 days (and of exposure in utero, 66 days). These durations of exposure resemble some of those used in rats that resulted in zidovudine cardiac toxicity,2 but do not resemble those in treated adults, in whom durations may be longer.

William Lewis, M.D.
Emory University, Atlanta, GA 30322

5 References

1. 1

   Lipshultz SE, Easley KA, Orav EJ, et al. Absence of cardiac toxicity of zidovudine in infants. N Engl J Med 2000;343:759-766
   Full Text | Web of Science | Medline

2. 2

   Lewis W, Papoian T, Gonzalez B, et al. Mitochondrial ultrastructural and molecular changes induced by zidovudine in rat hearts. Lab Invest 1991;65:228-236
   Web of Science | Medline

3. 3

   Lewis W, Grupp IL, Grupp G, et al. Cardiac dysfunction occurs in the HIV-1 transgenic mouse treated with zidovudine. Lab Invest 2000;80:187-197
   CrossRef | Web of Science | Medline

4. 4

   Lewis W, Gonzalez B, Chomyn A, Papoian T. Zidovudine induces molecular, biochemical, and ultrastructural changes in rat skeletal muscle mitochondria. J Clin Invest 1992;89:1354-1360
   CrossRef | Web of Science | Medline

5. 5

   Barbaro G, Di Lorenzo G, Grisorio B, Barbarini G. Incidence of dilated cardiomyopathy and detection of HIV in myocardial cells of HIV-positive patients. N Engl J Med 1998;339:1093-1099
   Full Text | Web of Science | Medline

Author/Editor Response

Dr. Lipshultz replies:

To the Editor: I agree with Dr. Lewis that it would be desirable to have more information on both the length of zidovudine therapy and the cumulative dose of zidovudine, as well as an assessment of late zidovudine cardiac toxicity in long-term survivors. We acknowledged these three limitations in our article.

Although we did not report measurable zidovudine cardiac toxicity after perinatal exposure and in previous work reached a similar conclusion with respect to older HIV-infected children,1 this does not rule out the possibility of a vulnerable subpopulation. The evidence that zidovudine can be associated with symptomatic myopathy in human skeletal muscle and in animals is powerful. The true effect of zidovudine on the development of cardiomyopathy in HIV-infected patients has been difficult to separate from the effects of increasing severity of HIV disease, a recognized confounding factor associated with cardiomyopathy.

Potentially vulnerable subpopulations at relatively high risk for zidovudine cardiotoxicity may include patients with a genetic predisposition to mitochondrial dysfunction; those with nutritional deficiencies, including deficiencies of carnitine and selenium; those receiving other medications known to affect mitochondrial function (e.g., anthracycline chemotherapy for Kaposi's sarcoma); and those with preexisting ventricular dysfunction due to advanced HIV disease or other causes. I agree with Dr. Lewis that research in this area should continue.

Steven E. Lipshultz, M.D.
University of Rochester Medical Center, Rochester, NY 14642

1 References

1. 1

   Lipshultz SE, Orav EJ, Sanders SP, Hale AR, McIntosh K, Colan SD. Cardiac structure and function in children with human immunodeficiency virus infection treated with zidovudine. N Engl J Med 1992;327:1260-1265
   Full Text | Web of Science | Medline

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