Cardiovascular Toxicology

, Volume 4, Issue 3, pp 271–279 | Cite as

Cardiovascular effects of HAART in infants and children of HIV-infected mothers

  • Karolina M. Zareba
  • Jill E. Lavigne
  • Steven E. Lipshultz


Over the past decade, the course of human immunodeficiency virus (HIV) infection has been markedly altered by highly active antiretroviral therapy (HAART). As advances in early diagnosis and aggressive therapy, as well as better supportive care, become available to more HIV-infected patients, survival is being prolonged and more patients are experiencing cardiac abnormalities. Cardiovascular manifestations of pediatric HIV infection have especially proven to be an ongoing challenge to practicing physicians, who face cardiac abnormalities ranging from asymptomatic cardiomyopathy to severe heart failure. Antiretroviral therapy has substantially decreased vertical transmission of HIV; however, studies of adults receiving HAART have found increased peripheral and coronary artery disease. Children exposed to this therapy in utero are thus at an increased risk for toxicity and cardiac abnormalities, regardless of their HIV status. Preliminary studies have reported complications including lactic acidosis and mitochondrial toxicity, as well as cardiomyopathy. Further studies are needed to explore the long-term effects and possible toxicities of prophylactic antiretroviral therapy on infants born to HIV-infected mothers.

Key Words

HIV AIDS cardiomyopathy dyslipidemia mitochondrial toxicity HAART prophylactic antiretroviral therapy 


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  1. 1.
    AIDS Epidemic Update December 2002. http://www. Accessed November 15, 2003.Google Scholar
  2. 2.
    Mofenson, L.M. and McIntyre, J.A. (2000). Advances and research directions in the prevention of mother-to-child HIV-1 transmission. Lancet 355:2237–2244.PubMedCrossRefGoogle Scholar
  3. 3.
    Lipshultz, S.E., Chanock, S., Sanders, S.P., Colan, S.D., Perez-Atayde, A. and McIntosh, K. (1989). Cardiovascular manifestations of human immunodeficiency virus infection in infants and children. Am. J. Cardiol. 63:1489–1497.PubMedCrossRefGoogle Scholar
  4. 4.
    Lipshultz, S.E. (1998). Dilated cardiomyopathy in HIV-infected patients. N. Engl. J. Med. 339:1153–1155.PubMedCrossRefGoogle Scholar
  5. 5.
    Lipshultz, S.E., Easley, K.A., Orav, E.J., Kaplan, S., Starc, T.J., Bricker, J.T., et al. (1998). Left ventricular structure and function in children infected with human immunodeficiency virus: the prospective P2C2 HIV Multicenter Study. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (P2C2 HIV) Study Group. Circulation 97:1246–1256.PubMedGoogle Scholar
  6. 6.
    Lipshultz, S.E., Easley, K.A., Orav, E.J., Kaplan, S., Starc, T.J., Bricker, J.T., et al. (2000). Cardiac dysfunction and mortality in HIV-infected children: the Prospective P2C2 HIV Multicenter Study. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (P2C2 HIV) Study Group. Circulation 102:1542–1548.PubMedGoogle Scholar
  7. 7.
    Lipshultz, S.E., Easley, K.A., Orav, E.J., Kaplan, S., Starc, T.J., Bricker, J.T., et al. (2002). Cardiovascular status of infants and children of women infected with HIV-1 (P2C2 HIV): a cohort study. Lancet 360:368–373.PubMedCrossRefGoogle Scholar
  8. 8.
    Starc, T.J., Lipshultz, S.E., Easley, K.A., Kaplan, S., Bricker, J.T., Colan, S.D., et al. (2002). Incidence of cardiac abnormalities in children with human immunodeficiency virus infection: the prospective P2C2 HIV study. J. Pediatr. 141:327–334.PubMedCrossRefGoogle Scholar
  9. 9.
    Al-Attar, I., Orav, E.J., Exil, V., Vlach, S.A., and Lipshultz, S.E. (2003). Predictors of cardiac morbidity and related mortality in children with acquired immunodeficiency syndrome. J. Am. Coll. Cardiol. 41:1598–1605.PubMedCrossRefGoogle Scholar
  10. 10.
    Fisher, S.D., Easley, K.A., and Orav, E.J. (2004). Mild dilated cardiomyopathy and increased left ventricular mass predict mortality: full-term results from the prospective P2C2 HIV Multicenter Study. J. Am. Coll. Cardiol., in press.Google Scholar
  11. 11.
    Hornberger, L.K., Lipshultz, S.E., Easley, K.A., Colan, S.D., Schwartz, M., Kaplan, S., et al. (2000). Cardiac structure and function in fetuses of mothers infected with HIV: the prospective PCHIV multicenter study. Am. Heart J. 140:575–584.PubMedCrossRefGoogle Scholar
  12. 12.
    Felker, G.M., Thompson, R.E., Hare, J.M., Hruban, R.H., Clemetson, D.E., Howard, D.L., et al. (2000). Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N. Engl. J. Med. 342:1077–1084.PubMedCrossRefGoogle Scholar
  13. 13.
    Lipshultz, S.E., Fisher, S.D., Lai, W.W., and Miller, T.L. (2003). Cardiovascular risk factors, monitoring, and therapy for HIV-infected patients. AIDS 17:S96-S122.PubMedGoogle Scholar
  14. 14.
    Heidenreich, P.A., Eisenberg, M.J., Kee, L.L., Somelofski, C.A., Hollander, H., Schiller, N.B., et al. (1995). Pericardial effusion in AIDS. Incidence and survival. Circulation 92:3229–3234.PubMedGoogle Scholar
  15. 15.
    Mesa, R.A., Edell, E.S., Dunn, W.F., and Edwards, W.D. (1998). Human immunodeficiency virus infection and pulmonary hypertension: two new cases and a review of 86 reported cases. Mayo Clin. Proc. 73:37–45.PubMedCrossRefGoogle Scholar
  16. 16.
    Jenson, H.B., and Pollock, B.H. (1998). Cardiac cancers in HIV-infected patients, in Cardiology in AIDS (Lipshultz, S.E., ed.), Chapman and Hall, New York, pp. 255–263.Google Scholar
  17. 17.
    Dube, M. P., Sprecher, D., Henry, W. K., Aberg, J.A., Torriani, F.J., Hodis, H.N., et al. (2000). Preliminary guidelines for the evaluation and management of dyslipidemia in adults infected with human immunodeficiency virus and receiving antiretroviral therapy: recommendations of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group. Clin. Infect. Dis. 31:1216–1224.PubMedCrossRefGoogle Scholar
  18. 18.
    Maggi, P., Serio, G., Epifani, G., Fiorentino, G., Saracino, A., Fico, C., et al. (2000). Premature lesions of the carotid vessels in HIV-1-infected patients treated with protease inhibitors. AIDS 14:F123-F128.PubMedCrossRefGoogle Scholar
  19. 19.
    Danner, S.A., Carr, A., Leonard, J.M., Lehman, L.M., Gudiol, F., Gonzales, J., et al. (1995). A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. European-Australian Collaborative Ritonavir Study Group. N. Engl. J. Med. 333: 1528–1533.PubMedCrossRefGoogle Scholar
  20. 20.
    Purnell, J.Q., Zambon, A., Knopp, R.H., Pizzuti, D.J., Achari, R., Leonard, J.M., et al. (2000). Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects. AIDS 14:51–57.PubMedCrossRefGoogle Scholar
  21. 21.
    Friis-Moller, N., Sabin, C.A., Weber, R., d’Arminio Monforte, A., El-Sadr, W.M., Reiss, P., et al. (2003). Combination antiretroviral therapy and the risk of myocardial infarction. N. Engl. J. Med. 349:1993–2003.PubMedCrossRefGoogle Scholar
  22. 22.
    Schambelan, M., Benson, C.A., Carr, A., Currier, J.S., Dube, M.P., Gerber, J.G., et al. (2002). Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel. J. Acquir. Immune Defic. Syndr. 31:257–275.PubMedGoogle Scholar
  23. 23.
    Hoffmann, C. and Jaeger, H. (2001). Cardiology and AIDS—HAART and the consequences. Ann. NY Acad. Sci. 946:130–144.PubMedCrossRefGoogle Scholar
  24. 24.
    Lipshultz, S.E., Fisher, S.D., Lai, W.W., and Miller, T.L. (2001). Cardiovascular monitoring and therapy for HIV-infected patients. Ann. NY Acad. Sci. 946:236–273.PubMedCrossRefGoogle Scholar
  25. 25.
    Scevola, D., Di Matteo, A., Lanzarini, P., Uberti, F., Scevola, S., Bernini, V., et al. (2003). Effects of exercise and strength training on cardiovascular status in HIV-infected patients receiving highly active antiretroviral therapy. AIDS 17:S123-S129.PubMedCrossRefGoogle Scholar
  26. 26.
    Lindegren, M.L., Byers, R.H., Jr., Thomas, P., Davis, S.F., Caldwell, B., Rogers, M., et al. (1999). Trends in perinatal transmission of HIV/AIDS in the United States. JAMA 282:531–538.PubMedCrossRefGoogle Scholar
  27. 27.
    Connor, E.M., Sperling, R.S., Gelber, R., Kiselev, P., Scott, G., O’Sullivan, M.J., et al. (1994). Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N. Engl. J. Med. 331:1173–1180.PubMedCrossRefGoogle Scholar
  28. 28.
    Mofenson, L.M. and Munderi, P. (2002). Safety of antiretroviral prophylaxis of perinatal transmission for HIV-infected pregnant women and their infants. J. Acquir. Immune Defic. Syndr. 30:200–215.PubMedGoogle Scholar
  29. 29.
    Dabis, F., Msellati, P., Meda, N., Welffens-Ekra, C., You, B., Manigart, O., et al. (1999). 6-month efficacy, tolerance and acceptability of a short regimen of oral zidovudine to reduce vertical transmission of HIV in breastfed children in Côte d’Ivoire and Burkina Faso: a double-blind placebo-controlled multicentre trial. Lancet 353:786–792.PubMedCrossRefGoogle Scholar
  30. 30.
    Shaffer, N., Chuachoowong, R., Mock, P. A., Bhadrakom, C., Siriwasin, W., Young, N.L., et al. (1999). Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomised controlled trial. Lancet 353:773–780.PubMedCrossRefGoogle Scholar
  31. 31.
    Wiktor, S.Z., Ekpini, E., Karon, J.M., Nkengasong, J., Maurice, C., Severin, S.T., et al. (1999). Short-course zidovudine for prevention of mother-to-child transmission of HIV-1 in Abidjan, Côte d’Ivoire: a randomised trial. Lancet 353:781–785.PubMedCrossRefGoogle Scholar
  32. 32.
    Guay, L.A., Musoke, P., Fleming, T., Bagenda, D., Allen, M., Nakabiito, C., et al. (1999). Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 354: 795–802.PubMedGoogle Scholar
  33. 33.
    Brinkman, K., ter Hofstede, H.J.M., Burger, D.M., Smeitink, J.A.M., and Koopmans, P.P. (1998). Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as a common pathway. AIDS 12:1735–1744.PubMedCrossRefGoogle Scholar
  34. 34.
    Lipshultz, S.E., Giantris, A.L., Lipsitz, S.R., Kimball Dalton, V., Asselin, B.L., Barr, R.D., et al. (2002). Continuous doxorubicin infusion is not cadioprotective: the Dana Farber 91-01 ALL protocol. J. Clin. Oncol. 20:1677–1682.PubMedCrossRefGoogle Scholar
  35. 35.
    Lewis, W., Haase, C.P., Raidel, S.M., Russ, R.B., Sutliff, R.L., Hoit, B.D., et al. (2001). Combined antiretroviral therapy causes cardiomyopathy and elevates plasma lactate in transgenic AIDS mice. Lab. Invest. 81:1527–1536.PubMedGoogle Scholar
  36. 36.
    Gerschenson, M., Erhart, S.W., Paik, C.Y., St. Claire, M.C., Nagashima, K., Skopets, B., et al. (2000) Fetal mitochondrial heart and skeletal muscle damage in Erythrocebus patas monkeys exposed in utero to 3′-azido-3′-deoxythymidine. AIDS Res. Hum. Retroviruses 16: 635–644.PubMedCrossRefGoogle Scholar
  37. 37.
    Ewings, E.L., Gerschenson, M., St. Claire, M.C., Nagashima, K., Skopets, B., Harbaugh, S.W., et al. (2000). Genotoxic and functional consequences of transplacental zidovudine exposure in fetal monkey brain mitochondria. J. Acquir. Immune Defic. Syndr. 24:100–105.PubMedGoogle Scholar
  38. 38.
    Poirier, M.C., Divi, R.L., Al-Harthi, L., Olivero, O.A., Nguyen, V., Walker, B., et al. (2003). Long-term mitochondrial toxicity in HIV-uninfected infants born to HIV-infected mothers. J. Acquir. Immune Defic. Syndr. 33:175–183.PubMedCrossRefGoogle Scholar
  39. 39.
    Alimenti, A., Burdge, D.R., Ogilvie, G.S., Money, D.M., and Forbes, J.C. (2003). Lactic acidemia in human immunodeficiency virus-uninfected infants exposed to perinatal antiretroviral therapy. Pediatr. Infect. Dis. J. 22:782–789.PubMedCrossRefGoogle Scholar
  40. 40.
    Blanche, S., Tardieu, M., Rustin, P., Slama, A., Barret, B., Firtion, G., et al. (1999). Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 354:1084–1089.PubMedCrossRefGoogle Scholar
  41. 41.
    Lipshultz, S.E., Orav, E.J., Sanders, S.P., Hale, A.R., McIntosh, K., and Colan, S.D. (1992). Cardiac structure and function in children with human immunodeficiency virus infection treated with zidovudine. N. Engl. J. Med. 327:1260–1265.PubMedCrossRefGoogle Scholar
  42. 42.
    Lipshultz, S.E., Easley, K.A., Orav, E.J., Kaplan, S., Starc, T.J., Bricker, J.T., et al. (2000). Absence of cardiac toxicity of zidovudine in infants. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study Group. N. Engl. J. Med. 343:759–766.PubMedCrossRefGoogle Scholar
  43. 43.
    Lavigne, J.E., Shearer, W.T., Thompson, B., Orav, E.J., Starc, T.J., Colan, S.D., et al., for the CHAART Study Group (2004). Cardiovascular outcomes of pediatric seroreverters perinatally exposed to HAART: design of a longitudinal clinical study. Cardiovascular Toxicology, in press.Google Scholar
  44. 44.
    Harmon, W.G., Dadlani, G.H., Fisher, S.D., and Lipshultz, S.E. (2002). Myocardial and pericardial disease in HIV. Curr. Treat. Options Cardiovasc. Med. 4(6):497–509.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2004

Authors and Affiliations

  • Karolina M. Zareba
    • 1
  • Jill E. Lavigne
    • 2
  • Steven E. Lipshultz
    • 3
    • 4
  1. 1.University of Rochester School of Medicine and DentistryRochester
  2. 2.Department of Pediatric CardiologyGolisano Children’s Hospital at Strong University of Rochester Medical CenterRochester
  3. 3.Department of Pediatrics (D820)University of Miami School of MedicineMiami
  4. 4.The Holtz Children’s HospitalMiami

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