Drug Safety

, Volume 30, Issue 10, pp 845–859

Mitochondrial Disorders among Infants Exposed to HIV and Antiretroviral Therapy

  • Michele Jonsson Funk
  • Suzanne E. Belinson
  • Jeanne M. Pimenta
  • Megan Morsheimer
  • David C. Gibbons
Review Article

Abstract

Although antiretroviral therapy (ART) is critical for preventing mother-to-child transmission of HIV, concern has been raised about the possibility that it may cause mitochondrial dysfunction in infants. There is adequate evidence for a mechanism by which exposure to nucleoside reverse transcriptase inhibitors (NRTIs) could lead to mitochondrial dysfunction; animal studies have shown evidence of mitochondrial dysfunction in the offspring of animals treated with NRTIs and mitochondrial disorders occur in adults treated with NRTIs. This systematic review synthesises the published research on mitochondrial dysfunction and disorders in infants exposed to HIV and antiretrovirals.

We found conflicting evidence regarding the possible association of in utero ART exposure with mortality and morbidity due to mitochondrial dysfunction. ART exposure in utero or postpartum was associated with persistent decreases in lymphocytes, neutrophils and platelets as well as an increased risk of transient lactic acidaemia, anaemia and mitochondrial DNA depletion, although these laboratory findings were generally not associated with clinical symptoms.

We conclude that large, prospective studies of HIV-exposed infants are needed to resolve the discrepant results regarding morbidity and mortality related to mitochondrial disorders, to ascertain the clinical significance of effects on laboratory values, to determine whether or not the incidence of mitochondrial disorders differs by regimen and to develop predictive models that might identify which infants are at the greatest risk. The challenges that remain to be addressed include the development of a sensitive but affordable screening algorithm in combination with specific diagnostic criteria; consistent collection of data on ART exposure and other risk factors, long-term follow-up of HIV-exposed but uninfected children and implementation in resource-limited settings.

Supplementary material

40264_2012_30100845_MOESM1_ESM.pdf (150 kb)
Supplementary material, approximately 153 KB.

References

  1. 1.
    Connor EM, Sperling RS, Gelber R, et al. 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 1994; 331(18): 1173–80PubMedCrossRefGoogle Scholar
  2. 2.
    Rates of mother-to-child transmission of HIV-1 in Africa, America, and Europe: results from 13 perinatal studies. The Working Group on Mother-To-Child Transmission of HIV. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 8 (5): 506–10Google Scholar
  3. 3.
    Mofenson LM. Perinatal exposure to zidovudine: benefits and risks. N Engl J Med 2000; 343(11): 803–5PubMedCrossRefGoogle Scholar
  4. 4.
    Blanche S, Tardieu M, Rustin P, et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 1999; 354(9184): 1084–9PubMedCrossRefGoogle Scholar
  5. 5.
    Venerosi A, Calamandrei G, Alleva E. Animal models of anti-HIV drugs exposure during pregnancy: effects on neurobehavioral development. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26(4): 747–61PubMedCrossRefGoogle Scholar
  6. 6.
    Lewis W, Day BJ, Copeland WC. Mitochondrial toxicity of NRTI antiviral drugs: an integrated cellular perspective. Nat Rev Drug Discov 2003; 2(10): 812–22PubMedCrossRefGoogle Scholar
  7. 7.
    Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med 1995; 1(5): 417–22PubMedCrossRefGoogle Scholar
  8. 8.
    Darin N, Oldfors A, Moslemi AR, et al. The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA anbormalities. Ann Neurol 2001; 49(3): 377–83 858PubMedCrossRefGoogle Scholar
  9. 9.
    Uusimaa J, Remes AM, Rantala H, et al. childhood encephalo-pathies and myopathies: a prospective study in a defined population to assess the frequency of mitochondrial disorders. Pediatrics 2000; 105(3): 598–603PubMedCrossRefGoogle Scholar
  10. 10.
    Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969–1996. Pediatrics 2000; 105(1): e10PubMedCrossRefGoogle Scholar
  11. 11.
    Dionisi-Vici C, Rizzo C, Burlina AB, et al. Inborn errors of metabolism in the Italian pediatric population: a national retrospective survey. J Pediatr 2002; 140(3): 321–7PubMedCrossRefGoogle Scholar
  12. 12.
    Bernier FP, Boneh A, Dennett X, et al. Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 2002; 59(9): 1406–11PubMedCrossRefGoogle Scholar
  13. 13.
    Walker UA, Collins S, Byrne E. Respiratory chain encephalomyopathies: a diagnostic classification. Eur Neurol 1996; 36(5): 260–7PubMedCrossRefGoogle Scholar
  14. 14.
    Scaglia F, Towbin JA, Craigen WJ, et al. Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics 2004; 114(4): 925–31PubMedCrossRefGoogle Scholar
  15. 15.
    Casula M, Bosboom-Dobbelaer I, Smolders K, et al. Infection with HIV-1 induces a decrease in mtDNA. J Infect Dis 2005; 191(9): 1468–71PubMedCrossRefGoogle Scholar
  16. 16.
    Miro O, Lopez S, Martinez E, et al. Mitochondrial effects of HIV infection on the peripheral blood mononuclear cells of HIV-infected patients who were never treated with antire-trovirals. Clin Infect Dis 2004; 39(5): 710–6PubMedCrossRefGoogle Scholar
  17. 17.
    Casula M, Weverling GJ, Wit FW, et al. Mitochondrial DNA and RNA increase in peripheral blood mononuclear cells from HIV-1-infected patients randomized to receive stavudine-containing or stavudine-sparing combination therapy. J Infect Dis 2005; 192(10): 1794–800PubMedCrossRefGoogle Scholar
  18. 18.
    Miura T, Goto M, Hosoya N, et al. Depletion of mitochondrial DNA in HIV-1-infected patients and its amelioration by antiretroviral therapy. J Med Virol 2003; 70(4): 497–505PubMedCrossRefGoogle Scholar
  19. 19.
    Cossarizza A, Moyle G. Antiretroviral nucleoside and nucleotide analogues and mitochondria. AIDS 2004; 18(2): 137–51PubMedCrossRefGoogle Scholar
  20. 20.
    Richman DD, Fischl MA, Grieco MH, et al. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo-controlled trial. N Engl J Med 1987; 317(4): 192–7PubMedCrossRefGoogle Scholar
  21. 21.
    Nolan D, Mallal S. Complications associated with NRTI therapy: update on clinical features and possible pathogenic mechanisms. Antivir Ther 2004; 9(6): 849–63PubMedGoogle Scholar
  22. 22.
    Lemberg DA, Palasanthiran P, Goode M, et al. Tolerabilities of antiretrovirals in paediatric HIV infection. Drug Saf 2002; 25(14): 973–91PubMedCrossRefGoogle Scholar
  23. 23.
    Venhoff N, Walker UA. Mitochondrial disease in the offspring as a result of antiretroviral therapy. Expert Opin Drug Saf 2006; 5(3): 373–81PubMedCrossRefGoogle Scholar
  24. 24.
    Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 2000; 22(6): 685–708PubMedCrossRefGoogle Scholar
  25. 25.
    Lonergan JT, McComsey GA, Fisher RL, et al., on behalf of the ESS40010 (TARHEEL) Study Team. Lack of recurrence of hyperlactatemia in HIV-infected patients switched from stavudine to abacavir or zidovudine. J Acquir Immune Defic Syndr 2004; 36(4): 935–42PubMedCrossRefGoogle Scholar
  26. 26.
    McComsey GA, Paulsen DM, Lonergan JT, et al. Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine. AIDS 2005; 19(1): 15–23PubMedCrossRefGoogle Scholar
  27. 27.
    Mhiri C, Baudrimont M, Bonne G, et al. Zidovudine myopathy: a distinctive disorder associated with mitochondrial dysfunction. Ann Neurol 1991; 29(6): 606–14PubMedCrossRefGoogle Scholar
  28. 28.
    Barret B, Tardieu M, Rustin P, et al. Persistent mitochondrial dysfunction in HIV-1-exposed but uninfected infants: clinical screening in a large prospective cohort. AIDS 2003; 17(12): 1769–85PubMedCrossRefGoogle Scholar
  29. 29.
    Herman JS, Easterbrook PJ. The metabolic toxicities of antiretroviral therapy. Int J STD AIDS 2001; 12(9): 555–62PubMedCrossRefGoogle Scholar
  30. 30.
    Brinkman K, Kakuda TN. Mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors: a looming obstacle for long-term antiretroviral therapy? Curr Opin Infect Dis 2000; 13(1): 5–1Google Scholar
  31. 31.
    Volberding PA, Baker KR, Levine AM. Human immunodeficiency virus hematology. Hematology Am Soc Hematol Educ Program 2003: 294–313Google Scholar
  32. 32.
    Gerschenson M, Erhart SW, Paik CY, et al. Fetal mitochondrial heart and skeletal muscle damage in Erythrocebus patas monkeys exposed in utero to 3′-azido-3′-deoxythymidine. AIDS Res Hum Retroviruses 2000; 16(7): 635–44PubMedCrossRefGoogle Scholar
  33. 33.
    Ewings EL, Gerschenson M, St Claire MC, et al. Genotoxic and functional consequences of transplacental zidovudine exposure in fetal monkey brain mitochondria. J Acquir Immune Defic Syndr 2000; 24(2): 100–5PubMedGoogle Scholar
  34. 34.
    Gerschenson M, Nguyen V, Ewings EL, et al. Mitochondrial toxicity in fetal Erythrocebus patas monkeys exposed trans-placentally to zidovudine plus lamivudine. AIDS Res Hum Retroviruses 2004; 20(1): 91–100PubMedCrossRefGoogle Scholar
  35. 35.
    European Collaborative Study. Exposure to antiretroviral therapy in utero or early life: the health of uninfected children born to HIV-infected women. J Acquir Immune Defic Syndr 2003; 32(4): 380–7CrossRefGoogle Scholar
  36. 36.
    Nucleoside exposure in the children of HIV-infected women receiving antiretroviral drugs: absence of clear evidence for mitochondrial disease in children who died before 5 years of age in five United States cohorts. J Acquir Immune Defic Syndr 2000; 25 (3): 261–8Google Scholar
  37. 37.
    Bulterys M, Nesheim S, Abrams EJ, et al. Lack of evidence of mitochondrial dysfunction in the offspring of HIV-infected women: retrospective review of perinatal exposure to antiretroviral drugs in the Perinatal AIDS Collaborative Transmission Study. Ann N Y Acad Sci 2000; 918: 212–21PubMedCrossRefGoogle Scholar
  38. 38.
    Culnane M, Fowler M, Lee SS, et al. Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. Pediatric AIDS Clinical Trials Group Protocol 219/076 Teams. JAMA 1999; 281(2): 151–7Google Scholar
  39. 39.
    Lipshultz SE, Easley KA, Orav EJ, et al. Absence of cardiac toxicity of zidovudine in infants. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study Group. N Engl J Med 2000; 343(11): 759–66Google Scholar
  40. 40.
    Bellón Cano JM, Sanchez-Ramon S, Ciria L, et al. The effects on infants of potent antiretroviral therapy during pregnancy: a report from Spain. Med Sci Monit 2004; 10 (5): CR179-84Google Scholar
  41. 41.
    Chotpitayasunondh T, Vanprapar N, Simonds RJ, et al. Safety of late in utero exposure to zidovudine in infants born to human immunodeficiency virus-infected mothers: Bangkok. Bangkok Collaborative Perinatal HIV Transmission Study Group. Pediatrics 2001; 107(1): E5PubMedCrossRefGoogle Scholar
  42. 42.
    Behrman R, Kliegman R, Jenson H. Nelson textbook of pediatrics. 17th ed. Philadelphia (PA): Saunders, 2004Google Scholar
  43. 43.
    Landreau-Mascaro A, Barret B, Mayaux MJ, et al. Risk of early febrile seizure with perinatal exposure to nucleoside analogues. Lancet 2002; 359(9306): 583–4859PubMedCrossRefGoogle Scholar
  44. 44.
    Alimenti A, Burdge DR, Ogilvie GS, et al. Lactic acidemia in human immunodeficiency virus-uninfected infants exposed to perinatal antiretroviral therapy. Pediatr Infect Dis J 2003; 22(9): 782–9PubMedCrossRefGoogle Scholar
  45. 45.
    Noguera A, Fortuny C, Munoz-Almagro C, et al. Hyperlactatemia in human immunodeficiency virus-uninfected infants who are exposed to antiretrovirals. Pediatrics 2004; 114(5): e598–603PubMedCrossRefGoogle Scholar
  46. 46.
    Giaquinto C, De Romeo A, Giacomet V, et al. Lactic acid levels in children perinatally treated with antiretroviral agents to prevent HIV transmission. AIDS 2001; 15(8): 1074–5PubMedCrossRefGoogle Scholar
  47. 47.
    Le Chenadec J, Mayaux MJ, Guihenneuc-Jouyaux C, et al. Perinatal antiretroviral treatment and hematopoiesis in HIV-uninfected infants. AIDS 2003; 17(14): 2053–61PubMedCrossRefGoogle Scholar
  48. 48.
    European Collaborative Study. Levels and patterns of neutrophil cell counts over the first 8 years of life in children of HIV-1-infected mothers. AIDS 2004; 18(15): 2009–17CrossRefGoogle Scholar
  49. 49.
    Lambert JS, Nogueira SA, Abreu T, et al. A pilot study to evaluate the safety and feasibility of the administration of AZT/3TC fixed dose combination to HIV infected pregnant women and their infants in Rio de Janeiro, Brazil. Sex Transm Infect 2003; 79(6): 448–52PubMedCrossRefGoogle Scholar
  50. 50.
    Fowler DA, Xie MY, Sommadossi JP. Protection and rescue from 2′,3′-dideoxypyrimidine nucleoside analog toxicity by hemin in human bone marrow progenitor cells. Antimicrob Agents Chemother 1996; 40(1): 191–5PubMedGoogle Scholar
  51. 51.
    Gribaldo L, Malerba I, Collotta A, et al. Inhibition of CFU-E/ BFU-E by 3′-azido-3′-deoxythymidine, chlorpropamide, and protoporphirin IX Zinc (II): a comparison between direct exposure of progenitor cells and long-term exposure of bone marrow cultures. Toxicol Sci 2000; 58: 96–101PubMedCrossRefGoogle Scholar
  52. 52.
    Panburana P, Sirinavin S, Phuapradit W, et al. Elective cesarean delivery plus short-course lamivudine and zidovudine for the prevention of mother-to-child transmission of human immunodeficiency virus type 1. Am J Obstet Gynecol 2004; 190(3): 803–8PubMedCrossRefGoogle Scholar
  53. 53.
    Bridges KR. Sideroblastic anemia: a mitochondrial disorder. J Pediatr Hematol Oncol 1997; 19(4): 274–8PubMedCrossRefGoogle Scholar
  54. 54.
    Poirier MC, Divi RL, Al-Harthi L, et al. Long-term mitochondrial toxicity in HIV-uninfected infants born to HIV-infected mothers. J Acquir Immune Defic Syndr 2003; 33(2): 175–83PubMedCrossRefGoogle Scholar
  55. 55.
    Divi RL, Walker VE, Wade NA, et al. Mitochondrial damage and DNA depletion in cord blood and umbilical cord from infants exposed in utero to Combivir. AIDS 2004; 18(7): 1013–21PubMedCrossRefGoogle Scholar
  56. 56.
    Shiramizu B, Shikuma KM, Kamemoto L, et al. Placenta and cord blood mitochondrial DNA toxicity in HIV-infected women receiving nucleoside reverse transcriptase inhibitors during pregnancy. J Acquir Immune Defic Syndr 2003; 32(4): 370–4PubMedCrossRefGoogle Scholar
  57. 57.
    Martin AM, Hammond E, Nolan D, et al. Accumulation of mitochondrial DNA mutations in human immunodeficiency virus-infected patients treated with nucleoside-analogue reverse-transcriptase inhibitors. Am J Hum Genet 2003; 72(3): 549–60PubMedCrossRefGoogle Scholar
  58. 58.
    Skladal D, Sudmeier C, Konstantopoulou V, et al. The clinical spectrum of mitochondrial disease in 75 pediatric patients. Clin Pediatr (Phila) 2003; 42(8): 703–10CrossRefGoogle Scholar
  59. 59.
    Moyle G. Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity. Clin Ther 2000; 22(8): 911–36; discussion 898PubMedCrossRefGoogle Scholar
  60. 60.
    Report on the global AIDS epidemic. Geneva: UNAIDS; 2006 May [online]. Availble from URL: http://www.unaids.org/en/HIV_data/2006GlobalReport/default.asp [Accessed 2007 Aug 23]
  61. 61.
    Brogly S, Ylitalo N, Mofenson L, et al. In utero nucleoside reverse transcriptase inhibitor exposure and signs of possible mitochondrial dysfunction in HIV-uninfected children in the pediatric AIDS clinical trials group protocols 219 & 219C [abstract no. THAB0103]. Programs & Abstracts from the XVI International AIDS Conference; 2006 Aug 13–18; Toronto (ON)Google Scholar
  62. 62.
    Taha TE, Kumwenda NI, Hoover DR, et al. Nevirapine and zidovudine at birth to reduce perinatal transmission of HIV in an African setting: a randomized controlled trial. JAMA 2004; 292(2): 202–9PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • Michele Jonsson Funk
    • 1
  • Suzanne E. Belinson
    • 1
    • 2
  • Jeanne M. Pimenta
    • 3
  • Megan Morsheimer
    • 2
  • David C. Gibbons
    • 4
  1. 1.Department of Epidemiology, CB#7521University of North CarolinaChapel HillUSA
  2. 2.Worldwide Epidemiology, GlaxoSmithKline Research & DevelopmentResearch Triangle ParkUSA
  3. 3.Worldwide Epidemiology, GlaxoSmithKline Research & DevelopmentGreenfordUK
  4. 4.Medicines Development, GlaxoSmithKline Research & DevelopmentKing of PrussiaUSA

Personalised recommendations