Safety of Stavudine during Pregnancy

    Hpital Necker Enfants Malades, Unité d'Immunologie Hématologie Pédiatrique, Paris, France

    In the 15 December 2004 issue of the Journal of Infectious Diseases, Wade et al. present a study that is inappropriately entitled "Pharmacokinetics and Safety of Stavudine in HIV-Infected Pregnant Women and Their Infants: Pediatric AIDS Clinical Trials Group Protocol 332" [1]. The pharmacokinetic work is necessary and commendable, but it is impossible to assess, even grossly, the tolerance to this molecule after perinatal exposure with such a small number of study participants (n = 10). It is not reasonable to include the notion of safety in the title and to conclude in the Abstract and Discussion that this molecule is safe to use during pregnancy.

    In addition, Wade et al. raised no questions concerning the potential interference of nucleoside analogues with mitochondrial [27] or nuclear [8] DNA in the fetus. Regardless of how we choose to interpret the increasing quantity of data from studies in animals and humans on this type of toxicity, these data cannot be ignored. I understand that it was not the aim of Wade et al.'s study to identify specific biological markers, but it is interesting to note that hypoglycemia (n = 1) and hyperkalemia (n = 3) may be such indicators.

    Furthermore, the limited hematologic data presented by Wade et al. should not be underemphasized: 5 of the 10 infants in their study developed grade 3 neutropenia, which does not correspond with what has been observed after exposure to zidovudine [9] or the combination of zidovudine and lamivudine [10].

    The issue of tolerance to nucleoside analogues after perinatal exposure is important. It deserves more than the type of superficial analysis presented by Wade et al., which may give hurried readers the impression that these molecules can be used safely during pregnancy. For most antiretroviral molecules, this has not yet been established by means of appropriate studies, both in terms of numbers of participants and appropriate biological markers.

    References

    1.  Wade NA, Unadkat JD, Huang S, et al. Pharmacokinetics and safety of stavudine in HIV-infected pregnant women and their infants: Pediatric AIDS Clinical Trials Group Protocol 332. J Infect Dis 2004; 190:216774. First citation in article

    2.  Gerschenson M, Nguyen V, Ewings EL, et al. Mitochondrial toxicity in fetal Erythrocebus patas monkeys exposed transplacentally to zidovudine plus lamivudine. AIDS Res Hum Retroviruses 2004; 20:91100. First citation in article

    3.  Alimenti A, Burdge DR, Ogilvie GS, Money DM, Forbes JC. Lactic acidemia in human immunodeficiency virus-uninfected infants exposed to perinatal antiretroviral therapy. Pediatr Infect Dis J 2003; 22:7829. First citation in article

    4.  Noguera A, Fortuny C, Munoz-Almagro C, et al. Hyperlactatemia in human immunodeficiency virus-uninfected infants who are exposed to antiretrovirals. Pediatrics 2004; 114:e598603. First citation in article

    5.  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; 17:176985. First citation in article

    6.  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; 18:101321. First citation in article

    7.  Cooper ER, DiMauro S, Sullivan M, et al. Biopsy-confirmed mitochondrial dysfunction in an HIV-exposed infant whose mother received combination antiretrovirals during the last 6 weeks of pregnancy [abstract TuPeB4394]. In: Program and abstracts of the XV International AIDS Conference (Bangkok). 2004. First citation in article

    8.  Poirier MC, Olivero OA, Walker DM, Walker VE. Perinatal genotoxicity and carcinogenicity of anti-retroviral nucleoside analog drugs. Toxicol Appl Pharmacol 2004; 199:15161. First citation in article

    9.  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; 331:117380. First citation in article

    10.  Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, et al. Lamivudine-zidovudine combination for prevention of maternal-infant transmission of HIV-1. JAMA 2001; 285:208393. First citation in article