New evidence suggests that first time in-utero exposure to Nucleoside Reverse Transcriptase Inhibitors (NRTI) during the third trimester may be associated with the development of Mitochondrial Dysfunction (MD) in uninfected children born to HIV infected mothers on therapy.
The study, reported in the upcoming issue of AIDS, analyzed data collected from 1037 HIV negative children, born of HIV infected mothers on therapy, between 1991 and 2002. 20 children were identified to have unexplained signs of Mitochondrial Dysfunction based on The French Pediatric Cohort criteria. Two types of associations were analyzed: Association between overall intranatal exposure to NRTI and occurrence of MD, and association between the ‘trimester of first exposure to NRTI’ and occurrence of MD.
Although, overall in-utero exposure to NRTI was not associated with MD, a significant association was found in children who were exposed for the first time during the third trimester. The children with MD (cases) were more likely to be exposed in-utero to Lamivudine (3TC, odds ratio 3.76) or Zidovudine-Lamivudine combination (ZDV/3TC, odds ratio 3.29) for the first time during third trimester, compared to non-cases. Upon adjustment for year of birth, the odds for third trimester exposure increased significantly to 10.57 (3TC) and 9.84 (ZDV/3TC).
Nucleoside Reverse Transcriptase Inhibitors like zidovudine (ZDV) and lamivudine (3TC) are antiretroviral drugs used in the management of HIV infection. These drugs act by inhibiting the HIV reverse transcriptase enzyme. They also happen to inhibit the mitochondrial DNA polymerase gamma, interfering with mitochondrial DNA replication in humans. This can potentially lead to Mitochondrial DNA depletion and Mitochondrial Dysfunction (MD).
NRTIs are given to HIV infected women during pregnancy and labor, and to the new born for a period of 6 weeks, to prevent the risk of perinatal mother-to-child HIV transmission. The use of Zidovudine in pregnancy has reduced perinatal transmission of HIV by 67.5%, as observed in a trial conducted in 1994, resulting in wide spread recommendation of this therapy. Similarly, the editorial in the April 2005 issue of the American Journal of Neuroradiology observed that short course therapies using NRTIs decreased perinatal transmission of HIV by 40-50% in developing countries.
While the benefits of NRTIs in preventing perinatal transmission have been acknowledged by the scientific community, the potential adverse effects on uninfected children has been a cause of significant concern. An article published in 2003 in AIDS noted that the use of NRTIs in the perinatal period was associated with persistent mitochondrial disease, characterized by neurological symptoms such as developmental retardation, seizures, behavioral disturbances, myopathies and hyperlactemia. The 18-month incidence of MD was found to be 0.26% in exposed children, compared to just 0.01% for pediatric neuromitochondrial diseases in the general population.
With current evidence implicating the time of ‘first exposure’ as a critical factor in the occurrence of mitochondrial disease, a new dimension to the approach towards perinatal HIV transmission and prevention has been unveiled.
References
1. Brogly SB, Ylitalo N, Mofenson LM, et al. In utero nucleoside reverse transcriptase inhibitor exposure and signs of possible mitochondrial dysfunction in HIV-uninfected children. AIDS. 2007 May 11;21(8):929-938.
2. Scott GB. Perinatal exposure to antiretroviral agents: Risks and Benefits. Am J Neuroradiol. 2005 Apr;26(4):689-92.
3. 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 Aug 15;17(12):1769-85
4. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type-1 with zidovudine treatment. N Eng J Med. 1994;331:1173–1180.
