Epidemiology and Social: Editorial Comment
Arguably, of all clinical trials the Pediatric AIDS Clinical Trial Group (PACTG) 076 study has had the greatest impact on the global HIV/AIDS epidemic . Certainly, the proof of principle that antiretroviral drugs can be used to interrupt mother-to-child transmission (MTCT) has led to tens if not hundreds of thousands of children born without HIV infection when approximately 25% of infants born to HIV-1-infected women would otherwise become infected either in utero or intrapartum. Unfortunately, no such intervention is without risk. In the Opinion piece in this issue, Blanche and colleagues  describe the potential risks of mitochondrial toxicity associated with the use of nucleoside reverse transcriptase inhibitors (NRTI) to interrupt MTCT. This is not a new concern, but one that has its origins prior to the initiation of the PACTG 076 study. In those early days, much concern was expressed over exposing a developing fetus to NRTI drugs. After much debate, the critical decision was made that the potential risks were outweighed by the potential benefit of preventing HIV-1 infection, which at that time was an invariably fatal disease.
Although Blanche et al. argue that there is ‘… no obvious reason why the fetus and newborn … should escape …’ the effects of mitochondrial toxicity associated with the use of any NRTI, strikingly few infants exposed to antiretroviral drugs in utero have been confirmed to have sustained mitochondrial toxicity with long-term consequences. However, we agree that the studies of such potential and real long-term effects are fraught with numerous difficulties.
Several clinical studies have found no significant impact of antiretroviral drug exposure in utero on neurological sequelae later in life [3,4]. Although Blanche and colleagues argue that the long-term effects are unknown, major neurological sequelae would be expected to occur shortly after birth, while more subtle and less-severe neurological sequelae, if they were to occur, might only be observed later in life. Perhaps the strongest indication that the use of antiretroviral drugs in utero is unlikely to be associated with serious complications is the failure to observe such findings in infants treated immediately after birth for HIV-1 infection and who have been maintained on antiretroviral drugs for many years.
Although we have argued that NRTI drugs are unlikely to have major negative consequences for more than a few susceptible developing fetuses, this should not be interpreted as lack of concern for such a scenario. Recently, we performed a study that examined HIV-1-infected children who began a combination of one or two NRTI plus efavirenz and nelfinavir . Of note, children receiving didanosine were found to have lower mitochondrial DNA to nuclear DNA ratios than children receiving other NRTI. However, of the five NRTI drugs that we evaluated, both in vivo and in vitro, zidovudine was one of the ones that had the least effect on mitochondrial DNA and RNA levels.
The potential toxicity risks associated with the use of antiretroviral agents to interrupt MTCT will continue to be debated regardless of the use of the current drug combinations and with future drugs as they become available and used during pregnancy. Well-designed studies that assess such potential toxicities are planned by the NICHD PHACS study, which will be initiated shortly. In the meantime, the overwhelming abundance of data support the benefit of interrupting MTCT with the use of zidovudine as part of a HAART regimen when compared with the potential risk of mitochondrial or other toxicities. Even with improved treatments, we must not lose sight of the life-long consequences of HIV-1 infection in the newborn.
1. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O'Sullivan MJ, 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; 331:1173–1180.
2. Blanche S, Tarieu M, Benhammou V, Warszawski J, Rustin P. Mitochondrial dysfunction following perinatal exposure to nucleoside analogues
3. The Perinatal Safety Review Working Group. 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 AIDS
4. European Collaborative Study. Exposure to antiretroviral therapy in utero or early life: the health of uninfected children born to HIV-infected women
. J AIDS
5. Saitoh A, Fenton T, Alvero C, Fletcher CV, Spector SA. Didanosine lowers mitochondrial DNA levels in peripheral blood mononuclear cells in HIV-1 infected children receiving HAART.13th Conference on Retroviruses and Opportunistic Infections.
Denver, February 2006 [abstract 696].