Transplacental Carcinogenesis Induced by Antiretrovirals, Twelve Years Later

The transmission of HIV from a positive mother to fetus ranges from 15% to 45%. This rate can be reduced to 2% with effective interventions such as antiretrovirals and Cesarean section (International Perinatal HIVG et al. 1999) Following the release of new guidelines in 2015, World Health Organization (WHO) advises that all pregnant and breastfeeding women should receive antiretroviral treatment (ART) irrespective of clinical stage of disease or CD4 count (WHO report, http://www.who.int/hiv/topics/mtct/about/en/). Twelve years ago, the EMM published a focused issue on “Health Risks of Perinatal Exposure to Nucleoside Reverse Transcriptase Inhibitors” (Walker and Poirier 2007). An exhaustive compilation of articles shaped what was an emerging field in the scientific arena with contributions about genetic mutations, cytogenetic abnormalities, and mitochondrial morphological and functional impairment. Today, 12 years later the field has grown the scope and an understanding of the risks of exposure as well as the expansion of the outreach of the secondary effects has been attained. The EMM focused issue reported mitochondrial compromise and perinatal health summarizing findings on mitochondrial integrity, function, DNA content, oxidative phosphorylation, and gene expression (Divi et al. 2007a, 2007b). The impact of mutations in mtDNA in the heart of mice and the synergy of the drug combination AZT+3TC (Chan et al. 2007) were reported and mtDNA mutations in human umbilical cord suggested the existence of hot spots for drug induced mtDNA mutation (Torres 2007). The contributions from animal models then, informed the clinic about potential toxicities that merited to be examined in humans. That brought a new understanding of the latent concerns about perinatal exposures to antiretrovirals in humans exposed therapeutically to the drugs (Olivero et al. 1997; Olivero 2007, 2008). Additionally, in the last 12 years a vast array of new agents has been developed and drug combinations increased in number and complexity, challenging scientists and the field. The understanding of the complex consequences of antiretroviral exposure in utero, brought to light the multifaceted mechanisms implied in antiretroviral-DNA interactions and other cellular toxicities associated with therapy and exposure. Today, a much more intricate landscape offers a deeper understanding of the extent of toxicities induced by ART. Some of them: aneuploidy (Andre-Schmutz et al. 2013), chromosomal instability (Borojerdi et al. 2009), centrosomal amplification (Borojerdi et al. 2009; Yu et al. 2009), reactive oxygen species production (Bialkowska et al. 2000; Smith et al. 2017), nuclear budding (Dutra et al. 2010), abnormal ciliogenesis (Divi et al. 2015), modulation of micro RNAs (Crespo-Mejias et al. 2014), among other effects. Pregnant women HIV positive are advised to take antiretroviral therapy unless known adverse effects to the mother, fetus, or infant, are reported. It is believed that the adverse effects outweigh the benefits to the woman (Minkoff and Augenbraun 1997). Twelve years ago, Wogan postulated that: “perinatal exposure to nucleoside analogs puts children at elevated risk of developing cancers later in life” (Wogan 2007). A more recent revision of the antiretroviral therapy in pregnancy by the WHO recommends that all pregnant and breastfeeding women should receive ART irrespective of clinical stage of disease or CD4 count (the most common marker used to define the onset of AIDS). Animal models have been extremely informative about the risks of combination therapy (multiple antiretrovirals) in utero, in non-human primates. Aneuploidy has been documented in cultured bone marrow cells from the offspring of non-human primates, Erythrocebus patas monkeys exposed to equivalent doses of antiretrovirals. The aneuploidy was present at birth, and persistence was documented at 1 and 3 years of age (Olivero et al. 2013). There is ample