Abstract
The universalization of antiretroviral (ARV) treatment coupled with increased ARV coverage among HIV-infected pregnant and lactating women is contributing to an emerging population of uninfected children born to HIV-positive mothers, exposed to both maternal HIV and ARVs from conception to early childhood. If the impacts of these exposures on the health of these children is questionable and the subject of many studies, the post-natal ARV prophylaxis given to them as part of the prevention of mother-to-child transmission (PMTCT) of HIV also needs to be rigorously evaluated, as these ARVs continue to be given to uninfected children. In this context, this thesis work consisted of evaluating the acute and long-term genomic toxicity of lopinavir/ritonavir (LPV/r) or lamivudine (3TC) used as infant prophylaxis for one year to prevent MTCT of HIV through breastfeeding in the PROMISE PEP trial conducted in four sub-Saharan African countries (South Africa, Burkina Faso, Uganda and Zambia) between November 2009 and May 2012. While this extended prophylaxis during the entire breastfeeding period has shown its efficacy, with transmission rates at one year of life of 1.4% and 1.5% for LPV/r and 3TC respectively, current World Health Organization guidelines recommend prophylaxis with nevirapine (NVP) or azidothymidine combined with NVP for a maximum of 12 weeks. Our work indicates that both prophylaxis regimens were associated with a significant prevalence of mitochondrial DNA depletion (decrease of mitochondrial copy number greater than or equal to 50% of the initial value) in the first year of life in children who are HIV-exposed uninfected. Our work also demonstrated the presence of deleted mitochondrial DNA in almost all children from the initiation of prophylaxis, thus indicating strong genomic instability. However, we found no association with the growth and neuropsychomotor development of these children at 6 years, at which point the depletion no longer persists and the deletions are irreversible. The shortening of telomere length observed at one year of age showed no association with the two ARVs and had no impact on the health of the children at 6 years. This thesis work contributes to the overall evaluation of the safety of ARV prophylaxis used in children who are HIV-exposed uninfected, but is also of interest to those who are infected and whose first-line treatment includes LPV/r and/or 3TC.