Abstract
Children who are human immunodeficiency virus (HIV)-exposed but uninfected (CHEU) accumulate maternal HIV and antiretroviral exposures through pregnancy, postnatal prophylaxis, and breastfeeding. Here, we compared the dynamics of mitochondrial DNA (mtDNA) parameters in African breastfed CHEU receiving lopinavir/ritonavir (LPV/r) or lamivudine (3TC) pre-exposure prophylaxis during the first year of life. The number of mtDNA copies per cell (MCN) and the proportion of deleted mtDNA (MDD) were assessed at day 7 and at week 50 post-delivery (PrEP group). mtDNA depletion was defined as a 50% or more decrease from the initial value, and mtDNA deletions was the detection of mtDNA molecules with large DNA fragment loss. We also performed a sub-analysis with CHEU who did not receive a prophylactic treatment in South Africa (control group). From day seven to week 50, MCN decreased with a median of 41.7% (interquartile range, IQR: 12.1; 64.4) in the PrEP group. The proportion of children with mtDNA depletion was not significantly different between the two prophylactic regimens. Poisson regressions showed that LPV/r and 3TC were associated with mtDNA depletion (reference: control group; LPV/r: PR = 1.75 (CI95%: 1.15–2.68), p < 0.01; 3TC: PR = 1.54 (CI95%: 1.00–2.37), p = 0.05). Moreover, the proportion of children with MDD was unexpectedly high before randomisation in both groups. Long-term health impacts of these mitochondrial DNA parameters should be investigated further for both CHEU and HIV-infected children receiving LPV/r- or 3TC- based regimens.
Highlights
The most recent Word Health Organisation (WHO) guidelines for the prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus 1 (HIV-1) recommend lifelong antiretroviral therapy (ART) for all pregnant or breastfeeding HIV-infected women independently of their CD4 count or HIV clinical stage [1]
After quality control assessment and mitochondrial DNA (mtDNA) confounds, a total of 139 children who are HIV-exposed but uninfected (CHEU) were included for further analysis: 46 children from Burkina Faso, 48 from South Africa, and 45 from Uganda (Figure 2)
To answer whether prophylaxis was responsible for mtDNA depletion and deletion, we performed a sub-analysis including a control group of South African CHEU not receiving prophylaxis (Figure 2). Both mitochondrial DNA copy number per cell (MCN) and deleted mitochondrial DNA (MDD) were site dependent and, due to the inaccessibility of samples from children who had not received prophylaxis for the three sites, we restricted this analysis to South African CHEU
Summary
The most recent Word Health Organisation (WHO) guidelines for the prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus 1 (HIV-1) recommend lifelong antiretroviral therapy (ART) for all pregnant or breastfeeding HIV-infected women independently of their CD4 count or HIV clinical stage [1]. Many unfavourable health outcomes have been reported in CHEU such as metabolic disorders [7,8], increased infectious disease morbidity and higher mortality [9,10,11,12], impaired growth [13,14,15,16,17,18], neurodevelopmental delays [17,19,20,21], altered immunity [10,22,23,24,25,26], and mitochondrial toxicity in comparison to never HIV-exposed children [27,28,29,30]. This prompted Powis and Siberry to advocate for the long-term follow up of CHEU irrespective of their HIV/ARV exposures [31]
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