Risk of cancer in children exposed to didanosine in utero

Hleyhel, Mira; Goujon, Stéphanie; Delteil, Clémence; Vasiljevic, Alexandre; Luzi, Stéphanie; Stéphan, Jean-Louis; Reliquet, Véronique; Jannier, Sarah; Tubiana, Roland; Dollfus, Catherine; Faye, Albert; Mandelbrot, Laurent; Clavel, Jacqueline; Warszawski, Josiane; Blanche, Stéphane

doi:10.1097/qad.0000000000001051

Cited by 22 publications

(24 citation statements)

References 24 publications

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“…Recent evidence raises concerns about the safety of certain antiretroviral drugs used in pregnancy, including increased risk for adverse birth outcomes [3,7–16], problems with pediatric growth and neurodevelopment [17] and future risk of cancer [6, 18–20]. Also, HIV-exposed, uninfected (HEU) children have increased morbidity and mortality when compared with HIV unexposed, uninfected (HUU) children.…”

Section: Introductionmentioning

confidence: 99%

Surveillance monitoring for safety of in utero antiretroviral therapy exposures: current strategies and challenges

Zash

Williams

Sibiude

et al. 2016

Expert Opinion on Drug Safety

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Introduction The use of antiretroviral therapy (ART) in pregnancy to prevent vertical HIV transmission has been one of the most successful public health programs in the last decade. As a result, an unprecedented number of women are taking ART at conception and during pregnancy. Given few randomized studies evaluating safety of different ART regimens in pregnancy, ongoing drug safety surveillance is critical. Areas Covered This review aims to provide a rationale for ART drug safety surveillance, describe changing patterns of ART use and summarize current surveillance efforts in both low-resource and high-resource settings. Additionally, biostatistical approaches to and challenges in analysis of observational surveillance data are discussed. Expert Opinion The global landscape of ART use in pregnancy is rapidly increasing and evolving. Any increase in adverse effects of in-utero exposure to ART has the potential to reduce the impact of improvements in infant morbidity and mortality gained from decreased vertical HIV transmission. ART drug safety surveillance should therefore be a critical piece of programs to prevent mother to child transmission in both high- and low-resource settings. Current surveillance efforts could be strengthened with long-term follow-up of exposed children, pooling of data across cohorts and standardized approaches to analysis.

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Section: Introductionmentioning

confidence: 99%

Surveillance monitoring for safety of in utero antiretroviral therapy exposures: current strategies and challenges

Zash

Williams

Sibiude

et al. 2016

Expert Opinion on Drug Safety

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“…US guidelines also acknowledge a need for “innovative methods” to provide follow-up of these children and encourage that information regarding in utero HIV/ARV exposure be “part of ongoing permanent medical records for children.” In addition to several HEU research cohorts in both countries, the United States also recently reported a linking system in one state to match subjects from the Perinatal HIV Surveillance database and the state's cancer registry to monitor malignancy risk in HEU children [16]. A similar linkage system had been developed earlier in France, where the national cancer registry was linked in an anonymized fashion [17,18] to the major research cohort with longitudinal monitoring of HEU infants until 18 to 24 months [19–21]. The UK also has a national surveillance system of HIV-infected pregnant women and their infants (National Study of HIV in Pregnancy and Childhood, or NSHPC), which follows HEU children up to 18 months.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, to avert the potential for major physical harm such as in the case of diethylstilboestrol exposure, disclosure is necessary in order to properly monitor HEU individuals into adulthood. Second, one could argue that in addition to childhood malignancies [16,17,23,36,37], there are a myriad of concerning data already surrounding malignancies as well as the mitochondrial [38–44], mental [45–47], bone [48–51], cardiovascular [52–54] and metabolic [55–57] health in HEU children as described herein.…”

Section: Discussionmentioning

confidence: 99%

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Disclosing in utero HIV/ARV exposure to the HIV‐exposed uninfected adolescent: is it necessary?

Jao

Hazra

Mellins

et al. 2016

Journal of the International AIDS Society

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IntroductionThe tremendous success of antiretroviral therapy has resulted in a diminishing population of perinatally HIV-infected children on the one hand and a mounting number of HIV-exposed uninfected (HEU) children on the other. As the oldest of these HEU children are reaching adolescence, questions have emerged surrounding the implications of HEU status disclosure to these adolescents. This article outlines the arguments for and against disclosure of a child's HEU status.DiscussionDisclosure of a child's HEU status, by definition, requires disclosure of maternal HIV status. It is necessary to weigh the benefits and harms which could occur with disclosure in each of the following domains: psychosocial impact, long-term physical health of the HEU individual and the public health impact. Does disclosure improve or worsen the psychological health of the HEU individual and extended family unit? Do present data on the long-term safety of in utero HIV/ARV exposure reveal potential health risks which merit disclosure to the HEU adolescent? What research and public health programmes or systems need to be in place to afford monitoring of HEU individuals and which, if any, of these require disclosure?ConclusionsAt present, it is not clear that there is sufficient evidence on whether long-term adverse effects are associated with in utero HIV/ARV exposures, making it difficult to mandate universal disclosure. However, as more countries adopt electronic medical record systems, the HEU status of an individual should be an important piece of the health record which follows the infant not only through childhood and adolescence but also adulthood. Clinicians and researchers should continue to approach the dialogue around mother–child disclosure with sensitivity and a cogent consideration of the evolving risks and benefits as new information becomes available while also working to maintain documentation of an individual's perinatal HIV/ARV exposures as a vital part of his/her medical records. As more long-term adult safety data on in utero HIV/ARV exposures become available these decisions may become clearer, but at this time, they remain complex and multi-faceted.

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“…Uninfected children exposed to HIV have subsequently been found to be lighter in weight at birth and had slightly accelerated growth in the first 2 years with less subcutaneous fat when compared with US references for these measures (Neri et al 2013). An increased risk of cancer has also been implicated for in utero didanosine (ddI, analog of adenosine) exposure (Hleyhel et al 2016). …”

Section: Origins and Consequences Of Mtdna Instabilitymentioning

confidence: 99%

Inherited mitochondrial genomic instability and chemical exposures

Chan

2017

Toxicology

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There are approximately 1,500 proteins that are needed for mitochondrial structure and function, most of which are encoded in the nuclear genome (Calvo et al. 2006). Each mitochondrion has its own genome (mtDNA), which in humans encodes 13 polypeptides, 22 tRNAs and 2 rRNAs required for oxidative phosphorylation. The mitochondrial genome of humans and most vertebrates is approximately 16.5 kbp, double-stranded, circular, with few non-coding bases. Thus, maintaining mtDNA stability, that is, the ability of the cell to maintain adequate levels of mtDNA template for oxidative phosphorylation is essential and can be impacted by the level of mtDNA mutation currently within the cell or mitochondrion, but also from errors made during normal mtDNA replication, defects in mitochondrial quality control mechanisms, and exacerbated by exposures to exogenous and/or endogenous genotoxic agents. In this review, we expand on the origins and consequences of mtDNA instability, the current state of research regarding the mechanisms by which mtDNA instability can be overcome by cellular and chemical interventions, and the future of research and treatments for mtDNA instability.

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Risk of cancer in children exposed to didanosine in utero

Abstract: There are strong arguments to suggest that didanosine displays transplacental oncogenicity. Although not extrapolable to other NRTIs, they stress the need for comprehensive evaluation of the transplacental genotoxicity of this antiretroviral class.

Cited by 22 publications

References 24 publications

Surveillance monitoring for safety of in utero antiretroviral therapy exposures: current strategies and challenges

Surveillance monitoring for safety of in utero antiretroviral therapy exposures: current strategies and challenges

Disclosing in utero HIV/ARV exposure to the HIV‐exposed uninfected adolescent: is it necessary?

Inherited mitochondrial genomic instability and chemical exposures

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