Antiretroviral exposure during pregnancy and adverse outcomes in HIV-exposed uninfected infants and children using a trigger-based design

Williams, Paige L.; Hazra, Rohan; Dyke, Russell B. Van; Yildirim, Cenk; Crain, Marilyn J.; Seage, George R.; Civitello, Lucy; Ellis, Angela; Butler, Laurie; Rich, Kenneth

doi:10.1097/qad.0000000000000916

Cited by 39 publications

(39 citation statements)

References 41 publications

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“…Among 2,680 SMARTT participants enrolled on December 31, 2012, 48% met a trigger and 25% met case status in one or more domains ( 7 ). After adjusting for birth cohort and other factors, there was no significant increase in the likelihood of meeting overall case status (case in any domain) with exposure to combination ARVs (cARV) or any ARV class (Figure 1 ).…”

Section: Trigger-based Design To Identify Adverse Eventmentioning

confidence: 99%

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The PHACS SMARTT Study: Assessment of the Safety of In Utero Exposure to Antiretroviral Drugs

et al. 2016

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The Surveillance Monitoring for ART Toxicities (SMARTT) cohort of the Pediatric HIV/AIDS Cohort Study includes over 3,500 HIV-exposed but uninfected infants and children at 22 sites in the US, including Puerto Rico. The goal of the study is to determine the safety of in utero exposure to antiretrovirals (ARVs) and to estimate the incidence of adverse events. Domains being assessed include metabolic, growth and development, cardiac, neurological, neurodevelopmental (ND), behavior, language, and hearing. SMARTT employs an innovative trigger-based design as an efficient means to identify and evaluate adverse events. Participants who met a predefined clinical or laboratory threshold (trigger) undergo additional evaluations to define their case status. After adjusting for birth cohort and other factors, there was no significant increase in the likelihood of meeting overall case status (case in any domain) with exposure to combination ARVs (cARVs), any ARV class, or any specific ARV. However, several individual ARVs were significantly associated with case status in individual domains, including zidovudine for a metabolic case, first trimester stavudine for a language case, and didanosine plus stavudine for a ND case. We found an increased rate of preterm birth with first trimester exposure to protease inhibitor-based cARV. Although there was no overall increase in congenital anomalies with first trimester cARV, a significant increase was seen with exposure to atazanavir, ritonavir, and didanosine plus stavudine. Tenofovir exposure was associated with significantly lower mean whole-body bone mineral content in the newborn period and a lower length and head circumference at 1 year of age. With ND testing at 1 year of age, specific ARVs (atazanavir, ritonavir-boosted lopinavir, nelfinavir, and tenofovir) were associated with lower performance, although all groups were within the normal range. No ARVs or classes were associated with lower performance between 5 and 13 years of age. Atazanavir and saquinavir exposure were associated with late language emergence at 1 year, but not at 2 years of age. The results of the SMARTT study are generally reassuring, with little evidence for serious adverse events resulting from in utero ARV exposure. However, several findings of concern warrant further evaluation, and new ARVs used in pregnancy need to be evaluated.

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Section: Trigger-based Design To Identify Adverse Eventmentioning

confidence: 99%

“…Retention has been excellent with 85% of static and 80% of dynamic participants remaining on study at 6 years. For additional characteristics of the SMARTT cohort, see Williams et al ( 7 ).…”

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confidence: 99%

The PHACS SMARTT Study: Assessment of the Safety of In Utero Exposure to Antiretroviral Drugs

et al. 2016

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“…The Surveillance Monitoring of ART Toxicities (SMARTT) Study conducted by the Pediatric HIV/AIDS Cohort study (PHACS) network is an NIH/NICHD-funded longitudinal cohort that examines short- and long-term outcomes among children exposed to HIV and ART in utero [54]. SMARTT employs an innovative trigger-based design to identify and evaluate adverse events.…”

Section: Art Safety Surveillance Programsmentioning

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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“…The Pediatric HIV/AIDS Cohort Study (PHACS) Surveillance Monitoring of Antiretroviral Toxicity (SMART) protocol was established in 2005 and follows two cohorts of HEU children, one closed to new enrollments that include over 1200 children and the other continuing to enroll HEU infants. The SMART study uses a trigger-based approach to explore possible signals, whereby more rigorous, pre-defined investigations in individual children are prompted if predetermined clinical or laboratory thresholds are met, with a recent analysis reassuringly showing no association between meeting a case criteria and any antiretroviral class, regimen, or individual drug ( 20 ).…”

Section: Approaches To Monitoring Outcomes In Heu Children In Other Cmentioning

confidence: 99%

Strategies for Monitoring Outcomes in HIV-Exposed Uninfected Children in the United Kingdom

Thorne

Tookey

2016

Front. Immunol.

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Surveillance of pregnancies in women living with HIV is carried out on a national basis in the United Kingdom (UK) through the National Study of HIV in Pregnancy and Childhood. There are currently around 1100–1200 HIV-exposed uninfected (HEU) infants born every year in the UK, where vertical transmission of HIV now occurs in fewer than 5 in every 1000 pregnancies. By the end of 2014, there was a cumulative total of more than 15,000 HEU children with any combination antiretroviral therapy (cART) exposure and more than 5000 with cART exposure from conception in the UK. HEU infants are increasingly being exposed to newer antiretroviral drugs for which less is known regarding both short- and long-term safety. In this commentary, we describe the approaches that have been taken to explore health outcomes in HEU children born in the UK. This includes the Children exposed to AntiRetroviral Therapy (CHART) Study, which was a consented follow-up study carried out in 2002–2005 of HEU children born in 1996–2004. The CHART Study showed that 4% of HEU children enrolled had a major health or development problem in early childhood; this was within expected UK norms, but the study was limited by small numbers and short-term follow-up. However, the problems with recruitment and retention that were encountered within the CHART Study demonstrated that comprehensive, clinic-based follow-up was not a feasible approach for long-term assessment of HEU children in the UK. We describe an alternative approach developed to monitor some aspects of their long-term health, involving the “flagging” of HEU infants for death and cancer registration with the UK Office for National Statistics. Some of the ethical concerns regarding investigation of long-term outcomes of in utero and perinatal exposure to antiretrovirals, including those relating to consent and confidentiality, are also discussed.

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Antiretroviral exposure during pregnancy and adverse outcomes in HIV-exposed uninfected infants and children using a trigger-based design

Cited by 39 publications

References 41 publications

The PHACS SMARTT Study: Assessment of the Safety of In Utero Exposure to Antiretroviral Drugs

The PHACS SMARTT Study: Assessment of the Safety of In Utero Exposure to Antiretroviral Drugs

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

Strategies for Monitoring Outcomes in HIV-Exposed Uninfected Children in the United Kingdom

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