Obesogenic Origins of Maternal and Child Metabolic Health Involving Dolutegravir

Overview

A total of 1900 pregnant women in the 1st trimester (633 women living with HIV (WLHIV) initiating Dolutegravir (DTG)-based antiretroviral therapy (ART) in pregnancy, 633 WLHIV continuing DTG use from pre-pregnancy, and 634 women without HIV) and their children will be enrolled and followed for two years. As part of this, mother-infant pairs will be required to attend up to 10 study visits separate from routine clinic visits, these visits include 3 antenatal visits (less than or equal to 14, 24-28 and 32-36 weeks) and 7 postnatal visits (<2 and 6 weeks, 3, 6, 12, 18 and 24 months). Measurements in mothers will include demographics and health status, HIV disease and ART use, intercurrent medical history including concomitant medication use, HIV viral load testing, ART adherence, HIV antibody testing in women without HIV; body composition, caloric intake, dysglycemia and insulin resistance (IR), lipid profiles, anthropometry, resting energy expenditure, hepatic steatosis, specimen collection (whole blood, plasma, serum, placenta and breastmilk), systemic and adipose inflammation, as well as metabolites, lipid subspecies and eicosanoids. Measurements in infants will include uterine gestational age and fetal growth, as well as metabolites, lipid subspecies and eicosanoids, body composition, dysglycemia and IR, lipid profiles, anthropometry, feeding, specimen collection (cord blood, whole blood, plasma and serum) and intercurrent medical history including concomitant medication use. Additional data on maternal health in pregnancy and birth outcomes will be abstracted from medical records.

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: December 31, 2024

Detailed Description

Dolutegravir (DTG)-based antiretroviral therapy (ART) is being scaled up as part of the preferred 1st-line ART regimen. However, DTG has recently been implicated as an obesogen that is associated with increased weight and adipose tissue gain compared to other antiretroviral agents. Obesity in pregnancy is associated with poor health outcomes for both mother and child as pregnancy is a critical period during which exposures leading to alterations in metabolic health may influence not only long-term maternal health but also fetal, neonatal, and ultimately child health. To address the gap of knowledge on the obesogenic effects of DTG in pregnant women living with HIV (WLHIV) and their children, the central objective of this proposal is to investigate the impact of DTG in pregnancy and its obesogenic effects on the metabolic health of WLHIV and their children, compared to women without HIV and their children.

Interventions

  • Device: Dolutegravir-based antiretroviral therapy
    • This study focuses on the impact of Dolutegravir (DTG)-based antiretroviral therapy (ART) on metabolic health of women and children in pregnancy, delivery and beyond. In order to understand the potential adverse effects of DTG, pregnant women living with HIV- both those initialing DTG-based ART in pregnancy as well as those who were established on DTG-based ART prior to pregnancy, will be less than or equal to 14 weeks’ gestation at enrollment to allow for detection of metabolic abnormalities as they begin to develop during the course of pregnancy. This is considered standard of care.

Arms, Groups and Cohorts

  • Pregnant women living with HIV initiating Dolutegravir (DTG) in pregnancy (iDTG)
    • Pregnant women living with HIV not on antiretroviral therapy (ART) at their 1st antenatal care visit and initiating DTG-based ART in pregnancy.
  • Pregnant women living with HIV already on DTG-based ART prior to pregnancy (cDTG)
    • Pregnant women living with HIV already on DTG-based ART prior to pregnancy and continuing DTG use through pregnancy.
  • HIV uninfected pregnant women
    • Pregnant women not living with HIV

Clinical Trial Outcome Measures

Primary Measures

  • Difference in excess gestational weight gain between pregnant women living with HIV and HIV negative pregnant women
    • Time Frame: <14 weeks (baseline), 32-34 weeks
    • This is to measure the difference in gestational weight gain between pregnant women living with HIV and HIV negative pregnant women during pregnancy in kg. The women will be weighed by a scale at the study visit.
  • Difference in gestational weight gain between iDTG and cDTG pregnant women
    • Time Frame: <14 weeks (baseline), 32-34 weeks
    • This is to measure the difference in gestational weight gain between pregnant women initiating DTG during pregnancy (iDTG) and pregnant women continuing DTG during pregnancy (cDTG) in kg. The mothers will be weighed by a scale at the study visit.
  • Change in adipose tissue mass compared between pregnant women living with HIV and HIV negative pregnant women
    • Time Frame: <14 weeks (baseline), 32-34 weeks
    • Comparison of percent adipose tissue mass per week between pregnant women living with HIV and HIV negative pregnant women during pregnancy.
  • Change in adipose tissue mass compared between iDTG and cDTG mothers
    • Time Frame: <14 weeks (baseline), 32-34 weeks
    • Comparison of percent adipose tissue mass per week between pregnant women initiating DTG during pregnancy (iDTG) and pregnant women continuing DTG during pregnancy (cDTG).
  • Differences in maternal metabolic health post-partum between mothers living with HIV and HIV negative mothers
    • Time Frame: <14 weeks antenatal, 24 weeks postpartum, and 24 months postpartum
    • Adiposity will be measured as the main indicator of metabolic health. This outcome focuses on the comparison between mothers living with HIV and HIV negative mothers during pregnancy. Differences in adipose accrual and/or retention will calculated as the difference in adipose (% per week) between the timepoint in question and baseline.
  • Differences in maternal metabolic health post-partum between iDTG and cDTG mothers
    • Time Frame: <14 weeks antenatal, 24 weeks postpartum, and 24 months postpartum
    • Adiposity will be measured as the main indicator of metabolic health. This outcome focuses on the comparison between mothers initiating DTG during pregnancy and mothers continuing DTG during pregnancy. Differences in adipose accrual and/or retention will calculated as the difference in adipose (% per week) between the timepoint in question and baseline.
  • Changes in adiposity in the child between HIV positive mothers and HIV negative mothers
    • Time Frame: <2 weeks, up to 2 years of age
    • Adiposity will be measured as the main indicator of metabolic health. This outcome focuses on the comparison between children whose mothers are HIV positive and those whose mothers are HIV negative. Differences in adipose accrual and/or retention will calculated as the difference in adipose (% per week) between the timepoint in question and baseline.
  • Changes in adiposity in the child between iDTG and cDTG mothers
    • Time Frame: <2 weeks, up to 2 years of age
    • Adiposity will be measured as the main indicator of metabolic health. This outcome focuses on the comparison between children whose mothers initiated DTG during pregnancy and those whose mothers continued DTG during pregnancy. Differences in adipose accrual and/or retention will calculated as the difference in adipose (% per week) between the timepoint in question and baseline.

Participating in This Clinical Trial

Inclusion Criteria

For All Women:

  • Confirmed pregnancy based on urine pregnancy test with viable gestation ≤ 14 weeks by ultrasound – Age 16 years or older – No stated intention to relocate permanently outside of Cape Town through 2 years postpartum For Women Living with HIV (WLHIV): – Confirmed HIV infection based on medical record review and/or HIV antibody testing during antenatal care For WLHIV continuing DTG in pregnancy (cDTG): – Confirmed use of tenofovir 300mg + lamivudine 300mg/emtricitabine 200mg + dolutegravir 50mg (TLD) for at least 3 months prior to estimated date of conception based on medical record review For WLHIV initiating DTG in pregnancy (iDTG): – No use of any antiretroviral agent for at least 3 months prior to the estimated date of conception – Planned initiation of TLD on the day of assessment or within 1 week thereafter For women without HIV (HIV-): – Confirmed HIV status by HIV antibody testing during antenatal care Exclusion Criteria:

  • In the opinion of the investigator, unable to provide informed consent due to mental or physical condition – In the opinion of the investigator, unable to undertake BodPod assessment due to mental (eg, active psychosis or severe claustrophobia) or physical condition (eg, weight >250 kg). – Currently being treated for any form of diabetes mellitus or hypertensive disorder based on participant self-report and medical record review

Gender Eligibility: Female

Participants are pregnant women- some living with HIV and some HIV uninfected.

Minimum Age: 16 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Columbia University
  • Collaborator
    • Northwestern University
  • Provider of Information About this Clinical Study
    • Principal Investigator: Elaine J. Abrams, MD, Senior Research Director – Columbia University
  • Overall Official(s)
    • Elaine J. Abrams, MD, Principal Investigator, ICAP at Columbia University
    • Jennifer Jao, MD, Principal Investigator, Northwestern University
  • Overall Contact(s)
    • Landon Myer, PhD, MBBCH, 021 406-6661, landon.myer@uct.ac.za

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