Obesogenic Origins of Maternal and Child Metabolic Health Involving Dolutegravir

Obesity Clinical Trial

— ORCHID  

Official title:

Obesogenic Origins of Maternal and Child Metabolic Health Involving Dolutegravir

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04991402
• Other study ID #: AAAT6112
• Secondary ID: 1R01HD104599
• Status: Recruiting
• Start date: September 21, 2021
• Est. completion date: December 31, 2024

Study information

• Verified date: March 2024
• Source: Columbia University
• Contact: Landon Myer, PhD, MBBCH
• Phone: 021 406-6661
• Email: landon.myer[@]uct.ac.za
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

A total of 1900 pregnant women in the 1st trimester and their children will be enrolled and followed for two years (ORCHID study main cohort). 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 18, 24-28 and 32-36 weeks) and 16 postnatal visits (<2 and 6 weeks, 3, 6, 12, 18, and 24 months). Participants will also be asked to engage in long-term follow-up, with visits occurring every 6 months through Month 60 (at 30, 36, 42, 48, 54, and 60 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, urine, 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.

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, this prospective cohort study will 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. Up to 1900 pregnant women will be enrolled and followed to delivery and then as mother-infant pairs through 5 years postpartum (ORCHID study main cohort).

Additionally, a nested cohort study will be conducted and enroll a subset of 108 pregnant women who are currently being followed as part of the parent ORCHID study's main cohort. This substudy will explore the associations of DTG (initiating and continuing DTG use during pregnancy) with longitudinal perturbations in subcutaneous adipose tissue (SAT) function and changes in weight and adipose tissue mass in pregnancy through 2 years postpartum in WLHIV using a comparison group of HIV-seronegative women. They will been seen at up to 3 different time points (up to 2 visits during pregnancy and 1 visit postpartum) separate from the parent study to undergo a fat biopsy procedure to extract SAT samples.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1900
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 16 Years and older

Eligibility

Inclusion Criteria:

For All Women:

• Confirmed pregnancy based on urine pregnancy test with viable gestation = 18 weeks and 6 days 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) on the day of assessment

For WLHIV initiating DTG in pregnancy (iDTG):

• Planned initiation of TLD on the day of assessment or within 1 week thereafter, including women switching from efavirenz-based regimen

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

Related Conditions & MeSH terms

• HIV
• Maternal Obesity Complicating Pregnancy
• Maternal Obesity During Childbirth
• Obesity
• Obesity, Infant
• Pediatric Obesity
• Pregnancy Complications

Intervention

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 18 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.

Locations

Country	Name	City	State
South Africa	Gugulethu Community Health Center	Cape Town
South Africa	Mitchell's Plain Community Health Center	Cape Town

Sponsors (7)

Lead Sponsor	Collaborator
Columbia University	Albert Einstein College of Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Northwestern University, Tufts University, University of Cape Town, University of Hawaii

Country where clinical trial is conducted

South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Difference in excess gestational weight gain between pregnant women living with HIV and HIV negative pregnant women	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.	<18 weeks (baseline), 32-34 weeks
Primary	Difference in gestational weight gain between iDTG and cDTG pregnant women	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.	<18 weeks (baseline), 32-34 weeks
Primary	Change in adipose tissue mass compared between pregnant women living with HIV and HIV negative pregnant women	Comparison of percent adipose tissue mass per week between pregnant women living with HIV and HIV negative pregnant women during pregnancy.	<18 weeks (baseline), 32-34 weeks
Primary	Change in adipose tissue mass compared between iDTG and cDTG mothers	Comparison of percent adipose tissue mass per week between pregnant women initiating DTG during pregnancy (iDTG) and pregnant women continuing DTG during pregnancy (cDTG).	<18 weeks (baseline), 32-34 weeks
Primary	Differences in maternal metabolic health post-partum between mothers living with HIV and HIV negative mothers	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.	<18 weeks antenatal, 24 weeks postpartum, and 24 months postpartum
Primary	Differences in maternal metabolic health post-partum between iDTG and cDTG mothers	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.	<18 weeks antenatal, 24 weeks postpartum, and 24 months postpartum
Primary	Changes in adiposity in the child between HIV positive mothers and HIV negative mothers	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.	<2 weeks, up to 2 years of age
Primary	Changes in adiposity in the child between iDTG and cDTG mothers	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.	<2 weeks, up to 2 years of age
Secondary	Changes in subcutaneous adipose tissue (SAT) function	The SAT sample will reveal information regarding adipocyte hypertrophy, hypoxia, increased fibrosis and inflammation, decreased SAT mitochondrial respiration, and any altered metabolome/lipidome.	<18 weeks (baseline), 32-34 weeks antenatal, 24 months postpartum