Obesogenic Origins of Maternal and Child Metabolic Health Involving Dolutegravir

Study Overview
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Brief Summary
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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 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, 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.

Detailed Description
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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 2 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.

Official Title
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Obesogenic Origins of Maternal and Child Metabolic Health Involving Dolutegravir

Conditions
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HIV, Obesity, Obesity, Infant, Maternal Obesity During Childbirth, Maternal Obesity Complicating Pregnancy

Intervention / Treatment
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* Device: Dolutegravir-based antiretroviral therapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Pregnant women living with HIV initiating Dolutegravir (DTG) in pregnancy (iDTG)<br>Pregnant women living with HIV initiating DTG-based ART in pregnancy at the 1st visit | Device: Dolutegravir-based antiretroviral therapy<br>* 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.<br>|
| Pregnant women living with HIV already on DTG-based ART prior to pregnancy (cDTG)<br>Pregnant women living with HIV already on DTG-based ART prior to enrollment and continuing DTG use through pregnancy | Device: Dolutegravir-based antiretroviral therapy<br>* 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.<br>|
| HIV uninfected pregnant women<br>Pregnant women not living with HIV | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Dolutegravir, Metabolic health, Maternal obesity, Pregnancy