Study of HIV-Infected and Uninfected Pregnant Woman/Child Dyads in Gaborone, Botswana

The Tshilo Dikotla Study: Metabolic Outcomes of Children HIV/ARV-Exposed Uninfected in Botswana (MOCHA)

The purpose of this study is to assess the early longitudinal metabolic effects including insulin sensitivity in HIV-exposed uninfected (HEU) children compared to HIV-unexposed uninfected (HUU) children; as well as to determine differences in the effects of neonatal zidovudine (AZT) vs. nevirapine (NVP) prophylaxis on early longitudinal changes in insulin sensitivity in the first 3 years of life.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus; HIV; Insulin Sensitivity
• Intervention / Treatment: Drug: Nevirapine; Drug: Zidovudine

Detailed Description

This study will consist of a nested randomized component of HIV-infected (HIV+) and -uninfected (HIV-) pregnant woman/child dyads in Botswana which will take place in Gaborone, Botswana at Botswana-Harvard AIDS Institute Partnership's (BHPs) clinical research facilities. A total of 300 HIV+ pregnant woman/fetus dyads on cART and 150 HIV- pregnant woman/fetus dyads will be evaluated for insulin sensitivity and followed through the child's 3rd birthday. Amongst HEU infants, participants will be randomized at birth 1:1 with 150 to receive neonatal AZT prophylaxis and 150 to receive neonatal NVP prophylaxis. Targeted metabolomics will be used to assess the role intermediary metabolites in insulin resistance and directly assess mitochondrial function using Seahorse XF96e technology. At the time of study enrollment, all women must be willing to exclusively breastfeed for the infant's first 6 months of life. If in utero and neonatal HIV/ARV exposures are found to be associated with derangements in intermediary metabolism such that HEU infants are at increased risk for insulin resistance by 3 years of age, this would impact screening and prevention strategies for diabetes in this vulnerable population and argue for further research to identify prenatal and neonatal ARV regimens with superior PMTCT efficacy but minimal adverse metabolic consequences.

• Study Type: Interventional
• Enrollment (Actual): 495
• Phase: Phase 4

Contacts and Locations

Study Locations

• Botswana
  • Gaborone, Botswana
    • Botswana-Harvard AIDS Institute Partnership

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• HIV-infected and uninfected pregnant women between 16-36 weeks GA are eligible for study enrollment.
• Women must be 18 years of older and able to provide informed consent for themselves and their infant to participate in the study.
• Participants must be Botswana citizens.
• Women must have evidence of HIV infection status. Women NOT documented as HIV seropositive must have documentation of HIV seronegativity during the present pregnancy at or after 32 weeks GA. Women who have an initial negative HIV test during the present pregnancy which was done at <32 weeks GA will need to undergo repeat testing on or after 32 weeks GA in accordance with national guidelines.
• HIV-uninfected women must be willing to undergo HIV pre-test counseling, rapid HIV testing and post-test counseling, referred to as HIV Testing and Counseling (HTC) during pregnancy.
• Women must be willing to remain in study area with their infant and attend scheduled study visits as described above until the child's 3rd birthday.
• For HIV-infected women, they must be on TDF/3TC or FTC/EFV or TDF/3TC or FTC/Dolutegravir at time of study enrollment or willing to initiate this treatment and continue throughout the period of breastfeeding, if not for their lifetime.
• At enrollment, all women must be willing to breastfeed exclusively for the first six months of life.

Exclusion Criteria:

•Pre-existing maternal diabetes mellitus.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Nevirapine; 150 HIV-Exposed Uninfected (HEU) infants on Nevirapine (NVP) Prophylaxis	Drug: Nevirapine; neonatal 4 weeks prophylactic; Other Names: NVP
ACTIVE_COMPARATOR: Zidovudine; 150 HIV-Exposed Uninfected (HEU) infants on Zidovudine (AZT) Prophylaxis	Drug: Zidovudine; neonatal 4 weeks prophylactic; Other Names: AZT
NO_INTERVENTION: HIV- unexposed Uninfected (HUU) Infants; 150 HIV- unexposed Uninfected (HUU) Infants

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Homeo-static Model Assessment-Insulin Resistance (HOMA-IR)	[glucose (mg/dL) X insulin ( μU/mL)405]	up to 3 years

Collaborators and Investigators

• Sponsor: Ann & Robert H Lurie Children's Hospital of Chicago
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Jennifer Jao, MD, MPH, Ann & Robert H Lurie Children's Hospital of Chicago

Publications and helpful links

General Publications

• Banda FM, Powis KM, Sun S, Makhema J, Masasa G, Yee LM, Jao J. Fetal biometry following in-utero exposure to dolutegravir-based or efavirenz-based antiretroviral therapy. AIDS. 2020 Dec 1;34(15):2336-2337. doi: 10.1097/QAD.0000000000002674. No abstract available.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 22, 2016
• Primary Completion (ACTUAL): March 31, 2022
• Study Completion (ACTUAL): March 31, 2022

Study Registration Dates

• First Submitted: March 3, 2017
• First Submitted That Met QC Criteria: March 16, 2017
• First Posted (ACTUAL): March 23, 2017

Study Record Updates

• Last Update Posted (ACTUAL): July 20, 2022
• Last Update Submitted That Met QC Criteria: July 18, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Nevirapine; Zidovudine
• Other Study ID Numbers: IRB 2019-2922; R01DK109881 (NIH); HRDC 00781 (OTHER: Botswana MOH - Health Research Development Committee)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes