PrEP in Breastfeeding Study

An Open-label, Short-duration, Repeat-dose Study of Breastmilk Excretion and Infant Absorption of Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine When Used by HIV-uninfected Lactating Women

The purpose of this study is to quantify the magnitude and extent of infant exposure to daily emtricitabine (FTC) /tenofovir disoproxil fumarate (TDF) via maternal breastmilk when taken pre-exposure prophylaxis (PrEP) by lactating HIV-uninfected women. The primary outcome is the steady state concentrations of emtricitabine and tenofovir in the infant plasma.

Study Overview

• Status: Completed
• Conditions: HIV Pre-exposure Prophylaxis During Breastfeeding
• Intervention / Treatment: Drug: FTC/TDF PrEP

Detailed Description

This is prospective, short-duration, open-label, single-arm, repeat-dose, pharmacokinetic study of daily FTC/TDF PrEP among HIV-uninfected lactating mother-infant pairs. PrEP will be administered to women through daily directly observed therapy for 10 consecutive days - sufficient to reach steady-state but discontinuing thereafter. No drug will be administered to the infant directly. Co-formulated FTC and TDF were dosed at 200 mg daily and 300 mg daily, respectively. The overall goal is to quantify the magnitude and degree to which breastfeeding infants are exposed to FTC/TDF when used as PrEP by HIV-uninfected lactating women. Maternal blood and breastmilk samples will be obtained concurrently (i.e., within 30 minutes of each other) regardless of the timing of food intake (i.e., non-fasting) on the 7th and 10th day. Peak samples will be obtained 1-2 hours after the maternal directly observed PrEP and trough samples were obtained at the end of the dosing interval (i.e., 23 to 24 hours after directly observed PrEP dose). A single infant blood sample will be obtained after the maternal 7th directly observed PrEP dose.

We will conduct quantitative measurements and analyses of infant plasma drug concentrations, infant-plasma to breastmilk and breastmilk to maternal plasma drug concentration ratios to characterize FTC and TDF transmission to breast feeding infants. Tenofovir and emtricitabine concentrations in plasma and breastmilk will be quantified via previously validated liquid chromatographic-tandem mass spectrometric (LC-MS/MS) methods in accordance with the recommendations included in the US Food and Drug Administration, Guidance for Industry, Bioanalytical Method Validation guidelines.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Kenya
  • Thika, Kenya
    • Partners in Prevention-Thika
• Uganda
  • Kampala, Uganda
    • Partners in Prevention-Infectious Diseases Institute LTD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

For infant's mother and father

• Able and willing to provide informed consent for the infant to participate in the study
• Of legal age ≥18 years to consent

For HIV-uninfected mother, in addition to the criteria noted immediately above:

• Willing to provide breast milk samples and breastfeed during the duration of the study 0-24 weeks postpartum
• Breastfeeding an infant
• HIV-uninfected based on negative HIV rapid tests, both at study screening and at the enrollment visit
• Adequate renal function, defined by normal creatinine levels and estimated creatinine clearance ≥60 mL/min
• Not infected with hepatitis B virus, as determined by a negative hepatitis B surface antigen test
• Not currently using PrEP
• Note: single mothers will be eligible to participate in this study. Where possible the father's permission was be obtained. When the father is unknown, incompetent, deceased, or not reasonably available, or when only the mother has the legal responsibility for the care and custody of the child, infant participation will be based on the mother's consent and documentation will be added to file.

For infant

• Infant born to eligible women (both male and female infants will be included)
• Age 0-24 weeks
• Otherwise infant has no serious infections or active clinically significant medical problems

Exclusion Criteria:

• Women breastfeeding more than one child
• Preterm babies or infants with low birth weight (i.e. ≤2000mg)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
OTHER: FTC-TDF; Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) PrEP: 200mg FTC /300 mg TDF	Drug: FTC/TDF PrEP; Daily oral directly observed FTC/TDF PrEP administered to breastfeeding HIV-uninfected women; Other Names: Truvada PrEP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Steady state plasma concentrations of emtricitabine and tenofovir in the infants of breastfeeding women using PrEP: Quantity of PrEP medications in the infant plasma.	Infant exposure measured as median (interquartile range) concentrations of emtricitabine and tenofovir infant plasma.	Time averaged: 10 days
Steady state plasma concentrations of emtricitabine and tenofovir in the infants of breastfeeding women using PrEP: Detectable and quantifiable concentrations of PrEP medications in the infant plasma.	Measure the proportion of infant plasma samples with concentrations of emtricitabine and tenofovir below the assay lower limit of quantification.	Time averaged: 10 days
Steady state concentrations of emtricitabine and tenofovir in plasma of HIV-uninfected women using PrEP.	Measure median (interquartile range) concentrations of emtricitabine and tenofovir in maternal plasma.	Time averaged: 10 days
Steady state concentrations of emtricitabine and tenofovir in breastmilk of HIV-uninfected women using PrEP.	Measure median (interquartile range) concentrations of emtricitabine and tenofovir in breast milk.	Time averaged: 10 days
Infant plasma-to-maternal breast milk emtricitabine and tenofovir concentration ratios.	Measure median (interquartile range) infant plasma-to-maternal breast milk emtricitabine and tenofovir concentration ratios.	Time averaged: 10 days
Infant daily dose of tenofovir and emtricitabine received from breastmilk	We will compute the infant drug dose received from breastmilk per day (infant Computed as the product of breast milk tenofovir and emtricitabine concentrations and the estimated volume of breast milk consumed by infant daily. We will assume the daily amount of breast milk consumed by the infant to be 150 mL/kg/day, the standardized milk consumption of the average milk intake of a fully breast-fed infant. Measure median (interquartile range) infant daily dose for tenofovir and emtricitabine from breastmilk.	Time averaged: 10 days
Infant dose fraction for tenofovir and emtricitabine.	Infant dose fraction (i.e., exposure index) represents the daily amount of drug dose an infant would ingest from breast milk as a percentage of the recommended pediatric therapeutic daily dose. Infant dose fraction will be computed as as: infant dose fraction (%) = infant dose from breast milk *100/infant therapeutic dose. Measure median (interquartile range) infant dose fraction.	Time averaged: 10 days
Maternal breastmilk emtricitabine and tenofovir to plasma concentration ratios.	Measure median (interquartile range) of maternal breastmilk emtricitabine and tenofovir to plasma concentration ratios.	Time averaged: 10 days
Serious adverse events in infants of breastfeeding HIV-uninfected women using PrEP.	Number of infants with serious adverse effects.	Time averaged: 10 days
Serious adverse events in breastfeeding HIV-uninfected women using PrEP.	Number of women with serious adverse effects.	Time averaged: 10 days

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: Bill and Melinda Gates Foundation
• Investigators: Study Director: Kenneth K Mugwanya, MBChB, MS, University of Washington

Publications and helpful links

General Publications

• Mugwanya KK, Hendrix CW, Mugo NR, Marzinke M, Katabira ET, Ngure K, Semiyaga NB, John-Stewart G, Muwonge TR, Muthuri G, Stergachis A, Celum CL, Baeten JM. Pre-exposure Prophylaxis Use by Breastfeeding HIV-Uninfected Women: A Prospective Short-Term Study of Antiretroviral Excretion in Breast Milk and Infant Absorption. PLoS Med. 2016 Sep 27;13(9):e1002132. doi: 10.1371/journal.pmed.1002132. eCollection 2016 Sep.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (ACTUAL): May 1, 2015
• Study Completion (ACTUAL): December 1, 2015

Study Registration Dates

• First Submitted: May 15, 2016
• First Submitted That Met QC Criteria: May 17, 2016
• First Posted (ESTIMATE): May 18, 2016

Study Record Updates

• Last Update Posted (ACTUAL): September 21, 2021
• Last Update Submitted That Met QC Criteria: September 14, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Women; Pharmacokinetics; HIV prevention; Tenofovir; Breastfeeding; Pre-exposure prophylaxis; Emtricitabine; Tenofovir disoproxil; Post-partum
• Additional Relevant MeSH Terms: 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; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
• Other Study ID Numbers: 46363

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data from the PrEP in Breastfeeding Study are available by contacting the International Clinical Research Center at the University of Washington (icrc@uw.edu).