PrEP in Breastfeeding Study

Study Overview
=================
Brief Summary
-----------------
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.

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.

Official Title
-----------------
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

Conditions
-----------------
HIV Pre-exposure Prophylaxis During Breastfeeding

Intervention / Treatment
-----------------
* Drug: FTC/TDF PrEP


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: FTC-TDF<br>Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) PrEP: 200mg FTC /300 mg TDF | Drug: FTC/TDF PrEP<br>* Daily oral directly observed FTC/TDF PrEP administered to breastfeeding HIV-uninfected women<br>* 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Tenofovir disoproxil, Pre-exposure prophylaxis, Breastfeeding, Emtricitabine, Tenofovir, Post-partum, HIV prevention, Women, Pharmacokinetics