Evaluating the Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure Prophylaxis for HIV Prevention During Pregnancy and Postpartum

Phase 2

Completed

Conditions: HIV Infections

Interventions: Drug: Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF)
Behavioral: Behavioral HIV risk reduction package
Behavioral: Enhanced adherence support

Registration Number: NCT03386578

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: The purpose of this study was to evaluate the pharmacokinetics, feasibility, acceptability, and safety of a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) as oral daily pre-exposure prophylaxis (PrEP) to prevent HIV during pregnancy and postpartum in adolescents and young women and their infants.

Detailed Description: This study evaluated the pharmacokinetics, feasibility, acceptability, and safety of FTC/TDF as oral daily PrEP to prevent HIV during pregnancy and postpartum in adolescents and young women and their infants. The study was conducted in two consecutive components: 1) Pharmacokinetics (PK) Component and 2) PrEP Comparison Component.

In the PK Component, women enrolled in one of two groups. Group 1 included pregnant women at 14 to 24 weeks' gestation and Group 2 included postpartum women who delivered 6 to 12 weeks prior to enrollment. Both groups received a fixed-dose combination of FTC/TDF administered once daily by direct observation from Day 0 through Week 12.

Mothers in the PK Component had weekly study visits through Week 12. Infants in Group 1, whose mothers enrolled during pregnancy, had study visits at birth and six weeks of life; infants in Group 2, who were enrolled with their mothers 6-12 weeks after birth, had study visits at Week 6 and Week 12. Study visits for mothers and infants in the PK Component included evaluation of drug levels and monitoring for adverse effects.

In the PrEP Comparison Component, pregnant women enrolled in one of two cohorts. Mothers in Cohort 1 chose to initiate PrEP at study entry, and mothers in Cohort 2 declined PrEP at entry. Participants in both Cohorts received a standard of care package of HIV prevention services, a study-specific behavioral risk reduction intervention, and periodic one-way short message service (SMS) messages to promote maternal and child health from Day 0 through Week 26. Cohort 1 opted to also receive daily oral FTC/TDF as PrEP and enhanced adherence support, including weekly two-way SMS messaging and feedback of drug levels with tailored adherence counseling. Participants who changed their mind about using PrEP during study participation were able to subsequently stop PrEP (Cohort 1) or initiate PrEP (Cohort 2/Step 2).

Mothers in the PrEP Comparison Component had regular study visits through delivery and Week 26 (postpartum). Infants in the PrEP Comparison Component had four study visits from birth through week 26 of life. For mothers, study visits included physical examinations, blood and urine collection, vaginal and (optional) rectal swab collection, vaginal secretions collection, ultrasounds, and dual-energy x-ray absorptiometry (DXA) scans. For infants, study visits included physical examinations, rectal swab and blood collection, and DXA scans.

In the PrEP Comparison Component analysis, maternal and infant participants were classified based on their PrEP exposure. The PrEP-exposed group included participants from Cohort 1 (throughout the entire study follow-up) and from Cohort 2/Step 2 (from Step 2 entry to the end of follow-up). The PrEP-unexposed group comprised participants from Cohort 2/Step 1 who did not enroll in Cohort 2/Step 2 (throughout the entire study follow-up) or who enrolled in Cohort 2/Step 2 (from study entry until enrolling in Cohort 2/Step 2).

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 780

Inclusion Criteria

At study entry, pregnant or recently delivered, in one of the following two enrollment windows:
- Group 1: Gestational age of 14 to 24 weeks.
- Group 2: 6 to 12 weeks postpartum.
Willing to initiate daily PrEP for 12 weeks under directly observed therapy.
HIV and Hepatitis B negative.
At screening:
- Grade 1 or normal alanine transaminase (ALT), hemoglobin (HB), absolute neutrophil count (ANC) and normal creatinine clearance (CrCl).
- Negative or trace proteinuria (less than Grade 1).
- Normal dipstick urine for glucose (less than Grade 1).
- Mother weighs greater than 35 kg.
Intention to stay within the study site's catchment area for at least 12 weeks (or through delivery).

Exclusion Criteria (PK Component and PrEP Comparison Component):

Any current significant uncontrolled, active or chronic disease process.
History of any of the following:
- Sickle cell anemia, chronic bleeding, blood transfusion within the past 120 days or other blood dyscrasias
- Bone fracture not explained by trauma
- Allergy/sensitivity to FTC/TDF or its components
Fetus has a known or suspected major congenital anomaly
Mother has confirmed renal insufficiency, a history of renal parenchymal disease or single kidney
Current use of prohibited medications listed in the protocol
Concurrent participation in any biomedical HIV prevention or investigational drug in an HIV vaccine or microbicide study
Past participation in an HIV vaccine study
Currently taking a PrEP regimen from non-study sources
Any other condition or adverse social situation
Past participation in IMPAACT 2009

PrEP Comparison Component (Cohorts 1 and 2) Inclusion Criteria:

At screening, evidence of a viable singleton pregnancy with gestational age of 32 weeks or less.
Within 14 days prior to study entry, negative HIV RNA test.
HIV and Hepatitis B negative.
At screening:
- Grade 1 or normal ALT, HB, ANC and normal CrCl.
- Negative or trace proteinuria (less than Grade 1).
- Normal dipstick urine for glucose (less than Grade 1).
Intention to stay within the study site's catchment area through 26 weeks postpartum
A cellular phone that is able to receive SMS messages, and for Cohort 1 only, is also able to send SMS messages.
Cohort 1 only: Willingness to take PrEP from pregnancy up to 26 weeks postpartum
Cohort 2 only: Unwillingness to take PrEP from pregnancy up to 26 weeks postpartum
Mother weighs greater than 35 kg
Mother is literate in one or more of the study languages

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Maternal PK Component Group 1	Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF)	Mothers enrolled during singleton pregnancy at 14-24 weeks' gestation received PrEP once daily under direct observation from day 0 through week 12.
Maternal PK Component Group 2	Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF)	Mothers enrolled postpartum within 6-12 weeks after delivery received PrEP once daily under direct observation from day 0 through week 12.
Maternal PrEP Comparison Cohort 1	Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF)	Mothers who initiated PrEP at study entry received daily oral PrEP, a behavioral HIV risk reduction package and enhanced adherence support from day 0 through postpartum week 26.
Maternal PrEP Comparison Cohort 1	Behavioral HIV risk reduction package	Mothers who initiated PrEP at study entry received daily oral PrEP, a behavioral HIV risk reduction package and enhanced adherence support from day 0 through postpartum week 26.
Maternal PrEP Comparison Cohort 1	Enhanced adherence support	Mothers who initiated PrEP at study entry received daily oral PrEP, a behavioral HIV risk reduction package and enhanced adherence support from day 0 through postpartum week 26.
Maternal PrEP Comparison Cohort 2/Step 1	Behavioral HIV risk reduction package	Mothers who declined PrEP initiation at study entry received a behavioral HIV risk reduction package from day 0 through postpartum week 26.
Maternal PrEP Comparison Cohort 2/Step 2	Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF)	Mothers from Cohort 2/Step 1 who subsequently chose to initiate PrEP during the study received daily oral PrEP and enhanced adherence support from Step 2 entry through postpartum week 26, along with the behavioral HIV risk reduction package.
Maternal PrEP Comparison Cohort 2/Step 2	Behavioral HIV risk reduction package	Mothers from Cohort 2/Step 1 who subsequently chose to initiate PrEP during the study received daily oral PrEP and enhanced adherence support from Step 2 entry through postpartum week 26, along with the behavioral HIV risk reduction package.
Maternal PrEP Comparison Cohort 2/Step 2	Enhanced adherence support	Mothers from Cohort 2/Step 1 who subsequently chose to initiate PrEP during the study received daily oral PrEP and enhanced adherence support from Step 2 entry through postpartum week 26, along with the behavioral HIV risk reduction package.

Primary Outcome Measures

Name	Time	Method
Estimated Threshold of Maternal Steady-state Tenofovir Diphosphate (TFV-DP) Concentration Levels Corresponding to Optimal Adherence in the PK Component	Measured from study week 1 to study week 12 during pregnancy for Maternal PK Component Group 1 and from study week 1 to study week 12 during postpartum for Maternal PK Component Group 2	TFV-DP concentration levels were measured using dried blood spots (DBS) collected weekly during pregnancy and postpartum. These concentrations accumulated each week, and the plateau observed in the concentration-time curve represents the steady-state TFV-DP concentration, achieved at week 12. Predicted TFV-DP concentration levels for each maternal participant were obtained using a population PK model, and descriptive statistics were generated. The estimated steady-state TFV-DP concentration threshold for optimal adherence during pregnancy and postpartum is the 25th percentile when taking 7 doses per week. For more details, refer to the published paper (PubMed ID: 33341883).
Proportion of Mothers With Optimal Adherence at Antepartum Study Week 4	Antepartum study week 4	TFV-DP concentration levels were measured using dried blood spots (DBS). Mothers with optimal adherence were identified based on TFV-DP concentration levels and the threshold established in the PK Component.
Proportion of Mothers With Optimal Adherence at Antepartum Study Week 8	Antepartum study week 8	TFV-DP concentration levels were measured using dried blood spots (DBS). Mothers with optimal adherence were identified based on TFV-DP concentration levels and the threshold established in the PK Component.
Proportion of Mothers With Optimal Adherence at Antepartum Study Week 12	Antepartum study week 12	TFV-DP concentration levels were measured using dried blood spots (DBS). Mothers with optimal adherence were identified based on TFV-DP concentration levels and the threshold established in the PK Component.
Proportion of Mothers With Optimal Adherence at Delivery	Delivery	TFV-DP concentration levels were measured using dried blood spots (DBS). Mothers with optimal adherence were identified based on TFV-DP concentration levels and the threshold established in the PK Component.
Proportion of Mothers With Optimal Adherence at Postpartum Week 6	Postpartum Week 6	TFV-DP concentration levels were measured using dried blood spots (DBS). Mothers with optimal adherence were identified based on TFV-DP concentration levels and the threshold established in the PK Component.
Proportion of Mothers With Optimal Adherence at Postpartum Week 14	Postpartum week 14	TFV-DP concentration levels were measured using dried blood spots (DBS). Mothers with optimal adherence were identified based on TFV-DP concentration levels and the threshold established in the PK Component.
Proportion of Mothers With Optimal Adherence at Postpartum Week 26	Postpartum Week 26	TFV-DP concentration levels were measured using dried blood spots (DBS). Mothers with optimal adherence were identified based on TFV-DP concentration levels and the threshold established in the PK Component.
Proportion of Maternal Visits With Optimal Adherence During Study Follow-up	Study entry through 26 weeks postpartum, up to one year	TFV-DP concentration levels were measured using dried blood spots (DBS). Mothers with optimal adherence were identified based on TFV-DP concentration levels and the threshold established in the PK Component.
Incidence Rate of Maternal Adverse Events Per 100 Person-years	Study entry through 26 weeks postpartum, up to one year	Adverse events (AEs) were graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. Maternal AEs were defined as the occurrence of at least one grade 2 (moderate) chemistry abnormality, or one grade 3 (severe), grade 4 (potentially life-threatening), or grade 5 (death) adverse event, during the study follow-up.
Number of Composite Adverse Pregnancy Outcomes	Measured at delivery	Adverse outcomes are defined as at least one of the following: spontaneous abortion (less than 20 weeks gestation), stillbirth (greater than or equal to 20 weeks gestation), preterm delivery (less than 37 weeks), or small for gestational age (less than 10th percentile using INTERGROWTH-21 norms)
Incidence Rate of Infant Grade 3 or Higher Adverse Events Per 100 Person-years	From birth through week 26	Adverse events were assessed according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. An infant grade 3 or higher adverse event was defined as a grade 3 (severe), grade 4 (potentially life-threatening), or grade 5 (death) adverse event.
Mean Infant Bone Mineral Content of Whole Body at Birth	Measured at birth	Infant bone mineral content was measured by a dual-energy x-ray absorptiometry (DXA) scan of the whole body (WB-BMC)
Mean Infant Bone Mineral Content of Lumbar Spine at Birth	Measured at birth	Infant bone mineral content was measured by a dual-energy x-ray absorptiometry (DXA) scan of the lumbar spine (LS-BMC)
Mean Infant Bone Mineral Content of Lumbar Spine at Week 26	Measured at week 26 post-birth	Infant bone mineral content was measured by a dual-energy x-ray absorptiometry (DXA) scan of the lumbar spine (LS-BMC)
Mean Infant Creatinine Levels at Birth in the PrEP Comparison Component	Measured at birth	Infant creatinine levels were obtained from the chemistry/hematology test results at the birth visit
Mean Infant Creatinine Levels at Week 26 in the PrEP Comparison Component	Measured at week 26 post-birth	Infant creatinine levels were obtained from the chemistry/hematology test results at week 26 visit
Mean Infant Creatinine Clearance (CrCl) Rate at Birth in the PrEP Comparison Component	Measured at birth	The infant creatinine clearance (CrCl) rate was calculated using creatinine levels and length based on the Schwartz equation.
Mean Infant Creatinine Clearance (CrCl) Rate at Week 26 in the PrEP Comparison Component	Measured at week 26 post-birth	The infant creatinine clearance (CrCl) rate was calculated using creatinine levels and length based on the Schwartz equation.
Mean Infant Length-for-age Z-score at Birth	Measured at birth	The infant length-for-age Z-score was calculated based on the infant's sex, length, and age (in days) using WHO child growth standards. The Z-scores range from a minimum of -6 to a maximum of +6. Higher Z-scores indicate better outcomes, reflecting closer adherence to the WHO standards for infant length-for-age. A Z-score of 0 means that the infant's length is exactly at the mean length of the reference population. Z-score between -2 and +2 is considered normal or average. Infants within this range are typically seen as having an appropriate length for their age. Z-score \< -3 is a threshold to identify severe stunting, indicating that the infant's length is significantly below the average and pointing to severe chronic undernutrition or other serious health concerns.
Mean Infant Length-for-age Z-score at Week 26	Measured at week 26 post-birth	The infant length-for-age z-score was calculated based on the infant's sex, length, and age (in days) using WHO child growth standards. The z-scores range from a minimum of -6 to a maximum of +6. Higher z-scores indicate better outcomes, reflecting closer adherence to the WHO standards for infant length-for-age. A Z-score of 0 means that the infant's length is exactly at the mean length of the reference population. Z-score between -2 and +2 is considered normal or average. Infants within this range are typically seen as having an appropriate length for their age. Z-score \< -3 is a threshold to identify severe stunting, indicating that the infant's length is significantly below the average and pointing to severe chronic undernutrition or other serious health concerns.

Secondary Outcome Measures

Name	Time	Method
Maternal Median Steady State TFV-DP Concentration Levels at Study Week 12 During Pregnancy and Postpartum	Assessed at study Week 12 during pregnancy for Maternal PK Component Group 1 and at study Week 12 during postpartum for Maternal PK Component Group 2	TFV-DP concentration levels were measured using dried blood spots (DBS). Concentrations measured at week 12 represent the steady-state TFV-DP concentration.

Trial Locations

Locations (7): MU-JHU Care Limited CRS
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Kampala, Uganda
Baylor-Uganda CRS
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Kampala, Uganda
Blantyre CRS
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Blantyre, Malawi
St Mary's CRS
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St. Mary's, Chitungwiza, Zimbabwe
Seke North CRS
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Chitungwiza, Zimbabwe
Harare Family Care CRS
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Harare, Zimbabwe
Wits RHI Shandukani Research Centre CRS
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Johannesburg, Gauteng, South Africa