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

NCT03386578 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: IMPAACT 200930020
• Study Type: interventional
• Target: 780
• Locations: 4 countries
• Sites: 7

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.

Conditions

HIV Infections

Outcome Measures

Primary Outcomes (21)

• Estimated Threshold of Maternal Steady-state Tenofovir Diphosphate (TFV-DP) Concentration Levels Corresponding to Optimal Adherence in the PK Component

  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).

  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

• Proportion of Mothers With Optimal Adherence at 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.

  Antepartum study week 4

• Proportion of Mothers With Optimal Adherence at 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.

  Antepartum study week 8

• Proportion of Mothers With Optimal Adherence at 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.

  Antepartum study week 12

• Proportion of Mothers With Optimal Adherence at 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.

  Delivery

• Proportion of Mothers With Optimal Adherence at 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.

  Postpartum Week 6

• Proportion of Mothers With Optimal Adherence at 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.

  Postpartum week 14

• Proportion of Mothers With Optimal Adherence at 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.

  Postpartum Week 26

• Proportion of Maternal Visits With Optimal Adherence During Study Follow-up

  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.

  Study entry through 26 weeks postpartum, up to one year

• Incidence Rate of Maternal Adverse Events Per 100 Person-years

  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.

  Study entry through 26 weeks postpartum, up to one year

• Number of Composite Adverse Pregnancy Outcomes

  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)

  Measured at delivery

• Incidence Rate of Infant Grade 3 or Higher Adverse Events Per 100 Person-years

  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.

  From birth through week 26

• Mean Infant Bone Mineral Content of Whole Body at Birth

  Infant bone mineral content was measured by a dual-energy x-ray absorptiometry (DXA) scan of the whole body (WB-BMC)

  Measured at birth

• Mean Infant Bone Mineral Content of Lumbar Spine at Birth

  Infant bone mineral content was measured by a dual-energy x-ray absorptiometry (DXA) scan of the lumbar spine (LS-BMC)

  Measured at birth

• Mean Infant Bone Mineral Content of Lumbar Spine at Week 26

  Infant bone mineral content was measured by a dual-energy x-ray absorptiometry (DXA) scan of the lumbar spine (LS-BMC)

  Measured at week 26 post-birth

• Mean Infant Creatinine Levels at Birth in the PrEP Comparison Component

  Infant creatinine levels were obtained from the chemistry/hematology test results at the birth visit

  Measured at birth

• Mean Infant Creatinine Levels at Week 26 in the PrEP Comparison Component

  Infant creatinine levels were obtained from the chemistry/hematology test results at week 26 visit

  Measured at week 26 post-birth

• Mean Infant Creatinine Clearance (CrCl) Rate at Birth in the PrEP Comparison Component

  The infant creatinine clearance (CrCl) rate was calculated using creatinine levels and length based on the Schwartz equation.

  Measured at birth

• Mean Infant Creatinine Clearance (CrCl) Rate at Week 26 in the PrEP Comparison Component

  The infant creatinine clearance (CrCl) rate was calculated using creatinine levels and length based on the Schwartz equation.

  Measured at week 26 post-birth

• Mean Infant Length-for-age Z-score 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.

  Measured at birth

• Mean Infant Length-for-age Z-score at Week 26

  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.

  Measured at week 26 post-birth

Secondary Outcomes (1)

• 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

Study Arms (10)

Maternal PK Component Group 1

EXPERIMENTAL

Mothers enrolled during singleton pregnancy at 14-24 weeks' gestation received PrEP once daily under direct observation from day 0 through week 12.

Drug: Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF)

Maternal PK Component Group 2

EXPERIMENTAL

Mothers enrolled postpartum within 6-12 weeks after delivery received PrEP once daily under direct observation from day 0 through week 12.

Drug: Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF)

Maternal PrEP Comparison Cohort 1

EXPERIMENTAL

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.

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

Maternal PrEP Comparison Cohort 2/Step 1

ACTIVE COMPARATOR

Mothers who declined PrEP initiation at study entry received a behavioral HIV risk reduction package from day 0 through postpartum week 26.

Behavioral: Behavioral HIV risk reduction package

Maternal PrEP Comparison Cohort 2/Step 2

EXPERIMENTAL

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.

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

Infant PK Component Group 1

NO INTERVENTION

Infants born to women in PK Component Group 1. Infants did not directly receive PrEP, but may have been exposed to PrEP through placental or breastmilk transfer.

Infant PK Component Group 2

NO INTERVENTION

Infants born to women in PK Component Group 2. Infants did not directly receive PrEP, but may have been exposed to PrEP through breastmilk transfer.

Infant PrEP Comparison Cohort 1

NO INTERVENTION

Infants born to women in PrEP Comparison Cohort 1. Infants did not directly receive PrEP, but may have been exposed to PrEP through placental or breastmilk transfer.

Infant PrEP Comparison Cohort 2/Step 1

NO INTERVENTION

Infants born to women in PrEP Comparison Cohort 2/Step 1. Infants were not exposed to PrEP during the study.

Infant PrEP Comparison Cohort 2/Step 2

NO INTERVENTION

Infants born to women in PrEP Comparison Cohort 2/Step 2. Infants did not directly receive PrEP, but may have been exposed to PrEP through placental or breastmilk transfer.

Interventions

Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) DRUG

200 mg/300 mg of FTC/TDF administered orally as a fixed-dose combination tablet once daily

Also known as: Truvada

Maternal PK Component Group 1; Maternal PK Component Group 2; Maternal PrEP Comparison Cohort 1; Maternal PrEP Comparison Cohort 2/Step 2

Behavioral HIV risk reduction package BEHAVIORAL

Included cohort-appropriate SMS messages.

Maternal PrEP Comparison Cohort 1; Maternal PrEP Comparison Cohort 2/Step 1; Maternal PrEP Comparison Cohort 2/Step 2

Enhanced adherence support BEHAVIORAL

Included two-way SMS messaging and tailored counseling with drug level feedback.

Maternal PrEP Comparison Cohort 1; Maternal PrEP Comparison Cohort 2/Step 2

Eligibility Criteria

• Age: 16 Years - 24 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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).

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Gilead Sciences: collaborator

Study Sites (7)

Blantyre CRS

Blantyre, Malawi

Location

Wits RHI Shandukani Research Centre CRS

Johannesburg, Gauteng, 2001, South Africa

Location

Baylor-Uganda CRS

Kampala, Uganda

Location

MU-JHU Care Limited CRS

Kampala, Uganda

Location

St Mary's CRS

Saint Mary's, Chitungwiza, Zimbabwe

Location

Seke North CRS

Chitungwiza, Zimbabwe

Location

Harare Family Care CRS

Harare, Zimbabwe

Location

Related Publications (1)

• Stranix-Chibanda L, Anderson PL, Kacanek D, Hosek S, Huang S, Nematadzira TG, Taulo F, Korutaro V, Nakabiito C, Masenya M, Lypen K, Brown E, Ibrahim ME, Yager J, Wiesner L, Johnston B, Amico KR, Rooney JF, Chakhtoura N, Spiegel HML, Chi BH; IMPAACT 2009 Team. Tenofovir Diphosphate Concentrations in Dried Blood Spots From Pregnant and Postpartum Adolescent and Young Women Receiving Daily Observed Pre-exposure Prophylaxis in Sub-Saharan Africa. Clin Infect Dis. 2021 Oct 5;73(7):e1893-e1900. doi: 10.1093/cid/ciaa1872.

  PMID: 33341883 RESULT

Related Links

• Related Info
• The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, July 2017
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

MeSH Terms

Conditions

HIV Infections

Interventions

Emtricitabine; Tenofovir; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Drug Combinations; Pharmaceutical Preparations

Results Point of Contact

• Title: IMPAACT Clinicaltrials.gov Coordinator
• Organization: Family Health International (FHI 360)

IMPAACT.ctgov@fstrf.org

(919) 405-1429

Study Officials

• Benjamin Chi, MD, MSc

  University of North Carolina, Chapel Hill

  STUDY CHAIR

• Lynda Stranix-Chibanda, MBChB, MMED

  University of Zimbabwe Faculty of Medicine and Health Sciences

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 18, 2017
• First Posted: December 29, 2017
• Study Start: July 3, 2018
• Primary Completion: October 25, 2023
• Study Completion: February 24, 2024
• Last Updated: February 19, 2025
• Results First Posted: February 19, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 3 months following publication and available throughout period of funding of the International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) Network by NIH.
• Access Criteria: * With whom? * Researchers who provide a methodologically sound proposal for use of the data that is approved by the IMPAACT Network. * For what types of analyses? * To achieve aims in the proposal approved by the IMPAACT Network. * By what mechanism will data be made available? * Researchers may submit a request for access to data using the IMPAACT "Data Request" form at: https://www.impaactnetwork.org/resources/study-proposals.htm. Researchers of approved proposals will need to sign an IMPAACT Data Use Agreement before receiving the data.

Locations

MA (1); ZI (3); UG (2); ZA (1)