Clinical trial NCT03386578: Evaluating the Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure Prophylaxis for HIV Prevention During Pregnancy and Postpartum
Official title: Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure Prophylaxis for Primary HIV Prevention During Pregnancy and Postpartum in Adolescents and Young Women and Their Infants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Gilead Sciences
First posted: 2017-12-29
Enrollment: 780
Sex: FEMALE
Minimum age (years): 16
Maximum age (years): 24
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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).

Eligibility criteria: PK Component (Groups 1 and 2) 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

Primary outcomes:
measure: Estimated Threshold of Maternal Steady-state Tenofovir Diphosphate (TFV-DP) Concentration Levels Corresponding to Optimal Adherence in the PK Component
timeFrame: 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
measure: Proportion of Mothers With Optimal Adherence at Antepartum Study Week 4
timeFrame: Antepartum study week 4
measure: Proportion of Mothers With Optimal Adherence at Antepartum Study Week 8
timeFrame: Antepartum study week 8
measure: Proportion of Mothers With Optimal Adherence at Antepartum Study Week 12
timeFrame: Antepartum study week 12
measure: Proportion of Mothers With Optimal Adherence at Delivery
timeFrame: Delivery
measure: Proportion of Mothers With Optimal Adherence at Postpartum Week 6
timeFrame: Postpartum Week 6
measure: Proportion of Mothers With Optimal Adherence at Postpartum Week 14
timeFrame: Postpartum week 14
measure: Proportion of Mothers With Optimal Adherence at Postpartum Week 26
timeFrame: Postpartum Week 26
measure: Proportion of Maternal Visits With Optimal Adherence During Study Follow-up
timeFrame: Study entry through 26 weeks postpartum, up to one year
measure: Incidence Rate of Maternal Adverse Events Per 100 Person-years
timeFrame: Study entry through 26 weeks postpartum, up to one year
measure: Number of Composite Adverse Pregnancy Outcomes
timeFrame: Measured at delivery
measure: Incidence Rate of Infant Grade 3 or Higher Adverse Events Per 100 Person-years
timeFrame: From birth through week 26
measure: Mean Infant Bone Mineral Content of Whole Body at Birth
timeFrame: Measured at birth
measure: Mean Infant Bone Mineral Content of Lumbar Spine at Birth
timeFrame: Measured at birth
measure: Mean Infant Bone Mineral Content of Lumbar Spine at Week 26
timeFrame: Measured at week 26 post-birth
measure: Mean Infant Creatinine Levels at Birth in the PrEP Comparison Component
timeFrame: Measured at birth
measure: Mean Infant Creatinine Levels at Week 26 in the PrEP Comparison Component
timeFrame: Measured at week 26 post-birth
measure: Mean Infant Creatinine Clearance (CrCl) Rate at Birth in the PrEP Comparison Component
timeFrame: Measured at birth
measure: Mean Infant Creatinine Clearance (CrCl) Rate at Week 26 in the PrEP Comparison Component
timeFrame: Measured at week 26 post-birth
measure: Mean Infant Length-for-age Z-score at Birth
timeFrame: Measured at birth
measure: Mean Infant Length-for-age Z-score at Week 26
timeFrame: Measured at week 26 post-birth
Secondary outcomes:
measure: Maternal Median Steady State TFV-DP Concentration Levels at Study Week 12 During Pregnancy and Postpartum
timeFrame: 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
Other outcomes:
Locations:
city: Blantyre
country: Malawi
facility: Blantyre CRS
city: Johannesburg
country: South Africa
facility: Wits RHI Shandukani Research Centre CRS
state: Gauteng
city: Kampala
country: Uganda
facility: Baylor-Uganda CRS
city: Kampala
country: Uganda
facility: MU-JHU Care Limited CRS
city: St. Mary's
country: Zimbabwe
facility: St Mary's CRS
state: Chitungwiza
city: Chitungwiza
country: Zimbabwe
facility: Seke North CRS
city: Harare
country: Zimbabwe
facility: Harare Family Care CRS
Study officials:
affiliation: University of North Carolina, Chapel Hill
name: Benjamin Chi, MD, MSc
role: STUDY_CHAIR
affiliation: University of Zimbabwe Faculty of Medicine and Health Sciences
name: Lynda Stranix-Chibanda, MBChB, MMED
role: STUDY_CHAIR
References:
citation: 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.