HIV Infections
Conditions
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).
Interventions
200 mg/300 mg of FTC/TDF administered orally as a fixed-dose combination tablet once daily
BEHAVIORALBehavioral HIV risk reduction package
Included cohort-appropriate SMS messages.
BEHAVIORALEnhanced adherence support
Included two-way SMS messaging and tailored counseling with drug level feedback.
Sponsors
Gilead Sciences
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
16 Years to 24 Years
Healthy volunteers
Yes
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Malawi, South Africa, Uganda, Zimbabwe
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Maternal PK Component Group 1 Mothers enrolled during singleton pregnancy at 14-24 weeks' gestation received PrEP once daily under direct observation from day 0 through week 12. | 20 |
| Maternal PK Component Group 2 Mothers enrolled postpartum within 6-12 weeks after delivery received PrEP once daily under direct observation from day 0 through week 12. | 20 |
| Maternal PrEP Comparison Cohort 1 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. | 229 |
| Maternal PrEP Comparison Cohort 2/Step 1 Mothers who declined PrEP initiation at study entry received a behavioral HIV risk reduction package from day 0 through postpartum week 26. | 121 |
| Maternal PrEP Comparison Cohort 2/Step 2 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. | 0 |
| Total | 390 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| PK Component | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| PK Component | Stillbirth/Abortion | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
| PrEP Comparison Component Step 1 | Death | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 9 | 5 | 0 |
| PrEP Comparison Component Step 1 | Enrolled to Cohort 2/Step 2 | 0 | 0 | 0 | 13 | 0 | 0 | 0 | 0 | 13 | 0 |
| PrEP Comparison Component Step 1 | Lost to Follow-up | 0 | 0 | 17 | 9 | 0 | 0 | 0 | 7 | 5 | 0 |
| PrEP Comparison Component Step 1 | Maternal Off-study During Pregnancy | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 10 | 5 | 0 |
| PrEP Comparison Component Step 1 | Stillbirth/Abortion | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 4 | 0 |
| PrEP Comparison Component Step 1 | Withdrawal by Subject | 0 | 0 | 9 | 4 | 0 | 0 | 0 | 5 | 1 | 0 |
Baseline characteristics
| Characteristic | Maternal PK Component Group 2 | Maternal PK Component Group 1 | Total | Maternal PrEP Comparison Cohort 1 | Maternal PrEP Comparison Cohort 2/Step 1 | Maternal PrEP Comparison Cohort 2/Step 2 |
|---|---|---|---|---|---|---|
| Age, Continuous PK Component | 20 years | 20 years | 20 years | — | — | — |
| Age, Continuous PrEP Comparison | — | — | 21 years | 21 years | 21 years | — |
| Gestational Age PK Component | — | 18 weeks | 18 weeks | — | — | — |
| Gestational Age PrEP Comparison | — | — | 24 weeks | 24 weeks | 25 weeks | — |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 20 Participants | 20 Participants | 390 Participants | 229 Participants | 121 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Malawi | 7 participants | 0 participants | 57 participants | 23 participants | 27 participants | — |
| Region of Enrollment South Africa | 0 participants | 4 participants | 44 participants | 29 participants | 11 participants | — |
| Region of Enrollment Uganda | 4 participants | 8 participants | 89 participants | 54 participants | 23 participants | — |
| Region of Enrollment Zimbabwe | 9 participants | 8 participants | 200 participants | 123 participants | 60 participants | — |
| Sex: Female, Male Female | 20 Participants | 20 Participants | 390 Participants | 229 Participants | 121 Participants | 0 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 | 1 / 229 | 0 / 121 | 0 / 13 | 0 / 18 | 0 / 20 | 9 / 217 | 5 / 112 | 0 / 13 |
| other Total, other adverse events | 1 / 20 | 2 / 20 | 123 / 229 | 46 / 121 | 5 / 13 | 1 / 18 | 4 / 20 | 120 / 217 | 44 / 112 | 4 / 13 |
| serious Total, serious adverse events | 3 / 20 | 0 / 20 | 30 / 229 | 4 / 121 | 0 / 13 | 1 / 18 | 0 / 20 | 26 / 217 | 8 / 112 | 0 / 13 |
Outcome results
Primary
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).
Time frame: 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
Population: Mothers from PK Component were included in this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maternal PK Component Group 1 | Estimated Threshold of Maternal Steady-state Tenofovir Diphosphate (TFV-DP) Concentration Levels Corresponding to Optimal Adherence in the PK Component | 965 fmol/punch |
| Maternal PK Component Group 2 | Estimated Threshold of Maternal Steady-state Tenofovir Diphosphate (TFV-DP) Concentration Levels Corresponding to Optimal Adherence in the PK Component | 1050 fmol/punch |
Primary
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.
Time frame: From birth through week 26
Population: Live-born infants from PrEP Comparison Component were included in the analysis. Primary analyses, as described in the SAP, were conducted in two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 were combined as the PrEP-exposed group. The incidence of adverse events was calculated per 100 person-years. Infant participants in Cohort 2/Step 2 contributed to person-years for both groups, with Cohort 2/Step 1 censored upon enrollment in Step 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maternal PK Component Group 1 | Incidence Rate of Infant Grade 3 or Higher Adverse Events Per 100 Person-years | 42.6 number of new cases per 100 person years |
| Maternal PK Component Group 2 | Incidence Rate of Infant Grade 3 or Higher Adverse Events Per 100 Person-years | 33.1 number of new cases per 100 person years |
Comparison: The incidence rate ratio of cumulative infant AEs between PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) and PrEP-unexposed (Cohort 2/Step 1) reference group was based on incidence per person-time follow-up. Cohort 2/Step 2 infants contributed person-time to both Cohort 2/Step 1 and Step 2.95% CI: [0.7, 2.38]
Primary
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.
Time frame: Study entry through 26 weeks postpartum, up to one year
Population: Mothers from the PrEP Comparison Component were included in the analysis. Primary analyses, as described in the SAP, were conducted in two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 were combined as the PrEP-exposed group. The incidence of adverse events was calculated per 100 person-years. Maternal participants in Cohort 2/Step 2 contributed to person-years for both groups, with Cohort 2/Step 1 censored upon enrollment in Step 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maternal PK Component Group 1 | Incidence Rate of Maternal Adverse Events Per 100 Person-years | 29.4 number of new cases per 100 person years |
| Maternal PK Component Group 2 | Incidence Rate of Maternal Adverse Events Per 100 Person-years | 18.2 number of new cases per 100 person years |
Comparison: The incidence rate ratio of cumulative maternal adverse events was calculated between PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) and the PrEP-unexposed (Cohort 2/Step 1) reference group based on incidence per person-time follow-up. Maternal participants in Cohort 2/Step 2 contributed person-time to both Cohort 2/Step 1 and Step 2.95% CI: [0.89, 2.94]
Primary
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)
Time frame: Measured at birth
Population: Infants from PrEP Comparison Component with available DXA data were included in this analysis. Primary analyses, as described in the SAP, were conducted in two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 were combined as the PrEP-exposed group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Maternal PK Component Group 1 | Mean Infant Bone Mineral Content of Lumbar Spine at Birth | 1.9 gram | Standard Deviation 0.5 |
| Maternal PK Component Group 2 | Mean Infant Bone Mineral Content of Lumbar Spine at Birth | 1.8 gram | Standard Deviation 0.4 |
Comparison: A two-sample t-test was used to evaluate the difference in mean infant lumbar-spine bone mineral content (WB-BMC) at birth between PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) and PrEP-unexposed group (Cohort 2/Step 1).p-value: 0.39t-test, 2 sided
Primary
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)
Time frame: Measured at week 26 post-birth
Population: Infants from PrEP Comparison Component with available DXA data were included in this analysis. Primary analyses, as described in the SAP, were conducted in two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 were combined as the PrEP-exposed group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Maternal PK Component Group 1 | Mean Infant Bone Mineral Content of Lumbar Spine at Week 26 | 3.2 gram | Standard Deviation 0.6 |
| Maternal PK Component Group 2 | Mean Infant Bone Mineral Content of Lumbar Spine at Week 26 | 3.1 gram | Standard Deviation 0.7 |
Comparison: A two-sample t-test was used to evaluate the difference in mean infant lumbar-spine bone mineral content (WB-BMC) at week 26 between PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) and PrEP-unexposed group (Cohort 2/Step 1).p-value: 0.12t-test, 2 sided
Primary
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)
Time frame: Measured at birth
Population: Infants from PrEP Comparison Component with available DXA data were included in this analysis. Primary analyses, as described in the SAP, were conducted in two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 were combined as the PrEP-exposed group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Maternal PK Component Group 1 | Mean Infant Bone Mineral Content of Whole Body at Birth | 68.2 gram | Standard Deviation 13.3 |
| Maternal PK Component Group 2 | Mean Infant Bone Mineral Content of Whole Body at Birth | 65.8 gram | Standard Deviation 12 |
Comparison: A two-sample t-test was used to evaluate the difference in mean infant whole-body bone mineral content (WB-BMC) at birth between PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) and PrEP-unexposed group (Cohort 2/Step 1).p-value: 0.18t-test, 2 sided
Primary
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.
Time frame: Measured at birth
Population: Infants from PrEP Comparison Component with available creatinine clearance data were included in this analysis. Primary analyses, as described in the SAP, were conducted in two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 were combined as the PrEP-exposed group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Maternal PK Component Group 1 | Mean Infant Creatinine Clearance (CrCl) Rate at Birth in the PrEP Comparison Component | 84.4 mL/min | Standard Deviation 61.6 |
| Maternal PK Component Group 2 | Mean Infant Creatinine Clearance (CrCl) Rate at Birth in the PrEP Comparison Component | 74.6 mL/min | Standard Deviation 33.7 |
Comparison: A two-sample t-test was used to evaluate the difference in mean infant creatinine clearance rate at birth between PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) and PrEP-unexposed group (Cohort 2/Step 1).p-value: 0.08t-test, 2 sided
Primary
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.
Time frame: Measured at week 26 post-birth
Population: Infants from PrEP Comparison Component with available creatinine clearance data were included in this analysis. Primary analyses, as described in the SAP, were conducted in two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 were combined as the PrEP-exposed group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Maternal PK Component Group 1 | Mean Infant Creatinine Clearance (CrCl) Rate at Week 26 in the PrEP Comparison Component | 143.3 mL/min | Standard Deviation 42.5 |
| Maternal PK Component Group 2 | Mean Infant Creatinine Clearance (CrCl) Rate at Week 26 in the PrEP Comparison Component | 140.1 mL/min | Standard Deviation 37.3 |
Comparison: A two-sample t-test was used to evaluate the difference in mean infant creatinine clearance rate at week 26 between PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) and PrEP-unexposed group (Cohort 2/Step 1)p-value: 0.52t-test, 2 sided
Primary
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
Time frame: Measured at birth
Population: Infants from PrEP Comparison Component with available creatinine data were included in this analysis. Primary analyses, as described in the SAP, were conducted in two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 were combined as the PrEP-exposed group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Maternal PK Component Group 1 | Mean Infant Creatinine Levels at Birth in the PrEP Comparison Component | 0.4 mg/dL | Standard Deviation 0.2 |
| Maternal PK Component Group 2 | Mean Infant Creatinine Levels at Birth in the PrEP Comparison Component | 0.3 mg/dL | Standard Deviation 0.1 |
Comparison: A two-sample t-test was used to evaluate the difference in mean infant creatinine levels at birth between PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) and PrEP-unexposed group (Cohort 2/Step 1).p-value: 0.7t-test, 2 sided
Primary
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
Time frame: Measured at week 26 post-birth
Population: Infants from PrEP Comparison Component with available creatinine data were included in this analysis. Primary analyses, as described in the SAP, were conducted in two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 were combined as the PrEP-exposed group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Maternal PK Component Group 1 | Mean Infant Creatinine Levels at Week 26 in the PrEP Comparison Component | 0.2 mg/dL | Standard Deviation 0 |
| Maternal PK Component Group 2 | Mean Infant Creatinine Levels at Week 26 in the PrEP Comparison Component | 0.2 mg/dL | Standard Deviation 0 |
Comparison: A two-sample t-test was used to evaluate the difference in mean infant creatinine levels at week 26 between PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) and PrEP-unexposed group (Cohort 2/Step 1).p-value: 0.58t-test, 2 sided
Primary
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.
Time frame: Measured at birth
Population: Infants from PrEP Comparison Component with available length-for-age z-score data were included in this analysis. Primary analyses, as described in the SAP, were conducted in two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 were combined as the PrEP-exposed group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Maternal PK Component Group 1 | Mean Infant Length-for-age Z-score at Birth | -0.4 Z-score | Standard Deviation 1.4 |
| Maternal PK Component Group 2 | Mean Infant Length-for-age Z-score at Birth | -0.6 Z-score | Standard Deviation 1.2 |
Comparison: A two-sample t-test was used to evaluate the difference in mean infant length-for-age z-score at birth between PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) and PrEP-unexposed group (Cohort 2/Step 1).p-value: 0.3t-test, 2 sided
Primary
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.
Time frame: Measured at week 26 post-birth
Population: Infants from PrEP Comparison Component with available length-for-age z-score data were included in this analysis. Primary analyses, as described in the SAP, were conducted in two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 were combined as the PrEP-exposed group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Maternal PK Component Group 1 | Mean Infant Length-for-age Z-score at Week 26 | -0.6 Z-score | Standard Deviation 1.2 |
| Maternal PK Component Group 2 | Mean Infant Length-for-age Z-score at Week 26 | -0.8 Z-score | Standard Deviation 1.1 |
Comparison: A two-sample t-test was used to evaluate the difference in mean infant length-for-age z-score at week 26 between PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) and PrEP-unexposed group (Cohort 2/Step 1).p-value: 0.06t-test, 2 sided
Primary
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)
Time frame: Measured at delivery
Population: Mothers from PrEP Comparison Component with available pregnancy outcome data were included in this analysis. All primary analyses, as described in the SAP, were conducted by two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 together were defined as the PrEP-exposed group and were analyzed together.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maternal PK Component Group 1 | Number of Composite Adverse Pregnancy Outcomes | 51 participants |
| Maternal PK Component Group 2 | Number of Composite Adverse Pregnancy Outcomes | 28 participants |
Comparison: Odds ratio comparing the proportion of mothers with adverse pregnancy outcomes between the PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) and PrEP-unexposed (Cohort 2/Step 1) reference group.95% CI: [0.52, 1.5]
Comparison: Test the differences in the proportion of mothers with adverse pregnancy outcomes between PrEP-exposed (Cohort 1 and Cohort 2/Step 2) and PrEP-unexposed (Cohort 2/Step 2) groups.p-value: 0.68Fisher Exact
Primary
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.
Time frame: Study entry through 26 weeks postpartum, up to one year
Population: Mothers from the PrEP Comparison PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) with PK data from any study visits were included in this analysis. All primary analyses, as described in the SAP, were conducted by two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 together were defined as the PrEP-exposed group and were analyzed together.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maternal PK Component Group 1 | Proportion of Maternal Visits With Optimal Adherence During Study Follow-up | 0.21 proportion of visits |
Primary
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.
Time frame: Antepartum study week 12
Population: Mothers from the PrEP Comparison PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) who were formally prescribed PrEP and had available PK data were included in this analysis. All primary analyses, as described in the SAP, were conducted by two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 together were defined as the PrEP-exposed group and were analyzed together.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maternal PK Component Group 1 | Proportion of Mothers With Optimal Adherence at Antepartum Study Week 12 | 0.27 proportion of participants |
Primary
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.
Time frame: Antepartum study week 4
Population: Mothers from the PrEP Comparison PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) who were formally prescribed PrEP and had available PK data were included in this analysis. All primary analyses, as described in the SAP, were conducted by two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 together were defined as the PrEP-exposed group and were analyzed together.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maternal PK Component Group 1 | Proportion of Mothers With Optimal Adherence at Antepartum Study Week 4 | 0.15 proportion of participants |
Primary
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.
Time frame: Antepartum study week 8
Population: Mothers from the PrEP Comparison PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) who were formally prescribed PrEP and had available PK data were included in this analysis. All primary analyses, as described in the SAP, were conducted by two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 together were defined as the PrEP-exposed group and were analyzed together.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maternal PK Component Group 1 | Proportion of Mothers With Optimal Adherence at Antepartum Study Week 8 | 0.23 proportion of participants |
Primary
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.
Time frame: Delivery
Population: Mothers from the PrEP Comparison PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) who were formally prescribed PrEP and had available PK data were included in this analysis. All primary analyses, as described in the SAP, were conducted by two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 together were defined as the PrEP-exposed group and were analyzed together.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maternal PK Component Group 1 | Proportion of Mothers With Optimal Adherence at Delivery | 0.31 proportion of participants |
Primary
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.
Time frame: Postpartum week 14
Population: Mothers from the PrEP Comparison PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) who were formally prescribed PrEP and had available PK data were included in this analysis. All primary analyses, as described in the SAP, were conducted by two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 together were defined as the PrEP-exposed group and were analyzed together.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maternal PK Component Group 1 | Proportion of Mothers With Optimal Adherence at Postpartum Week 14 | 0.17 proportion of participants |
Primary
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.
Time frame: Postpartum Week 26
Population: Mothers from the PrEP Comparison PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) who were formally prescribed PrEP and had available PK data were included in this analysis. All primary analyses, as described in the SAP, were conducted by two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 together were defined as the PrEP-exposed group and were analyzed together.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maternal PK Component Group 1 | Proportion of Mothers With Optimal Adherence at Postpartum Week 26 | 0.15 proportion of participants |
Primary
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.
Time frame: Postpartum Week 6
Population: Mothers from the PrEP Comparison PrEP-exposed group (Cohort 1 and Cohort 2/Step 2) who were formally prescribed PrEP and had available PK data were included in this analysis. All primary analyses, as described in the SAP, were conducted by two groups: PrEP-exposed and PrEP-unexposed. Cohort 1 and Cohort 2/Step 2 together were defined as the PrEP-exposed group and were analyzed together.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Maternal PK Component Group 1 | Proportion of Mothers With Optimal Adherence at Postpartum Week 6 | 0.20 proportion of participants |
Secondary
Maternal Median Steady State TFV-DP Concentration Levels at Study Week 12 During Pregnancy and Postpartum
TFV-DP concentration levels were measured using dried blood spots (DBS). Concentrations measured at week 12 represent the steady-state TFV-DP concentration.
Time frame: 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
Population: Evaluable participants from PK Components were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Maternal PK Component Group 1 | Maternal Median Steady State TFV-DP Concentration Levels at Study Week 12 During Pregnancy and Postpartum | 965 fmol/punch |
| Maternal PK Component Group 2 | Maternal Median Steady State TFV-DP Concentration Levels at Study Week 12 During Pregnancy and Postpartum | 1406 fmol/punch |
p-value: <0.01Wilcoxon (Mann-Whitney)