Hiv
Conditions
Keywords
pre-exposure prophylaxis, PrEP, pregnancy, postpartum, HIV prevention, pharmacokinetics, TAF, TDF
Brief summary
This study will establish benchmarks of TFV-DP concentrations as measures of adherence following daily dosing with Tenofovir Alafenamide (TAF) compared with Tenofovir Disoproxil Fumarate (TDF) during pregnancy and postpartum. Study Investigators will recruit from an ongoing observational cohort study in Cape Town, South Africa, PrEP-PP (recruitment ongoing through July, 2021; NIMH R01MH116771; PI Coates & Myer). Findings form this PK sub-study will be used to inform future PrEP in pregnancy and postpartum studies and develop benchmarks of the relative PK between TDF and TAF.
Detailed description
This study will establish benchmarks of TFV-DP concentrations as measures of adherence following daily dosing with Tenofovir Alafenamide (TAF) compared with Tenofovir Disoproxil Fumarate (TDF) during pregnancy and postpartum. Study Investigators will recruit from an ongoing observational cohort study in Cape Town, South Africa, PrEP-PP (recruitment ongoing through July, 2021; NIMH R01MH116771; PI Coates & Myer). Findings form this PK sub-study will be used to inform future PrEP in pregnancy and postpartum studies and develop benchmarks of the relative PK between TDF and TAF. Study aims. (1) To establish benchmarks of TFV-DP concentrations as measures of adherence following daily dosing with TAF vs TDF in pregnancy and again in postpartum; (2) To compare the difference of TFV-DP within TDF and TAF for pregnancy vs. postpartum, and to establish adherence benchmarks of levels of TFV in breastmilk in postpartum women and compare with TDF sample. The study will take place in an urban township in Cape Town (Gugulethu) with high HIV incidence that spans the different socioeconomic, cultural, and ethnic groups in South Africa. We selected this community because of the high HIV prevalence there in pregnant and breastfeeding women, and because of the high number of mothers visiting every month for ANC and labour/delivery.
Interventions
DRUGTenofovir alafenamide
Daily DOT fixed dose combination of 200 mg emtricitabine (FTC) and 25 mg tenofovir alafenamide (TAF)
DRUGTenofovir Disoproxil Fumarate
Daily DOT fixed dose combination of 200 mg emtricitabine (FTC) and 300 mg tenofovir disoproxil fumarate (TDF)
Sponsors
University of Cape Town
Desmond Tutu HIV Foundation
Gilead Sciences
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
This phase III study is a randomised control trial (RCT) of up to 60 pregnant women who will be recruited at first antenatal visit (ANC) from the Gugulethu Midwife and Obstetrics Unit. Participants will be randomized into the TDF vs TAF arm: TDF Arm: Women will receive a fixed dose combination of 200 mg emtricitabine (FTC) and 300 mg tenofovir disoproxil fumarate (TDF) administered once daily under direct observation for 8 weeks during pregnancy and again for 8 weeks in postpartum period TAF Arm: Fixed dose combination of 200 mg emtricitabine (FTC) and 25 mg tenofovir alafenamide (TAF) administered once daily under direct observation for 8 weeks during pregnancy and again for 8 weeks in postpartum period Women will provide their own controls, providing pregnant and postpartum samples.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. \>18 years old 2. confirmed HIV-negative (confirmed with a 4th generation antigen HIV test) at time of study entry 3. intend on giving birth in the MOU facility 4. confirmed to be 14-24 weeks pregnant 5. without psychiatric or medical contraindications to PrEP 6. estimated creatinine clearance (CrCI) \>60mL/min 7. resides close to clinic (\<10km) 8. has a smart phone that can take video footage (with data bundle from study) 9. agrees to provide video phone footage of taking a pill a day for 8 weeks during pregnancy and again for 8 weeks in postpartum period
Exclusion criteria
Individuals not meeting the above criteria or meeting any of the following criteria will be excluded: 1. Concurrent enrolment in another HIV-1 vaccine or prevention trial 2. History of renal disease 3. Current clinical diagnosis of hypertension 4. Exhibiting psychotic symptoms 5. Currently or history of taking an anti-psychotic medication 6. Positive Hepatitis B surface antigen (HBsAg) test on screening 7. History of bone fracture not related to trauma 8. Any other medical, psychiatric or social condition which in the opinion of the investigators would affect the ability to consent and/or participate in the study 9. Any maternal or fetal complication, obstetric or medical, detected during routine care or study procedures that requires referral of pregnant or postpartum women/infants to secondary or tertiary obstetric or medical care.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tenofovir Diphosphate (TFV-DP) Levels in Plasma and Intracellular Levels in Pregnant Women on Daily PrEP | 8 week period during Pregnancy | Levels of TFV-DP (geometric mean), comparing the drugs TAF to TDF, observed in pregnancy. Note: Observation of daily PrEP dosing spanned 16 weeks in total, including 8 weeks during pregnancy and 8 weeks in postpartum. Once participants had completed their 8 weeks of in-pregnancy observation, observation of therapy was paused until they entered the postpartum phase. |
| Tenofovir Diphosphate (TFV-DP) Levels in Plasma and Intracellular Levels in Postpartum Women on Daily PrEP | 8 week period during Postpartum (up to 1 year from baseline pregnancy visit) | Levels of TFV-DP (geometric mean), comparing the drugs TAF to TDF, observed in postpartum period. Note: Observation of daily PrEP dosing spanned 16 weeks in total, including 8 weeks during pregnancy and 8 weeks in postpartum. Once participants had completed their 8 weeks of in-pregnancy observation, observation of therapy was paused until they entered the postpartum phase. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tenofovir Diphosphate (TFV-DP) Concentrations in Plasma and Intracellular Levels Comparing Pregnancy Against Postpartum Women | Pregnancy (TVF-DP measures via DBS collected weekly, reported 8 weeks after start of pregnancy observation); Postpartum (TVF-DP measures via DBS collected weekly, reported 8 weeks after start of postpartum observation, up to 1 year from baseline). | Plasma and intracellular concentrations of tenofovir and plasma TFV-DP in antenatal and postpartum groups intra-individual comparisons. Note: TFV-DP measures were obtained by DBS once a week during periods of observation. Observation of daily PrEP dosing spanned 16 weeks in total, including 8 weeks during pregnancy and 8 weeks in postpartum. Once participants had completed their 8 weeks of in-pregnancy observation, observation of therapy was paused until they entered the postpartum phase. |
Countries
South Africa
Participant flow
Recruitment details
Between June 2022 and October 2022, the study enrolled participants from a large, urban clinic outside of Cape Town, South Africa. Inclusion criteria required the women to: (1) be aged 18 and older; (2) test HIV-negative; (3) be between 20-30 weeks of gestation; (4) own a smart phone; and (5) to consent to daily video observations of taking a PrEP pill.
Pre-assignment details
We received IRB approval to increase the sample size to up to 30 participants per group to account for potential attrition and pregnancy loss (total up to N=60 women).
Participants by arm
| Arm | Count |
|---|---|
| TAF Arm Fixed dose combination of 200 mg emtricitabine (FTC) and 25 mg tenofovir alafenamide (TAF) delivered under direct observation for 8 weeks during pregnancy and 8 weeks in postpartum period
Tenofovir alafenamide: Daily DOT fixed dose combination of 200 mg emtricitabine (FTC) and 300 mg tenofovir disoproxil fumarate (TDF) | 20 |
| TDF Arm Fixed dose combination of 200 mg emtricitabine (FTC) and 300 mg tenofovir disoproxil fumarate (TDF) delivered under direct observation for 8 weeks during pregnancy and 8 weeks in postpartum period
Tenofovir Disoproxil Fumarate: Daily DOT fixed dose combination of 200 mg emtricitabine (FTC) and 25 mg tenofovir alafenamide (TAF) | 19 |
| Total | 39 |
Baseline characteristics
| Characteristic | TAF Arm | TDF Arm | Total |
|---|---|---|---|
| Age, Continuous | 28 years | 29 years | 28 years |
| Age, Customized Age, Categorical 18-25 years | 6 Participants | 6 Participants | 12 Participants |
| Age, Customized Age, Categorical >25 years | 14 Participants | 13 Participants | 27 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 20 Participants | 19 Participants | 39 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment South Africa | 20 Participants | 19 Participants | 39 Participants |
| Sex: Female, Male Female | 20 Participants | 19 Participants | 39 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 19 |
| other Total, other adverse events | 0 / 20 | 0 / 19 |
| serious Total, serious adverse events | 9 / 20 | 5 / 19 |
Outcome results
Primary
Tenofovir Diphosphate (TFV-DP) Levels in Plasma and Intracellular Levels in Postpartum Women on Daily PrEP
Levels of TFV-DP (geometric mean), comparing the drugs TAF to TDF, observed in postpartum period. Note: Observation of daily PrEP dosing spanned 16 weeks in total, including 8 weeks during pregnancy and 8 weeks in postpartum. Once participants had completed their 8 weeks of in-pregnancy observation, observation of therapy was paused until they entered the postpartum phase.
Time frame: 8 week period during Postpartum (up to 1 year from baseline pregnancy visit)
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| TAF Arm | Tenofovir Diphosphate (TFV-DP) Levels in Plasma and Intracellular Levels in Postpartum Women on Daily PrEP | 666 TFV-DP PBMC (fmol/10^6 cells) |
| TDF Arm | Tenofovir Diphosphate (TFV-DP) Levels in Plasma and Intracellular Levels in Postpartum Women on Daily PrEP | 73 TFV-DP PBMC (fmol/10^6 cells) |
Primary
Tenofovir Diphosphate (TFV-DP) Levels in Plasma and Intracellular Levels in Pregnant Women on Daily PrEP
Levels of TFV-DP (geometric mean), comparing the drugs TAF to TDF, observed in pregnancy. Note: Observation of daily PrEP dosing spanned 16 weeks in total, including 8 weeks during pregnancy and 8 weeks in postpartum. Once participants had completed their 8 weeks of in-pregnancy observation, observation of therapy was paused until they entered the postpartum phase.
Time frame: 8 week period during Pregnancy
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| TAF Arm | Tenofovir Diphosphate (TFV-DP) Levels in Plasma and Intracellular Levels in Pregnant Women on Daily PrEP | 580 TFV-DP PBMC (fmol/10^6cells) |
| TDF Arm | Tenofovir Diphosphate (TFV-DP) Levels in Plasma and Intracellular Levels in Pregnant Women on Daily PrEP | 71 TFV-DP PBMC (fmol/10^6cells) |
Secondary
Tenofovir Diphosphate (TFV-DP) Concentrations in Plasma and Intracellular Levels Comparing Pregnancy Against Postpartum Women
Plasma and intracellular concentrations of tenofovir and plasma TFV-DP in antenatal and postpartum groups intra-individual comparisons. Note: TFV-DP measures were obtained by DBS once a week during periods of observation. Observation of daily PrEP dosing spanned 16 weeks in total, including 8 weeks during pregnancy and 8 weeks in postpartum. Once participants had completed their 8 weeks of in-pregnancy observation, observation of therapy was paused until they entered the postpartum phase.
Time frame: Pregnancy (TVF-DP measures via DBS collected weekly, reported 8 weeks after start of pregnancy observation); Postpartum (TVF-DP measures via DBS collected weekly, reported 8 weeks after start of postpartum observation, up to 1 year from baseline).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| TAF Arm | Tenofovir Diphosphate (TFV-DP) Concentrations in Plasma and Intracellular Levels Comparing Pregnancy Against Postpartum Women | TFV-DP steady-state concentration in Pregnancy (at 8-weeks follow up via DBS) | 611.3 TDF:fmol/3mm punch; TAF:fmol/3mm punch |
| TAF Arm | Tenofovir Diphosphate (TFV-DP) Concentrations in Plasma and Intracellular Levels Comparing Pregnancy Against Postpartum Women | TFV-DP steady-state concentration in Postpartum (at 8-weeks follow up via DBS) | 940.5 TDF:fmol/3mm punch; TAF:fmol/3mm punch |
| TDF Arm | Tenofovir Diphosphate (TFV-DP) Concentrations in Plasma and Intracellular Levels Comparing Pregnancy Against Postpartum Women | TFV-DP steady-state concentration in Pregnancy (at 8-weeks follow up via DBS) | 410.0 TDF:fmol/3mm punch; TAF:fmol/3mm punch |
| TDF Arm | Tenofovir Diphosphate (TFV-DP) Concentrations in Plasma and Intracellular Levels Comparing Pregnancy Against Postpartum Women | TFV-DP steady-state concentration in Postpartum (at 8-weeks follow up via DBS) | 518.3 TDF:fmol/3mm punch; TAF:fmol/3mm punch |