1. IMPAACT Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure Prophylaxis for Primary HIV Prevention during Pregnancy and Breast Feeding in Adolescents and Young Women

2. Protocol Team
Protocol Co-Chairs: Benjamin Chi, MD, MSc & Lynda Stranix-Chibanda, MBChB, MMED
Protocol Vice Chair: Sybil Hosek, PhD
Protocol Team:
Geri Donenberg, PhD,
Rivet Amico, PhD,
Deborah Kacanek, ScD,
Sharon Huang, MS,
Lisa Hightow-Weidman, MD, MPH,
John Shepard, PhD,
Nicole Tobin, MD,
Savita Pahwa, MD,
Lisa Frenkel, MD,
Jennifer Kiser, PharmD,
Pete Anderson, PharmD

3. HIV Prevention for Adolescents during Pregnancy

4. UNAIDS, 2016; UNICEF, 2016

5. HIV in Pregnancy/Postpartum
Cumulative incidence:
3.8 per 100 person-years
(95%CI: 2.0,4.6)
Pregnancy: 4.7 ( )
Postpartum: 2.9 ( )
Drake AL et al. PLosMed 2014;11:e

6. Acute HIV infection associated with greater MTCT risk
Drake AL et al. PLosMed 2014;11:e

7. 2015 WHO Recommendation Key populations: Sero-discordant couples
Commercial sex workers
Men who have sex with men
Intravenous drug users

8. PrEP in pregnancy: Guidelines Vary
WHO Guidance: ‘Although additional surveillance is important, at the present time, given the available safety data, there does not appear to be a safety-related rationale for discontinuing PrEP during pregnancy and breastfeeding for HIV-uninfected women receiving PrEP who become pregnant and remain at continuing risk of HIV acquisition’. South Africa NDOH Guidance: PrEP is contraindicated by the MCC, until we have further guidance from WHO and MCC we will continue to not offer PrEP to pregnant women. Southern African HIV Clinician Society Guidance: The use of TDF/FTC as PrEP in pregnant or breastfeeding women is contra-indicated. However, as the risk of seroconversion during pregnancy is high, the risks and benefits of PrEP should be discussed with potential PrEP users, allowing these women at high risk of HIV acquisition to make an informed decision regarding PrEP use.
Mofenson L, et al. AIDS 2016
WHO Guidance July 2016
Bekker LG, et al. SA Journal of HIV Med. 2016
South African HIV Clinician Society/WITS RHI, 2017

9. World Health Organization (WHO) TECHNICAL BRIEF: Preventing HIV during pregnancy and breastfeeding in the context of PrEP, 2017

10. However…
While the data for PrEP use in HIV-negative pregnant women are reassuring…more data are needed on TDF and TDF/FTC safety during this period.
Further research is needed on:
adverse pregnancy outcomes with preconception ART use, whether there are differences by type of ART regimen, and the ultimate effects on neonatal and infant mortality.
the effects of in utero TDF exposure on infant bone development and growth, and the use of TDF during breastfeeding to see if it increases the normal loss of bone mineral density observed during breastfeeding and whether it reverses when breastfeeding stops or it persists.
Adolescents will require more adherence support and enhanced comprehensive SRH information
World Health Organization (WHO) TECHNICAL BRIEF: Preventing HIV during pregnancy and breastfeeding in the context of PrEP, 2017

11. Study Schema

12. Study Sites
Kampala, Uganda: Baylor CRS & Makerere University - JHU CRS
Blantyre, Malawi (JHU)
Harare, Zimbabwe: Family Care Center, Saint Mary’s & Seke North
Johannesburg, South Africa: Shandukani WRHI

13. Pharmacokinetic (PK) Component

14. PK Component Objectives
The primary objective  
To determine the concentration of tenofovir diphosphate (TFV-DP) associated with adequate adherence to TDF/FTC among women observed ingesting daily oral PrEP during pregnancy and postpartum.
The secondary objective  
To compare TFV-DP concentrations observed in pregnant and postpartum women.

15. PK Component
Designed to establish drug thresholds for optimal adherence to PrEP during pregnancy
Refines adherence outcome measure
Informs drug level-based counseling
15-20 participants in each of two groups:
Antepartum: weeks gestation
Postpartum: 6-10 weeks postpartum
Pregnant women > 16 yrs eligible
Willing to take daily TDF/FTC under “direct observation”

16. PK Component
12 weeks of PK monitoring, with weekly DBS specimens for drug levels
Followed by an observational period to 6 weeks postpartum
Specimens to be shipped for central testing
Intensive monitoring of drug adherence
This may include
directly observed therapy (DOT) at the clinic,
DOT at the home, via community health workers, or
“real-time” video-based monitoring via smartphone, tablet, or computer.

17. PrEP Comparison Component

18. Primary Objectives
To characterize PrEP adherence among HIV-uninfected women aged years who initiate once-daily TDF/FTC in pregnancy
To compare maternal and infant adverse events (including pregnancy outcomes) between women who initiate PrEP and those who decline PrEP

19. Secondary Objectives
To identify individual, social, and structural barriers and facilitators to PrEP uptake during pregnancy
To compare between the PrEP and non-PrEP cohorts:
Reported sexual risk behavior and incidence of STIs
HIV incidence
HIV drug resistance among HIV-infected mothers and infants

20. Exploratory Objective
To describe the composition of and changes in the maternal vaginal microbiome and infant gut microbiomes according to PrEP exposure
Putignani et al., 2014, Pediatric Research

21. Study population (n=300) At least 16 years and less than 25 years
Confirmed pregnancy at ≤ 32 weeks
HIV negative by HIV RNA screening
No history of chronic disease
For PrEP cohort:
Willingness to take PrEP through pregnancy to 26 weeks postpartum
Access to cell phone to receive SMS messages

22. Study endpoints Adherence Safety (maternal and pregnancy)
Tenofovir diphosphate (TFV-DP) levels via DBS
Safety (maternal and pregnancy)
Adverse pregnancy outcomes:
Stillbirth
Low birthweight
Preterm delivery <37 weeks gestation
Maternal AE outcomes:
Grade 3 or higher signs and symptoms
Grade 2 or higher chemistry abnormalities
Grade 3 or higher pregnancy-related diagnosis 

23. Study endpoints Safety (infant) HIV-related outcomes
Infant safety outcome measures:
Infant death
Creatinine clearance
Anthropometric growth
Bone mineral content 
HIV-related outcomes
HIV drug resistance in women (and infants) who become infected while on PrEP

24. Adherence Intervention
integrated Next Step Counseling (iNSC).
All maternal participants in both cohorts.
Drug level monitoring with feedback.
Starting at Week 4 visit
SMS Adherence Support.
1-way personalized stage-based messages to support maternal and child healthcare (e.g. MAMA platform); also receive weekly 2-way text messages that provide general adherence support (i.e., “are you doing OK?”).

25. Qualitative Component
Provides deeper insight into feasibility
In-depth individual interviews - up to 60 women
Purposive sampling based on PrEP initiation and adherence stratified by pregnancy or postpartum periods
Group
Antepartum
Postpartum
Adherent PrEP participants 10
Non-Adherent PrEP participants
Participants who decline PrEP

26. Issues for Consideration

27. Anticipated Challenges
Completing 12 weeks of DOT may be intrusive for participants
Opening PrEP Comparison phase is dependent on PK completion
Rate of uptake is uncertain
Negative stigma surrounding PrEP use in women
Staff trained to counsel participants
Will monitor and address social harms

28. Issues of Minor Consent
Ethics review in South Africa may be a challenge given the wording of their guidelines
although this trial will provide the evidence they say is necessary for an indication
Obtaining parental consent for minors (if required)
Especially challenging if minor is living on their own
Some countries will consider minors emancipated due to pregnancy (parenting) and allow for self-consent

29. Thank You

30. Acknowledgements