1. ADOLESCENT PrEP STUDIES Shorai Mukaka, MBchB (UZ) 05 MAY 2017

2. Outline
Background
HPTN 082 study
MTN 034 study
IMPAACT 2009 study

3. Background
There has been global progress in HIV management in the last decade, however, the epidemic remains uncontrolled.
It exerts an especially high toll in sub‐Saharan Africa, where women and young women are up to twice as likely to be infected as young men.
There has been a rise in the total population of young men and women in Africa since the beginning of the epidemic
In 2015, the youth population made up close to 20% of the continent’s population, and is expected to more than double by 2055.(United Nations, Department of Economic and Social affairs, Population Division. Youth population trends and sustainable development. May Population Facts No /1).
Rates of HIV in young women remain unacceptably high, and hence there is need to target this population in order to curb the epidemic

4. Demographic Shift in Southern Africa in10-29 year olds

5. HIV Prevention interventions
Education
Condoms
Treatment of HIV+
PrEP
Vaccine
Testing
PEP
Microbicide
There are a number of proven HIV prevention interventions
More HIV prevention strategies are under research
Of the proven methods, some require the participation or consent of a male partner which presents operational challenges in the provision of HIV prevention strategies to young women.

6. HIV prevention interventions
The FDA approved Truvada for oral PrEP in 2012.
In 2014, the World Health Organization (WHO) developed recommendations for offering oral PrEP containing the antiviral drug tenofovir disoproxil fumarate (TDF), alone or in combination with emtricitabine (FTC), to select key populations at high risk of HIV infection. The WHO further expanded these recommendations in to include all persons at high risk of HIV infection.
Since then, a number of countries, Zimbabwe included, have adopted the WHO guidelines on oral PrEP and incorporated them into their national guidelines

7. Substantial risk = incidence rate of > 3.0 per 100 person-years
PrEP WHO guidelines
The WHO 2015 guidelines now include the use of antiretroviral drugs for HIV prevention for all populations at substantial risk of acquiring HIV, those with an incidence of HIV >3/100 p yrs. This expands the previous recommendation for PrEP in key populations identified; sero-discordant couples, commercial sex workers, MSM and IDUs.
Substantial risk = incidence rate of > 3.0 per 100 person-years

8. HIV prevention interventions
The expansion of the WHO recommendations’ scope was supported by mounting evidence that oral PrEP regimens containing TDF, when followed consistently, were safe, cost-effective, and highly efficacious in reducing HIV infection risk. However, there is limited data on safety, adherence, and acceptability of PrEP for adolescent and young adult females living in high-risk regions, like, sub-Saharan Africa when compared with data collected on other populations

9. A Phase IV randomized multi-site prospective feasibility study to assess PrEP acceptance and adherence among HIV-uninfected young women who are offered open-label daily oral PrEP with adherence support

10. Primary Objectives
To assess the proportion and characteristics of young HIV- uninfected women who accept versus decline PrEP at enrollment.
To assess the difference in PrEP adherence in young women randomized to the enhanced (using drug level feedback) versus standard of care adherence support

11. Secondary Objectives
Timing of PrEP acceptance among women who initially decline PrEP at enrollment but elect to accept PrEP during follow up.
Correlates of early and delayed acceptance of PrEP.
Adverse events and HIV incidences
Proportion who discontinue PrEP, timing, & factors associated with PrEP discontinuation

12. Eligibility: select inclusion criteria
16-25
Mobile phone (w/SMS)
VOICE risk score
Sexually active
HBV uninfected and willing to receive HBV vaccine if susceptible to HBV
HIV negative
Interest in PrEP (HPRM)

13. Study summary
The study is being conducted at 3 sites African sites including Spilhaus. (Spilhaus Clinic, Zimbabwe, the Emavundleni Research Centre in Cape Town, South Africa and Wits RHI in Johannesburg, South Africa
HIV-uninfected women ages 16-25
400 young women who accept PrEP at enrollment and up to 200 young women who decline PrEP at enrollment.
12 months of follow-up per participant.

15. Behavioral data collection
CASI (Partnership characteristics, partner’s HIV status, HIV risk perception,study participation disclosure etc)
Qualitative interviews (25 per site, 75 total) done at weeks 13 and 26
-Factors that influence women’s uptake and Adherence of PrEP
-Experience among those randomized to get drug level feedback

16. Study progress Regulatory application and stakeholder engagement
Activation- 14 Nov 2016
First Sreening-17 November 2016
First Enrollment-08 December 2016
As of 03 May-136 Screened
-80 Enrolled
We plan to complete accrual by May/Jun 2017
Last follow up Jun/Jul 2018
Results are expected shortly thereafter

17. Reversing the Epidemic in Africa with Choices in HIV Prevention
MTN 034
Reversing the Epidemic in Africa with Choices in HIV Prevention

18. MTN 034
A Phase 2a Crossover Trial Evaluating the Safety of and Adherence to a Vaginal Matrix Ring Containing Dapivirine and Oral Emtricitabine/Tenofovir Disoproxil Fumarate in an Adolescent and Young Adult Female Population

19. Rationale
Results from two Phase 3 safety and efficacy trials of the dapivirine VR, MTN-020 (ASPIRE) and IPM 027 (The Ring Study) found the VR to be safe and effective in reducing HIV-1 infection.
In The Ring Study, dapivirine VR use reduced the risk of HIV-1 infection by 30.7% relative to placebo, and a 37.5% reduction in HIV-1 infection was observed in a subgroup analysis of women olderthan 21 years of age.

20. Rationale
In ASPIRE, dapivirine VR use resulted in a 27% relative reduction in HIV-1 incidence overall, a 37% reduction in an analysis defined early in the study excluding data from two study sites with lower retention and adherence, and a 56% reduction in a post-hoc analysis among women older than 21 years of age.
HIV-1 protection was not observed for women aged 18-21, and objective markers of adherence were lower in this subgroup compared to women older than 21. More recent analyses of ASPIRE results presented at the 2016 International AIDS Conference in Durban, South Africa suggest the dapivirine VR may lead to reductions in HIV- 1 incidence of 56%-65% when used consistently, and may even be as high as 75%-92% for perfect ring use.
The low effectiveness and adherence results observed among young women in The Ring Study and ASPIRE make it clear that gaps still exist in our understanding of how best to incorporate the dapivirine VR into the HIV-1 prevention toolkit for this population

21. Study population and design
Healthy, HIV-uninfected, sexually active adolescent and young adult females, years old (inclusive)
60 participants per site
open-label, multi-site, two-sequence, crossover, randomized trial
Approximately 73 weeks of follow-up per participant

22. Study design
Participants will be randomized (1:1) to one of two sequences of a monthly dapivirine 24 weeks and daily oral truvada tablets taken for 24 weeks.
After completing the randomized sequence of two study product use periods, participants will then select between the two study products to use in the final 24 weeks of the trial. Participants will be able to choose either or neither study product every 4 weeks during the third product use period.

23. Period 1(24 Weeks)
Period 2(24 Weeks)
Period 3(24 Weeks)
Sequence A
Vaginal (dapivirine 25 mg VR)
Oral Daily FTC/ TDF tablet)
Free choice (dapivirine
25 mg VR or daily FTC/TDF tablet) or neither
Sequence B
Oral (Daily FTC/ TDF tablet)

24. Primary objectives Safety
• To compare the safety profiles of FTC/TDF oral tablet administered daily and dapivirine vaginal matrix ring (25 mg) inserted once every 4 weeks during the first 24 weeks of use of each study product in an adolescent and young adult female population
Adherence
• To compare adherence to the FTC/TDF oral tablet administered daily and to the dapivirine vaginal matrix ring (25 mg) inserted once every 4 weeks during the first 24 weeks of use of each study product in an adolescent and young adult female population

25. Other objectives Acceptability Study product preference
Vaginal Microenvironment
HIV Incidence

26. Timelines Study is going through regulatory submissions
Activation expected in Q32017
Accrual planned to end Q3 2018
To complete follow up in 2020 then results shortly thereafter

27. A protocol in development
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
A protocol in development
Welcome to IMPAACT 2009 – a protocol in development by the HIV Prevention Scientific Committee. This presentation provides a brief overview of the protocol. The latest protocol draft was circulated earlier – your comments are vital to ensure scientific relevance and operational efficiency.

28. There are currently few interventions being implemented to help women to remain HIV-free during pregnancy, breastfeeding and beyond. More effort is needed to address this gap. This may be particularly important for adolescent women, who may have less experience with and information about HIV.
And we were reminded in the UNAIDS Gap Report of 2014 of the need to develop HIV prevention strategies for pregnant women, providing the rationale for this trial – IMPAACT 2009.
UNAIDS Gap Report 2014

29. Primary Objectives
To characterize PrEP adherence among HIV-uninfected women aged years who initiate once-daily TDF-FTC from <32 weeks to 6 months postpartum
To compare maternal and infant adverse events (including pregnancy outcomes) between women who initiate PrEP and those who decline PrEP

30. Secondary Objectives
To identify individual, social, and structural barriers and facilitators to PrEP uptake during pregnancy
To compare reported sexual risk behavior and incidence of sexually transmitted infections between the PrEP and non-PrEP cohorts
To compare HIV incidence in women between the two cohorts
To compare HIV drug resistance in HIV-infected mothers and infants from the two cohorts

31. Study Population HIV uninfected women Pregnant Aged 16-24 years
At risk of acquiring HIV
Sample size 350 in total (~100 in Zimbabwe)
Malawi, South Africa, South Africa and Uganda will also take part

32. Study Design Cohort study, no randomisation
Women will choose to start PrEP in pregnancy (~200) or not (~100)
They can change their mind later
Study visits every month x 3, then every 3 months until 6 months after delivery
All get SMS messages about general health matters
PrEP users also get SMS adherence messages and have drug levels tested in near real time

34. Study endpoints Pregnancy? Adherence
Tenofovir disoproxil fumarate-diphosphate (TFV-DP) levels measured through dried blood spots.
Safety (maternal and infant)
Adverse pregnancy outcomes will include a composite  of the following:
Stillbirth
Birthweight <2500 g
Preterm delivery of less than 37 weeks gestation
Maternal AE outcome will be a composite of the following:
Grade 3 or higher signs and symptoms
Grade 2 or higher chemistry abnormalities
Grade 3 or higher pregnancy-related diagnosis 
However, the many physiological changes of pregnancy affect the way drugs are handled by the body and there are no pharmacokinetic data for TFV-DP in pregnancy. This information is needed for the adherence counselling sessions, so a PK lead-in stage was added to IMPAACT 2009.

35. Acknowledgements
We sincerely thank our participants, YCAB, UZ- UCSF staff , our funders and stakeholders: Zimbabwe National Family Planning Council, Ministry of Health and Child Care, Harare City Health Department, Ministry of Higher and Tertiary Education.