1. Overview of PrEP studies: UZCHS-CTRC experience
Portia Hunidzarira
University of Zimbabwe College of Health Sciences-Clinical Trials Research Centre

2. Outline Introduction Studies conducted by UZCHS-CTRC involving :
Oral PrEP
Vaginal rings
Long acting Injectable PrEP
Conclusion

3. Introduction
Oral Truvada (FTC/TDF) was FDA Approved for use for prevention on July 16,2012.
However, effectiveness is largely dependent on adherence .
Newer, safer products that do not need to be taken every day are needed for people who may not want to take a daily pill or who may find it difficult to take a pill every day
Across the major PrEP RCTs (Table 1 [9–15]), the association between efficacy and estimated adherence( detectable drug)is clear and approximates a sigmoid dose-response curve .Larger effects were reported by trials with higher proportions of participants with drug detected, leading many to conclude that the drugs work if taken . Reports to date from these trials suggest multiple levels of ecologic influences on adherence to study product.
Several PrEP studies have been completed in over 13 countries involving more than 20,000 people with diverse HIV risk behaviors. All of these studies used one or two drugs as PrEP, either TDF (Viread) or the combination drug TDF/emtricitabine (FTC), called Truvada®.
This slide highlights the levels of efficacy related to adherence in 9 PrEP research studies. Adherence was measured by detectible drug levels in blood.
The level of protection depends on how consistently participants used oral PrEP
Greater levels of protection were found among those who adhered well to the daily dosing regimen
Other than low adherence, no factors have yet been identified that influence the effectiveness of PrEP
Adherence (%) adjudicated by drug levels
Abdool Karim, SS IAS 2014

4. Understanding HIV Prevention in adolescents & young African women
Women in sub-Saharan Africa are at risk for HIV and new effective methods of HIV prevention are needed
HIV prevalence up to 8 times more in young women than men*
Given lower adherence & efficacy with Truvada (FTC/TDF) & dapivirine (DPV) ring among young women in clinical trials there is :
Need to understand acceptability and adherence to oral PrEP & vaginal rings in adolescents & young women
*Abdool Karim, TUSS0602, AIDS2016
If we empower young women and adolescents to prevent HIV, we will fast track the end of HIV epidemic UNAIDS 2015.
Given lower adherence & efficacy with Truvada (FTC/TDF) & dapivirine (DPV) ring among young women in clinical trials:
Need to assess biological factors that may influence safety & efficacy of products in adolescents & young women
Need to understand acceptability and adherence to oral PrEP & vaginal rings
Need safety data in <18 year old women for regulatory approvals
Thank you

5. Purpose - to assess acceptability and adherence of oral PrEP among HIV-uninfected young women (16-25yrs) in Southern Africa.
Study size young women who accept PrEP at enrollment and up to 200 young women who decline PrEP at enrollment.
Study sites – Spilhaus - Harare, Emavundhleni – Cape Town, Wits – Johannesburg
Status- study follow-up complete
Results –
94% of young women who enrolled in HPTN 082 initiated PrEP
Two-thirds of women attended at least one PrEP adherence support club in the first 3 months
The majority used PrEP at 3 months; 84% had detectable intracellular TFV –DP levels in DBS
Adherence in HPTN 082 was significantly higher than in VOICE and FEM-PrEP, which assessed PrEP use by plasma TFV levels
A Phase IV randomized multi-site prospective study to assess PrEP acceptance and adherence among HIV-uninfected young women.
Study sites – Spilhaus - Harare, Emavundhleni – Cape Town, Wits – Johannesburg
Adherence in HPTN 082 was significantly higher than in VOICE and FEM-PrEP, which assessed PrEP use by plasma TFV levels
Follow-up visits were at 1, 2, 3, 6, 9 and 12 months.
• The first participant was enrolled October 2016 and follow-up was completed in October 2018.
Adherence at 3 months was assessed by tenofovir-diphosphate (TFV-DP) in dried blood spots. High adherence is defined as TFV-DP >700 fmol/punch (>4 doses/week), which was associated with high protection in men, and medium adherence as fmol/punch (2-3 doses/week)
2019 CROI Conference

6. The Dapivirine Vaginal Ring
The dapivirine ring was developed by the International Partnership for Microbicides (IPM)
The ring contains an ARV -- dapivirine -- to offer women potentially longer-acting protection against HIV
It is the first vaginal ring being tested for HIV prevention
The ring is designed to be worn for a month at a time
The ring slowly releases dapivirine into the cervix and vagina over the month it is worn
20 early phase (Phase I/II) studies have shown dapivirine is safe as both a gel and ring
The dapivirine ring was developed by the International Partnership for Microbicides (IPM), a nonprofit organization based in the US and South Africa. The ring’s development was made possible by a public-private partnership with Janssen Sciences Ireland UC, a Janssen pharmaceutical company of Johnson & Johnson, which granted IPM a royalty-free license in 2004 to develop the antiretroviral (ARV) drug dapivirine as a microbicide for women in developing countries. That license has since expanded to a worldwide rights agreement.
Dapivirine was originally tested by Janssen as an HIV treatment (11 studies). Dapivirine belongs to a class of ARVs called non-nucleoside reverse transcriptase inhibitors (NNRTIs) that blocks the ability of HIV to multiply inside cells.
The dapivirine ring is similar to vaginal rings that are used for hormone delivery in the United States and Europe. The ring, made of a flexible silicone material that measures 56mm (about 2 ¼ inches) in diameter and 7.7mm thick (3/8 inch). Each ring contains 25mg of the ARV dapivirine. When placed inside the vagina, the ring slowly releases the drug over time. Studies have shown that the ring can deliver dapivirine to vaginal tissue for a month or longer, with minimal absorption elsewhere in the body. Studies to date have also shown that the dapivirine ring is safe and well-tolerated by women.
If the dapivirine ring is found to be safe and effective, IPM will seek regulatory approval for product licensure and collaborate with key partners to help ensure the ring is made available to women in developing countries at a low cost and as soon as possible.
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20 Phase I/II studies of dapivirine as a gel or ring have shown it to be safe
The 20 dapivirine ring and gel studies include:
Gel: Completed (1 Tibotec study; IPM 003, 004, 005B, 012, 014A, 014B, 020, IPM 010/ MTN 012)
Ring: Completed (IPM 001, 008, 013, 015, 018, 024, 028, 029, 034); Finalizing CSR (033)
Combo ring: Completed (IPM 026/MTN 013)

7. ASPIRE and The Ring Study
Two phase III clinical trials – MTN-020/ASPIRE and IPM 027/The Ring Study – showed that the monthly dapivirine vaginal ring was safe and reduced HIV risk
Higher levels of protection were seen in women who used the ring most regularly
27%
reduction
31%
reduction
Baeten et al., Nel et al., NEJM 2016

8. Phase III Trial Locations
The Ring Study: 7 Research Centres n = 1959
South Africa (n=1762):
Kwa-Zulu Natal (3 sites)
North-West
Western Cape
Limpopo
Uganda:
Masaka
ASPIRE: 15 NIH Clinical Research Sites n= 2629
South Africa (n=1426):
Kwa-Zulu Natal (7 sites)
Gauteng
Kampala
Zimbabwe: (n=678)
Harare (3 sites)
Malawi:
Blantyre
Lilongwe
The Ring Study
Enrolment
Total Number Screened
Total Number
Enrolled
South Africa: Kwa-Zulu Natal
2038
1064
South Africa: North West
795
482
South Africa: Western Cape
116 97
South Africa: Limpopo
150
119
Uganda: Masaka
325
197
ASPIRE
Enrolment
Total
Number Screened
Total Number
Enrolled
Malawi: Blantyre
199
130
Malawi: Lilongwe
200
142
South Africa: Western Cape
217
166
South Africa: Kwa-Zulu Natal
2853
1047
South Africa: Gauteng
401
213
Uganda: Kampala
408
253
Zimbabwe: Chitungwiza
835
448
Zimbabwe: Harare – Spilhaus
403
230
ASPIRE is one of two Phase III trials of the dapivirine ring
Both ASPIRE and The Ring Study (IPM-027) were designed to support potential approval and licensure of the dapivirine ring

9. MTN-025/HOPE
MTN-025/HOPE was a multi-center open-label extension study (a phase IIIb trial) of the dapivirine vaginal ring (25 mg, replaced monthly).
The population was HIV-1 uninfected women who had previously participated in MTN-020/ASPIRE.
The primary objectives of MTN-025/HOPE were to assess adherence and safety in an open-label setting.
Secondary objectives included assessing HIV-1 incidence and HIV-1 antiretroviral resistance.

10. Enrollment
For MTN-025/HOPE, 1643 women were screened and 1456 women were enrolled, 59% of those HIV-1 uninfected at the completion of MTN-020/ASPIRE.
Most common reasons for not enrolling were having acquired HIV-1 (30%) & wanting to become pregnant (29%)
Participants were from 14 sites in 4 countries:
Malawi (n=157, 11%)
South Africa (n=707, 49%)
Uganda (n=172, 12%)
Zimbabwe (n=420, 29%)

11. MTN-025/HOPEHOPE Results Summary
Most women who enrolled chose to accept the ring (92% at enrollment), and used it with higher adherence than in ASPIRE
The ring is very safe
The ring reduced HIV risk by 39%

12. HOPE and its “Sister Study”
Both studies suggest interest in, adherence to, and HIV-1 risk reduction effectiveness of the dapivirine vaginal ring when used in an open-label setting, making the dapivirine vaginal ring a potential HIV-1 prevention option for women.

13. What’s next for the ring?
The dapivirine ring is currently under regulatory review by the European Medicines Agency (EMA) through the Article 58 procedure, which allows the EMA, in cooperation with the World Health Organization (WHO), to provide a scientific opinion on the ring’s use in low- and middle-income countries.
Separately, IPM plans to submit applications to the South African Health Products Regulatory Authority (SAHPRA) and to the U.S. Food and Drug Administration (FDA).
If approved, the dapivirine ring would be the first biomedical HIV prevention product exclusively for women – and the first long-acting product.
These submissions and the review process take time.
If approved, the dapivirine ring would be the first biomedical HIV prevention product exclusively for women – and the first long-acting product.

14. Additional Research with the Ring
Studies to better understand HIV prevention needs of younger women and adolescent girls are ongoing (MTN-034/REACH).
Safety studies of ring use during pregnancy (MTN-042/DELIVER) and breastfeeding (MTN-043/B-PROTECTED) are also being planned.
Other studies looking at a 3-month ring and a ring that includes both a contraceptive and dapivirine are underway.
REACH (MTN-034) is an ongoing study evaluating safety of and adherence to the dapivirine ring and oral Truvada used as PrEP in girls ages at sites in Kenya, South Africa, Uganda, and Zimbabwe. The DELIVER (MTN-042) and B-PROTECTED (MTN-043) studies are designed to assess the safety of the dapivirine ring and oral PrEP in pregnant and breastfeeding women, respectively. DELIVER and B-PROTECTED are expected to begin later this year at sites in Malawi, South Africa, Uganda, and Zimbabwe.

15. Long acting Injectable PrEP
To evaluate the relative safety and efficacy of injectable PrEP Cabotegravir (CAB) vs. daily oral Truvada (TDF/FTC) for HIV prevention.
Phase 3 superiority trial
Randomized, Double Blind,
Double Dummy
All study volunteers receive one active and one inactive product
20 sites in 7 countries in SSA
5 sites in Zimbabwe, 3 in Chitungwiza and 2 in Harare .
3,200 women

16. Study update Study opened November 07, 2017 All Sites activated
2 048 women enrolled (64%) as of 20 August 2019
Zimbabwe currently has 614 women enrolled across 5 sites
Retention – high, >92% for all visit types
Study ongoing, results expected 2023

17. In conclusion,
Women need choices and their preferences are not all the same.
Even the most effective product cannot protect against HIV if it is not used. Higher adherence results in higher protection.
Long acting PrEP may remedy adherence issues.
If approved, the dapivirine ring would be the first biomedical HIV prevention product exclusively for women – and the first long-acting product.
Involving young women and adolescents in HIV prevention study is necessary to ending the HIV epidemic.

18. Acknowledgements UZ-CHS-CTRC
Clinic staff, recruiters and investigators
Study participants and Community
Sponsors and collaborators