2. Implants and transdermal drug delivery systems for HIV prevention
Charles Flexner, MD
Johns Hopkins University
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3. Dr. Flexner is disclosing the following potential conflicts as recommended by the Conference:
Research grants and contracts: Gilead
Consulting: Cipla, Merck, Mylan, ViiV Healthcare
Stockholder and equity: none to report.
Patents and intellectual property: none to report.

4. Why implants?

5. Long Acting ARV Implants
Potential advantages over injectables
Removable (inert, or early bioerodable forms)
More consistent and predictable drug release
PK not dependent on injection site
May remain in place for years (inert, non-degradable subcutaneous versions)
Potential disadvantages over injectables
Specialized device required for insertion
Minor surgical procedure to remove
Should be removed (if not bioerodable)
Regulated as both a drug and a device
Difficulty moving to a generic marketplace

6. Use of LAIs in Hormonal Contraception
Over 40 million women worldwide use injectable contraception, and nearly half (47%) of modern contraception users in sub-Saharan Africa rely on injectable contraceptives to prevent pregnancy.
Returning to a health care provider for an injection every 2-3 months is considered a disadvantage of DMPA. Discontinuation rates of injectable contraceptives in sub-Saharan Africa are high, contributing to the growing popularity of longer-acting implants.
Norplant-2 (levonorgestrel; JadelleTM, Levoplant, Sinoplant – 2 rods, 5-year duration) is now used by millions of women in SSA. Cost per generic implant is less than $15 USD (~$3 pppy for effective hormonal contraception).
- Fok WK. Curr Opin Obstet Gynecol. 2017;29:

7. The Implant Quandry –
Inert or Bioerodable?

8. Example of a Bioerodable Implant
- Courtesy Eric Appel, Stanford University

9. Example of a Bioerodable Implant
- Courtesy Eric Appel, Stanford University

10. Nonerodable Implants: Tenofovir alafenamide (TAF)

11. LA ARV Implants – Tenofovir Alafenamide
M Gunawardana et al., Antimicrob Agents Chemother 2015; 59: 3913

12. LA ARV Implants – Tenofovir Alafenamide
M Gunawardana et al., Antimicrob Agents Chemother 2015; 59: 3913

13. Implant Candidate MK-8591 (EFdA): Formulations Release Effective Drug Concentrations for >180 days
- Barrett SE et al. Antimicrob Agents Chemother 2018; DOI: /AAC
>180-day extended release from solid state implant formulations after a single injection in rats.
Data suggest the potential to provide coverage for durations up to 1 year.

14. 4’-Ethynyl-2-fluoro-2’-deoxyadenosine (EFdA)
Unique properties
Unique mechanism of action (translocation inhibitor)
Exceedingly potent (possible dose in humans of <5 mg/day)
Lack of cross-resistance with most NRTI’s
Minor impact of M184V
More active against HIV-2 than other NRTI’s
Long half-life of intracellular TP (>72 hours) in rhesus macaques
Possibility of once-weekly oral dosing
Possibility of implant formulation with dosing interval of >one year

15. Implants – A Note of Caution

17. Transdermal drug delivery?
Microneedles

18. Transcutaneous ARV Delivery Systems
Potential advantages over injectables
Removable
Can be applied by the patient or family member
PK not dependent on placement site (?)
May remain in place for days or weeks
Also appropriate for short-duration drug delivery (per day or week)
Potential disadvantages over injectables
Limited number of drug candidates
Complex manufacturing
Expensive to manufacture
Regulated as both a drug and a device
Difficulty moving to a generic marketplace

19. - Vora et al. J Contr Release 2017

20. - Vora LK et al. J Contr Release 2017

21. - Vora et al. J Contr Release 2017

22. What is it like to wear a microneedle patch?

23. Estimated cabotegravir concentrations after applying a 30-60 cm2 microneedle patch (adults)
- Rajoli et al. CROI 2018

24. Acknowledgements longactinghiv.org
Johns Hopkins University Amer Al-Khouja David Meyers Caren Freel Meyers Jane McKenzie-White Stanford University Eric Appel
Univ. of Liverpool Rajoth Rajoli Saye Khoo Andrew Owen Marco Siccardi FUNDING SOURCES Bill and Melinda Gates Foundation NIAID, R24 AI (LEAP) NIAID, R01 AI
I would like to thank our patients and my coleage for all their hard work on this study.
longactinghiv.org