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Stepping up the pace: New Prevention Technologies

Stepping up the pace: New Prevention Technologies. Kenneth H. Mayer Fenway Health Beth Israel Deaconess Medical Center Harvard Medical School Harvard School of Public Health.

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Stepping up the pace: New Prevention Technologies

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  1. Stepping up the pace: New Prevention Technologies Kenneth H. Mayer Fenway Health Beth Israel Deaconess Medical Center Harvard Medical School Harvard School of Public Health

  2. HIV Prevention: Increasing Choices Decrease Source of HIV Infection Decrease Host Susceptibility to HIV Infection • Barrier protection • Blood screening • Harm reduction for PWUD • ART • Maternal-to-child transmission • Decrease partner’s viral load • Treatment of acute HIV infection • Barrier protection • Circumcision • Vaccines • Immunoprophylaxis • ART • - Oral • - Topical (Gel, Film, Ring) • - Injectable Alter Behavior: Exposure, Adherence • Condom promotion • Individual-level interventions • Couples interventions • Community-based interventions • Structural interventions .

  3. New Prevention Technologies • Isn’t treatment expansion sufficient? • PrEP: If used consistently, will work • How to optimize delivery? • New Pills, Rings, Films, Injectables • Multi-Purpose Technologies • Immunoprophylactics • E-Technology and HIV prevention • Next Gen Circumcision • Combination Prevention for PWUD • The cost of success vs. status quo • Choice: One size will never fit all

  4. Even with optimal implementation of 2013 WHO guidance, HIV incidence remains too high(Futures Group, 2013)

  5. What about those who did not benefit? • Adherence • Engaged in study, but not interested in PrEP • Medical Mistrust • Pharmacology • Genital inflammation (STI, sexual violence?) (Auerbach, Marrazzo, VanDamme, Van der Straten, Stadler, Tolley, Hendrix, AbdoolKarim, Saethre, Corneli)

  6. High Levels of Adherence are Feasible: US PrEP Demonstration Project: (2012-2014) • STD clinics in San Francisco, Miami, Washington, DC (n=831) • MSM, transgender women Clinic referrals (63%) • Self-referrals (37%): and clinic referrals • Offered up to 48 weeks of open-label emtricitabine/tenofovir DF • Accepted PrEP: 60.4% • 77% had TDF-DP levels consistent with taking >4 doses/week • PrEPuse associated with higher-risk sexual behaviors Tenofovir-DP Levels (Week 4) Miami (n=157) Washington, DC (n=100) San Francisco (n=300) 52% 43% 43% 40% 35% Samples (%) 27% 18% 14% 11% 5% 4% 4% 2% 2% 0% 250-550 >550-950 >950 <250 BLD Doses/Week: <2 <2 2 4 >4 Tenofovir-DP (fmol/punch)* BLD: below limit of detection. *femtomole/punch: measure of flux density. Cohen SE, et al. 21st CROI. Boston, 2014. Abstract 954.; R Grant, AIDS 2014, LB Tuesday

  7. How to improve chemoprophylaxis effectiveness? Novel adherence strategies New oral PrEP drugs and dosing strategies Alternative delivery systems and formulations Vaginal & Rectal Microbicides Injectables: ARVs and mAbs Intravaginal rings

  8. Priorities for New Technologies

  9. Available & Emerging Multipurpose Technologies Female Condom Male Condom Drug combinations Injectable ART, mAbs , HC Use rates are low in some settings, difficult to negotiate Drug/device combinations ElectrospunNanofibers/Films The future of MPTs…protection from HIV, other STDs, +/- pregnancy

  10. “On demand” Products: Gels • Tenofovir Gel (CONRAD) • Effective in preventing HIV (39%) and HSV-2 (51%) in CAPRISA 004, but not VOICE • Confirmatory trial (FACTS 001) :2,900 HIV-negative 18-30 yr old South African women enrolled, evaluating coitally-dependent gel, results 2015 • Rectal optimized gel being studied in Phase 2 study in 360 MSM and transgender women in MTN017 in Peru, South Africa, Thailand and US • New Topical Gels • MIV-150 (NNRTI) + Zinc Acetate + LNG (Pop Council) • Griffithsin: inhibits gp120 and gp41 binding (NCI/Palmer) • 5P12-RANTES: co-receptor blocker (Mintaka) • IQP-0528: NNRTI and entry blocker (IMquest)

  11. Maraviroc • CCR5 blocker with established safety profile as marketed oral therapeutic (Pfizer/ViiV) • Phase II study for oral PrEP +/-FTC or TDF (HPTN 069) 400 MSM/200 women • Licensed to IPM in 2008 for microbicide indication in developing world • Clinical development: • Maraviroc rings alone and in combination with dapivirine • Next-Gen: • Maraviroc gel (rectal use)- Magee Women’s Research Institute • Maraviroc/tenofovir gel combination in early preclinical development

  12. Microbicide Rings • Long-acting: monthly or longer • Could potentially improve adherence • Better adherence → ↑effectiveness • Easy to use, comfortable • Flexible ring, can be self-inserted • Rarely felt by women or male partners • Little or no impact on sexual activity • Suitable for developing world • Relatively low manufacturing cost • Good safety and acceptability data • Potential for drug combinations

  13. Dapivirine (TMS 120) • Highly potent ARV: NNRTI • Developed by Janssen • Originally tested as oral therapeutic • Licensed to IPM in 2004 • Development as vaginal microbicide for HIV prevention • 15 Phase I/II safety studies (Dapivirinering or gel) • Good safety profile in all studies to date • Safety data on more than 700 study participants • Dapivirine Ring Licensure Program started in 2012, results expected in 2015/2016

  14. Dapivirine Ring Licensure Program

  15. Sustained-Release Devices: Combination Intravaginal Rings (IVRs) • 60-day Dapivirine + LNG IVR(IPM) • Combines the ARV dapivirine (DPV) + LNG (silicon ring) • DPV+LNG ring formulation and testing are underway • 90-day Tenofovir + LNG IVR (CONRAD; IPM) • Combines TFV with the hormonal contraceptive, LNG • Segment or matrix formulation • 30-day MZL Combination IVR (Population Council) • Combines MIV-150 + Zinc Acetate + LNG • Early pharmacology studies underway • Nuvaring(Merck) • 44 million users since 2002 • Matrix, non-latex, novel polymer • Vicriviroc and MK-2048 (ISTI) combinations under study

  16. “On demand” Products: Devices + Active Agents 1. SILCS Contraceptive Barrier (PATH, CONRAD, NICHD) • “One size fits most” silicone diaphragm that does not need to be fitted by a clinician; intended for OTC provision • 6-mo typical use pregnancy rate comparable to standard fitted diaphragm when used with a contraceptive gel (10.4%) • 5-yr shelf life; re-use for up to 3 yrs + 2. Plus Tenofovir Gel (CONRAD) • SILCS barrier as a delivery device for TFV gel • Would provide a non-hormonal method of protection from pregnancy, HIV and HSV-2 • Designed for effective protection for up to 24 hrs

  17. LongActingInjectable Nano-Suspensions: TMC278LA (Rilpivirine; PATH) Cabotegravir (GSK ‘744; ViiV) • NNRTI (Rilpivirine) • Oral formulation in CompleraTM • Long acting: up to 3 months? • Multiple trials: • Dose ranging PK; PK/PD • Phase-2: HPTN 076 • Integrase inhibitor • Similar to Dolutegravir • Safe in humans with oral run-in • Activity up to 3 months? • NHP model efficacy • Phase 2: Éclair and HPTN 077

  18. W Spreen, CROI, 2014

  19. MPT Long Acting Injectables • 2 or more drugs administered simultaneously Depo Provera Long-acting Injectable ARVs Rilpivirine Cabotegravir +/- Cyclofem Other HC or non-HC or STD rx?

  20. Antibody targets to block HIV transmission

  21. VRC01 • Isolated from long term non-progressor • Binds to HIV-1 gp120 envelope protein • Prevented SHIV infection in NHP • Protected vs. rectal, vaginal and oral challenges • Broad and potent neutralizing activity • May provide inform development of effective vaccine • Phase I evaluation began September, 2013 in VRC • HVTN 104 evaluating subQ and IV dosing: q monthly? • PEP for infants (IMPAACT) • PEP for Adults? • Mucosal administration as a topical film (Anderson IPCP)

  22. E-technology • Where people meet partners • Where people get information • Aps may enhance -self-assessment of risk -monitoring PrEP adherence

  23. New technologies and PrEPadherence • ↑ treatment adherence with text messaging (Lester, Lancet, 2010) • Wisepill: cell-phone size device, provides real time signal when pillbox opened • Life-Steps intervention has been modified for PrEP use, including daily SMS with pts (Safren) • Next step counseling in iPrEXOle, augmented by electronic diary in SF and Chicago was associated with ↑ adherence (Amico) • Feedback on drug levels been studied as adjunct to counseling (Landovitz) • Use of taggents and pills containing electronic sensing devices under study (Van der Straten) • Augmented lower tech approaches, e.g. home visits are effective (Haberer, JAIDS, 2014)

  24. Medical male circumcision research to policy and scale-up – 25 years 1989 - 1999 2000-2006 2007 2008-2013 Uganda WHO and UNAIDS Recommendations Kenya Bongaarts, AIDS 1989 South Africa

  25. Evidence-Based Strategies to Reduce HIV Transmission Among PWUD Primary & Secondary Secondary Only VoluntaryCounseling and Testing Access to clean needles and syringes Access to ART Opiate substitution therapy XR-Naltrexone Buprenorphine Consider PrEP Voluntary

  26. Integrating Buprenorphine Into HIV Clinical Care Settings Prescribed ART Viral Suppression Altice FL et al, JAIDS, 2011

  27. Cost effectiveness of PrEP improves when offered to highest risk persons Buchbinder, Lancet ID, 2014

  28. Cost effectiveness of New Prevention Technologies (R. Walensky) Halve PrEP drug & program costs Halve PrEP drug cost CAPRISA 004 CAPRISA 004 cost-saving cost-saving iPrEx iPrEx South Africa South Africa

  29. Purview paradox: contradictory beliefs about which providers will prescribe PrEP(Krakower, AIDS and Behavior, 2014)

  30. New Technologies may provide tools for more efficient risk screening

  31. Eco-Social Issues and New Prevention Technologies Policy Community -HIV testing guidelines -HIV treatment guidelines -Siloed funding sources -Treatment funding - Prevention -Coordination -Quality indicators -Service coordin. -Reim- bursement -Workforce - Incarceration Relations -Stigma -Poverty -Social norms -Neighborhood -Employment -Corrections Health System -Organization -CBOs -Clinic proximity -Clinic culture -Appointments -Supportive svcs -Integrated svcs Individual -Sex Partners -Family -Friends -Social Networks -Med Providers -Case Managers Communication Factors -Trust -Communication -Longevity -Concordance Predisposing Need Enabling -Age -Race/ethnicity -Sex - Gender -Sexuality -Mental health -Substance use -Symptoms -Concomitant illness -Health beliefs -Past experiences -Insurance -Housing -Transport -Income -Social support -Food security -Correctional system

  32. Constrained Resources in an Promising Erawww.hivresourcetracking.org

  33. New Prevention Technologies, 2014 • PrEP works when used • New meds and dosing regimens for oral PrEP may improve uptake, ↓cost • FACTS 001 success may → 1st approved topical • Rectal gels may offer new anal protection • Rings may offer MPT opportunities • Injectable PrEP could improve adherence • ↑ uptake of circumcision is important • State-of-the-art harm reduction for IDU is needed • Optimizing social media may facilitate safer sex counseling and med adherence • Vaccine and Cure research is still needed

  34. To Optimize New Prevention Opportunities • Increased investment is needed Short term ↑ expense = long term cost ↓ • Increased political will is needed • Commitment to equity is needed • Respect for human rights is essential Coercion to use new modalities is unacceptable Community input throughout development is essential

  35. Many thanks Salim Abdool Karim Rick Altice Rivet Amico Deborah Anderson Judith Auerbach Rachel Baggaley StefBaral Susan Buchbinder Connie Celum NomitaChandhiok Heidi Crane Gustavo Doncel Wafaa El-Sadr David Glidden Robert Grant Trip Gulick Tim Hallett Gottfried Hirnschall Bethany Holt Doug Krakower RaphyLandovitz Sandy Lehrman Albert Liu Gita Ramjee Renee Ridzon Alex Rinehart Joe Romano Jim Rooney Zeda Rosenberg Steve Safren Julia Samuelson William Spreen John Stover Jim Turpin RochellWalensky Mitchell Warren Ariane Van Der Straten Fulvia Veronese Kevin Whaley The Fenway Institute colleagues NIAID, NIMH, NICHD, CDC, HRSA, Mass DPH, Gilead, ViiV, Merck HPTN, HVTN, MTN, ATN www.thefenwayinstitute.org

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