1. www.aids2014.org 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 Barrier protectionBarrier protection Blood screeningBlood screening Harm reduction for PWUDHarm reduction for PWUD ARTART -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 ●Condom promotion ●Individual-level interventions ●Couples interventions ●Community-based interventions ●Structural interventions Decrease Source of HIV Infection Decrease Host Susceptibility to HIV Infection Alter Behavior: Exposure, Adherence.

3. www.aids2014.org 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, Abdool Karim, 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 ● PrEP use associated with higher-risk sexual behaviors <250 250-550>550-950 BLD Samples (%) 18% 43% 14% 5% 2% Tenofovir-DP Levels (Week 4) >950 Cohen SE, et al. 21 st CROI. Boston, 2014. Abstract 954.; R Grant, AIDS 2014, LB Tuesday 2% 11% 27% 4% 52% 43% 40% 35% Miami (n=157) Washington, DC (n=100) San Francisco (n=300) Doses/Week: 4 Tenofovir-DP (fmol/punch)* BLD: below limit of detection. 0% *femtomole/punch: measure of flux density.

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

8. “On Demand”  Used around time of intercourse  For those who have intermittent sex or want more direct control over their protection Priorities for New Technologies Sustained Release  User-initiated, does not require daily action  Should increase adherence and effectiveness Long-acting Injectable  Co-administration of products targeting separate indications  Equal duration of effectiveness for the co-administered products

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

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: o Maraviroc rings alone and in combination with dapivirine Next-Gen: o Maraviroc gel (rectal use)- Magee Women’s Research Institute o Maraviroc/tenofovir gel combination in early preclinical development

12. Microbicide Rings Long-acting: monthly or longer o Could potentially improve adherence o Better adherence → ↑ effectiveness Easy to use, comfortable o Flexible ring, can be self-inserted o Rarely felt by women or male partners o Little or no impact on sexual activity Suitable for developing world o Relatively low manufacturing cost o 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 (Dapivirine ring 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. 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 + 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 “On demand” Products: Devices + Active Agents

17. Long Acting Injectable Nano-Suspensions: NNRTI (Rilpivirine) Oral formulation in Complera TM 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 Cabotegravir (GSK ‘744; ViiV) TMC278LA (Rilpivirine; PATH)

18. W Spreen, CROI, 2014

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

20. Antibody targets to block HIV transmission Target ClassAntibodies (specific targets) HIV specific antigens NIH45-46 (CD4 binding site) 3BNC117 and 3BNC60 (CD4 binding site) 10-1074 (glycan/V3 loop) PGT121 (glycan/V3 loop) VRC01 (gp120) 10E8 (several sites) HIV binding sites on macrophages Ibalizumab (CD4 binding site) PRO140 (CCR5) Host derived antigens on both free virus and infected cells Anti-CD36 Anti-LFA-1/CD11a Anti-TSG101 Anti-GM3 Uninfected Dendritic and epithelial cells Anti-CD169 Anti-ICAM-1 Reproductive tract coating antigens HC4 (SAGA-1, male tract specific glycoform of CD52)

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)

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

24. New technologies and PrEP adherence 24  ↑ 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 iPrEX Ole, 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)

25. 2000-20062007 WHO and UNAIDS Recommendations Medical male circumcision research to policy and scale-up – 25 years 1989 - 1999 Bongaarts, AIDS 1989 2008-2013 Uganda South Africa Kenya

27. 27 Evidence-Based Strategies to Reduce HIV Transmission Among PWUD Access to clean needles and syringes Opiate substitution therapy XR-Naltrexone Buprenorphine Voluntary Counseling and Testing Consider PrEP Voluntary Primary & SecondarySecondary Only Access to ART

28. Altice FL et al, JAIDS, 2011 Integrating Buprenorphine Into HIV Clinical Care Settings Prescribed ARTViral Suppression

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

30. Cost effectiveness of New Prevention Technologies (R. Walensky) Annual HIV incidence (%) 11 10 9 8 7 6 5 4 3 2 1 2030405060708090 PrEP efficacy (%) CAPRISA 004 iPrEx South Africa cost- saving Annual HIV incidence (%) 11 10 9 8 7 6 5 4 3 2 1 2030405060708090 PrEP efficacy (%) cost-saving very cost-effective for South Africa (<$5,400/LY) cost-effective for South Africa (>$5,400/LY) cost- saving Halve PrEP drug cost Halve PrEP drug & program costs South Africa iPrEx CAPRISA 004

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

32. New Technologies may provide tools for more efficient risk screening Electronic Patient Reported Outcomes, CNICS H. Crane D. Smith JAIDS 2012

33. 33 Policy -HIV testing guidelines -HIV treatment guidelines -Siloed funding sources -Treatment funding - Prevention -Coordination -Quality indicators -Service coordin. -Reim- bursement -Workforce - Incarceration Eco-Social Issues and New Prevention Technologies Community -Stigma -Poverty -Social norms -Neighborhood -Employment -Corrections Health System -Organization -CBOs -Clinic proximity -Clinic culture -Appointments -Supportive svcs -Integrated svcs -Sex Partners -Family -Friends -Social Networks -Med Providers -Case Managers Communication Factors -Trust -Communication -Longevity -Concordance Relations Individual Predisposing -Age -Race/ethnicity -Sex - Gender -Sexuality -Mental health -Substance use Enabling -Insurance -Housing -Transport -Income -Social support -Food security -Correctional system Need -Symptoms -Concomitant illness -Health beliefs -Past experiences

34. Constrained Resources in an Promising Era www.hivresourcetracking.org

35. www.aids2014.org New Prevention Technologies, 2014 PrEP works when used New meds and dosing regimens for oral PrEP may improve uptake, ↓cost FACTS 001 success may → 1 st 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

36. www.aids2014.org 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

37. www.aids2014.org Many thanks Salim Abdool Karim Rick Altice Rivet Amico Deborah Anderson Judith Auerbach Rachel Baggaley Stef Baral Susan Buchbinder Connie Celum Nomita Chandhiok Heidi Crane Gustavo Doncel Wafaa El-Sadr David Glidden Robert Grant Trip Gulick Tim Hallett Gottfried Hirnschall Bethany Holt Doug Krakower Raphy Landovitz 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 Rochell Walensky 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