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 www.aids2014.org HIV Prevention: Increasing Choices Decrease Source of 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 Decrease Host Susceptibility to 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 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 www.aids2014.org Even with optimal implementation of 2013 WHO guidance, HIV incidence remains too high (Futures Group, 2013) 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) High Levels of Adherence are Feasible: US PrEP Demonstration Project: (2012-2014) ● STD clinics in San Francisco, Miami, Washington, DC (n=831) - Self-referrals (37%): and clinic referrals ● Offered up to 48 weeks of openlabel emtricitabine/tenofovir DF - 60 MSM, transgender women Clinic referrals (63%) Accepted PrEP: 60.4% • 77% had TDF-DP levels consistent with taking >4 doses/week ● PrEP use associated with higher-risk sexual behaviors BLD: below limit of detection. Miami (n=157) Washington, DC (n=100) San Francisco (n=300) 50 Samples (%) - Tenofovir-DP Levels (Week 4) 52% 43% 43% 40% 40 35% 30 27% 20 18% 14% 11% 10 5% 2% 0 2% 0% 250-550 <250 BLD Doses/Week: <2 4% 4% <2 2 4 >550-950 >4 Tenofovir-DP (fmol/punch)* *femtomole/punch: measure of flux density. Cohen SE, et al. 21st CROI. Boston, 2014. Abstract 954.; R Grant, AIDS 2014, LB Tuesday >950 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 Priorities for New Technologies “On Demand” Used around time of intercourse For those who have intermittent sex or want more direct control over their protection 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 Available & Emerging Multipurpose Technologies Female Condom Male Condom Use rates are low in some settings, difficult to negotiate Drug combinations Drug/device combinations Electrospun Injectable ART, mAbs , HC Nanofibers/Films The future of MPTs…protection from HIV, other STDs, +/- pregnancy “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) 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 developing world indication in • 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 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 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 Dapivirine Ring Licensure Program IPM 027 • Long-term safety and efficacy study The Ring Study • 1950 participants, ongoing (2012-2015/16) in Africa MTN-020 ASPIRE Additional safety studies • Safety and efficacy study • 2,629 participants, ongoing (2012-2015) in Africa • Drug-drug interactions (data analysis) • Male condom functionality (data analysis) • Female condom functionality (ongoing) • Extended use PK (ongoing) • Safety in women >45 (ongoing) • Safety in adolescents (ATN 023) 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 “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 + Long Acting Injectable Nano-Suspensions: TMC278LA (Rilpivirine; PATH) • • • • NNRTI (Rilpivirine) Oral formulation in CompleraTM Long acting: up to 3 months? Multiple trials: – Dose ranging PK; PK/PD – Phase-2: HPTN 076 Cabotegravir (GSK ‘744; ViiV) • • • • • • 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 W Spreen, CROI, 2014 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? Antibody targets to block HIV transmission Target Class HIV specific antigens HIV binding sites on macrophages Antibodies (specific targets) 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) Ibalizumab (CD4 binding site) PRO140 (CCR5) Host derived antigens on both free Anti-CD36 Anti-LFA-1/CD11a virus and infected cells Anti-TSG101 Anti-GM3 Uninfected Dendritic and epithelial cells Reproductive tract coating antigens Anti-CD169 Anti-ICAM-1 HC4 (SAGA-1, male tract specific glycoform of CD52) 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) ARV-Based Prevention Pipeline (March 2014) PRE-CLINICAL PHASE I PHASE III PHASE II PHASE IV R IPM Pop Council IPM IPM GSK CONRAD IPM IPM IPM IPM Janssen CONRAD HPTN/ACTG CONRAD CONRAD ACTIVE DRUG R IPM IPCP NIAID IPM Albert Einstein TaiMed CONRAD R IPM Pop Council ImQuest Pop Council IPM RTI PBS CDC DAR Darunavir TFV Tenofovir prodrug DAP Dapivirine TDF Tenofovir disoproxil fumarate GRF Griffithsin Vaginal tablet TFV/ FTC Tenofovir/ emtricitabine Vaginal gel Rectal gel TDF/ FTC Tenofovir disoproxil fumarate/emtricitabine IQP IQP-0528 MIV 150 MIV 150 5P12 5P12-RANTES TMC 278 Ripilvirine 744 MVA Maraviroc MAb Monoclonal antibody RAL Raltegravir No drug tested currently Mintaka Vaginal film IPM PBS Pop Council Tenofovir Oral pills Vaginal ring Pop Council TFV IPM DELIVERY SYSTEM ImQuest Gilead IPM Phosphate buffered saline R Long acting injectable Thin film polymer Nano-fiber Adapted from AVAC Report 2013: Research & Reality. www.avac.org/report2013 DS003 DS003 (BMS793) GSK 744 E-technology • Where people meet partners • Where people get information • Aps may enhance -self-assessment of risk -monitoring PrEP adherence New technologies and PrEP adherence ↑ 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) 24 Medical male circumcision research to policy and scale-up – 25 years 1989 - 1999 2000-2006 Uganda 2007 2008-2013 WHO and UNAIDS Recommendations Kenya 5.82 million Bongaarts, AIDS 1989 HIV Prevalence (%) 25 South Africa 20 15 10 5 0 0 20 40 60 80 Circumcision prevalence (%) 100 2008 2009 2010 Year 2011 2012 2013 Evidence-Based Strategies to Reduce HIV Transmission Among PWUD Primary & Secondary Access to clean needles and syringes Opiate substitution therapy XR-Naltrexone Buprenorphine 27 Secondary Only Voluntary Counseling and Testing Access to ART Consider PrEP Voluntary Integrating Buprenorphine Into HIV Clinical Care Settings Prescribed ART Viral Suppression Altice FL et al, JAIDS, 2011 Cost effectiveness of PrEP improves when offered to highest risk persons Buchbinder, Lancet ID, 2014 Cost effectiveness of New Prevention Technologies (R. Walensky) Halve PrEP drug & program costs Halve PrEP drug cost 11 11 Annual HIV incidence (%) costsaving 9 8 7 6 5 iPrEx 4 South Africa 3 8 7 6 5 3 1 1 30 40 50 60 70 PrEP efficacy (%) 80 90 iPrEx 4 2 20 costsaving 9 2 10 CAPRISA 004 10 Annual HIV incidence (%) CAPRISA 004 10 South Africa 10 20 30 40 50 60 70 PrEP efficacy (%) cost-saving very cost-effective for South Africa (<$5,400/LY) cost-effective for South Africa (>$5,400/LY) 80 90 Purview paradox: contradictory beliefs about which providers will prescribe PrEP (Krakower, AIDS and Behavior, 2014) HIV providers: Primary care providers are in the best position Primary care providers: to prescribe PrEP It would not be feasible to prescribe PrEP New Technologies may provide tools for more efficient risk screening D. Smith JAIDS 2012 Electronic Patient Reported Outcomes, CNICS H. Crane Eco-Social Issues and New Prevention Technologies Policy Community -HIV testing guidelines -HIV treatment guidelines Relations -Stigma Individual Predisposing Enabling -Age -Race/ethnicity -Sex - Gender -Sexuality -Mental health -Substance use -Siloed funding sources -Poverty -Sex Partners -Social norms -Treatment funding -Family -Neighborhood - Prevention -Friends -Employment -Coordination Need -Social Networks -Corrections -Med Providers -Symptoms -Concomitant -Case Managers -Insurance -Housing Health System illness -Transport -Organization -Quality -Health beliefs Communication -Income -CBOs Factors indicators -Social support -Past -Clinic proximity -Service -Trust -Food security experiences -Communication -Clinic culture coordin. -Correctional -Appointments -Longevity system -Reim-Concordance -Supportive svcs bursement -Integrated svcs -Workforce - Incarceration 33 Constrained Resources in an Promising Era www.hivresourcetracking.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 → 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 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 www.aids2014.org Many thanks www.aids2014.org 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
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