Post on 22-Feb-2016
description
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
HIV Prevention: Increasing Choices
• 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
● Condom promotion● Individual-level interventions● Couples interventions● Community-based interventions● Structural interventions
Decrease Sourceof HIV Infection
Decrease Host Susceptibilityto HIV Infection
Alter Behavior:Exposure, Adherence
.
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
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)
- 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
0
10
20
30
40
50
60
<250 250-550 >550-950BLD
Sam
ples
(%)
18%
43%
14%
5%2%
Tenofovir-DP Levels (Week 4)
>950
Cohen SE, et al. 21st CROI. Boston, 2014. Abstract 954.; R Grant, AIDS 2014, LB Tuesday
2%
11%
27%
4% 4%
52%
43%40%
35%
Miami (n=157)Washington, DC (n=100)San Francisco (n=300)
Doses/Week: <2 <2 2 4 >4
Tenofovir-DP (fmol/punch)*BLD: below limit of detection.
0%
*femtomole/punch: measure of flux density.
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
“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
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
“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 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 Instituteo Maraviroc/tenofovir gel combination in early preclinical
development
Microbicide Rings• Long-acting: monthly or longer
o Could potentially improve adherenceo Better adherence → ↑ effectiveness
• Easy to use, comfortableo Flexible ring, can be self-insertedo Rarely felt by women or male partnerso Little or no impact on sexual activity
• Suitable for developing worldo Relatively low manufacturing costo 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
• Long-term safety and efficacy study• 1950 participants, ongoing (2012-2015/16) in Africa
IPM 027The Ring Study
• Safety and efficacy study• 2,629 participants, ongoing (2012-2015) in Africa
MTN-020ASPIRE
• 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)
Additional safety studies
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
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
Long Acting Injectable Nano-Suspensions:
• 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
Cabotegravir (GSK ‘744; ViiV)TMC278LA (Rilpivirine; PATH)
W Spreen, CROI, 2014
MPT Long Acting Injectables
+/-
2 or more drugs administered simultaneously
Long-acting Injectable
ARVs Rilpivirine
Cabotegravir
Depo ProveraCyclofem
Other HC or non-HCor STD rx?
Antibody targets to block HIV transmission Target Class Antibodies (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-CD36Anti-LFA-1/CD11aAnti-TSG101Anti-GM3
Uninfected Dendritic and epithelial cells
Anti-CD169Anti-ICAM-1
Reproductive tract coating antigens 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)
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
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)
2000-2006 2007
WHO and UNAIDS Recommendations
Medical male circumcision research to policy and scale-up – 25 years
1989 - 1999
0
5
10
15
20
25
0 20 40 60 80 100Circumcision prevalence (%)
HIV
Pre
vale
nce
(%)
Bongaarts, AIDS 1989
2008-2013
Uganda
South Africa
Kenya
2008 2009 2010 2011 2012 2013Year
5.82 million
27
Evidence-Based Strategies to Reduce HIV Transmission Among PWUD
Access to clean
needles and syringes
Opiate substitution therapyXR-NaltrexoneBuprenorphine
VoluntaryCounselingand Testing
ConsiderPrEPVoluntary
Primary & Secondary Secondary Only
Access to ART
Altice FL et al, JAIDS, 2011
Integrating Buprenorphine Into HIV Clinical Care Settings
Prescribed ART Viral Suppression
Cost effectiveness of PrEP improves when offered to highest risk persons
Buchbinder, Lancet ID, 2014
Cost effectiveness of New Prevention Technologies (R. Walensky)
Annual
HIV incidence (
%)
11
10
9
8
7
6
5
4
3
2
1
10 20 30 40 50 60 70 80 90PrEP efficacy (%)
CAPRISA 004
iPrEx
South Africa
cost-saving
Annual
HIV incidence (
%)
11
10
9
8
7
6
5
4
3
2
1
10 20 30 40 50 60 70 80 90PrEP 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
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
to prescribe PrEPPrimary care providers: It would not be feasible
to prescribe PrEP
New Technologies may provide tools for more efficient risk screening
Electronic Patient Reported Outcomes, CNICS H. Crane
D. Smith JAIDS 2012
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
RelationsIndividual
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
Constrained Resources in an Promising Erawww.hivresourcetracking.org
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 → 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 thanksSalim Abdool KarimRick AlticeRivet AmicoDeborah AndersonJudith AuerbachRachel BaggaleyStef BaralSusan BuchbinderConnie CelumNomita ChandhiokHeidi CraneGustavo DoncelWafaa El-SadrDavid GliddenRobert GrantTrip GulickTim HallettGottfried HirnschallBethany HoltDoug KrakowerRaphy LandovitzSandy LehrmanAlbert LiuGita RamjeeRenee RidzonAlex RinehartJoe RomanoJim RooneyZeda RosenbergSteve SafrenJulia SamuelsonWilliam SpreenJohn StoverJim TurpinRochell WalenskyMitchell WarrenAriane Van Der StratenFulvia VeroneseKevin Whaley
The Fenway Institute colleaguesNIAID, NIMH, NICHD, CDC, HRSA, Mass DPH, Gilead, ViiV, Merck HPTN, HVTN, MTN, ATNwww.thefenwayinstitute.org