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
www.aids2014.org
HIV Prevention: Increasing Choices
Decrease Source
of HIV Infection
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Barrier protection
Blood screening
Harm reduction for PWUD
ART
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Maternal-to-child transmission
Decrease partner’s viral load
Treatment of acute HIV infection
Decrease Host Susceptibility
to HIV Infection
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Barrier protection
Circumcision
Vaccines
Immunoprophylaxis
ART
- Oral
- Topical (Gel, Film, Ring)
- Injectable
Alter Behavior:
Exposure, Adherence
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Condom promotion
Individual-level interventions
Couples interventions
Community-based interventions
Structural interventions
New Prevention Technologies
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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)
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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)
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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)
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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)
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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
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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)
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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
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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
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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