Transcript Stepping up the pace: New Prevention Technologies

STATUS AND TRENDS IN BIOMEDICAL HIV PREVENTION
Kenneth H. Mayer, MD
CAPACITY BUILDING IN HIV PREVENTION IN PERU
UNAIDS, NOVEMBER 13TH, 2014
thefenwayinstitute.org
HIV Prevention: Increasing Choices
Decrease Source
of HIV Infection
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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
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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
Evidence Supports Combination ART
for Prevention of HIV Transmission
● Transmission only occurs from persons with HIV
● HIV RNA level is single greatest risk factor for HIV
transmission
● Combination ART can lower HIV RNA level to
undetectable levels
● Observational evidence in heterosexual couples
● Previous modeling work suggests considerable potential
● Knowing one’s HIV status is key to prevention with
combination ART
● When to start combination ART is not known for
certainty
HPTN 052:
Stable Heterosexual Couples
Phase 3 study
Delayed ART
CD4 <250 cells/mm3
Randomization
1:1
Americas, African, Asian sites
(n=1763 couples)
Similar baseline demographic characteristics
and sexual history/behavior both arms
and between HIV-negative partner and HIVpositive, treatment naïve index patient
Stable, healthy, sexually active,
serodiscordant couples
CD4 350-550 cells/mm3
Early ART
CD4 350 to 550 cells/mm3
Primary Endpoints
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Transmission
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Cohen MS, et al. N Engl J Med. 2011;365:493-505.
Virologically linked transmission events
Clinical
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WHO stage 4 clinical events
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Pulmonary TB
-
Severe bacterial infection and/or death
HPTN 052: HIV Prevention in
Stable Heterosexual Couples
● DSMB halts trials after a median
follow-up: 1.7 years
HIV RNA <400 copies/mL
• Early ART: 90%
• Delayed ART: 93%
● Linked HIV transmission to HIVnegative partner (n=28)
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Early therapy (n=1)
• 0.1 per 100 person-years
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Delayed therapy (n=27)
• 1.7 per 100 person-years
● Early ART led to a 96% reduction
of sexual transmission of HIV in
serodiscordant couples
Cohen MS, et al. N Engl J Med. 2011;365:493-505.
HR: 0.04
(95% CI 0.01-0.27)
(P<0.001)
Cumulative Probability
-
Linked HIV Transmission
Delayed
ART
Early
ART
0
1
2
3
Years
4
5
Ecologic Studies:
Impact of ART on New HIV Diagnoses
Washington, DC
San Francisco
British Columbia,
Canada
Data source
Health department
AIDS surveillance
Health department
AIDS surveillance
Disease and treatment
databases
National HIV
surveillance data and
behavioral surveys
Estimation of
suppressive
ART
Annual mean and
total or most recent
HIV RNA
Annual mean and total
CVL
Number infected
receiving ART
Prevalence positive on
ART
Sexual risk behaviors
Estimation of
HIV
incidence
Reported new
diagnoses
Report new diagnoses
(STARHS method)
New positive test/100
population
Annual number of MSM
notified as HIV infected
No association
between CVL and
new diagnoses
Reductions in CVL
associated with fewer
new infections (though
not with STARHS
method)
Rising numbers of ART
recipients and HIV RNA
<500 copies/mL
associated with
decreased HIV
diagnoses/year
Increasing numbers
treated coincides with
stable numbers of newly
notified HIV positives
suggests reduced
infectiousness
Results
CVL: community viral load.
Castel AD, et al. AIDS. 2012;26:345-353.
Das M, et al. PloS One. 2010;5:e11068.
Montaner JS, et al. Lancet. 2010;376:532-539.
Cowen S, et al. 18th IAC. Vienna, 2010. Abstract MoAC0103.
Denmark
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)
PrEP clinical questions
Symptoms: Start-up, GI, uncommon
Renal: uncommon with monitoring
Bone: focus on youth ATN 110/113
Selection for resistance: rare, almost all 184V
Risk compensation vs. reaching those at risk
Other STI: need for frequent monitoring; HSV-2?
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Other approaches: Two ring studies; FACTS 001
High Levels of Adherence are Feasible:
US PrEP Demonstration Project: (2012-2014)
● STD clinics in San Francisco, Miami,
Washington, DC (n=831)
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Self-referrals (37%): and clinic
referrals
● Offered up to 48 weeks of openlabel emtricitabine/tenofovir DF
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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)
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Samples (%)
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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
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
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)
Ongoing and Planned Phase 3/4 Research,
Including Demonstration Projects
 Phase 3 studies are continuing to evaluate PrEP in various
demographic groups
 Gilead is committed to post-marketing demonstration studies in the
U.S. and globally
 Collaborators: ANRS, CDC, FHI, MRC, NIAID (DAIDS), NICHD
(ATN), SFDPH, U. Washington, and Gilead Sciences
Population
Studies
Participants
MSM
17
14,100
Heterosexual Men & Women
Serodiscordant Couples
8
10,201
25
24,301
Total
ANRS = French National Agency for AIDS Research; CDC = Centers for Disease Control and Prevention; FHI = Family Health
International; MRC = Medical Research Council (UK); NIAID = National Institute of Allergy and Infectious Diseases; DAIDS =
Division of AIDS; NICHD = National Institute of Child Health and Human Development; SFDPH = San Francisco Department of
Public Health
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Lively Discussion and Debate in the Blogosphere
• Brief video testimonials developed regarding PrEP users’ decisions and
motivations to take PrEP and experiences taking PrEP
• Also: www.myprepexperience.blogspot.com AIDS Foundation of Chicago
Proportion of Participants Reporting PrEP
Awareness, Interest, and Use (Mayer, HIV R4P, 2014)
Overall Sample
6683/4759
27.3
Heard of PrEP
Reported Condomless Anal Sex
3826/3141
P<0.001
31.1
Heard of PrEP
47.1
43.8
50.8
Interested in PrEP
P=0.08
53.6
1.2
Taken PrEP
P=0.002
Wave 1
Wave 2
20
40
54.1
Interested in PrEP
P=0.002
60.4
P=0.004
1.9
0
P<0.001
60
80
100
Wave 1
2
Taken PrEP
Wave 2
3.1
0
20
40
60
80
100
Factors Associated with PrEP Use
among US MSM
Multivariable Model, Manhunt Survey, CROI, 2014
Characteristic
College graduate or above (vs. less
than college education)
Ever diagnosed with an STI
Used PEP
Comfortable talking with provider
about MSM sex
Multivariable
OR (95% CI)
5.33
(1.25 to 22.7)
2.74
(1.36 to 5.52)
16.0
(8.24 to 31.2)
4.19
(1.51 to 11.6)
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/Hosek)
 Feedback on drug levels been studied as
adjunct to counseling (Landovitz)
 SexPro App being developed (Buchbinder/Lama)
 Augmented lower tech approaches,
e.g. home visits are effective (Haberer, JAIDS, 2014)
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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
www.thefenwayinstitute.org/prepinfo
Cost effectiveness of PrEP improves when
offered to highest risk persons
Buchbinder, Lancet ID, 2014
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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Combination Antiretroviral Prevention
Interventions to Increase Testing
Enroll in Care
Test
HIV Negative
HIV Positive
Linkage
To Care
Risk Assessment
PrEP, Adherence
Counseling
Positive
Prevention
Address concomitant concerns:
depression, substance use, relationship
dynamics
.
Decrease in
HIV Transmission
ART
Initiation
Treat
Adherence
to ART
Maintain Viral
Suppression
Many
thanks
Salim Abdool Karim
Rick Altice
Rivet Amico
Susan Buchbinder
Nomita Chandhiok
Heidi Crane
Wafaa El-Sadr
David Glidden
Robert Grant
Trip Gulick
Bethany Holt
Doug Krakower
Raphy Landovitz
Albert Liu
Alex Rinehart
Jim Rooney
Zeda Rosenberg
Steve Safren
Rochell Walensky
Mitchell Warren
Kevin Whaley
The Fenway Institute colleagues
NIAID, NIMH, NICHD, CDC, HRSA,
Mass DPH, Gilead, ViiV, Merck
HPTN, HVTN, MTN, ATN
www.thefenwayinstitute.org