Upload
cornelius-maxwell
View
217
Download
1
Embed Size (px)
Citation preview
thefenwayinstitute.org
STATUS AND TRENDS IN BIOMEDICAL HIV PREVENTION
Kenneth H. Mayer, MDCAPACITY BUILDING IN HIV PREVENTION IN PERU
UNAIDS, NOVEMBER 13TH, 2014
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
.
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 Americas, African, Asian sites
(n=1763 couples)
Stable, healthy, sexually active,serodiscordant couples
CD4 350-550 cells/mm3
Randomization1:1
Early ARTCD4 350 to 550 cells/mm3
Primary Endpoints• Transmission
- Virologically linked transmission events
• Clinical- WHO stage 4 clinical events
- Pulmonary TB
- Severe bacterial infection and/or death
Similar baseline demographic characteristicsand sexual history/behavior both arms
and between HIV-negative partner and HIV-positive, treatment naïve index patient
Cohen MS, et al. N Engl J Med. 2011;365:493-505.
Delayed ARTCD4 <250 cells/mm3
HPTN 052: HIV Prevention inStable 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 HIV-negative partner (n=28)
- Early therapy (n=1)• 0.1 per 100 person-years
- 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
Cu
mu
lati
ve P
rob
abili
ty
0 1 2 3 4 5
Linked HIV Transmission
EarlyART
DelayedART
Cohen MS, et al. N Engl J Med. 2011;365:493-505.
Years
HR: 0.04(95% CI 0.01-0.27)
(P<0.001)
Ecologic Studies:Impact of ART on New HIV Diagnoses
Washington, DC San FranciscoBritish Columbia,
Canada Denmark
Data source Health departmentAIDS surveillance
Health departmentAIDS 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
Results 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
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.
CVL: community viral load.
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?
Other approaches: Two ring studies; FACTS 001
10
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
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)
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)
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 & WomenSerodiscordant Couples 8 10,201
Total 25 24,301
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
17
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
P<0.001
P=0.08
Proportion of Participants Reporting PrEP Awareness, Interest, and Use (Mayer, HIV R4P, 2014)
P=0.002
P<0.001
P=0.002
P=0.004
Overall Sample 6683/4759
Reported Condomless Anal Sex 3826/3141
Factors Associated with PrEP Use among US MSM Multivariable Model, Manhunt Survey, CROI, 2014
New technologies and PrEP adherence
21
↑ 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)
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
www.thefenwayinstitute.org/prepinfo
Cost effectiveness of PrEP improves when offered to highest risk persons
Buchbinder, Lancet ID, 2014
25
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
Decrease inHIV Transmission
Maintain ViralSuppression
Treat
Enroll in Care
Address concomitant concerns:depression, substance use, relationship
dynamics
Combination Antiretroviral Prevention
HIV Negative
Test
Interventions to Increase Testing
PositivePrevention
LinkageTo Care
Adherence to ART
ART Initiation
.
Risk Assessment PrEP, Adherence
Counseling
HIV Positive
Many thanksSalim Abdool KarimRick AlticeRivet AmicoSusan BuchbinderNomita ChandhiokHeidi CraneWafaa El-SadrDavid GliddenRobert GrantTrip GulickBethany HoltDoug KrakowerRaphy LandovitzAlbert LiuAlex RinehartJim RooneyZeda RosenbergSteve SafrenRochell WalenskyMitchell WarrenKevin Whaley
The Fenway Institute colleaguesNIAID, NIMH, NICHD, CDC, HRSA, Mass DPH, Gilead, ViiV, Merck HPTN, HVTN, MTN, ATNwww.thefenwayinstitute.org