Transcript Slides - View the full AIDS 2016 programme

PrEP: A work in progress
Kenneth H. Mayer, M.D.
Fenway Health/Harvard Medical school
HPTN Satellite
IAS 2016, Durban
July 20th, 2016
PrEP Is Effective:
Adherence Is Critical
Partners PrEP (FTC/TDF)
Partners PrEP (TDF)
TDF2
Effectiveness (%)
iPrEx
CAPRISA
VOICE (TDF gel)
FEM-PrEP
VOICE
(FTC/TDF)
VOICE(TDF)
0
10
20
30
40
50
60
70
80
90
Participants Samples With Detectable Drug Levels (%)
Pearson correlation: 0.86 (P=0.003).
AVAC Report 2013. http://www.avac.org/sites/default/files/resource-files/AVAC%20Report%202013_0.pdf.
100
44
OLE, demo, feasibility,
implementation
studies planned,
ongoing, completed
globally
22
5
New since
October
In Africa
8
8
Regulatory approvals
(Canada, France,
Israel, Kenya, Peru,
South Africa,
Switzerland*, US)
New since
October
2
7
New since
October
*Approved for
off-label use
Global
recommendation
(WHO, 2015)
1
New since
October
(PEPFAR, Oct
2015)
3
National strategies
2+
National
strategies in
development
International PrEP Demonstration Projects With
Emtricitabine/Tenofovir DF (2011-2015)
•
Individual PrEP demonstration projects
with emtricitabine/tenofovir DF n=32
projects in 16 countries)
HIV Seroconversion Rates
4
Overall rate:
0.96 (0.7-1.20)
•
0 HIV seroconversion rate
– 17 projects with 2467 participants
– Follow-up: 1315 person-years exposure
•
Total HIV seroconversions (n=67)
– Highest rates in MSM 18 to 25 years of
age (7.7/100 person-years)
– Available intracellular data showed
undetectable or very low TFV-DP levels
(<2 tablets/ week) in nearly all of those
with seroconversion
Mcallister S, et al. ASM Microbe 2016. Boston, 2016.
HIV Incidence
(per 100 person-years)
– 8478 participants with 7061 cumulative
years exposure
3
2.07
(0.05-11.5)
2
1.03
1
(0.8-1.3)
0.25
(0.03-0.9)
0
Men
(n=7002)
Women
(n=1388)
Transgender
(n=76)
•
•
•
•
•
24.7% sexually active MSM=492,000
18.5% of PWID=115,000
0.4% of heterosexual adults=624,000
Data derived from national probability surveys
Defining risk for heterosexuals has been
challenging (especially for women)
(HPTN 064: HIV incidence 0.32%)
Unique Individuals Starting FTC/TDF for PrEP in US,
2012 to 2015 (by quarter)
16000
79,684 unique individuals started FTC/TDF for PrEP:
14000
1,671 in Q4 2012 → 14,000 in Q4 2015
12000
10000
738% increase
8000
6000
4000
2000
0
Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
2012
2012
2013
2013
2014
2014
2015
2015
7
Region and State Use of FTC/TDF for PrEP
2012-2015
South
Northeast
TX
FL
GA
DC
NC
MD
VA
TN
LA
6.8%
5.7%
3.7%
3.3%
1.7%
1.5%
1.2%
1.0%
0.9%
AL
NY
MA
PA
NJ
CT
RI
NH
ME
VT
15.9%
5.1%
4.7%
2.5%
0.8%
0.5%
0.2%
0.2%
0.1%
Midwest
West
IL
MN
OH
MO
MI
IN
WI
KS
IA
5.4%
2.5%
2.1%
1.2%
1.2%
1.0%
0.6%
0.5%
0.3%
CA
WA
AZ
CO
OR
NV
UT
NM
HI
16.7%
3.5%
1.8%
1.5%
1.2%
0.6%
0.5%
0.4%
0.2%
0.5%
NE
0.2%
ID
0.2%
SC
0.4%
ND
0.1%
MT
0.1%
KY
0.4%
SD
0.0%
WY
0.1%
OK
0.4%
AK
0.0%
MS
0.3%
DE
0.3%
AR
0.2%
WV
0.1%
CA, NY, TX, FL, & IL account for 50.5% of unique individuals starting FTC/TDF for PrEP
8
US States with Highest Rates of FTC/TDF for PrEP
2012-2015
State
Number of individuals
starting
State
Percent of population
population**
starting (%)
Massachusetts
4,950
6,794,422
0.073
New York
12,588
19,795,791
0.064
Illinois
4,302
12,859,995
0.033
Florida
5,675
20,271,272
0.028
California
10,437
39,144,818
0.027
New Jersey
2,301
8,958,013
0.026
Pennsylvania
2,878
12,802,503
0.022
Georgia
2,230
10,214,860
0.022
Texas
5,120
27,469,114
0.019
Ohio
2,156
11,613,423
0.019
*US Census Bureau population estimate, 1 July 2015.
9
FTC/TDF for PrEP Utilization Compared With Population
and New HIV Infections
Estimated Population
Distribution
by Race/Ethnicity,
2014, USa
Total FTC/TDF for PrEP Utilization
by Race/Ethnicity,
Sept 2015, USb
Estimated New HIV
Infections,
2014, USc
44%
74%
62%
12%
27%
12%
18%
4%
3% 2%
AA
10%
White
Hispanics
Asians
23%
3% 2%
Multiracial/Other
FTC/TDF for PrEP use among AA and Hispanics is low relative to the
rate of new HIV infections
a. https://www.census.gov/quickfacts/table/PST045215/00
b. These data represent 43.7% (n=21,463) of unique individuals who have started TVD for PrEP from 2012-3Q2015.
c. Other indicates American Indian or Alaska Native, and Native Hawaiian or other Pacific Islander. CDC. HIV Surveillance Report, 2014
10
Bush S, et al. ASM/ICAAC 2016; Boston, MA. #2651
Men and Women Starting FTC/TDF for PrEP in US, 2012 to
2015
42,545
40000
4-YearTotal: 79,684
35000
Men:
30000
Women: 18,812
35,232
60,872
21,906
25000
20000
16,855
15000
10000
5000
9,023
6,210
2,740 3,470
3,708
5,315
7,313
5,051
0
2012
2013
2014
2015
11
Real world PrEP: PROUD Study
• ↓ new HIV infections with
immediate versus deferred
PrEP (3 versus 20 cases)
HIV Incidence
10
– 86% reduction (P=0.0002)
– HIV infection predated
start of ART (n=1)
– No drug/not adherent
(n=2)
• Number needed to treat to
prevent 1 HIV infection: 13
McCormack S, et al. Lancet. 2016;387:53-60.
HIV Incidence
(per 100 person-years)
• Incident HIV infection in the
immediate group
9
8.9
(6.0-12.7)
8
7
86%
Reduction
(P=0.0002)
6
5
4
3
1.3
2
(0.4-3.0)
1
0
Deferred
Immediate
(n=269)
(n=276)
PrEP Use and HIV/STI Incidence in a
Clinical Practice Setting
 Analysis of PrEP use and HIV/STI incidence in PrEP users in
large healthcare system (Kaiser Permanente San Francisco)
from 2012 to 2015
 1045 referrals for PrEP; 801 individuals with ≥ 1 intake visit
 657 initiated PrEP (82%*); mean duration of use 7.2 mos
 Key results (PrEP initators):
– After 12 months, 50% diagnosed with any STI
– 33% rectal STI; 33% chlamydia; 28% gonorrhea
– No HIV diagnoses (388 PY follow-up)
– After 6 mos PrEP, self-reported condom use was decreased in
41% of individuals
*Of persons with ≥ 1 intake visit.
Volk JE, et al. Clin Infect Dis. 2015;61:1601-1603.
Preexposure prophylaxis for HIV prevention in a
large integrated healthcare system: adherence, renal
safety, and discontinuation (Marcus J, JAIDS, 7/16)
• 972 pts, 850 py f/u
• Mean self-reported adherence 92%; no seroconversions
• ↓ adherence associated with Black race, ↑co-payment,
cigarette smoking
• 22.5% discontinued PrEP
• ↑ discontinuation associated with being female,
drug/alcohol use
• Only 0.6% discontinued because of ↑ creatinine
• Increasing diagnoses of rectal chlamydia and urethral
gonorrhea
1200
1400
960
1000
1200
PrEP trends: Fenway
Health, 2010-2014
600
Fenway Heath:
Incident STDs
1000
Total Patients
Total Patients
800
1329
537
400
800
600
400
200
102
5
0
2010
Spearman
p< .001
200
Spearman p<
.001
162
20
0
2011
2012
2013
2014
Time
-PrEP was first used by 5 pts outside of
a clinical trial in 2011
->83% of PrEP initiators still using PrEP.
-100 new PrEP starts a month
2015
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Time
-Since 2005, 1/2 of new syphilis diagnoses
were in HIV+ patients, while 80% of incident
GC/CT infections were in HIV- MSM.
-36% of MSM who initiated PrEP in 2014 had a
recent bacterial STD.
Questions about “PrEP 1.0”
•
•
•
•
•
•
•
•
•
Longer Term Adherence/Engagement
Adverse events
Transmitted drug resistance
Efficacy in women
Less than daily use
How to optimize efficacy in key populations
Provider readiness
Consumer readiness
Cost: who pays?
PrEP Cascade: Providence, Jackson, St. Louis
(Chan et al, JIAS, 2016)
iPrEx OLE: Probability of eGFR Decreasing to
<70 mL/min Within a Year
– Tenofovir DF: 4.4 (P=0.45)
– Emtricitabine: 4.5 (P=0.027)
• Probability of decreasing to
<70 mL/min if hair drug levels
in 3rd or 4th quartiles
– <40 years of age: <4%
– 40-50 years of age: 19% to 21%
– >50 years of age: 23% to 24%
• Potential implications for
patients starting PrEP
– Monitor renal function if >40 years of age
and a baseline eGFR <90 mL/min
Gandhi M, et al. 23rd CROI. Boston, 2016. Abstract 866.
Hair Drug Levels and eGFR
Probability of eGFR Falling <70 mL/min
• Odds ratio of decreasing to
<70 mL/min if hair drug levels
in 4th quartile
40
30
Years of age
<40
40-49
>50
~7
doses/week
~4
doses/week
24%
23%
20
~2
doses/week
19%
12%
10
6%
10%
5%
0
3rd
4th
1st
2nd
Quartile of Hair Drug Concentrations
21%
iPrEx DXA Substudy:
Recovery of BMD After Stopping PrEP
Hip BMD
2
Placebo
TFV-DP concentration at week 24
>16 fmol/M
<16 fmol/M
1
0.5
0
-0.5
*
-1
Placebo
TFV-DP concentration at week 24
>16 fmol/M
<16 fmol/M
1.5
Change in BMD (%)
Change in BMD (%)
1.5
Spine BMD
2
*
-1.5
1
0.5
0
-0.5
-1
-1.5
*
*P<0.001
-2
0
Week
24
Stop
PrEP
Week 24
After Stop
Average annualized recovery after stopping
PrEP: 1.13% (P=0.002 versus placebo)
OLE
Entry
-2
*P<0.001
0
Week
24
*
Stop
PrEP
Average annualized recovery after stopping
PrEP: 1.81% (P=0.01 versus placebo)
<25 years of age: full recovery of hip and spine BMD within 24 weeks of stopping PrEP.
>25 years of age: full recovery of spine BMD within 24 weeks of stopping PrEP; hip BMD recovered by OLE entry.
Grant R, et al. 23rd CROI. Boston, 2016. Abstract 48LB.
Week 24
After Stop
OLE
Entry
Case Report: MSM on PrEP Who Seroconverted With
Multi-Class Resistant HIV-1
• Seroconverted 24 months after
long-term adherence to PrEP
Tenofovir-DP
(Dried Bold Spots)
• Phenotypic resistance
• Results consistent with exposure to prior
E/C/F/TDF failure
• Re-suppressed with darunavir/r +
raltegravir
• First case of breakthrough HIV
infection with long-term adherence
to PrEP
Tenofovir-DP (fmol/punch)
• Multiple thymidine analog mutations
• NNRI and INSTI mutations
2500
Observed in
Patient
2297
2000
1560
1500
Expected
1000
722
500
Expected
0
20 Days
of Dosing
Knox DC, et al. 23rd CROI. Boston, 2016. Abstract 169aLB.
Steady-State
(>8 Weeks)
PrEP and women :
Varying Concentrations in Mucosal Tissues
Emtricitabine
Tenofovir DF
10000
Rectal tissue
Vaginal tissue
Cervical tissue
10000
1000
Concentration (ng/g)
Concentration (ng/g)
1000
100
10
100
10
1
1
0.1
Rectal tissue
Vaginal tissue
Cervical tissue
1
2
5
7
10
14
Time After Single Dose (days)
0.1
1
2
5
10
14
Time After Single Dose (days)
Open-label, 14-day pharmacokinetic study in HIV-negative female (n=7) and male (n=8) volunteers.
Entry criteria included: 18-50 years of age; BMI 18-30 kg/m2; weight >50 kg; no HCV or HBV; nonpregnant women
who were premenopausal and had regular menstrual cycles.
Patterson KB, et al. Sci Transl Med. 2011;3:112re4.
7
Ipergay Trial: Event-Driven PrEP
• On-demand PrEP remained
highly effective
• 1 new HIV infection during
OLE
• No RT resistant mutations
• New STIs during OLE (33%)
• Generally well tolerated
• Drug-related GI AEs (10%)
• Sexual behavior
• No significant difference
compared with double-blind
phase
• 1 SC in OLE, not on drug, with
final data: incidence 0.19%
9
HIV Incidence
(per 100 person-years)
• 1.3 months in OLE, no detectable
drug since entering OLE
HIV Incidence
10
8
7
6.6
6
86%
Reduction
(P=0.002)
5
4
3
2
0.91
1
0
0.40
Placebo
(n=212)
On-Demand
PrEP (DB)
On-Demand
PrEP (OLE)
(n=219)
(n=248)
Molina J-M, et al. 23rd CROI. Boston, 2016. Abstract 886
HPTN 067/ADAPT Study: Potential for less than daily PrEP
depends on population/location
Cape Town
(WSM)
Harlem
(MSM/TGW)
Bangkok
(MSM/TGW)
100
100
91%
100
95%
86%
60
46%
40
32%
60
40
20
20
0
Patients (%)
Patients (%)
66%
80
Patients (%)
80
80
Daily
Time
Event
0
60
56%
50%
40
39%
20
Daily
Time
With sex in the past 7 days.
Cape Town and Bangkok (tenofovir diphosphate >9.1 fmol/M PBMC).
Harlem (tenofovir >5 ng/mL plasma).
Bekker LG, et al. 8th IAS Conference. Vancouver, 2015. Abstract MOSY0103.
Holtz TH, et al. J Int AIDS Soc. 2015;18(suppl 4):25-26. Abstract MOAC0306LB.
Mannheimer S, et al. J Int AIDS Soc. 2015;18(suppl 4):24-25. Abstract MOAC0305LB.
Event
0
Daily
Time
Event
DD. Glidden, 7/18/16
Randomized Evidence:
IPERGAY
86% Effectiveness in MSM1
Biological
Efficacy
Adherence/
Acceptability
Animal
Studies
Pharmacology
Rectal Protection
Macaques
Identification of
Protective Level8
IPERGAY drug levels
82-86% detection in plasma2
ADAPT Study
Coverage of Sex in
6/6 protected6
Bangkok: 74% of MSM3
Protective as
New York: 52% of MSM4
daily7
Onset of
Protection9,10
Cape Town: 52% of women5
1. Molina, 2015
3. Holtz, 2015
5. Bekker, 2015
2. Fonsart, 2014 4. Mannheimer, 2015
8. Anderson, 2012
6,7 Garcia-Lerma, 2008, 2010
9. Seifert, 2015
10. Cottrell, 2016
HPTN 073: PrEP Uptake and Use by Black MSM in
Washington, DC, Los Angeles, and Chapel Hill
• HIV-negative black MSM (n=226)
– <25 years of age (40%), unemployed (27%),
no health insurance (31%)
10
• Accepting PrEP and counseling
sessions
• HIV-positive partner: 96% (23/24)
• Casual partners of unknown/HIVpositive status: 86% (104/120)
– Completed 12 months of PrEP: 92%
HIV Incidence (%)
– Overall: 79% (178/226)
8
HIV Incidence
Over 12 Months
7.7%
P=NS
6
4
2.9%
2
• Self-reported adherence
– >90%: 67%
– Seroconverters (n=5)
• 2 reported discontinuing PrEP at 50
and 272 days prior to seroconversion
0
Declined
PrEP
(n=42)
Accepted
PrEP
(n=178)
Wheeler D, et al. 23rd CROI. Boston, 2016. Abstract 883LB.
HPTN 073: Key Findings
(D Wheeler and S Fields)
• Theory-based, culturally-tailored programs can ↑ PrEP
uptake, ↑adherence, ↑ program retention for BMSM
• ↑ uptake of PrEP among BMSM and
↑ acceptance of C4 could be basis for program
development to ↓ HIV incidence for BMSM
• Incidence of 3% suggests further tailoring may be helpful
(still less than for YBMSM in HPTN 061)
• Almost 10% screened out b/c hepatic or renal issues,
meaning that addressing unmet clinical needs is
important and also suggests other PrEP regimens needed
ATN 110/113 (Hosek et al)
– Young MSM 15 to 22 y.o.
– PrEP plus individual versus group
CDC EBI for risk reduction in YMSM
– HIV incidence in ATN 110: 3.3%
ATN 113: HIV incidence 6.4%
(better than HPTN 061: 9% in < 30 y.o.)
– Youth were more adherent during first 3 months of
the study, when they had monthly visits, raising
question of whether more frequent contact would
enhance adherence?
– ? Role of apps, internet?
Need to improve communication about sexual
risk behaviors and PrEP in primary care




Survey of 1,394 MSM using partner-seeking website
42% were uncomfortable discussing male-male sex with their PCP
Even when comfortable, few MSM had discussed PrEP with their PCP
Most MSM perceived that PCPs would be unwilling to prescribe PrEP
**Versus other healthcare provider, the Internet, or other source
Krakower et al. IAS 2015
A majority of HIV specialists would
prescribe PrEP; only 1 in 3 has done so
National survey of ID physicians
(n=415) from IDSA’s Emerging
Infections Network
Krakower et al. Clin Inf Dis 2015
How to improve chemoprophylaxis effectiveness?
Novel adherence
strategies
New oral PrEP drugs and
dosing strategies
Hard-to-reach
populations; PWUD
Alternative delivery systems and formulations
Vaginal & Rectal
Microbicides
(MTN 017)
Intravaginal rings
(Dapivirine, Tenofovir
+/- Contraception)
Injectables:
ARVs and mAbs
(Cabotegravir,
VRC01)
Salim and Quarraisha
Abdool Karim
Linda-Gail Bekker
Staci Bush
Phil Chan
Demetre Daskalaskis
Sheldon Fields
Charlene Flash
Monica Gandhi
Marcy Gelman
David Glidden
Robert Grant
Chris Grasso
Henia Handler
Sybil Hosek
Douglas Krakower
Ken Levine
Albert Liu
Harvey Makadon
Kevin Maloney
Scott McAllister
Matthew Mimiaga
Amy Nunn
Rupa Patel
Jim Pickett
Sari Reisner
Jim Rooney
Steven A. Safren
Patrick Sullivan
Rodney Vanderwarker
Mitchell Warren
Darrell Wheeler
NIAID, NIMH, NICHD, NIDA,
MDPH, Gilead