Download A Phase II Randomized, Double-Blind, Study of the Safety and

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the work of artificial intelligence, which forms the content of this project

Document related concepts

Traveler's diarrhea wikipedia, lookup

HIV/AIDS wikipedia, lookup

India HIV/AIDS Alliance wikipedia, lookup

Transcript
A PEP and PrEP Update
Jeffrey D. Klausner, MD, MPH
Black AIDS Institute-UCLA
African-American University
September 2014
Special thanks to
Raphael Landovitz, MD, MSc
Definitions
• PMTCT
– Prevention of Mother-to-Child Transmission
of HIV
• ART during pregnancy, during labor/delivery,
and treatment of the infant after birth (x 6
weeks)
– AZT alone reduced MTCT from 25% to 8%†
– Current ART reduces MTCT to 1%‡
†Connor
et al, NEJM 1994
‡Shapiro
et al, NEJM 2010
Definitions
• PEP
– Post-exposure prophylaxis
– Strategy of administering ART to uninfected, at-risk
individuals, after they have had a high-risk exposure
to someone who is (or might be) HIV-infected
– Think of: “Morning after” pill(s)
– AZT reduced risk in HCWs by 81%†
– Current CDC Guidelines recommend 2- or 3-drug
antiretroviral treatment up to 72 hours after
exposure for 4 weeks following exposure
www.aidsinfo.nih.gov
†Cardo
et al, NEJM 1997
Definitions
• PrEP
– Pre-exposure prophylaxis
– Strategy of administering ART to uninfected,
at-risk individuals
– Think of: malaria prevention, birth control pill
– MSM: iPrEx study
– Women: FEM-PrEP study, VOICE (MTN-003)
– Heterosexual Couples: TDF2 and Partners
PrEP
PRE-EXPOSURE PROPHYLAXIS
(PREP)
PREP IN MSM:
THE IPREX STUDY
•
•
•
Phase III study of PrEP with fixed dose combination emtricitabine/tenofovir
(FTC/TDF) or placebo
Study population: HIV uninfected MSM or transgendered women from South
America, South Africa, Thailand and U.S. (N=2499)
Ten were HIV-infected at enrollment, but inadvertently enrolled anyway
Efficacy through study end (mITT): 42% (95% CI: 18% to 60%)
0.12
Cumulative Probability
of HIV Infection
•
iPrEx
Placebo
FTC/TDF (Truvada)
0.10
P = .002
0.08
0.06
0.04
0.02
0
0
12 24 36 48 60 72 84 96 108 120 132 144
Wks Since Randomization
Pts at Risk, n
Placebo 1248 1198 1157 1119 1030 932 786 638 528 433 344 239 106
FTC/TDF 1251 1190 1149 1109 1034 939 808 651 523 419 345 253 116
Grant R, et al. CROI 2011. Abstract 92.
Recorded Adherence and Efficacy
% of Visits
Efficacy
95% CI
<50%
50-90%
>90%
18%
33%
49%
16%
34%
68%
-54 - 54
-20 - 64
36 - 84
Grant et al. NEJM 2010
Drug Level Correlates of
Protection in iPrEx
• STRAND study determined median
levels of TFV in PBMCs after 2x (11
fmol/mL), 4x (32 fmol/mL), and 7x (42
fmol/mL) per week dosing of TDF
• iPrEx seroconverters had median 11
fmol/mL
• iPrEx non-seroconverters had median
16 fmol/mL
Anderson P. et al, Sci Transl Med, 2012
How long do TFV/FTC
concentrations last in serum?
(Single dose)
Patterson, K. Sci Transl Medicine, 2011.
iPrEx Drug Level Model
• Model: 90% reduction in HIV
incidence at 16 fmol/mL (IQR
3-28)
– 2x/week dosing would be
predicted to provide 76%
efficacy (56-96%)
– 4x/week dosing would be
predicted to provide 96%
efficacy (90->99%)
– 7x/week dosing would be
predicted to provide 99%
efficacy (96->99%)
iPrEX(Cases with
STRAND
100
n:
1st evidence HIV)
2/wk
4/wk
7/wk
cases
controls
21
21
22
48
144
100%
100%
8%
44%
11
32
42
11
16
6-13
25-39
31-47
4-15
9-27
10
1
Any Drug % Detected 100%
Median:
OQR:
Anderson P. et al, Sci Transl Med. 2012.
18
PREP IN HETEROSEXUAL
MEN AND WOMEN:
TDF2 AND PARTNERS PREP
Partners PrEP Study:
Trial Design
Double-Blind
Randomization
1:1
Phase 3, Double-Blind Study
Kenya, Uganda
Serodiscordant, heterosexual
couples (n=4758)
(HIV-positive partner not yet
eligible for ART)
Normal liver, renal,
hematologic values/function
Tenofovir DF qd (n=1845)
Primary Endpoints
HIV infection in HIV-negative partner
Safety
Emtricitabine/Tenofovir DF qd (n=1579)
Follow-Up
Up to 36 months
(7337 person-years)
Placebo (n=1584)
All patients received comprehensive HIV prevention services.
Baeten J et al, CROI 2012, Abstract #29, Seattle, WA.
Partners PrEP Study:
Results
HIV Incidence
• Both PrEP treatment arms
significantly reduced the risk of
HIV acquisition
TDF
TDF/FTC
Men
71% (37-87)
84% (54-94)
Women
63% (20-83)
66% (28-84)
• Both PrEP treatment arms were
safe and well tolerated
– No difference in AEs, labs,
SAEs, deaths
– No difference in renal function
• No evidence of risk
compensation
HIV Incidence
(per 100-person-years)
– Similar results between arms
and genders, location, VL strata
1.99
67% (44-81%)
Reduction
(P<0.0001)
75% (55-87%)
Reduction
(P<0.0001)
0.65
0.50
Placebo
Tenofovir Emtricitabine/
DF
Tenofovir DF
Baeten J et al, CROI 2012, Abstract #29, Seattle, WA.
Partners PrEP
• Resistance
– 2 of 8 acute seroconverters on therapy
• 1 K65R (TDF)
• 1 M184V (TDF/FTC)
– 0 of 27 seroconversions ON STUDY
had treatment emergent resistance
– 4 with NNRTI resistance (2 TDF, 1
TDF/FTC, 1 PBO)
Baeten J et al, CROI 2012, Abstract #29, Seattle, WA.
Baeten J et al, NEJM 2012.
Partners PrEP
• Adherence/Drug levels
– Case cohort: 30 seroconverter cases, 200
controls in active arms (randomly selected)
– TDF testing at mos 1, 3, 6, 12, 24, 36 +
seroconversion (if applicable)
Cases
(TDF 17, TDF/FTC 12)
Cohort
(N=198)
Visits prior to
seroconversion
Visit at
seroconversion
All Visits
TDF
56%
31%
83%
TDF/FTC
56%
25%
81%
If detectable drug (@ 0.3 ng/mL):
• TDF efficacy 86%
• TDF/FTC efficacy 90%
Donnell D et al, CROI 2012, Abstract #30, Seattle, WA.
Baeten J et al, NEJM 2012.
Partners PrEP
• 9 seroconverters had detectable drug
– 4 had drug levels > 40 ng/mL
– 4 had lower, but consistently detectable
levels
• 3 adherence patterns noted
– 70% stayed > 40 ng/mL at most time points
– 10% had low but detectable levels
– 20% had undetectable levels – consistently
• Self-report, pill count, and drug levels
well correlated (!)
Donnell D et al, CROI 2012, Abstract #30, Seattle, WA.
TDF2 Study: PrEP in
Heterosexual Adults
• Phase 2 trial in heterosexual
men and women (n=1200) in
Botswana
HIV Seroconversion (ITT)
– Women: 45%
– Married: 94%
– Completed study: 67%
– HIV seroconversion (n=33)
• Daily oral emtricitabine/tenofovir
DF (n=9 [2 males/7 females])
• Placebo (n=24 [10 males/14
females])
63%
Reduction
(P=0.013)
Proportion
• Primary results
Placebo
(n=599)
Emtricitabine/
Tenofovir DF
(n=601)
0
1
2
3
Years
Thigpen MC, et al. NEJM 2012.
Summary of Oral PrEP
Efficacy Data
Murnane et al, CROI 2013, Abstract #1000
Adherence and Efficacy in PrEP Trials
% of blood samples
with tenofovir detected
HIV protection efficacy
in randomized
comparison
Partners PrEP
FTC/TDF arm
81%
75%
TDF2
79%
62%
iPrEx
51%
44%
FEM-PrEP
26%
6%
Donnell et al CROI 2012
Grant et al N Engl J Med 2010
Van Damme et al CROI 2012
Paxton et al FDA 2012
WHAT ARE THE CONCERNS?
Risk Compensation
• PrEP trials have not seen risk compensation
But ….
– These were trials in which participants knew they
might be getting a “placebo”
– People were counseled REPEATEDLY that the
pill had not been shown to “work” yet, so
condoms MUST be used all the time
• What will happen now that we know it
works, and there are no more placebos?
Implementation
• Who should be delivering PrEP?
• What services should be co-packaged with
PrEP?
• Where should PrEP be delivered?
• When should people/laboratory testing be
done (at what interval)?
• How will PrEP and its services be paid for?
• Will the people most at risk use it and
adhere to it?
CDC Guidance for PrEP for
MSM: (Interim: 1/27/11)
• Before starting:
– Document HIV Antibody- and r/o acute infection
– CrCl >60, screen for STIs and HBV
• Prescribe FTC/TDF daily X 90 days
– Provide risk reduction, adherence counseling,
condoms
• On treatment:
– Check HIV Antibody every 2-3 months
– Check kidney function at 3 months and yearly
– Risk reduction, condoms, STI assessments/rx
http://www.cdc.gov/hiv/prep/index.htm
http://www.cdc.gov/hiv/pdf/PrEPguidelines2014.pdf
CDC PrEP Guidance 2014
•
•
•
•
•
Daily oral PrEP with the fixed-dose combination of tenofovir disoproxil fumarate
(TDF) 300 mg and emtricitabine (FTC) 200 mg has been shown to be safe and
effective in reducing the risk of sexual HIV acquisition in adults; therefore,
PrEP is recommended as one prevention option for sexually-active adult MSM
(men who have sex with men) at substantial risk of HIV acquisition (IA)
PrEP is recommended as one prevention option for adult heterosexually active
men and women who are at substantial risk of HIV acquisition. (IA)
PrEP is recommended as one prevention option for adult injection drug users
(IDU) at substantial risk of HIV acquisition. (IA)
PrEP should be discussed with heterosexually-active women and men whose
partners are known to have HIV infection (i.e., HIV-discordant couples) as one of
several options to protect the uninfected partner during conception and
pregnancy so that an informed decision can be made in awareness of what is
known and unknown about benefits and risks of PrEP for mother and fetus (IIB)
Community Discussion
• What will be the adverse effects profile in
other populations?
• Who will pay for it? If it is effective in
demonstration projects, will it be made
available to those most at risk?
• Will biomedical prevention increase health
disparities?
• What will the real world risk-compensation
consequences be?
• Resistance
What’s next?
• Open label “demonstration projects” of
daily FTC/TDF
• Intermittent FTC/TDF dosing (HPTN 066,
067, ANRS Study in France/Quebec)
• Daily dosing of alternative agents (HPTN
069)
• Long(er) acting preparations (TMC278LA
and S/GSK1265744), Topical patches,
vaginal rings (Dapivirine, TDF, others)
• Daily FTC/TDF in IDUs
Thank you!
Questions?