Download State of the evidence from oral and topical PrEP efficacy

State of the evidence from oral and
topical PrEP efficacy trials
What we know and what we still need to know.
Javier R. Lama, MD, MPH
Director, HIV Prevention Intervention Studies
IMPACTA PERU Clinical Trials Unit
Lima, Peru
Rationale or PrEP for HIV Prevention
• Prophylaxis to reduce the risk of an infectious
disease is well established
– E.g.: Malaria for travelers
• Evidence for HIV prevention based on
– Prevention of mother to child transmission
– Non-human primate studies
• Protection after mucosal challenge
The Right Drug? Tenofovir for PrEP
• Potent
– Potent antiretroviral activity, rapidly active
• Safe and well-tolerated:
– Substantial treatment safety experience
• Easy to use:
– Once-daily dosing, few drug interactions
HYPOTHESIS
Oral TDF, oral FTC/TDF, or vaginal tenofovir gel prior to
HIV exposure, as PrEP, will reduce risk of HIV infection
Oral HIV PrEP Efficacy Trials
Efficacy: 44%, 95 CI: 15 ̶ 63%
Infections Numbers: 64 – 36 = 28 averted
n = 2,499 men who have sex with men and transgender women;
Brazil, Ecuador, Peru, South Africa, Thailand, United States
Grant RM, Lama JR, Anderson P, et al. N Engl J Med 2010;363:2587-99.
Efficacy TDF:
67%, 95% CI: 44 ̶ 81%
FTC/TDF: 75%, 95% CI: 55 ̶ 87%
Infections Numbers
TDF: 52 – 17 = 35 averted*
TDF-FTC: 52 – 13 = 39 averted*
n = 4,747 heterosexual men and women with HIV infected partners;
Kenya, Uganda
* Each intervention when compared to placebo
Baeten JM, Donnell D, Ndase P, et al. N Eng J Med 2012; 367(5):399-410
TDF-2 Study
Efficacy: 62%, 95% CI: 22 - 83%
Infections Numbers: 52 – 17 = 35 averted
n = 1,219 heterosexual men and women;
Bostwana
Thigpen MC, Kebaabetswe PM, Paxton LA, et al. N Eng J Med 2012; 367(5):423-34
Bangkok Tenofovir Study
Efficacy 49%, 95% CI: 10 ̶ 72%
Infections Numbers: 33 – 17 = 16 averted
n = 2,413 men and women who inject drugs;
Thailand
Choopanya K, Martin M, Suntharasamai P, et al. Lancet 2013; 381(9883):2083-90
Lesson 1
Oral tenofovir-based PrEP works
Oral TDF and FTC/TDF PrEP Study
Effect Size
(95% CI)
FTC/TDF for HIV
discordant couples
(Partners PrEP)
75% (55; 87)
TDF for HIV
discordant couples
(Partners PrEP)
67% (44; 81)
TDF for young
heterosexuals
(TDF-2)
63% (22; 83)
TDF/FTC for
injecting drug users
(Bangkok TDF)
49% (10; 72)
TDF for MSM and
TW
(iPrEx)
44% (15; 63)
Efficacy
0
10
20
30
40
50
60
70
80
90 100%
Modified from: Abdool Karim SS. Lancet 2013; 381(9883):2060-2.
Dose Response Relationship between
Adherence and PrEP
Reported
Efficacy
Study
FTC/TDF Partners PrEP
Adherence*
75%
HIV Protection
Estimate
90%
81%
TDF Partners PrEP
67%
86%
TDF2
63%
79%
78%
Bangkok TDF
49%
67%
70%
iPrEx
44%
51%
92%
* Based on tenofovir blood levels in non-seroconverters
Modified from Baeten JM, Haberer JE, Liu AY, Sista N. J Acq Defic Synd 2013; 63(Supp 2):S122-9.
Detected Drug in Infected vs.
Uninfected Participants
Drug Detection Rate (%)
100
80
51%
60
44%
P = .77
40
11% 8%
20
P = .001
Months
0
0
>21 15-21 9-15 3-9
0-3 0-3
Pre-HIV Infection
Time Points
3-9 9-15 15-21 >21
Post-HIV Infection
Time Points
Case (seroconverters)
Control (non-seroconverters)
Adherence is an important factor in iPrEX efficacy
- 51% drug detected in non-seroconverters
- HIV infection occurred during periods of low drug exposure
Anderson PL, Glidden DV, Liu A, et al. Sci Transl Med 2012; 4 (151) 151ra125.
Partners PrEP Case-Cohort Analysis
Detection of Tenofovir in Plasma
Cases
(TDF = 17, FTC/TDF = 12)
Visits Prior to
Seroconversion
Cohort
(N = 198)
Seroconversion
Visits
All Visits
TDF arm
35/63
56%
6/17
31%
363/437
83%
FTC/TDF arm
20/36
56%
3/12
25%
375/465
81%
• 82% of visits in cohort who remained HIV uninfected had
detectable levels of drug
• 25-31% of seroconverters had detectable tenofovir at
seroconversion visit
• 56% had detectable tenofovir at earlier visits
Donnell D, et al. 19th CROI 2012: Seattle, WA. Abstract 30.
FEM-PrEP Efficacy: 6%, 95% CI: -52 ̶ 41%
n = 2,120 women;
Kenya, South Africa, Tanzania
Van Damme L, Corneli A, Ahmed K, et al. N Eng J Med 2012; 367(5):411-22.
Efficacy TDF:
-49%, 95% CI: -130 ̶ 3%
FTC/TDF: -4%, 95% CI: -50 ̶ 30%
n = 3,019 women in oral PrEP or placebo,
South Africa, Uganda, Zimbabwe
Marrazzo J, Ramjee G, Nair G, et al. 20th CROI, 2013; Atlanta, GA. Abstract 26LB.
Oral TDF and FTC/TDF PrEP Study
Effect Size
(95% CI)
FTC/TDF for HIV discordant
couples (Partners PrEP)
75% (55; 87)
TDF for HIV discordant
couples
(Partners PrEP)
67% (44; 81)
TDF for young
heterosexuals
(TDF-2)
63% (22; 83)
TDF/FTC for injecting drug
users
(Bangkok TDF)
49% (10; 72)
TDF/FTC for MSM
and TW
(iPrEx)
44% (15; 63)
TDF/FTC for
women
(FEM-PrEP)
6% (-52; 41)
TDF/FTC for
women
(VOICE)
-4% (-49; 27)
TDF for
women
(VOICE)
-49% (-129; 3)
Efficacy
-70 -60 -50 40 -30 -20 -10 0
10
20
30 40 50 60 70 80 90 100%
Modified from: Abdool Karim SS. Lancet 2013; 381(9883):2060-2.
Dose Response Relationship between
Adherence and PrEP
Reported
Efficacy
Study
Adherence*
HIV Protection
Estimate
FTC/TDF Partners PrEP
75%
TDF Partners PrEP
67%
TDF2
63%
79%
78%
Bangkok TDF
49%
67%
70%
iPrEx
44%
51%
92%
FEM-PrEP
6%
35%-38% / 26%
No Protection
FTC/TDF VOICE
-4%
TDF VOICE
-49%
81%
90%
86%
<30%
≈50% never
No Protection
No Protection
* Based on tenofovir levels in non-seroconverters
Modified from Baeten JM, Haberer JE, Liu AY, Sista N. J Acq Defic Synd 2013; 63(Supp 2):S122-9.
Lesson 2
Oral tenofovir-based PrEP works
when taken
Topical HIV PrEP Efficacy Trials
Efficacy: 39%, 95 CI: 6 ̶ 60%
Infections Numbers: 60 – 38 = 22 averted
n = 889 women;
South Africa
Probability of HIV infection
0.20
0.18
Placebo
0.16
0.14
p=0.019
p=0.017
0.12
Tenofovir
Tenofovir
vaginal gel
0.10
0.08
0.06
0.04
0.02
0.00
0.0
Months of follow-up
0.5
6
1.0
12
Years
1.5
18
2.0
24
2.5
30
88
97
98
Cumulative HIV endpoints
37
65
Cumulative women-years
432
833
1143
1305
1341
6.0 vs 11.2
5.2 vs 10.5
5.3 vs 10.2
5.6 vs 9.4
5.6 vs 9.1
47%
(0.069)
50%
(0.007)
47%
(0.004)
40%
(0.013)
39%
(0.017)
(0.019)
HIV incidence rates
(Tenofovir vs Placebo)
Effectiveness
(p-value)
Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Sience 2010; 329(5996):1168-74.
Impact of adherence* on effectiveness of
tenofovir gel
# HIV
N
HIV incidence
TFV
Placebo
Effect
High adherers
(>80% gel adherence)
36
336
4.2
9.3
54%
Intermediate adherers
(50-80% adherence)
20
181
6.3
10.0
38%
Low adherers
(<50% gel adherence)
41
367
6.2
8.6
28%
* Reported adherence
21
Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Sience 2010; 329(5996):1168-74.
Efficacy TFV gel: 15%, 95% CI: -20% ̶ 40%
n = 2,010 women in tenofovir or placebo vaginal gel;
South Africa, Uganda, Zimbabwe
Marrazzo J, Ramjee G, Nair G, et al. 20th CROI, 2013; Atlanta, GA. Abstract 26LB.
Plasma Tenofovir Detection in Random
Cohort Sample
Level of detection
≥ 3 ng/mL
Marrazzo J, Ramjee G, Nair G, et al. 20th CROI, 2013; Atlanta, GA. Abstract 26LB.
Plasma Tenofovir Detection During Study
Participation*
Samples with TFV
detected averaged across
women (mean)
Women with TFV not
detected in any samples
TDF
FTC/TDF
TFV Gel
30%
29%
25%
58%
50%
55%
At routine quarterly visits among participants in the random sample of active arms.
Marrazzo J, Ramjee G, Nair G, et al. 20th CROI, 2013; Atlanta, GA. Abstract 26LB.
Lesson 3
Vaginal tenofovir gel-based PrEP
works when used
Tenofovir-based Rectal Microbicides
for HIV PrEP
RMP-02/MTN-006: Safety, acceptability, PK,
and PD responses to rectal administration of
TFV 1% vaginally-formulated gel and oral TDF
Number of Gastrointestinal
Adverse Events
Proportion of Participants
“Liking the Product”
35
60
30
50
25
40
20
30
15
20
10
5
10
0
0
Mild
Moderate
TFV 1% Gel
Severe
Placebo Gel
Liking the product
TFV 1% Gel
Placebo
Anton PA, Cranston RD, Kashuba A, et al. AIDS Res Hum Retroviruses 2012; 28(11):1412-21.
RMP-02/MTN-006: Safety, acceptability, PK,
and PD responses to rectal administration of
TFV 1% vaginally-formulated gel and oral TDF
• Tissue TFV-DP Concentrations
Cmax 30 min after single rectal
exposure was 6–10 times greater
than TDF exposure
It was 5.7 times greater following
7-day versus single rectal
exposure
• PK–PD correlation with ex vivo
tissue susceptibility to
infection
In vivo exposure correlated ex
vivo tissue susceptibility to
infection
Anton PA, Cranston RD, Kashuba A, et al. AIDS Res Hum Retroviruses 2012; 28(11):1412-21.
MTN-007: Rectal Safety and Acceptability
Study of TFV Reduced-Glycerin 1% Gel
Proportion of Participants with
Gastrointestinal Adverse Events
Likelihood of
Future Product Use
40
100
35
90
80
30
70
25
60
20
50
15
40
10
30
20
5
0
10
TFV gel
Nonoxinol-9
Diarrhea (G1/G2/G3)
Placebo
No treatment
Flatulence (G1/G2)
0
TFV gel
Placebo
Mcgowan I, Hoesley C, Cranston RD, et al. PLoS ONE 8(4): e60147.
MTN-017: Expanded Safety and Acceptability
of oral FTC/TDF and Rectally-Applied TFV
Reduced-Glycerin 1% Gel
Product
Break
(1 week)
Period 2
(8 weeks)
Product
Break
(1 week)
Product
Sequence
Period 1
(8 weeks)
Period 3
(8 weeks)
1
Daily FTC/TDF
Daily rectal gel
Rectal gel before
and after sex
2
Rectal gel before
and after sex
Daily FTC/TDF
Daily rectal gel
3
Daily rectal gel
Rectal gel before
and after sex
Daily FTC/TDF
4
Daily rectal gel
Daily FTC/TDF
Rectal gel before
and after sex
5
Daily FTC/TDF
Rectal gel before
and after sex
Daily rectal gel
6
Rectal gel before
and after sex
Daily Rectal gel
Daily FTC/TDF
Microbicides Trials Network. http://www.mtnstopshiv.org/
Lesson 4
We don´t know much about rectal
tenofovir-based PrEP
PK Predicts that Topical TFV May Have
Greater Efficacy than Oral TDF in Women
Vaginal tenofovir gel achieves ≥130 greater vaginal tissue concentrations
than oral tenofovir (daily dosing)
Hendrix CW, Chen BA, Guddera V, et al. PLoS One. 2013;8(1):e55013.
PK Predicts that Oral
TDF May Be “Fragile”
to Adherence in
Women
Oral tenofovir results in
higher concentrations in
rectal tissue than cervical
and vaginal tissue
TFV
TFV-diphospate
Patterson KB, Prince HA, Kraft E, et al. Sci Transl Med 2011; 3(112):112re4.
Lesson 5
Intensive PK studies were informative
in developing products & interpreting
trial results
Missed Doses Diminish PrEP Efficacy
• Due to lack of adherence and missed visits, PrEP
trial results likely underestimate true efficacy
• Important if missed doses and missed visits are
not at random
– Those who have challenges with monthly visits may
have characteristics that place them at higher HIV risk
– Patterns of adherence may matter if missed doses
occur during periods of higher risk behavior
Adherence Measurements
• Self-report and pill counts clearly
overestimate adherence
• Drug levels in case-cohort analyses are
informative in interpreting efficacy
• Electronic monitoring to capture patterns of
adherence
• Qualitative research to understand risk
perceptions, product acceptability, use
patterns
FEM-PrEP:
Adherence Measurements
Drug
Placebo
Reported
Usually/always took study pill
95%
95%
Reported
Easy/very easy to take pills
97%
96%
Measured
Pills taken
(based on number returned)
86%
89%
26-40%
NA
Measured
Effective drug levels in blood near
time of infection
Van Damme L, et al. 19th CROI 2012: Seattle, WA. Abstract LB32.
Potential ‘Drivers’ of Adherence
• Risk perception may differ in populations
• HIV negative partners in serodiscordant couples
know their risk
• Risk perception in people with partners of
unknown HIV serostatus?
• Adherence may reflect risk perception and
patterns of sexual behavior
• What other factors influence use of product?
Lesson 6
Adherence is the ‘Achilles’ heel:
How to measure? How to motivate?
Summary:
We have learned a lot, and have much to learn
about oral and mucosal tenofovir-based PrEP
1.
2.
3.
4.
Tenofovir-based PrEP works
Oral tenofovir-based PrEP works when taken
Vaginal tenofovir-based PrEP works when used
We don´t know much about rectal tenofovir-based
PrEP.
5. Intensive PK studies were informative in developing
products and interpreting trial results
6. Adherence is the ‘Achilles’ heel for PrEP
• How to measure? How to motivate?
• All biomedical interventions are behavioral
Yet, Much Left to Learn…
• Biology
– Do inflammation, acute infection, & others interfere with PrEP?
– What is the minimum blood/tissue concentration for PrEP
efficacy?
– Safety of oral & topical products in pregnancy and adolescents
– Safety & efficacy of iso-osmolar tenofovir gel in MSM
– PK, adherence & risk behavior with intermittent oral FTC/TDF
dosing
• Behavior
– More detail on adherence and adherence over time in PrEP
trials
– Patterns of adherence and relationship to behavior
– Understanding risk perception in different populations
– Adherence, risk perception, and PrEP use in ‘real world settings’
PrEP at the Cross-Roads:
Moving Forward with Disparate Efficacy Results
• Whether?
• How?
How to Move Forward?
Demonstration Projects, Regulatory Approval,
Normative Guidance and Government Support
• Demonstration Projects
Study
Population (N)
iPrEx Open Label
Extension
MSM and transgender women
(n=2499)
Partners PrEP Study
(post-placebo phase)
CDC 494 / TDF2 Open
Label Extension
Locations
Brazil, Ecuador, Peru,
South Africa,
Thailand, US
Heterosexual men and women
with known HIV infected partners
Kenya, Uganda
(HIV serodiscordant couples)
(N=4747 couples)
Heterosexual men and women
Botswana
(N=1219)
US PrEP Demonstration
Project (Demo Project)
MSM and transgender women in
STD clinic setting (n=500)
US (San Francisco,
Miami, DC)
Partners Demonstration
Project
Heterosexual men and women
with known HIV infected partners
Kenya, Uganda
(HIV serodiscordant couples)
(N=1000 couples)
14 US sites
Timeline
Enrollment began: June 2011
Results expected: 2014
Enrollment began: July 2011
Results expected: 2013
Enrollment began: February 2013
Results expected: 2014
Enrollment began: September 2012
Results expected: 2014
Enrollment began: November 2012
Results expected: 2014/2015
Enrollment began: December 2012
Results expected: Q4 2014
Enrollment began: November 2012
Results expected: November 2015
ATN 110 and 113
Young MSM, ages 15-22 (N=300)
PROUD
Gay men in genito-urinary
medicine clinics (N=500)
CCTG 595
MSM and transgender women
(N=400)
PATH - PrEP
375 MSM and transgender
women (N=375)
US (Los Angeles)
HPTN 073
Black MSM (N=225)
US (Los Angeles,
Washington DC,
Chapel Hill)
Enrollment planned: June 2013
Results expected: December 2015
SCOPE
Female sex workers (N=500)
Kenya
Enrollment planned: June 2013
Results expected: 2014
United Kingdom
US (Long Beach, Los
Angeles, San Diego,
Torrance)
Enrollment planned: Q1-2 2013
Results expected: 2016
Enrollment planned: April 2013
Results expected: 2017
How to Move Forward?
Demonstration Projects, Regulatory Approval,
Normative Guidance and Government Support
• Demonstration Projects
• Normative guidance (e.g., WHO, US CDC)
• Government approvals and support
Whether to Move Forward with PrEP
Efficacy Estimates from 0-75%?
• Remember: efficacy is ≈90% if product is used
• Primary prevention remains essential
• Whether to move forward should not be a
debate
– When we have 2-9% incidence in trial populations
– Nothing else for primary prevention with this high
efficacy
• Priority is to learn about strategic use of
tenofovir-based PrEP
Tenofovir is a First-Generation PrEP Agent:
We Must Move Forward Smartly
Pill
Gel
Vaginal film
Vaginal ring
Injectable
Landmark health research is a process of continued development
We need a choice of strategies to meet different needs
Adherence remains important with less user-dependent strategies (i.e.,
vaginal rings & injectable PrEP)
Strategies to Improve PrEP Delivery and Adherence
Novel adherence
strategies
New PrEP drugs and
dosing strategies
Alternative delivery systems and formulations
Rectal Microbicides:
MTN-017 (TFV rectal gel)
Intra-vaginal rings:
ASPIRE (Dapivirine)
Injectable PrEP:
HPTN 076 (TMC278LA)
Acknowledgements
•
•
•
•
•
•
•
•
•
Jared Baeten
Chris Beyrer
Connie Celum
Ross Cranston
Robert Grant
Kenneth Mayer
Jeanne Marrazzo
Ian McGowan
Jorge Sanchez
• International AIDS Society
•