javier r. lama, md, mph director , hiv prevention intervention studies
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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, MPHDirector, HIV Prevention Intervention Studies
IMPACTA PERU Clinical Trials UnitLima, 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
HYPOTHESISOral 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 avertedn = 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.
Baeten JM, Donnell D, Ndase P, et al. N Eng J Med 2012; 367(5):399-410* Each intervention when compared to placebo
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
TDF-2 StudyEfficacy: 62%, 95% CI: 22 - 83%Infections Numbers: 52 – 17 = 35 avertedn = 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 StudyEfficacy 49%, 95% CI: 10 ̶ 72%Infections Numbers: 33 – 17 = 16 avertedn = 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
0 10 20 30 40 50 60 70 80 90 100%
Efficacy
Effect Size (95% CI)
Oral TDF and FTC/TDF PrEP Study
TDF for young heterosexuals (TDF-2)
63% (22; 83)
FTC/TDF for HIV discordant couples (Partners PrEP)
75% (55; 87)
Modified from: Abdool Karim SS. Lancet 2013; 381(9883):2060-2.
TDF for MSM and TW(iPrEx)
44% (15; 63)
TDF/FTC for injecting drug users(Bangkok TDF)
49% (10; 72)
TDF for HIV discordant couples (Partners PrEP)
67% (44; 81)
Dose Response Relationship between Adherence and PrEP
Study Reported Efficacy Adherence* HIV Protection
Estimate
FTC/TDF Partners PrEP 75%81%
90%
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
Adherence is an important factor in iPrEX efficacy- 51% drug detected in non-seroconverters- HIV infection occurred during periods of low drug exposure
8%
44%
11%
51%P = .77
100
80
60
40
20
00 9-15 0-3 >21
Pre-HIV InfectionTime Points
Drug
Det
ectio
n Ra
te (%
)
3-9 0-3 3-9 9-15 15-2115-21>21
Post-HIV InfectionTime Points
MonthsCase (seroconverters)Control (non-seroconverters)
P = .001
Anderson PL, Glidden DV, Liu A, et al. Sci Transl Med 2012; 4 (151) 151ra125.
Cases(TDF = 17, FTC/TDF = 12)
Cohort(N = 198)
Visits Prior to Seroconversion
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.
Partners PrEP Case-Cohort AnalysisDetection of Tenofovir in Plasma
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.
Marrazzo J, Ramjee G, Nair G, et al. 20th CROI, 2013; Atlanta, GA. Abstract 26LB.
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
Effect Size (95% CI)
Oral TDF and FTC/TDF PrEP Study
0 10 20 30 40 50 60 70 80 90 100%
TDF for young heterosexuals (TDF-2) 63% (22; 83)
FTC/TDF for HIV discordant couples (Partners PrEP)
75% (55; 87)
Modified from: Abdool Karim SS. Lancet 2013; 381(9883):2060-2.
TDF/FTC for MSM and TW(iPrEx)
44% (15; 63)
TDF/FTC for injecting drug users(Bangkok TDF)
49% (10; 72)
TDF for HIV discordant couples (Partners PrEP)
67% (44; 81)
TDF/FTC for women (FEM-PrEP)
6% (-52; 41)
TDF for women (VOICE)
-49% (-129; 3)
TDF/FTC for women(VOICE)
-4% (-49; 27)
-70 -60 -50 40 -30 -20 -10
Efficacy
Dose Response Relationship between Adherence and PrEP
Study Reported Efficacy Adherence* HIV Protection
Estimate
FTC/TDF Partners PrEP 75%81%
90%
TDF Partners PrEP 67% 86%
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% <30%≈50% never
No Protection
TDF VOICE -49% 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 avertedn = 889 women; South Africa
Prob
abili
ty o
f HIV
infe
ctio
n
0.0 0.5 1.0 1.5 2.0 2.5
YearsMonths of follow-up 6 12 18 24 30
Cumulative HIV endpoints 37 65 88 97 98
Cumulative women-years 432 833 1143 1305 1341
HIV incidence rates(Tenofovir vs Placebo) 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
Effectiveness (p-value)
47%(0.069)
50% (0.007)
47% (0.004)
40% (0.013)
39% (0.019)
p=0.019
Tenofovir
Placebo
0.20
0.18
0.16
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
p=0.017
(0.017)
Tenofovir vaginal gel
Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Sience 2010; 329(5996):1168-74.
21
# HIV NHIV incidence
EffectTFV Placebo
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%
Impact of adherence* on effectiveness of tenofovir gel
Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Sience 2010; 329(5996):1168-74.
* Reported adherence
Marrazzo J, Ramjee G, Nair G, et al. 20th CROI, 2013; Atlanta, GA. Abstract 26LB.
Efficacy TFV gel: 15%, 95% CI: -20% ̶ 40% n = 2,010 women in tenofovir or placebo vaginal gel;South Africa, Uganda, Zimbabwe
Plasma Tenofovir Detection in Random Cohort Sample
Marrazzo J, Ramjee G, Nair G, et al. 20th CROI, 2013; Atlanta, GA. Abstract 26LB.
Level of detection ≥ 3 ng/mL
Plasma Tenofovir Detection During Study Participation*
Marrazzo J, Ramjee G, Nair G, et al. 20th CROI, 2013; Atlanta, GA. Abstract 26LB.
TDF FTC/TDF TFV Gel
Samples with TFV detected averaged across women (mean)
30% 29% 25%
Women with TFV not detected in any samples 58% 50% 55%
At routine quarterly visits among participants in the random sample of active arms.
Lesson 3
Vaginal tenofovir gel-based PrEP works when used
Tenofovir-based Rectal Microbicides for HIV PrEP
Mild Moderate Severe0
5
10
15
20
25
30
35
Number of Gastrointestinal Adverse Events
TFV 1% Gel Placebo Gel
Liking the product0
10
20
30
40
50
60
Proportion of Participants “Liking the Product”
TFV 1% Gel Placebo
RMP-02/MTN-006: Safety, acceptability, PK, and PD responses to rectal administration of TFV 1% vaginally-formulated gel and oral TDF
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
Anton PA, Cranston RD, Kashuba A, et al. AIDS Res Hum Retroviruses 2012; 28(11):1412-21.
• Tissue TFV-DP Concentrations Cmax 30 min after single rectal exposure was 6–10 times greater than TDF exposureIt was 5.7 times greater following 7-day versus single rectal exposure
• PK–PD correlation with ex vivo tissue susceptibility to infectionIn vivo exposure correlated ex vivo tissue susceptibility to infection
TFV gel Nonoxinol-9 Placebo No treatment0
5
10
15
20
25
30
35
40
Proportion of Participants with Gastrointestinal Adverse Events
Diarrhea (G1/G2/G3) Flatulence (G1/G2)
Series10
102030405060708090
100
Likelihood ofFuture Product Use
TFV gel Placebo
Mcgowan I, Hoesley C, Cranston RD, et al. PLoS ONE 8(4): e60147.
MTN-007: Rectal Safety and Acceptability Study of TFV Reduced-Glycerin 1% Gel
Product Sequence
Period 1(8 weeks)
Product Break
(1 week)Period 2
(8 weeks)Product Break
(1 week)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
MTN-017: Expanded Safety and Acceptability of oral FTC/TDF and Rectally-Applied TFV Reduced-Glycerin 1% Gel
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
Patterson KB, Prince HA, Kraft E, et al. Sci Transl Med 2011; 3(112):112re4.
Oral tenofovir results in higher concentrations in rectal tissue than cervical and vaginal tissue
TFV
TFV-diphospate
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
Drug Placebo
ReportedUsually/always took study pill 95% 95%
ReportedEasy/very easy to take pills 97% 96%
MeasuredPills taken(based on number returned) 86% 89%
MeasuredEffective drug levels in blood near time of infection 26-40% NA
Van Damme L, et al. 19th CROI 2012: Seattle, WA. Abstract LB32.
FEM-PrEP:Adherence Measurements
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. Tenofovir-based PrEP works2. Oral tenofovir-based PrEP works when taken3. Vaginal tenofovir-based PrEP works when used4. We don´t know much about rectal tenofovir-based
PrEP.5. Intensive PK studies were informative in developing
products and interpreting trial results6. 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) Locations Timeline
iPrEx Open Label Extension
MSM and transgender women (n=2499)
Brazil, Ecuador, Peru, South Africa, Thailand, US
Enrollment began: June 2011Results expected: 2014
Partners PrEP Study (post-placebo phase)
Heterosexual men and women with known HIV infected partners
(HIV serodiscordant couples) (N=4747 couples)
Kenya, Uganda Enrollment began: July 2011Results expected: 2013
CDC 494 / TDF2 Open Label Extension
Heterosexual men and women(N=1219) Botswana Enrollment began: February 2013
Results expected: 2014
US PrEP Demonstration Project (Demo Project)
MSM and transgender women in STD clinic setting (n=500)
US (San Francisco, Miami, DC)
Enrollment began: September 2012Results expected: 2014
Partners Demonstration Project
Heterosexual men and women with known HIV infected partners
(HIV serodiscordant couples) (N=1000 couples)
Kenya, Uganda Enrollment began: November 2012Results expected: 2014/2015
ATN 110 and 113 Young MSM, ages 15-22 (N=300) 14 US sites Enrollment began: December 2012Results expected: Q4 2014
PROUD Gay men in genito-urinary medicine clinics (N=500) United Kingdom Enrollment began: November 2012
Results expected: November 2015
CCTG 595 MSM and transgender women (N=400)
US (Long Beach, Los Angeles, San Diego, Torrance)
Enrollment planned: Q1-2 2013 Results expected: 2016
PATH - PrEP 375 MSM and transgender women (N=375) US (Los Angeles)
Enrollment planned: April 2013 Results expected: 2017
HPTN 073 Black MSM (N=225)US (Los Angeles, Washington DC, Chapel Hill)
Enrollment planned: June 2013Results expected: December 2015
SCOPE Female sex workers (N=500) Kenya Enrollment planned: June 2013Results expected: 2014
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
Gel Vaginal ring
Tenofovir is a First-Generation PrEP Agent:We Must Move Forward Smartly
Vaginal film InjectablePill
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
Intra-vaginal rings:ASPIRE (Dapivirine)
Rectal Microbicides:MTN-017 (TFV rectal gel)
Injectable PrEP:HPTN 076 (TMC278LA)
Novel adherence strategies
Alternative delivery systems and formulations
New PrEP drugs and dosing strategies
Acknowledgements• Jared Baeten• Chris Beyrer• Connie Celum• Ross Cranston• Robert Grant• Kenneth Mayer• Jeanne Marrazzo• Ian McGowan• Jorge Sanchez
• International AIDS Society
•