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

•