1. 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

2. 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

3. 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

4. Oral HIV PrEP Efficacy Trials

5. 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:
The overall modified intention to treat efficacy was 44% including everyone who was enrolled and became infected after enrollment.
90% of infections occurred during the first 2 years of the study observation. The last year of study observation involves relatively few visits and less than 10% of the seroconversions. There is no statistically significant evidence that efficacy changed with longer use.
The overall efficacy includes both those who took the pill and were consistent in returning for visits, and those who did not take the pill or were lost to follow-up for periods of time.

6. 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

7. TDF-2 Study
Efficacy: 62%, 95% CI: % 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

8. 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):

9. Oral tenofovir-based PrEP works
Lesson 1
Oral tenofovir-based PrEP works

10. Effect Size (95% CI) Oral TDF and FTC/TDF PrEP Study Efficacy
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 %
Modified from: Abdool Karim SS. Lancet 2013; 381(9883):

11. 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%
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.

12. Detected Drug in Infected vs. Uninfected Participants
100 80
51%
44% 60
P = .77
Drug Detection Rate (%) 40
11% 8% 20
P = .001
Months
>21
15-21
9-15
3-9
0-3
0-3
3-9
9-15
15-21
>21
Case (seroconverters) Control (non-seroconverters)
Pre-HIV Infection Time Points
Post-HIV Infection Time Points
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.

13. Visits Prior to Seroconversion Seroconversion Visits
Partners PrEP Case-Cohort Analysis Detection of Tenofovir in Plasma
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
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.

14. 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):

15. 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.

16. Effect Size (95% CI) Oral TDF and FTC/TDF PrEP Study Efficacy
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 %
Modified from: Abdool Karim SS. Lancet 2013; 381(9883):

17. 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%
70%
iPrEx
44%
51%
92%
FEM-PrEP 6%
35%-38% / 26%
No Protection
FTC/TDF VOICE
-4%
<30%
≈50% never
TDF VOICE
-49%
* 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.

18. Oral tenofovir-based PrEP works when taken
Lesson 2
Oral tenofovir-based PrEP works when taken

19. Topical HIV PrEP Efficacy Trials

20. Efficacy: 39%, 95 CI: 6 ̶ 60% Infections Numbers: 60 – 38 = 22 averted n = 889 women; South Africa
p=0.017
(0.017)
Tenofovir vaginal gel
Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Sience 2010; 329(5996):

21. Impact of adherence* on effectiveness of tenofovir gel
# HIV N
HIV incidence
Effect
TFV
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%
* Reported adherence
Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Sience 2010; 329(5996):

22. 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.

23. 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.

24. Plasma Tenofovir Detection During Study Participation*
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.
Marrazzo J, Ramjee G, Nair G, et al. 20th CROI, 2013; Atlanta, GA. Abstract 26LB.

25. Vaginal tenofovir gel-based PrEP works when used
Lesson 3
Vaginal tenofovir gel-based PrEP works when used

26. Tenofovir-based Rectal Microbicides for HIV PrEP

27. 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):

28. 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):

29. MTN-007: Rectal Safety and Acceptability Study of TFV Reduced-Glycerin 1% Gel
Mcgowan I, Hoesley C, Cranston RD, et al. PLoS ONE 8(4): e60147.

30. Rectal gel before and after sex
MTN-017: Expanded Safety and Acceptability of oral FTC/TDF and Rectally-Applied TFV Reduced-Glycerin 1% Gel
Product Sequence
Period 1
(8 weeks)
Product Break
(1 week)
Period 2
Period 3 1
Daily FTC/TDF
Daily rectal gel
Rectal gel before and after sex 2 3 4
Daily rectal gel 5 6
Daily Rectal gel
Microbicides Trials Network.

31. We don´t know much about rectal tenofovir-based PrEP
Lesson 4
We don´t know much about rectal tenofovir-based PrEP

32. 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.

33. PK Predicts that Oral TDF May Be “Fragile” to Adherence in Women
TFV
TFV-diphospate
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
Patterson KB, Prince HA, Kraft E, et al. Sci Transl Med 2011; 3(112):112re4.

34. Lesson 5
Intensive PK studies were informative in developing products & interpreting trial results

35. 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

36. 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

37. Adherence Measurements
FEM-PrEP:
Adherence Measurements
Drug
Placebo
Reported
Usually/always took study pill
95%
Easy/very easy to take pills
97%
96%
Measured
Pills taken
(based on number returned)
86%
89%
Effective drug levels in blood near time of infection
26-40% NA
Van Damme L, et al. 19th CROI 2012: Seattle, WA. Abstract LB32.

38. 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?

39. Adherence is the ‘Achilles’ heel: How to measure? How to motivate?
Lesson 6
Adherence is the ‘Achilles’ heel: How to measure? How to motivate?

40. Summary: We have learned a lot, and have much to learn about oral and mucosal tenofovir-based PrEP
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.
Intensive PK studies were informative in developing products and interpreting trial results
Adherence is the ‘Achilles’ heel for PrEP
How to measure? How to motivate?
All biomedical interventions are behavioral

41. 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’

42. PrEP at the Cross-Roads: Moving Forward with Disparate Efficacy Results
Whether?
How?

43. How to Move Forward? Demonstration Projects, Regulatory Approval, Normative Guidance and Government Support
Demonstration Projects

44. iPrEx Open Label Extension MSM and transgender women (n=2499)
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 2011
Results 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 2011
Results expected: 2013
CDC 494 / TDF2 Open Label Extension
Heterosexual men and women
(N=1219)
Botswana
Enrollment began: February 2013
US PrEP Demonstration Project (Demo Project)
MSM and transgender women in STD clinic setting (n=500)
US (San Francisco, Miami, DC)
Enrollment began: September 2012
Partners Demonstration Project
Heterosexual men and women with known HIV infected partners (HIV serodiscordant couples) (N=1000 couples)
Enrollment began: November 2012
Results expected: 2014/2015
ATN 110 and 113
Young MSM, ages (N=300)
14 US sites
Enrollment began: December 2012 Results expected: Q4 2014
PROUD
Gay men in genito-urinary medicine clinics (N=500)
United Kingdom
Results expected: November 2015
CCTG 595
MSM and transgender women (N=400)
US (Long Beach, Los Angeles, San Diego, Torrance)
Enrollment planned: Q
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 2013 Results expected: December 2015
SCOPE
Female sex workers (N=500)
Kenya
Enrollment planned: June 2013

45. 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

46. 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

47. 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) 47

48. 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)
Injectable PrEP:
HPTN 076 (TMC278LA)
Intra-vaginal rings:
ASPIRE (Dapivirine)

49. Acknowledgements Jared Baeten Chris Beyrer Connie Celum Ross Cranston
Robert Grant
Kenneth Mayer
Jeanne Marrazzo
Ian McGowan
Jorge Sanchez
International AIDS Society