1. Pre-exposure Prophylaxis (PrEP): Review of Available Data and Models of Implementation
Mark Thrun, MD
Associate Professor, Division of Infectious Diseases
University of Colorado Denver
Director, HIV/STD Prevention and Control
Denver Public Health

2. Disclosures of Financial Relationships
This speaker has no financial relationships with commercial entities to disclose.
This speaker will not discuss any off-label use or investigational product during the program.
This slide set has been peer-reviewed to ensure that there are no conflicts of interest represented in the presentation.

3. Objectives
Provide an overview of human studies utilizing systemic antiretrovirals (ARVs) as PrEP
Provide evidence of ARV agents used as microbicides as PrEP
Discuss barriers to the implementation of PrEP

4. “No one knows whether PrEP will work
“No one knows whether PrEP will work. Even if it does, it will need to be used in combination with current HIV prevention methods, including safer sex, use of male and female condoms, treatment of sexually transmitted infections, risk reduction counseling, clean needles, and male circumcision. PrEP will never be a silver bullet and will not replace any of these current strategies.” AIDS Vaccine Advocacy Coalition – 2008

5. “No one knows whether PrEP will work
“No one knows whether PrEP will work. Even if it does, it will need to be used in combination with current HIV prevention methods, including safer sex, use of male and female condoms, treatment of sexually transmitted infections, risk reduction counseling, clean needles, and male circumcision. PrEP will never be a silver bullet and will not replace any of these current strategies.” AIDS Vaccine Advocacy Coalition – 2008

6. Courtesy Robert Grant, 2011

8. PrEP for conditions transmitted via sex not new: Medical contraception
Patient with knowledge of impending risk
Seeks out provider recommendation and/or prescription
Opportunity for education
Pregnancy avoidance techniques
Side effects and risks of medication
Risks of pregnancy if non-compliant
Presentation of pregnancy if prophylaxis not efficacious

9. NHBS Survey of MSM re: PrEP
To assess knowledge and attitudes towards PrEP in the prevention of HIV among MSM.
Supplemental PrEP-specific questions were included in the 2008 National HIV Behavioral Surveillance (NHBS) cycle in Denver, CO
Analysis limited to participants who did not report being HIV-positive
Descriptive frequencies presented

10. NHBS Overview
On-going surveillance activities conducted nationally in rotating 12-month cycles in three populations at high risk for HIV
Men who have sex with men (MSM)
Injection drug users (IDU)
High risk heterosexuals (HET)
Standardized core questionnaire across sites and populations (+ optional local questions)
A minimum of 500 persons per metropolitan area interviewed during each cycle
Anonymous and voluntary

11. National HIV Behavioral Surveillance System
CDC funded, 20+ participating sites
12 month cycles in 3 target populations
MSM2 cycle
Venue-based sampling
IDU2 cycle
Respondent-driven sampling
HET2 cycle
Respondent-driven sampling
Formative Research
Key Informant Interviews (N = 10)
Focus Group Interviews (N = 30)
Venue Identification
Formative Research
Key Informant Interviews (N = 10)
Focus Group Interviews (N = 30)
Seed Identification
Formative Research
Key Informant Interviews (N = 10)
Focus Group Interviews (N = 30)
Seed Identification
Surveillance Activities
Anonymous survey (N = 500)
Voluntary and anonymous HIV testing
Surveillance Activities
Anonymous survey (N = 500)
Voluntary and anonymous HIV testing
Surveillance Activities
Anonymous survey (N = 500)
Voluntary and anonymous HIV testing

12. NHBS-MSM2 (2008) Venue-based, time-space sampling
Eligibility criteria:
- Male, at least 18 years of age
- Lives in the participating MSA
- Able to complete the interview in English or Spanish
- Not previously participated in NHBS-MSM2
Interviewer administered survey via handheld ipaq
HIV testing:
- Rapid Oral OraQuick
- Confirmatory Oral OraSure

13. Result of most recent HIV test
NHBS-MSM2
N=612
N (%)
Negative
443 (72.4)
Positive
105 (17.2)
Never obtained results
24 (3.9)
Indeterminate
20 (3.3)
Refused to answer
5 (0.8)
Don’t know
15 (2.5)
Participants who reported being positive did not get the PrEP questions.

14. Race / Ethnicity White, non-Hispanic 315 (62.1) Black, non-Hispanic
NHBS-MSM2
N=507
N (%)
White, non-Hispanic
315 (62.1)
Black, non-Hispanic
19 (3.8)
Hispanic
138 (27.2)
Other*
35 (6.9)
Demographic slides represent people who answered the PrEP questions.
* Asian, Pacific Islander, American Indian, and Alaskan Native

15. Education < High School 200 (39.4) High School 158 (31.2)
NHBS-MSM2
N=507
N (%)
< High School
200 (39.4)
High School
158 (31.2)
> High School
149 (29.4)

16. Age
NHBS-MSM2
N=507
N (%)
18 – 24
93 (18.3)
25 – 34
143 (28.2)
35 – 44
126 (24.9)
45 – 54
88 (17.4)
≥ 55
57 (11.2)

17. PrEP Question Introduction
Scientists are currently doing studies to find new ways of preventing people from becoming infected with HIV. In these studies, people take a pill every day that contains the same medicine that is used to treat people who are infected with HIV. Scientists want to know if taking this medicine will prevent people exposed to HIV from becoming infected with it. They call this method pre-exposure prophylaxis or PrEP.

18. Ever heard of PrEP before today?
NHBS-MSM2
N=507
N (%) No
402 (79.3)
Yes
104 (20.5)
Don’t Know
1 (0.2)

19. Few or no side effects
If studies showed that PrEP has few or no side effects, would you be willing to take PrEP pills every day to try to protect yourself from becoming infected with HIV?
NHBS-MSM2
N=507
N (%) No
177 (34.9)
Yes
322 (63.5)
Don’t Know/Refuse
8 (1.6)
If participant answered no, they skipped to question about reasons why people would not take PrEP.

20. 75% effective No 36 (10.9) Yes 288 (87.3) Don’t Know/Refuse 6 (1.8)
If studies showed that PrEP prevents HIV infection in three quarters or 75% of the people who take it, would you be willing to take PrEP pills every day to try to protect yourself from becoming infected with HIV?
NHBS-MSM2
N=330
N (%) No
36 (10.9)
Yes
288 (87.3)
Don’t Know/Refuse
6 (1.8)
If participant answered no, they skipped to question about reasons why people would not take PrEP.

21. 50% effective No 73 (24.8) Yes 215 (73.1) Don’t Know/Refuse 6 (2.1)
If studies showed that PrEP prevents HIV infection in half or 50% of the people who take it, would you be willing to take PrEP pills every day to try to protect yourself from becoming infected with HIV?
NHBS-MSM2
N=294
N (%) No
73 (24.8)
Yes
215 (73.1)
Don’t Know/Refuse
6 (2.1)

22. Low risk for infection
Please tell me if the following are reasons why you might not consider taking PrEP: Because you think you are at low risk for HIV infection.
NHBS-MSM2
N=507
N (%) No
254 (50.1)
Yes
246 (48.5)
Don’t Know/Refuse
7 (1.4)

23. Consistent condom use
Please tell me if the following are reasons why you might not consider taking PrEP: Because you use condoms consistently
NHBS-MSM2
N=507
N (%) No
275 (54.2)
Yes
226 (44.9)
Don’t Know/Refuse
6 (1.2)

24. Condom use and PrEP
If you were taking PrEP pills every day, would you use condoms less frequently, more frequently, or about as frequently as before?
NHBS-MSM2
N=507
N (%)
Less frequently
50 (9.9)
More frequently
36 (7.1)
About as frequently
410 (80.9)
Don’t Know/Refuse
11 (2.2)

25. Sexual activity and PrEP
If you were taking PrEP pills every day, would you have sex with fewer people, more people, or about the same number of people?
NHBS-MSM2
N=507
N (%)
Fewer people
22 (4.3)
More people
23 (4.5)
Same number
454 (89.6)
Don’t Know/Refuse
8 (1.6)

26. How effective is oral pre-exposure prophylaxis at prevention HIV?
39%
44%
63%
73%
91%
100%

27. iPrEx Males, > 18 years Normal renal and liver function
Sexual risk in the last 6 months
Unprotected anal intercourse with male partner with HIV or HIV unknown male partner
Anal sex with more than 3 males
Exchange sex
New STI
Randomized to placebo or tenofovir/emtricitabine every day

28. In addition to medication
Monthly counseling
Risk behavior
Adherence
Monthly HIV testing
Frequent STD screening

29. Baseline demographics
NEJM, Nov 23, 2010: Courtesy Robert Grant, 2011

30. 44% reduction in incident HIV in treatment versus placebo arm
NEJM, Nov 23, 2010: Courtesy Robert Grant, 2011

31. Self-reported adherence associated with efficacy
Effectiveness
> 90% adherence
73% (41-88%)
> 50% adherence
50% (18-70%)
NEJM, Nov 23, 2010: Courtesy Robert Grant, 2011

32. Detectable drug associated with protection
Participants who remained HIV-negative
Participants who became HIV-positive
% with drug in their blood
54% 8%
NEJM, Nov 23, 2010: Courtesy Robert Grant, 2011

33. PrEP very efficacious….if you can take it
NEJM, Nov 23, 2010: Courtesy Robert Grant, 2011

34. Effective across subgroups
NEJM, Nov 23, 2010: Courtesy Robert Grant, 2011

35. Nausea noted in some in 1st month
NEJM, Nov 23, 2010: Courtesy Robert Grant, 2011

36. Few side effects
NEJM, Nov 23, 2010: Courtesy Robert Grant, 2011

37. Resistance mutations
NEJM, Nov 23, 2010: Courtesy Robert Grant, 2011

38. Vaginal PrEP could rescue HIV transmission by how much?
39%
44%
63%
73%
91%
100%

39. Microbicide Gel - Tenofovir
Caprisa 004 study – double-blind RCT
Tenovovir 1% gel vs. Placebo gel
Gel was used intra-vaginally, peri-coitally – within 12 hours before and 12 hours after sex
Adherence determined as proportion of sexual acts where a pre- and post-dose were administered
About 900 heterosexual women, South Africa
Karim, Science, 2010

40. CDC TDF2
HIV negative partners of HIV-infected persons randomized to TDF/FTC or placebo
599 Placebo: 24 infections
601 TDF/FTC: 9 infections
62.6% reduction in risk
Sub-analysis of those with drug (<30 since last pickup) : 78% reduction in risk

41. Kaplan-Meier time to HIV Infection Placebo 60 infections, Tenofovir 38 infections
55% reduction in good adherers
Karim, Science, 2010

42. UW Partners PrEP
4,758 HIV-negative partners of HIV-infected persons randomized to:
Placebo: 47 infections
TDF: 18 infections – 62% reduction
TDF/FTC: 13 infections – 73% reduction

43. UW Partners PrEP
Baeten, NELM, 2012

44. Fem-PrEP Study of daily oral tenofovir/emtricitabine in women
Enrolled 1,951 women in Kenya, South Africa, Tanzania
Planned stop at 72 end points (HIV infection)
New HIV infections at 5% per year
Study discontinued at 56 endpoints
28 HIV infections each in control and treatment arms
Unlikely to achieve statistical significance

45. Reported condom use decreased in patients on PrEP (in iPrEx) by how much?5%
10%
25%
50%

46. No behavioral disinhibition
NEJM, Nov 23, 2010: Courtesy Robert Grant, 2011

47. Partners decreased
NEJM, Nov 23, 2010

48. Condom use increased
NEJM, Nov 23, 2010

49. More questions than answers

50. Who would be a high-risk person eligible for PrEP?
Risk category?
MSM
Heterosexuals
Injection drug users
Specific risk behaviors?
Multiple partners
Frequent unprotected anal or vaginal intercourse
Race/ethnicity?

51. Once eligibility is defined, how would patients be identified?
Patient self-referral?
Challenge in getting the word out
Marketing directly to patients
Community based organization referral?
CRCS plus PrEP
Provider recommendation?
Do providers ask enough about risk to even know who is at high risk?
Provider bias/attitudinal barriers

52. From what setting would PrEP be prescribed?
Subspecialists
Currently most HIV meds are prescribed by HIV experts comfortable with their use
Many HIV care providers see few patients at risk for HIV
Would HIV experts be willing to take this on?
Primary care
Would likely be the primary clinician caring for persons at risk
Would primary care clinicians be willing to take on this role?
Would the prescribing clinician be comfortable counseling about risk?

53. What about patients not seen in care regularly?
44 million people in the US without health insurance
What is the role of STD clinics – presumptively the location in which many at-risk persons will present?
What is the role of other publicly funded entities? Health departments, etc?

54. Who would pay? Tenofovir retail price for 30 days: $500-600
Would insurance cover cost?
Would identification of high risk place people at risk for losing insurance?
What about those without insurance?
Would this create a two-tiered prevention program?
Those with money vs. those without?
Not dissimilar to nPEP

55. Who performs follow-up?
Initial labs (e.g. Creat, Hep B screening)
Side effect monitoring
Discussion of symptoms
Laboratory monitoring
Discussions of adherence
Potential for seroconversion
How often HIV tested
Is subsequent resistance an issue?
When should therapy end?
Monogamous relationship

56. Who provides ongoing risk behavior counseling?
Will meds result in higher risk behaviors?
Literature from PEP suggests counseling important
Providers reticent to ask detailed questions
Would mandatory risk discussions play a role?
What about those patients that continue to put themselves at risk?
Should they continue to receive PrEP?
Are they the ideal patient for PrEP?
Education about episodic use (T dance, disco dosing)

57. Pre-exposure prophylaxis for HIV
Patient with knowledge of impending risk
Seeks out provider recommendation and/or prescription
Opportunity for education
Disease avoidance techniques
Side effects and risks of medication
Risks of exposure to disease if non-compliant
Presentation of disease if prophylaxis not efficacious

58. Guidance is available (and planned)
Formal HHS guidance due 2012

59. Before PrEP Test for HIV
Test for Acute HIV if any symptoms of primary infection
Confirm ongoing risk
Check creatinine

60. During PrEP HIV test every 3 months Adherence counseling every visit
Risk discussion and counseling every 3 months
STI screening every 6 months
Creatinine/BUN at 3 months and yearly

61. Discontinue PrEP
Test for HIV
Link into care if positive

62. Conclusions
PrEP has enormous potential as a part of our prevention armamentarium
If:
We are able to easily identify those at highest risk
Cost issues are addressed
It is made part of a spectrum of prevention services
Formal HHS guidance will be helpful and pending

63. “As we enter an era that could bring all effective prevention tools, biomedical and behavioral, together in a concerted and integrated way, what’s needed is a behavioral paradigm that encompasses all these interventions and the behaviors that underlie them.”
Kees Rietmeijer

64. Thanks
Dawn Smith – CDC
Robert Grant – UCSF
Alia Al-Tayyib – DPH