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

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.

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

“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

“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

Courtesy Robert Grant, 2011

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

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

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

National HIV Behavioral Surveillance System CDC funded, 20+ participating sites 12 month cycles in 3 target populations MSM2 cycle - 2008 Venue-based sampling IDU2 cycle - 2009 Respondent-driven sampling HET2 cycle - 2010 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

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

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.

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

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)

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)

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.

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)

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.

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.

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)

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)

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)

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)

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)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 http://www.cdc.gov/nchhstp/newsroom/PrEPHeterosexuals.html

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

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

UW Partners PrEP Baeten, NELM, 2012

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 http://www.fhi360.org/en/Research/Projects/FEM-PrEP.htm

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

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

Partners decreased NEJM, Nov 23, 2010

Condom use increased NEJM, Nov 23, 2010

More questions than answers

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?

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

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?

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?

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

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

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)

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

Guidance is available (and planned) Formal HHS guidance due 2012 http://www.cdc.gov/hiv/prep/

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

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

Discontinue PrEP Test for HIV Link into care if positive

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

“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 - 2010

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