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 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 HYPOTHESIS Oral 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 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;363:2587-99. 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.

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 Study Efficacy: 62%, 95% CI: 22 - 83% 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

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):2083-90

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

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 0 10 20 30 40 50 60 70 80 90 100% Modified from: Abdool Karim SS. Lancet 2013; 381(9883):2060-2.

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.

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.

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.

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.

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.

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 -70 -60 -50 40 -30 -20 -10 0 10 20 30 40 50 60 70 80 90 100% Modified from: Abdool Karim SS. Lancet 2013; 381(9883):2060-2.

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.

Oral tenofovir-based PrEP works when taken 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 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):1168-74.

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):1168-74.

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.

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.

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.

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

Tenofovir-based Rectal Microbicides for HIV PrEP

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 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):1412-21.

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.

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. http://www.mtnstopshiv.org/

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

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

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.

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?

Adherence is the ‘Achilles’ heel: How to measure? How to motivate? 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 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

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

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 15-22 (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: 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 2013 Results expected: December 2015 SCOPE Female sex workers (N=500) Kenya Enrollment planned: June 2013

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

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

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)

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