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Javier R. Lama, MD, MPH Director , HIV Prevention Intervention Studies

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.

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Javier R. Lama, MD, MPH Director , HIV Prevention Intervention Studies

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  1. State of the evidence from oral and topical PrEP efficacy trialsWhat 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. RationaleorPrEPfor HIV Prevention • Prophylaxisto reduce therisk of aninfectiousdiseaseiswellestablished • E.g.: Malaria fortravelers • Evidencefor HIV preventionbasedon • Prevention of mothertochildtransmission • Non-human primate studies • Protectionaftermucosalchallenge

  3. TheRightDrug? Tenofovir forPrEP • 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 PrEPEfficacy Trials

  5. Efficacy: 44%, 95 CI: 15 ̶ 63% InfectionsNumbers: 64 – 36 = 28 averted n = 2,499 menwhohave sex withmen and transgenderwomen; Brazil, Ecuador, Peru, South Africa, Thailand, UnitedStates Grant RM, Lama JR, Anderson P, et al. N Engl J Med 2010;363:2587-99.

  6. Efficacy TDF:67%, 95% CI: 44 ̶ 81% FTC/TDF: 75%, 95% CI: 55 ̶ 87%InfectionsNumbers TDF: 52 – 17 = 35 averted* TDF-FTC: 52 – 13 = 39 averted* n = 4,747 heterosexual men and women with HIV infected partners; Kenya, Uganda * Eachinterventionwhencomparedto placebo Baeten JM, Donnell D, Ndase P, et al. N Eng J Med 2012; 367(5):399-410

  7. TDF-2 Study Efficacy: 62%, 95% CI: 22 - 83%InfectionsNumbers: 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%InfectionsNumbers: 33 – 17 = 16 averted n = 2,413 men and womenwhoinjectdrugs; Thailand Choopanya K, Martin M, Suntharasamai P, et al. Lancet 2013; 381(9883):2083-90

  9. Lesson 1 Oral tenofovir-basedPrEPworks

  10. Oral TDF and FTC/TDF PrEPStudy Effect Size (95% CI) 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 for MSM and TW (iPrEx) TDF/FTC for injecting drug users (Bangkok TDF) 44% (15; 63) 49% (10; 72) Efficacy 0 10 20 30 40 50 60 70 80 90 100% Modifiedfrom: Abdool Karim SS. Lancet 2013; 381(9883):2060-2.

  11. Dose Response Relationship between Adherence and PrEP * Based on tenofovir blood levels in non-seroconverters ModifiedfromBaeten JM, Haberer JE, Liu AY, Sista N. J AcqDeficSynd 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 0 Months 0 >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 InfectionTime Points Post-HIV InfectionTime 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. SciTransl Med 2012; 4 (151) 151ra125.

  13. Partners PrEPCase-Cohort AnalysisDetection of Tenofovir in Plasma • 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):411-22.

  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. Oral TDF and FTC/TDF PrEPStudy Effect Size (95% CI) 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 MSM and TW (iPrEx) 44% (15; 63) TDF/FTC for injecting drug users (Bangkok TDF) TDF/FTC for women (FEM-PrEP) TDF/FTC for women (VOICE) TDF for women (VOICE) -4% (-49; 27) 6% (-52; 41) -49% (-129; 3) 49% (10; 72) Efficacy 0 10 20 30 40 50 60 70 80 90 100% -70 -60 -50 40 -30 -20 -10 Modifiedfrom: Abdool Karim SS. Lancet 2013; 381(9883):2060-2.

  17. Dose Response Relationship between Adherence and PrEP * Based on tenofovirlevels in non-seroconverters ModifiedfromBaeten JM, Haberer JE, Liu AY, Sista N. J AcqDeficSynd 2013; 63(Supp 2):S122-9.

  18. Lesson 2 Oral tenofovir-basedPrEPworks whentaken

  19. Topical HIV PrEPEfficacy Trials

  20. Efficacy: 39%, 95 CI: 6 ̶ 60%InfectionsNumbers: 60 – 38 = 22 avertedn = 889 women; South Africa p=0.017 Tenofovir vaginal gel (0.017) Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Sience 2010; 329(5996):1168-74.

  21. Impact of adherence* on effectiveness of tenofovir gel * Reportedadherence Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Sience 2010; 329(5996):1168-74.

  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* At routinequarterlyvisitsamongparticipantsin therandomsample of active arms. Marrazzo J, Ramjee G, Nair G, et al. 20th CROI, 2013; Atlanta, GA. Abstract 26LB.

  25. Lesson 3 Vaginal tenofovir gel-basedPrEPworkswhenused

  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-formulatedgel and oral TDF Anton PA, Cranston RD, Kashuba A, et al.AIDS Res Hum Retroviruses 2012; 28(11):1412-21.

  28. RMP-02/MTN-006: Safety, acceptability, PK, and PD responses to rectal administration of TFV 1% vaginally-formulatedgel and oral TDF • TissueTFV-DP Concentrations Cmax30 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.

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

  30. 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/

  31. Lesson 4 Wedon´tknowmuchabout rectal tenofovir-basedPrEP

  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. PLoSOne. 2013;8(1):e55013.

  33. PK Predicts that Oral TDF May Be “Fragile” to Adherence in Women TFV Oral tenofovir results in higher concentrations in rectal tissue than cervical and vaginal tissue TFV-diphospate • Patterson KB, Prince HA, Kraft E, et al. SciTranslMed 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. FEM-PrEP: Adherence Measurements 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. 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. 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

  45. 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

  46. 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) InjectablePrEP: HPTN 076 (TMC278LA) Intra-vaginal rings: ASPIRE (Dapivirine)

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

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