1. Preparing for PrEP: Answers for LGBT Community–Based Primary Care Practices on Emerging Strategies to Reduce Risk of HIV Acquisition This program is supported by an educational grant from

2. clinicaloptions.com/hiv Preparing for PrEP About These Slides  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. clinicaloptions.com/hiv Preparing for PrEP Faculty Connie Celum, MD, MPH Professor, Department of Medicine University of Washington Seattle, Washington Albert Liu, MD, MPH Director, HIV Prevention Intervention Studies HIV Research Section San Francisco Department of Public Health Assistant Clinical Professor Department of Medicine University of California, San Francisco San Francisco, Californi a Jared M. Baeten, MD, PhD Associate Professor Department of Global Health and Medicine University of Washington Seattle, Washington Susan Buchbinder, MD Director, HIV Research Section San Francisco Department of Public Health Associate Clinical Professor Departments of Medicine, Epidemiology, and Biostatistics University of California, San Francisco San Francisco, California

4. clinicaloptions.com/hiv Preparing for PrEP Disclosures Jared M. Baeten, MD, PhD, has no significant financial relationships to disclose. Susan Buchbinder, MD, has no significant financial relationships to disclose. Connie L. Celum, MD, MPH, has disclosed that she has served on an advisory board for Merck. Albert L. Liu, MD, MPH, has no significant financial relationships to disclose.

5. Pre-Exposure Prophylaxis: Breakthroughs and Challenges

6. PrEP Background

7. clinicaloptions.com/hiv Preparing for PrEP Pre- vs Postexposure Prophylaxis 0 hr 36 hr 72 hr HIV 1 mos3 mos5 mos

8. clinicaloptions.com/hiv Preparing for PrEP Pre- vs Postexposure Prophylaxis HIV infection 0 hr 36 hr 72 hr HIV 1 mos3 mos5 mos

9. clinicaloptions.com/hiv Preparing for PrEP Pre- vs Postexposure Prophylaxis Postexposure prophylaxis HIV infection 0 hr 36 hr 72 hr1 mos3 mos5 mos HIV

10. clinicaloptions.com/hiv Preparing for PrEP Pre- vs Postexposure Prophylaxis Pre-exposure prophylaxis HIV infection 0 hr 36 hr 72 hr1 mos3 mos5 mos HIV

11. clinicaloptions.com/hiv Preparing for PrEP Pre- vs Postexposure Prophylaxis HIV Postexposure prophylaxis 0 hr 36 hr 72 hr1 mos3 mos5 mos HIV

12. clinicaloptions.com/hiv Preparing for PrEP Pre- vs Postexposure Prophylaxis HIV Pre-exposure prophylaxis 0 hr 36 hr 72 hr1 mos3 mos5 mos HIV

13. clinicaloptions.com/hiv Preparing for PrEP TDF and FTC/TDF for PrEP  Among the anti-HIV medications currently available, most data in animal and human trials gained with –Tenofovir (TFV or TDF) –Fixed-dose emtricitabine/tenofovir (FTC/TDF)

14. Breakthroughs in PrEP

15. clinicaloptions.com/hiv Preparing for PrEP Pre-Exposure Prophylaxis Initiative (iPrEx): Fully Enrolled as of December 2009 Lima Iquitos Guayaquil Sao Paulo Rio de Janeiro Boston San Francisco Cape Town Chiang Mai Sites11 Participants2499 Grant RM, et al. N Engl J Med. 2010;363:2587-2599 Grant R, et al. CROI 2011. Abstract 92. 56% 15% 12% 9% 5% 4%.

16. clinicaloptions.com/hiv Preparing for PrEP iPrEx: Eligibility  Male sex at birth  18 yrs of age or older  HIV-seronegative status  Evidence of risk for acquisition of HIV infection Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

17. clinicaloptions.com/hiv Preparing for PrEP iPrEx: Baseline Demographics Characteristic, % Overall (N = 2499) Age  Younger than 25 yrs 50  25-39 yrs 40  40 yrs or older 10 Completed some college 43 Race  White 17  Black 9  Asian 5  Mixed/other 69  Latino 72 Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

18. clinicaloptions.com/hiv Preparing for PrEP iPrEx: Baseline Risk Characteristics Risk CharacteristicOverall (N = 2499) Mean number of sex partners in past 12 wks18 Unprotected anal sex with partner with positive/unknown HIV status in past 6 mos, % 80 Transactional sex in past 6 mos, %41 HIV-positive sexual partner in past 6 mos, %2 Self-reported STD in past 6 mos, %25 Syphilis seropositivity, %13 HSV-2 seropositivity, %36 Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

19. clinicaloptions.com/hiv Preparing for PrEP iPrEx: Enrollment and Follow-up 4905 screened 1251 (50%) FTC/TDF 1248 (50%) placebo 2 HIV infections8 HIV infections 48 HIV infections 83 HIV infections Before PrEP During PrEP 4 HIV infections 2 HIV infections After PrEP 54 HIV infections 93 HIV infections Total infections 2499 enrolled Grant R, et al. CROI 2011. Abstract 92.

20. clinicaloptions.com/hiv Preparing for PrEP iPrEx: Efficacy  Efficacy through study end (mITT): 42% (95% CI: 18% to 60%) P =.002 Placebo FTC/TDF Cumulative Probability of HIV Infection 0.12 0.10 0.08 0.06 0.04 0.02 0 14401224364860728496108120132 Wks Since Randomization Pts at Risk, n Placebo FTC/TDF 12481198115711199327866385284333442391030106 12511190114911099398086515234193452531034116 Grant R, et al. CROI 2011. Abstract 92.

21. Challenges of PrEP

22. Drug Resistance

23. clinicaloptions.com/hiv Preparing for PrEP iPrEx: Breakthrough Infections and Resistance  New HIV infections (91 samples tested) [1] –No drug resistance in participants on FTC/TDF –2 with minor variant drug resistance on placebo (1 to TDF, 1 to FTC)  HIV infections already present at enrollment –2 cases of FTC resistance in FTC/TDF arm [2] –Resistance dropped to undetectable levels within 6 mos after stopping PrEP [1] 1. Liegler T, et al. CROI 2011. Abstract 97LB. 2. Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

24. Safety and Tolerability

25. clinicaloptions.com/hiv Preparing for PrEP iPrEx: Adverse Events Adverse EventFTC/TDF (n = 1251) Placebo (n = 1248) P Value %Events% Any grade 3/4 event 1224813285.51 Death < 11 4.18 Serious adverse event 576587.57 Elevated creatinine 228115.08 Creatinine elevation confirmed on next visit 0.47.000.06 Grant R, et al. CROI 2011. Abstract 92.

26. clinicaloptions.com/hiv Preparing for PrEP iPrEx: Percent BMD Change From Baseline Spine (L1-L4)Total Hip Mean, SE, and P values by linear mixed model. Mulligan K, et al. CROI 2011. Abstract 94LB. Graphics used with permission. 1.2 0.9 0.6 0.3 0.0 -0.3 -0.6 -0.9 -1.2 0244872 Wk FTC/TDF Placebo P =.001P =.143P =.049 FTC/TDF Placebo %% 1.2 0.9 0.6 0.3 0.0 -0.3 -0.6 -0.9 -1.2 0244872 Wk P <.001 P =.002P =.540 24719912459 25620312459 Placebo FTC/TDF 24719912459 25620212559 Pts at Risk, n

27. clinicaloptions.com/hiv Preparing for PrEP Fracture Rates  BMD changes with TDF or FTC/TDF were small; no evidence of negative effect on health  No differences in fracture rates between groups [1-3]  All fractures were trauma related  Need longer follow-up to evaluate effects on bone density and fracture risk over time 1. Grohskopf L, et al. AIDS 2010. Abstract FRLBC102. 2. Mulligan K, et al. CROI 2011. Abstract 94LB. 3. Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

28. clinicaloptions.com/hiv Preparing for PrEP iPrEx: Nausea on History Grant RM, et al. N Engl J Med. 2010;363:2587-2599. Placebo FTC/TDF 12 10 8 6 4 2 0 Patients Reporting Nausea (%) 96012243648607284 Wks Since Randomization

29. clinicaloptions.com/hiv Preparing for PrEP iPrEx: Weight Gain Placebo FTC/TDF 4 3 2 1 0 Patients Reporting Weight Gain (%) 96012243648607284 Wks Since Randomization Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

30. Adherence

31. clinicaloptions.com/hiv Preparing for PrEP Grant R, et al. CROI 2011. Abstract 92 95% CI Efficacy FTC/TDF Placebo Incidence/100 Patient-Yrs 7 6 5 4 3 2 1 0 < 50%50% to 90%> 90% -54% to 54% 16% -20% to 64% 34% 36% to 84% 68% Recorded Adherence (Pill Use) and Efficacy iPrEx: Recorded Adherence and Efficacy

32. clinicaloptions.com/hiv Preparing for PrEP iPrEx: Drug Levels by HIV Status in FTC/TDF Group TDF Diphosphate Level (pmol/10 6 cells) 2/34 Detectable 100 75 50 25 0 21/42 Detectable Case (HIV Positive) Control (HIV Negative) Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

33. clinicaloptions.com/hiv Preparing for PrEP Correlates of Drug Detectability  179 samples from 7 sites (2 US, 4 South America, 1 South Africa) were evaluated after Wk 24 visit  Overall detection rate –TFV-DP: 50% –FTC-TP: 62% Anderson P, et al. CROI 2011. Abstract. 96LB. Parameter nDrug Detected, % US vs non-US  US 3497  Non-US 14550 Age  ≥ 25 yrs 10173  < 25 yrs 7844 Recent reported sex  URAI 4976  Sex, not URAI 10759  No sex 2335

34. Risk Behavior

35. clinicaloptions.com/hiv Preparing for PrEP iPrEx: Numbers of Sexual Partners Grant R, et al. CROI 2011. Abstract 92.. Placebo, mean partners FTC/TDF, mean partners 20 15 10 5 0 Sexual Partners in Previous 12 Wks (n) 96012243648607284 Placebo, median partners FTC/TDF, median partners Wks Since Randomization

36. clinicaloptions.com/hiv Preparing for PrEP iPrEx: Condom Use With High-Risk Sex Placebo FTC/TDF 100 80 60 40 0 Receptive Intercourse Using Condoms (% of Partners) 13201260728496108120 Wks Since Randomization 20 243248 Grant R, et al. CROI 2011. Abstract 92.

37. clinicaloptions.com/hiv Preparing for PrEP Potential for Risk Compensation  Internet survey, December 2010; N = 662 7% 6% 76% 10% Given that the daily PrEP pill is 44% effective in preventing HIV, how would this affect your use of condoms if you were taking the pill? Use condoms less frequently Use condoms more frequently No change condom use Would not use the pill Buchbinder S, et al. HIV Research Section, San Francisco Dept of Public Health, unpublished data; 2010.

38. clinicaloptions.com/hiv Preparing for PrEP  Almost 70% reported they would likely use PrEP if it were ≥ 80% effective in preventing HIV –> 35% of these reported likelihood of decreased condom use while on PrEP Golub SA, et al. J Acquir Immune Defic Syndr. 2010;54:548-555. PrEP and Predicted Condom Use Among High-Risk MSM

39. clinicaloptions.com/hiv Preparing for PrEP A Perspective on “Risk Compensation”  Effect of 90% male circumcision ± 30% risk reduction Hallett TB, et al. PLoS One. 2008;3:e2212.. No intervention Circumcision intervention only Reductions in risk behavior Reductions in risk behavior + circumcision Intervention Incidence Rate (per 100 Yrs) 2.0 1.5 1.0 0.5 0

40. clinicaloptions.com/hiv Preparing for PrEP Limitations of Current Data  Only ~ 10% of iPrEx population from the US –Arguably, prevention benefit should not differ by geography  Long-term adherence and adherence at time of HIV exposure unknown (in those who became infected)  Long-term health effects of FTC/TDF in HIV negative and HIV seroconverters unknown  Adherence, risk behavior, PrEP interest likely to be different now that results are known compared with clinical trial population CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68. Grant RM. N Engl J Med. 2010;363:2587-2599.

41. clinicaloptions.com/hiv Preparing for PrEP iPrEx OLE: Open-Label Extension  Participants in iPrEx offered 18-mo study extension  All offered condoms, counseling, STI monitoring, linkage to services –HIV positives followed for clinical progression –HIV negatives offered open-label FTC/TDF –Can take immediately, within 48 wks, or not at all  For all HIV negatives –Monthly visits x 3 mos (at enrollment and when initiating PrEP) –Quarterly visits for HIV testing, clinical monitoring http://iprexole.com/1pages/aboutus/aboutus-whatisiprexole.php.

42. clinicaloptions.com/hiv Preparing for PrEP iPrEx OLE Objectives  When provided open-label FTC/TDF with known efficacy...  Primary objectives –Changes in pill taking and drug exposure –Changes in risk behavior –Extended safety  Secondary objectives –Seroconversion rate –Effects on clinical progression in HIV positives, including resistance –Provide posttrial access http://iprexole.com/1pages/aboutus/aboutus-whatisiprexole.php.

43. clinicaloptions.com/hiv Preparing for PrEP iPrEx OLE Ancillary Studies  Methods of measuring drug exposure –Hair  Methods of assessing risk –Different types of questionnaires  Pilot counseling strategies –Nonjudgmental “next step” counseling –SMS text messaging for adherence  Methods to monitor and improve safety –Home HIV testing –Longer-term DEXA data http://iprexole.com/1pages/aboutus/aboutus-whatisiprexole.php.

44. Other Studies of ART for Prevention

45. Treatment of HIV-Infected Persons for Prevention of Transmission

46. clinicaloptions.com/hiv Preparing for PrEP HPTN 052: Immediate vs Delayed ART for HIV Prevention in Serodiscordant Couples Cohen MS, et al. N Engl J Med. 2011;365: 493-505.. Immediate HAART Initiate HAART at CD4+ cell count 350-550 cells/mm 3 (n = 886 couples) Delayed HAART Initiate HAART at CD4+ cell count ≤ 250 cells/mm 3 * (n = 877 couples) HIV-infected, sexually active serodiscordant couples; CD4+ cell count of the infected partner: 350-550 cells/mm 3 (N = 1763 couples) *Based on 2 consecutive values ≤ 250 cells/mm 3.  Primary efficacy endpoint: virologically linked HIV transmission  Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe bacterial infection and/or death  Couples received intensive counseling on risk reduction and use of condoms DSMB recommended release of results as soon as possible following April 28, 2011, review; follow-up continues but all HIV-infected partners offered ART after release of results

47. clinicaloptions.com/hiv Preparing for PrEP HPTN 052: HIV Transmission Reduced by 96% in Serodiscordant Couples Single transmission in patient in immediate HAART arm believed to have occurred close to time therapy began and prior to suppression of genital tract HIV Total HIV-1 Transmission Events: 39 (4 in immediate arm and 35 in delayed arm; P <.0001) Linked Transmissions: 28 Unlinked or TBD Transmissions: 11 P <.001 Immediate Arm: 1 Delayed Arm: 27 Cohen MS, et al. N Engl J Med. 2011;365: 493-505..

48. clinicaloptions.com/hiv Preparing for PrEP HPTN 052: Multivariate Analysis of Factors Associated With Linked Transmissions VariableHR95% CI Treatment, immediate vs delayed0.040.01-0.28 Baseline CD4+ count, per 100 cells/mm 3 increment1.241.00-1.54 Baseline HIV-1 RNA, per 1 log 10 copies/mL increment 2.851.51-5.41 Baseline condom use, 100% vs < 100%0.330.12-0.91 Sex of infected partner, male vs female0.730.33-1.65 Cohen MS, et al. N Engl J Med. 2011;365: 493-505..

49. clinicaloptions.com/hiv Preparing for PrEP HPTN 052: Analysis of Primary Clinical Events During Follow-up  41% reduction in HIV-related clinical events in HIV-infected patients randomized to immediate vs delayed therapy –Excess events in delayed arm driven mainly by TB (33 vs 17 cases), particularly extrapulmonary TB (17 vs 3 cases) (P =.002) Failure Probability 0.00 0.10 0.15 0.20 0.25 Years Since Randomization 012345 0.05 HR: 0.59, 95% CI: 0.40-0.88 Delayed Immediate 873 880 697 698 316 331 85 84 31 35 24 28 Number at risk Cohen MS, et al. N Engl J Med. 2011;365: 493-505..

50. clinicaloptions.com/hiv Preparing for PrEP What Do These Results Mean for Others?  Likely that ART prevents transmission in others, although –Only 2 couples from US in HPTN 052 –Other routes of transmission (needles, anal intercourse) and clades (HIV subtypes) may have different transmission biology –No protection for outside partnerships (28% of infections)  Larger problems –HIV testing (in US, 21% HIV-positive people unaware of status) [1] –Access to treatment (estimated < 20% US HIV-positive people have undetectable HIV-1 RNA) [2] –Willingness of asymptomatic patients to take ART; long-term adherence 1. HIV in the United States. CDC Web site.. 2. Gardner EM, et al. Clin Infect Dis. 2011;52:793-800.

51. Other PrEP Trials

52. clinicaloptions.com/hiv Preparing for PrEP Ongoing PrEP Trials Global Advocacy for HIV Prevention..

53. clinicaloptions.com/hiv Preparing for PrEP CAPRISA 004: 1% TFV Vaginal Gel for Prevention of HIV in Women  Randomized, placebo-controlled, double-blind, proof-of-concept study conducted at 2 sites in South Africa 1% Tenofovir Gel* (n = 445) Placebo Gel* (n = 444) HIV-uninfected women, at high risk of HIV, ≥ 2 vaginal sex acts within 30 days of screening (N = 889) *Gel applied using “BAT 24” regimen: 1 gel dose up to 12 hrs before sex; 1 gel dose as soon after sex as possible within 12 hrs after sex; maximum of 2 doses to be used within 24-hr period. Study continued until 92 HIV infections observed Abdool Karim, Q, et al. Science. 2010;329:1168-1174. Abdool Karim Q, et al. AIDS 2010. Abstract TUSS0202.

54. clinicaloptions.com/hiv Preparing for PrEP Mos of Follow-up612182430 Cumulative HIV endpoints3765889798 Cumulative women-yrs432833114313051341 HIV incidence rates (TDF vs placebo) 6.0 vs 11.25.2 vs 10.55.3 vs 10.25.6 vs 10.25.6 vs 9.1 Effectiveness, % (P value) 47 (.064) 50 (.007) 47 (.004) 40 (.013) 39 (.017) HIV Incidence in CAPRISA 004  No K65R resistance mutations among seroconverters Abdool Karim, Q, et al. Science. 2010;329:1168-1174. 0.20 0.18 0.16 0.14 0.12 0.10 0.08 0.06 0.04 0.02 0 Probability of Infection Placebo TDF P =.017

55. clinicaloptions.com/hiv Preparing for PrEP CAPRISA: Impact of Adherence on Effectiveness of 1% TFV Vaginal Gel Adherence GroupHIV Infections, n HIV Incidence Effect, % TFVPlacebo High (> 80% adherence) (n = 336) 364.29.354 Intermediate (50% to 80% adherence) (n = 181) 206.310.038 Low (< 50% adherence) (n = 367) 416.28.628 Abdool Karim, Q, et al. Science. 2010;329:1168-1174.

56. clinicaloptions.com/hiv Preparing for PrEP Partners PrEP: TDF vs TDF/FTC vs Placebo in HIV-Serodiscordant Couples Baeten J, et al. IAS 2011. Abstract MOAX0106. HIV-negative partners in HIV-serodiscordant heterosexual couples (N = 4747) Oral Tenofovir QD (n = 1584) Oral Tenofovir/Emtricitabine QD (n = 1579) Oral Placebo* (n = 1584) *Placebo arm terminated early on July 10, 2011, by data and safety monitoring board. Follow-up: 36 mos

57. clinicaloptions.com/hiv Preparing for PrEP Partners PrEP: Both PrEP Strategies Significantly Reduce HIV Acquisition  Both PrEP strategies associated with significant reduction in HIV transmission vs placebo in both men and women –TDF efficacy: 68% in women, 55% in men –TDF/FTC efficacy: 62% in women, 83% in men Baeten J, et al. IAS 2011. Abstract MOAX0106. Primary Efficacy Outcome, mITT Analysis TDF (n = 1584) TDF/FTC (n = 1579) Placebo (n = 1584) HIV acquisitions, n181347 HIV incidence/100 PY0.740.531.92 Efficacy vs placebo, % (95% CI) 62 (34-78) 73 (49-85) --  P value.0003<.0001--

58. clinicaloptions.com/hiv Preparing for PrEP Partners PrEP: Other Outcomes  Rates of death, serious adverse events, laboratory events low and not significantly different between arms –Mild GI effects, primarily during Mo 1  No significant difference in pregnancy rates between treatment arms  Reported unprotected sexual behavior decreased on study, with similar decline observed across arms –One third of participants in each arm reported sex outside relationship Baeten J, et al. IAS 2011. Abstract MOAX0106.

59. clinicaloptions.com/hiv Preparing for PrEP TDF2: PrEP With TDF/FTC in HIV-Negative Heterosexuals in Botswana Thigpen MC, et al. IAS 2011. Abstract WELBC01. Oral Tenofovir/Emtricitabine (n = 601) Oral Placebo (n = 599) HIV-uninfected adults, heterosexually active, aged 18-39 yrs (N =1219)* ≥ 12-mo follow-up *n = 19 patients excluded for failure to start study medication or HIV infection.

60. clinicaloptions.com/hiv Preparing for PrEP TDF2: PrEP With TDF/FTC Significantly Reduces HIV Acquisition Thigpen MC, et al. IAS 2011. Abstract WELBC01.  9 vs 24 patients seroconverted in TDF/FTC vs placebo arms, respectively  Overall protective efficacy of TDF/FTC: 62.6% (95% CI: 21.5-83.4; P =.0133) Failure Probability 0.02 0.04 0 0.06 0.08 0123 Yrs TDF/FTC Placebo 0.10 Time to Seroconversion (ITT Analysis)

61. clinicaloptions.com/hiv Preparing for PrEP TDF2: Other Outcomes Thigpen MC, et al. IAS 2011. Abstract WELBC01.  Reduction in HIV acquisition with TDF/FTC observed in both men and women –Study underpowered to demonstrate sex-based differences in outcomes  Medication adherence (pill count) not significantly different between arms

62. clinicaloptions.com/hiv Preparing for PrEP Disappointing Results of PrEP in Women: FEM-PrEP and VOICE  FEM-PrEP: Phase III study of oral TDF/FTC planned for 3900 high-risk women in Africa (1951 enrolled) –Announced April 18, 2011, that study was ended prematurely because of lack of efficacy –56 new infections, evenly divided between arms  VOICE: Phase IIB placebo-controlled trial of > 5000 women in South Africa, Uganda, and Zimbabwe –Daily oral TDF; daily oral TDF/FTC; daily vaginal TFV 1% gel  DSMB stopped the daily oral TDF arm in September 2011 for lack of efficacy –Other arms continue These data are available in press release format only, have not been peer reviewed, may be incomplete, and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data.

63. clinicaloptions.com/hiv Preparing for PrEP Questions  Why differences between these study and the other TDF- based studies? –Penetration of drug in vaginal tissue? (But promising data on oral PrEP in women in Partners [TDF and TDF/FTC] and TDF2 [TDF] trials) –Adherence? –Degree of exposure?

64. clinicaloptions.com/hiv Preparing for PrEP Ongoing Studies  Phase I-III: safety and efficacy –In different populations: serodiscordant couples, high-risk women, IDUs –Comparing oral TDF and FTC/TDF; TFV vaginal gel –Intermittent use: scheduled and coital –Newer agents: rilpivirine long-acting IM injections  Open label –Impact of taking PrEP on pill taking, risk practices –Extended safety information

65. Concluding Thoughts

66. clinicaloptions.com/hiv Preparing for PrEP “Treatment... costs are unsustainable. Greater emphasis must be placed on preventing new infections.” – Institute of Medicine Report Brief, November 2010 Institute of Medicine of the National Academies. Preparing for the future of HIV/AIDS in Africa: a shared responsibility. November 29, 2010.

67. clinicaloptions.com/hiv Preparing for PrEP United States, 1968-1976 Reductions in Death From Heart Disease  Age-adjusted mortality from CHD fell by 50% in US from 1980-2000 –~ 1/2 from risk factor reduction –~ 1/2 from treatment Ford ES, et al. N Engl J Med. 2007;356:2388-2398. TreatmentsRisk factorsUnexplained 050100 Decrease in Deaths (%) New Zealand, 1974-1981 The Netherlands, 1978-195 United States, 1980-1990 IMPACT Scotland, 1975-1994 IMPACT New Zealand, 1982-1993 IMPACT England and Wales, 1981-2000 IMPACT United States, 1980-2000 (our study) Finland, 1972-1992 IMPACT Finland, 1982-1997 40546 4060 464410 43507 355510 35605 385210 47449 2476 23 53 24

68. clinicaloptions.com/hiv Preparing for PrEP How Medical Breakthroughs Happen The Leukemia & Lymphoma Society. Facts 2010-2011. 90 80 70 50 40 30 20 0 Survival Rates (%) 5-Yr Relative Survival Rates for Acute Lymphocytic Leukemia in Children Younger Than 15 Yrs of Age, Diagnosed 1964-2006 60 10 3% 58% 66% 71% 73% 78% 83% 84% 87% 89%* Yrs 1964 1975-771978-801981-831984-861987-891990-921993-951996-981999-06 *The difference in rates between 1975-1977 and 1999-2006 is statistically significant (P <.05). 100

69. Pre-Exposure Prophylaxis: Practical Guidance for Prescribers

70. The Data and the Need

71. clinicaloptions.com/hiv Preparing for PrEP HIV Diagnoses Among Adult/Adolescent Males by Transmission Group: 2006-2009  40 states and 5 US dependent areas CDC. HIV surveillance in men who have sex with men (MSM). 2011. Male-to-male sexual contact Heterosexual contact* Other † Injection drug use Yr of Diagnosis 2006200720082009 0 5000 10,000 15,000 20,000 25,000 Diagnoses (n) *Heterosexual contact with a person known to have or to be at high risk for HIV infection. † Includes hemophilia, blood transfusion, perinatal exposure, and risk factor not reported or identified. Note: Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been statistically adjusted to account for reporting delays and missing risk-factor information but not for incomplete reporting. Male-to-male sexual contact and injection drug use

72. clinicaloptions.com/hiv Preparing for PrEP HIV Diagnoses Among Adult/Adolescent MSM by Age Group: 2006-2009  40 states and 5 US-dependent areas 35-44 25-34 45-54  55 Yr of Diagnosis 2006200720082009 0 1000 3000 4000 6000 7000 Diagnoses (n) 13-24 5000 2000 CDC. HIV surveillance in men who have sex with men (MSM). 2011 Note: Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been statistically adjusted to account for reporting delays and missing risk-factor information but not for incomplete reporting.

73. clinicaloptions.com/hiv Preparing for PrEP HIV Diagnoses Among MSM 13-24 Yrs by Race: 2006-2009  40 states and 5 US-dependent areas Hispanic/Latino* 2006200720082009 0 500 1500 2000 3000 3500 2500 1000 American Indian/Alaska Native White Black Multiple races Asian Native Hawaiian/Other Pacific Islander *Hispanics/Latinos can be of any race. Note: Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been statistically adjusted to account for reporting delays and missing risk-factor information but not for incomplete reporting. Data exclude men who reported sexual contact with other men and injection drug use. CDC. HIV surveillance in men who have sex with men (MSM). 2011. Diagnoses (n) Yr of Diagnosis

74. Are We Ready to Give PrEP to Men in the United States?

75. clinicaloptions.com/hiv Preparing for PrEP Some Say We Should, Some Say We Should Not, and Experience Is Limited  Are the clinical trial data sufficient (and sufficiently real world) to implement?  Will risk behaviors change and will that undermine PrEP prevention benefits?

76. clinicaloptions.com/hiv Preparing for PrEP  Note: This is interim guidance  CDC and other USPHS agencies are developing formal guidelines for the use of PrEP by MSM in the US –Projected publication: late 2011  Additional guidance for other populations will become available as data from newer studies are more fully analyzed CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68.

77. clinicaloptions.com/hiv Preparing for PrEP Goals of CDC Interim PrEP Guidance  CDC interim guidance released to reinforce: –TDF/FTC is the only proven effective PrEP regimen for MSM –Daily dosing of PrEP is the only proven effective regimen –Intermittent use efficacy unknown –PrEP efficacy was demonstrated with HIV testing and other prevention services –Until analyses complete from other PrEP trials, PrEP recommended only for MSM populations CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68.

78. clinicaloptions.com/hiv Preparing for PrEP Before Initiating PrEP: Risk Assessment  Remember, if you don’t ask, they [often] won’t tell

79. clinicaloptions.com/hiv Preparing for PrEP Before Initiating PrEP: Risk Assessment  Guidance applies only to MSM  Components of CDC behavioral risk assessment –Risk-reduction measures (eg, condoms) not used or used consistently –Risk for HIV acquisition is high –Frequent partner changes –Partners with HIV-positive or unknown HIV status –Geographic setting with high HIV prevalence CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68.

80. clinicaloptions.com/hiv Preparing for PrEP Will Men Be Interested in PrEP?  After yrs of telling men not to get HIV because the medications are awful –Messaging about safety and tolerability of FTC/TDF is important –Helping men decide whether they would likely benefit from PrEP is essential

81. clinicaloptions.com/hiv Preparing for PrEP CDC: PrEP Eligibility  HIV uninfected –Antibody negative, immediately before starting PrEP –If patient has symptoms consistent with acute HIV infection, either wait for 1 mo and confirm HIV negative and/or test for acute HIV infection  Adequate renal function –Creatinine clearance ≥ 60 mL/min (Cockcroft-Gault)  Additional recommended actions –Screen for hepatitis B infection –If HBV uninfected and susceptible → vaccine (MSM in United States should be vaccinated against HBV) –If HBV infected, treat for HBV (potentially with FTC/TDF) –Screen and treat STDs CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68.

82. clinicaloptions.com/hiv Preparing for PrEP Prescribing PrEP  Coformulated FTC 200 mg/TDF 300 mg, 1 tablet daily  No more than 90-day supply  Renewable only if HIV testing confirms the patient remains HIV uninfected –Anticipate, at minimum, quarterly HIV testing CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68. Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

83. clinicaloptions.com/hiv Preparing for PrEP Counseling  Continued behavioral risk reduction  Importance of PrEP adherence –No data on intermittent, “event-driven” use  Adverse events –Very well tolerated and safe –May experience mild nausea in first few wks

84. clinicaloptions.com/hiv Preparing for PrEP Follow-up  HIV testing –Every 2-3 mos; document negative result  Evaluate and support adherence  Continued risk-reduction counseling –Assess for STD symptoms at each visit –Screen asymptomatic patients every 6 mos  Renal safety –Test creatinine after 3 mos on PrEP and annually thereafter CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68.

85. clinicaloptions.com/hiv Preparing for PrEP Discontinuing PrEP  HIV testing –If HIV positive, stop PrEP –Resistance testing –Establish linkage to HIV care –If HIV negative, risk-reduction support services  If person has chronic hepatitis B infection –Check liver function tests (case reports of hepatitis flares after discontinuing FTC/TDF) CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68.

86. clinicaloptions.com/hiv Preparing for PrEP PrEP Safety  PrEP with FTC/TDF or any other medication currently has no label indication –FTC/TDF manufacturer is pursuing a label change with the FDA  Serious adverse events –Should be reported to the FDA’s MedWatch (www.fda.gov/safety/medwatch)www.fda.gov/safety/medwatch CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68.

87. clinicaloptions.com/hiv Preparing for PrEP PrEP Reimbursement  Public or private insurance may or may not cover the costs associated with PrEP –ADAP funds cannot be used to pay for PrEP  CDC is working with insurance companies about payment –Encouraging response; awaiting decisions

88. clinicaloptions.com/hiv Preparing for PrEP Unknowns  Populations in which PrEP can be used effectively and safely –Long-term toxicity in HIV-negative person unknown  Adherence –Long term –Intermittent use  Resistance –Longer time between HIV tests –Persistence and spread of resistant virus, if occurs  Behavior –How much will behavior change if PrEP is partially protective? –How much will that reduce efficacy?

89. clinicaloptions.com/hiv Preparing for PrEP  Daily FTC/TDF shown to have moderate efficacy for HIV-1 prevention among MSM –High efficacy among those with high adherence –PrEP is a promising HIV prevention strategy for MSM  Daily TDF and FTC/TDF safe and efficacious among heterosexual couples and young heterosexuals  Additional data forthcoming on daily tenofovir gel, oral FTC/TDF in women, and TDF in IDUs  CDC and WHO guidelines forthcoming  Providers should be prepared to do risk assessment, counseling, and prescribe for high-risk MSM  Risk assessment and counseling tools to aid providers and prospective users are under development Summary: Prescribing PrEP