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PrEP and My Patients: Guidance for LGBT Community–Based Primary Care Providers on Novel Strategies to Reduce Risk of HIV Acquisition. This program is supported by an educational grant from. About These Slides. Our thanks to the presenters who gave permission to include their original data

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    1. PrEP and My Patients: Guidance for LGBT Community–Based Primary Care Providers on Novel Strategies to Reduce Risk of HIV Acquisition This program is supported by an educational grant from

    2. About These Slides • Our thanks to the presenters who gave permission to include their original data • 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 Users are asked to honor this intent • These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) DisclaimerThe materials published on the Clinical Care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. Faculty Who Contributed to This Program Susan Buchbinder, MD Associate Clinical Professor Departments of Medicine, Epidemiology, and Biostatistics University of California, San Francisco Director, HIV Research Section San Francisco Department of Public Health San Francisco, California Jared M. Baeten, MD, PhD Associate Professor Department of Global Health and Medicine University of Washington Seattle, Washington

    4. Faculty Who Contributed to This Program (cont’d) Connie Celum, MD, MPH Professor, Department of Global Health and Medicine University of Washington Seattle, Washington Albert Liu, MD, MPH Assistant Clinical Professor Department of Medicine University of California, San Francisco Director, HIV Prevention Intervention Studies HIV Research Section San Francisco Department of Public Health San Francisco, California

    5. 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 no significant financial relationships to disclose. Albert L. Liu, MD, MPH, has no significant financial relationships to disclose.

    6. Antiretroviral Therapy for Preventing HIV Acquisition: Available Data and Ongoing Trials

    7. PrEP Background

    8. After infection Time of transmission Prior to exposure Using Antiretroviral Medications for HIV-1 Prevention PrEP PEP ART • Advantages • Demonstrated efficacy • Challenges • Adherence • Delivery • Cost-effectiveness • Resistance • Advantages • Shorter course than PrEP • Challenges • Limited data • Recognition of risk • Initiation < 48 hrs • Adherence • Public health impact • Advantages • Clinical benefits and reduced infectiousness • Challenges • Scale up; resources • Long-term adherence • Long term toxicity • Resistance

    9. Tenofovir for PrEP • Completed clinical trials of PrEP have tested tenofovir • Oral TDF, oral TDF/FTC, vaginal gel • Potent: rapid antiretroviral activity • Safe: Substantial treatment safety experience • Easy: Once-daily dosing, few drug-drug interactions • Evidence that concept should work • Animal models and postnatal prophylaxis of breastfeeding infants showed high levels of protection

    10. Breakthroughs in PrEP

    11. iPrEx: Eligibility • Male sex at birth (N = 2499) • 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.

    12. iPrEX Study Sites San Francisco 9% Boston Chiang Mai 5% Iquitos 12% Guayaquil Sao Paulo Lima 15% 56% Rio de Janeiro Cape Town 4% Grant R, et al. CROI 2011. Abstract 92.

    13. iPrEx: Baseline Demographics Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

    14. iPrEx: Efficacy • Efficacy through study end (mITT): 42% (95% CI: 18% to 60%) 0.12 Placebo FTC/TDF 0.10 0.08 Cumulative Probability of HIV Infection 0.06 P = .002 0.04 0.02 0 0 12 24 36 48 60 72 84 96 108 120 132 144 Wks Since Randomization Pts at Risk, n Placebo 1248 1198 1157 1119 1030 932 786 638 528 433 344 239 106 FTC/TDF 1251 1190 1149 1109 1034 939 808 651 523 419 345 253 116 Grant R, et al. CROI 2011. Abstract 92.

    15. Challenges of PrEP

    16. Drug Resistance

    17. 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.

    18. Safety and Tolerability

    19. iPrEx: Adverse Events • No significant differences in adverse events between arms Grant R, et al. CROI 2011. Abstract 92.

    20. iPrEx: BMD Changes and Fracture Rates • BMD changes were small (~1%); no evidence of negative effect on health[1] • No differences in fracture rates between groups[1,2] • All fractures were trauma related • Need longer follow-up to evaluate effects on bone density and fracture risk over time 1. Liu AY, et al. Plos One. 2011;6:e23688.2. Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

    21. iPrEx: Nausea on History 12 FTC/TDF Placebo 10 8 6 Patients Reporting Nausea (%) 4 2 0 0 12 24 36 48 60 72 84 96 Wks Since Randomization Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

    22. iPrEx: Weight Gain 4 Placebo FTC/TDF 3 2 Patients Reporting Weight Gain (%) 1 0 0 12 24 36 48 60 72 84 96 Wks Since Randomization Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

    23. Adherence

    24. iPrEx: Detected Drug in Infected vs Uninfected Participants Drug Detection at Visit with First Evidence ofHIV Infection for Case 100 HIV infection occurred during periods of low drug exposure 80 51% 44% 60 P = .77 Drug Detection Rate (%) 40 11% 8% P = .001 20 Months 0 0 >21 15-21 9-15 3-9 0-3 0-3 3-9 9-15 15-21 >21 CaseControl Pre-HIV InfectionTime Points Post-HIV InfectionTime Points Number ofTime Points 3159 2796 61145 90207 3579 48144 73 130 71 36 21 Anderson PL, et al. CROI 2012. Abstract 31LB.

    25. TDF Levels in PMBC With 2, 4, or 7 Days of DOT: Understanding iPrEX Results iPrEx Visit WithFirst Evidence of HIV STRAND 2/wk21 4/wk21 7/wk22 Cases48 Controls144 n: 0% 18% 100 TFV-DP (fmoI/106 cells) 10 1 % Detected:Median:IQR: 100116-13 1003225-39 1004231-47 8114-15 44169-27 Anderson PL, et al. CROI 2012. Abstract 31LB.

    26. Risk Behavior

    27. iPrEx: Numbers of Sexual Partners 20 Placebo, mean partners FTC/TDF, mean partners Placebo, median partners 15 FTC/TDF, median partners Sexual Partners in Previous 12 Wks (n) 10 5 0 0 12 24 36 48 60 72 84 96 Wks Since Randomization Grant R, et al. CROI 2011. Abstract 92.

    28. iPrEx: Condom Use With High-Risk Sex Placebo 100 FTC/TDF 80 60 Receptive Intercourse Using Condoms (% of Partners) 40 20 0 0 12 24 32 48 60 72 84 96 108 120 132 Wks Since Randomization Grant R, et al. CROI 2011. Abstract 92.

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

    30. 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.

    31. What We Are Poised to Learn • PrEP use when MSM know iPrEx results (adherence, risk practices) • iPrEx Open-Label Extension (OLE) • Demonstration projects • What is intermittent dosing and should we consider it? • (Answer: Not yet . . . ) • Efficacy and safety of new drugs and new delivery systems • Long-acting injectables • Rectal microbicides • Vaginal rings

    32. How Much Is Enough? A Primary Prevention Comparison 1. Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

    33. How Much Is Enough? A Primary Prevention Comparison 1. Grant RM, et al. N Engl J Med. 2010;363:2587-2599. 2. Shepherd J, et al. N Engl J Med. 1995;333:1301-1307.

    34. Other Studies of ART for Prevention

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

    36. Partners PrEP: Both PrEP Strategies Significantly Reduce HIV Acquisition • Both PrEP strategies associated with significant reduction in HIV acquisition vs placebo in both men and women • TDF efficacy: 71% in women, 63% in men • TDF/FTC efficacy: 66% in women, 84% in men Baeten J, et al. CROI 2012. Abstract 29.

    37. Partners PrEP: Other Outcomes • Rates of death, serious adverse events, laboratory events low and not significantly different between arms • Mild GI effects and fatigue, primarily during Month 1 • Reported unprotected sexual behavior decreased on study, with similar decline observed across arms • No resistance to TDF or FTC in those who acquired HIV after randomization (n = 27) • Resistance mutations found in 2/8 retrospectively found to have acute HIV-1 at PrEP initiation • K65R (n = 1); M184V (n = 1) Baeten J, et al. CROI 2012. Abstract 29.

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

    39. TDF2: PrEP With TDF/FTC Significantly Reduces HIV Acquisition • 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) • Reduction in HIV acquisition with TDF/FTC observed in both men and women but study underpowered to demonstrate sex-based differences in outcomes Time to Seroconversion (ITT Analysis) 0.10 Placebo 0.08 0.06 Failure Probability 0.04 TDF/FTC 0.02 0 0 1 2 3 Yrs Thigpen MC, et al. IAS 2011. Abstract WELBC01.

    40. 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 (2120 randomized) • Announced April 18, 2011, that study was ended early because of lack of efficacy • 35 vs 33 new HIV infections in the placebo and FTC/TDF arms[1] • TFV blood levels that use was too low (< 40%) to assess efficacy • 4 vs 1 patient with M184V/I in the TDF/FTC and placebo arms • VOICE: Phase IIB placebo-controlled trial of > 5000 women in South Africa, Uganda, and Zimbabwe[2] • Daily oral TDF; daily oral TDF/FTC; daily vaginal TFV 1% gel • DSMB stopped the daily oral TDF arm in September 2011 and the daily vaginal gel arm in November 2011, both for lack of efficacy • Daily oral TDF/FTC arm continues 1. Van Damme L, et al CROI 2012. Abstract 32LB. 2. 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.

    41. Questions That Arise From These Data • Why were there differences between these studies and the other TDF-based studies? • Adherence? • Penetration of drug in vaginal tissue? • But promising data on oral PrEP in women in Partners (TDF and TDF/FTC) and TDF2 (TDF) trials • Degree of HIV exposure? • Genital inflammation?

    42. What Have We Learned? • We have proof-of-concept that antiretroviral agents provide primary protection against HIV-1 • Adherence to PrEP is critical for its effectiveness • Key component of new PrEP strategies and execution of future PrEP trials • Biomedical prevention is behavioral • We still have much to learn about biologic and behavioral factors that drive HIV-1 risk in women and how those may undermine PrEP benefits

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

    44. HPTN 052: Immediate vs Delayed ART for HIV Prevention in Serodiscordant Couples • 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 Immediate HAART Initiate HAART at CD4+ cell count 350-550 cells/mm3 (n = 886 couples) HIV-infected, sexually active serodiscordant couples; CD4+ cell count of the infected partner: 350-550 cells/mm3 (N = 1763 couples) Delayed HAARTInitiate HAART at CD4+ cell count ≤ 250 cells/mm3* (n = 877 couples) *Based on 2 consecutive values ≤ 250 cells/mm3. Cohen MS, et al. N Engl J Med. 2011;365: 493-505.

    45. 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 Delayed Arm: 27 Immediate Arm: 1 P < .001 Cohen MS, et al. N Engl J Med. 2011;365: 493-505.

    46. 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)

    47. Why Use PrEP if Treatment Is So Effective?

    48. Challenges in Linkage to Care and Successful Treatment Estimated that only 19% of HIV-infected individuals in the US have undetectable HIV viral load 1,200,000 100% 1,000,000 79% 800,000 59% 600,000 1,106,400 40% 32% 874,056 400,000 24% 655,542 19% 200,000 437,028 349,622 262,217 209,773 0 On ART Need ART HIV Infected Linked to Care HIV Diagnosed Retained in Care Adherent/Undetectable Gardner EM, et al. Clin Infect Dis. 2011;52:793-800.

    49. What Will It Take to Substantially Reduce HIV Transmission in an Entire Population? Undiagnosed HIVNot linked to careNot retained in careART not requiredART not utilizedViremic on ARTUndetectable HIV-1 RNA 1,200,000 1,000,000 800,000 600,000 Number of Individuals 400,000 66% 34% 200,000 28% 22% 21% 19% 0 Current DX90% Engage90% Treat90% VL < 50 in 90% Dx, Engage, Tx, and VL < 50 in 90% Answer: Treatment AND Prevention Gardner EM, et al. Clin Infect Dis. 2011;52:793-800.

    50. Concluding Thoughts