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Raphael J. Landovitz, MD, MSc Associate Professor of Medicine

“Everything” You Need to Know About Preexposure Prophylaxis and Postexposure Prophylaxis in 30 Minutes. Raphael J. Landovitz, MD, MSc Associate Professor of Medicine University of California Los Angeles Center for Clinical AIDS Research and Education Los Angeles, California.

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Raphael J. Landovitz, MD, MSc Associate Professor of Medicine

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  1. “Everything” You Need to Know About Preexposure Prophylaxis and Postexposure Prophylaxis in 30 Minutes Raphael J. Landovitz, MD, MSc Associate Professor of Medicine University of California Los Angeles Center for Clinical AIDS Research and Education Los Angeles, California Washington, DC: August 24, 2016

  2. Financial Relationships With Commercial Entities • Dr Landovitz has received research grants awarded to his institution from Gilead Sciences, Inc. He has served as a consultant to Gilead Sciences, Inc. (Updated 07/12/16)

  3. Learning Objectives After attending this presentation, participants will be able to: • Identify who should be considered for preexposure prophylaxis (PrEP) • Describe monitoring and lab testing approaches used for PrEP • Recognize candidates for transitioning from postexposure prophylaxis (PEP) to PrEP

  4. Effectiveness of Daily TDF/FTC in Clinical Trials Partners PrEP VOICE (TDF/FTC) (TDF) (TDF/FTC) 71% 63% 84% 66% 49% 80% CI: 20-83 CI: 37-87 CI: 28-84 CI: 54-94 TDF2 (TDF/FTC) FEM-PrEP (TDF/FTC) iPrEx (TDF/FTC) PROUD (TDF/FTC) -4.4% -49% CI: +3 to -129 CI: +27 to -149 42% 86% 6% CI: 58-96 CI: 15-63 CI: -22-81 CI: 25-97 CI: -52-41

  5. Effectiveness and Adherence in Trials of Oral and Topical TDF-Based Prevention Effectiveness and Adherence in Trials of Oral and Topical TDF-Based Prevention CAPRISA 004 (tenofovir gel, BAT-24 dosing)iPrExTDF2Partners PrEP (TDF)Partners PrEP (TDV/FTC)FEM-PrEPVOICE (TDF)VOICE (TDF/FTC)VOICE (tenofovir gel, daily dosing) 100 80 60 40 20 Effectiveness (%) 0 -20 -40 -60 10 20 30 40 50 60 70 80 90 Percentage of Participants’ Samples That Had Detectable Drug Levels(Calculations based on analyses involving a subset of total trial participants) Higher adherence associated with greater protection AVAC Report 2013

  6. Maximizing the Potential Effectiveness TDF/FTC (7x/week) TDF/FTC (~1x/24) 99% 94% CI: 96 - 99 CI: -17 - 100 Some adherence forgiveness with retained protection 6-7 doses per week likely required Donnell D et al, JAIDS. 2014. Cottrell ML et al, JID, 2016. Anderson P et al, Sci Transl Med. 2012.

  7. PrEP Is Well Tolerated; Discontinuations Due to Adverse Events Are Rare • No difference in proportion of participants reporting any AE (RR: 1.01; 95% CI: 0.99-1.03, P = .27) or any grade 3/4 AE in PrEP vs placebo arms • Several studies noted subclinical declines in renal functioning and BMD among PrEP users Risk Ratio and 95% CI 0.01 0.1 1 10 100 Favors PrEP Favors Placebo Slide credit: clinicaloptions.com WHO. Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV.

  8. iPrEX OLE: PrEP Reduces Incidence of HIV Even With Incomplete Adherence • Open-label extension of iPrEX trial; N = 1603 (75% receiving PrEP) • 100% adherence was not required to attain full benefit from PrEP • Benefit of 4-6 tablets/wk similar to 7 tablets/wk • 2-3 tablets/wk also associated with significant risk reduction • Higher levels of sexual risk taking at baseline associated with greater adherence to PrEP HIV Incidence and Drug Concentrations < 2 Tablets/Wk 2-3 Tablets/Wk 4-6 Tablets/Wk 7 Tablets/Wk Off PrEP HIV Incidence per 100 Person-Yrs 5 4 3 On PrEP 2 1 TFV-DP in fmol/punch 0 1500 LLOQ 350 500 700 1000 1250 0 Grant R, et al. IAC 2014. Abstract TUAC0105LB. Grant R, et al. Lancet Infect Dis. 2014;14:820-829. Slide credit: clinicaloptions.com

  9. iPrEX Bone Mineral Density Substudy • iPrEX substudy: dual-energy x-ray absorptiometry assessment (N = 498) • Small net decrease in spine and total hip BMD with TDF/FTC vs PBO at Wk 24 (-0.91% and -0.61%, respectively; P = .001 for both) • No difference in fracture rate between groups (P = .62) Mean Net Treatment Difference in BMD Change, Placebo – TDF/FTC (95% CI) 1.0 Spine (L1-L4) 0.5 0.0 Treatment Difference (%) -0.5 -1.0 -1.5 -2.0 24 Wk 48 72 96 .001 .064 P value .004 .111 1.0 Total Hip 0.5 0.0 Treatment Difference (%) -0.5 -1.0 -1.5 -2.0 Wk 24 48 72 96 P value .001 <.001 .176 .246 Slide credit: clinicaloptions.com Mulligan K, et al. Clin Infect Dis. 2015;61:572-580.

  10. iPrEx BMD Substudy: BMD Recovery After Discontinuation of TDF/FTC PrEP • Data compared for TFV-DP < or ≥ 16 fmol/M viable PBMC, concentration associated with 90% reduction in HIV infection risk in MSM/TGW Age < 25 Yrs Hip Spine Age < 25 Yrs 3.0 2.0 PlaceboWk 24 TFV-DP < 16 Wk 24 TFV-DP ≥ 16 1.5 2.0 1.0 1.0 0.5 0 0 -1.0 -0.5 -2.0 -1.0 * -1.5 -3.0 Change in BMD From iPrEx Enrollment (%) 3.0 Age ≥ 25 Yrs Age ≥ 25 Yrs 2.0 1.5 2.0 1.0 1.0 0.5 0 *P < .001; †P < .05 0 -1.0 -0.5 * -2.0 * -1.0 * * † -3.0 -1.5 BL Wk 24 D/c 6-Mos Post d/c OLE Enroll BL Wk 24 D/c 6-Mos Post d/c OLE Enroll Slide credit: clinicaloptions.com Grant R, et al. CROI 2016. Abstract 48LB.

  11. Cumulative TFV/FTC Exposure During PrEP Assoc. With Decline in Renal Fxn • Higher TFV exposure associated with greater eGFR decreases in 2 studies • iPrEx OLE[1] (n = 220): hair sampling for exposure • US Demo Project[2] (n = 557): dried blood spot sampling for exposure • In both studies, eGFR decrease to < 70 mL/min more frequent among those with BL eGFR < 90 mL/min and older persons (older than 40-45 yrs) Change in eGFR From BL vs Concentration of TFV or FTC in Hair[1] Trend P Value .008 .006 TFV FTC 0 -2 % Change in Mean eGFR From Baseline (95% CI) -4 -6 ~ 2 doses/wk ~ 4 doses/wk ~ 7 doses/wk -8 Lowest Second Third Highest Quartile of Hair Drug Concentrations 1. Gandhi M, et al. CROI 2016. Abstract 866. 2. Liu AY, et al. CROI 2016. Abstract 867. Slide credit: clinicaloptions.com

  12. Case Report: Multiclass Resistant HIV Infection Despite High Adherence to PrEP • 43-yr-old MSM acquired multiclass resistant HIV-1 infection following 24 mos of oral once-daily TDF/FTC PrEP • Pharmacy records, blood concentration analyses, and clinical history support recent and long-term adherence to PrEP • PrEP failure likely result of exposure to PrEP-resistant, multiclass resistant HIV-1 strain Slide credit: clinicaloptions.com Knox DC, et al. CROI 2016. Abstract 169aLB.

  13. PrEP Demonstration: High Adherence in STD/Community-Based Clinics • Prospective, open-label study of 48 wks of daily oral TDF/FTC PrEP for MSM/TGW (N = 557) • 3 US STD or community-based clinics in San Francisco, Miami, and Washington, DC • Of pts with at least 2 DBS tested (n = 272), 62.5% had protective TFV levels (consistent with ≥ 4 doses/wk) at all visits • 3% had TFV levels consistent with < 2 doses/wk • PrEP dispensation interrupted in 15%: most commonly due to AE concerns or low perceived risk • Overall STI incidence remained stable during follow-up (90/100 PY) Level of engagement BLQ No visit < 2 doses/wk 4-7 doses/wk 2-3 doses/wk San Francisco, California 100 80 60 Engagement, % of Participants 40 20 0 4(n = 109) 12(n = 114) 24(n = 121) 36(n = 121) 48(n = 124) Weeks of PrEP Slide credit: clinicaloptions.com Liu AY, et al. JAMA Intern Med. 2016;176:75-84.

  14. PrEP Use and HIV/STI Incidence in a Clinical Practice Setting • Analysis of PrEP use and HIV/STI incidence in PrEP users in large healthcare system (Kaiser Permanente San Francisco) from 2012 to 2015 • 1045 referrals for PrEP; 801 individuals with ≥ 1 intake visit • 657 initiated PrEP (82%*); mean duration of use 7.2 mos • Key results (PrEP initiators): • No HIV diagnoses (388 PY follow-up) • After 12 months, 50% diagnosed with any STI • 33% rectal STI; 33% chlamydia; 28% gonorrhea • After 6 mos PrEP, self-reported condom use was decreased in 41% of individuals *Of persons with ≥ 1 intake visit. Slide credit: clinicaloptions.com Volk JE, et al. Clin Infect Dis. 2015;61:1601-1603.

  15. STI Screening and Incidence During PrEP • Analysis of STI occurrence in pts in SPARK, a PrEP demonstration project at a NY health care center[1] • Pts screened for STIs every 3 mos while receiving PrEP; also visited clinic if experienced symptoms • CDC PrEP guidelines suggest STI screening every 6 mos[2] • At all time points, majority of pts (> 71%) had rectal STIs 1. Golub S, et al. CROI 2016. Abstract 869.2. CDC. PrEP Guidelines. 2014. Slide credit: clinicaloptions.com

  16. “What about IPERGAY?” or Does less-than-daily dosing work?

  17. IPERGAY: Efficacy • 86% risk reduction seen in PrEP arm (95% CI: 40% to 98%; P = .002) 0.20 0.16 0.12 Kaplan-Meier Estimate of Time to HIV Infection 0.08 0.04 Placebo 14 infections; incidence 6.6/100 PY 0 Probability of HIV Infection P = .002 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Mos TDF/FTC 2 infections; incidence 0.91/100 PY Pts at Risk, nPlaceboTDF/FTC 141141 7482 5558 4143 201199 *Event-driven PrEP strategy not FDA approved. Slide credit: clinicaloptions.com Molina JM, et al. N Engl J Med. 2015;373:2237-2246.

  18. HPTN 067/ADAPT: PrEP Strategies • International, randomized, open-label phase II trial; results reported from Harlem (N = 179), Bangkok (N = 178), and Cape Town (N = 179) cohorts Wk 30 Wk 0 Wk 6 Wk 34 Daily PrEP 1 dose daily • HIV-negative MSM • TGW (Bangkok and Harlem*) • Women (Cape Town) • at risk for HIV infection Lead-in period of directly observed therapy Final study visit Time-Driven PrEP* 1 dose twice weekly +1 dose after sex Event-Driven PrEP* 1 dose before and1 dose after sex TDF/FTC PrEP given at standard dose. *Participants instructed to take no more than 2 doses/day or 7 doses/wk. Mannheimer S, et al. IAS 2015. Abstract MOAC0305LB. Holtz TH, et al. IAS 2015. Abstract MOAC0306LB. Bekker L, et al. CROI 2015. Abstract 978LB. Slide credit: clinicaloptions.com

  19. HPTN 067/ADAPT: Coverage of Sex Acts According to PrEP Strategy Daily Time driven Event driven 100 85 84 74‡ 75 80 66 56 60 52 52* 47*† Complete Coverage (%) 40 20 0 Harlem Bangkok Cape Town§ *P = .001 vs daily. †P = .47 vs event driven. ‡P = .02 vs daily arm, P = .04 vs time-driven arm. §P < .001 comparing 3 arms. Complete coverage: taking ≥ 1 PrEP dose within 4 days before sex and ≥ 1 dose within 24 hrs after sex. Mannheimer S, et al. IAS 2015. Abstract MOAC0305LB. Holtz TH, et al. IAS 2015. Abstract MOAC0306LB. Bekker L, et al. CROI 2015. Abstract 978LB. Slide credit: clinicaloptions.com

  20. TFV and FTC Concentration in Rectal Tissue • Early detection of FTC in rectal tissue at high concentrations similar to HIV-infected patients on ART • TFV is only detectable at 24h post drug intake at high concentrations Molina JM, IAS 2015, Abstract MOSY0102

  21. CDC Guidance on PrEP for HIV Prevention: Candidates Slide credit: clinicaloptions.com CDC. PrEP Guidelines. 2014.

  22. CDC Guidance on PrEP for HIV Prevention: Approaches Slide credit: clinicaloptions.com CDC. PrEP Guidelines. 2014.

  23. PARTNER: Risk of HIV Transmission With Condomless Sex on Suppressive ART • Observational study of rate of HIV transmission in heterosexual and MSM serodiscordant couples (N = 767 couples) • HIV+ partner on suppressive ART • Condoms not used • No linked transmissions recorded in any couple during study period • Uncertainty over risk remains, particularly regarding receptive anal sex with ejaculation Risk Behaviors, % 80 100 0 20 40 60 HT♀ Vaginal sex with ejaculation HT♂ Vaginal sex Receptive anal sex Receptive anal sex with ejaculation MSM Only insertive anal sex Rate of Within-Couple Transmission Events per 100 CYFU, % (95% CI) 4 0 1 2 3 Vaginal sex with ejaculation (CYFU = 192) HT♀ HT♂ Vaginal sex (CYFU = 272) Receptive anal sex with ejaculation (CYFU = 93) Receptive anal sex without ejaculation (CYFU = 157) MSM Insertive anal sex (CYFU = 262) Estimated rate 95% CI Slide credit: clinicaloptions.com Rodger A, et. al JAMA 2016.

  24. Opposites Attract Study: HIV Transmission in Male Serodiscordant Couples • Observational study of HIV transmission in serodiscordant MSM in Australia, Brazil, Thailand: interim analysis[1] • On ART, 84% (of whom 83% had HIV-1 RNA < 200 c/mL); nonmonogamous relationship, 43%[1];any condomless anal intercourse (CLAI) with outside partners in previous 3 mos: 17%[2] • No linked HIV transmission in ~ 6000 acts of CLAI 1. Grulich A, et al. CROI 2015. Abstract 1019LB. 2. Bavinton BR, et al. AIDS 2015. Abstract TUAC0306. Slide credit: clinicaloptions.com

  25. CDC: Time to Achieving Protection on PrEP • Time from initiation of daily TDF/FTC to maximal protection against HIV infection is unknown • No scientific consensus on what intracellular concentrations are protective for either drug or the protective contribution of each drug in specific body tissues • TDF and FTC PK vary by tissue • Preliminary PK data on lead-time to achieve maximal intracellular TFV-DP concentrations with daily TDF dosing: • Blood: ~ 20 days • Rectal tissue: ~ 7 days • Cervicovaginal tissues: 20 days • Penile tissues: no data Slide credit: clinicaloptions.com CDC. PrEP Guidelines. 2014.

  26. CDC Guidance on PrEP for HIV Prevention: Candidates Slide credit: clinicaloptions.com CDC. PrEP Guidelines. 2014.

  27. CDC Guidance on PrEP for HIV Prevention: Approaches Slide credit: clinicaloptions.com CDC. PrEP Guidelines. 2014.

  28. CDC Guidelines: PEP for Adults With Non-Occupational HIV Exposure Slide credit: clinicaloptions.com CDC nPEP Guideline. 2016.

  29. PEP to PrEP Transition • PEP is a response to an acute exposure • Some pts who present for PEP may be at recurrent risk for HIV • When monitoring PEP, ascertain if the pt would benefit from PrEP • It is important to confirm if the pt is HIV infected prior to transitioning from PEP to PrEP • PEP entails taking up to 3 medications daily for 28 days; PrEP entails 1 pill/day while risk persists • Counseling about the importance of adherence is indicated Jain S, et al. Clin Infect Dis. 2015;60(suppl 3):S200-S204.NY nPEP Guideline. 2014. Slide credit: clinicaloptions.com

  30. PEP to PrEP Transition – But HOW? • No formal guidelines, no data (“Data Free Zone”) • The concern: Could PEP “fail” – that is – patient is actually HIV infected, suppressed and antibody response attenuated due to 3-drug PEP – and now transition to PrEP (2 drugs) will lead to viral resistance • Any hiatus in PrEP/PEP in a high-risk individual is a window for HIV acquisition. • No perfect way to rule out HIV acquisition between test acquisition and resulting IN ANY CIRCUMSTANCE • My strategy: Perform Ag/Ab test at Week 4 of PEP (while still on PEP) and then seamlessly de-escalate to 2-drug PrEP.

  31. Thank you!

  32. “Everything” You Need to Know About Preexposure Prophylaxis and Postexposure Prophylaxis in 30 Minutes Raphael J. Landovitz, MD, MSc Associate Professor of Medicine University of California Los Angeles Center for Clinical AIDS Research and Education Los Angeles, California Washington, DC: August 24, 2016

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