Select Daily Oral TDF/FTC PrEP Trials: Effectiveness Improves With Adherence 100 Partners PrEP[5] Efficacy 75% Adherence 81% 80 PROUD[6] Efficacy 86% Adherence ~100% 60 Effectiveness (%)* VOICE/FEM-PrEP[1,2] Efficacy 0%/6% Adherence 29%/≤ 37% TDF2[4] Efficacy 62% Adherence 80% 40 iPrEx[3] Efficacy 44% Adherence 51% 20 20 40 60 80 100 Adherence (%)† FTC, emtricitabine; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate. References 1. Marrazzo JM, et al. N Engl J Med. 2015;372:509-518. 2. Van Damme L, et al. N Engl J Med. 2012;367:411-422. 3. Grant RM, et al. N Engl J Med. 2010;363:2587-2599. 4. Thigpen MC, et al. N Engl J Med. 2012;367:423-434. 5. Baeten JM, et al. N Engl J Med. 2012;367:399-410. 6. McCormack S, et al. Lancet. 2016;387:53-60. Overall, these randomized clinical trials of PrEP using TDF/emtricitabine have shown that HIV incidence decreases with patient adherence. The y axis depicts the effectiveness of HIV protection in each trial while the x axis documents each trial’s adherence level. Adherence was based on pill counts or the detection of study drug in plasma.   A very clear and strong linear relationship exists where greater adherence across the study population tracks with greater HIV protection. This emphasizes how important it is to be adherent to PrEP. The TDF2, Partners PrEP, and PROUD studies all demonstrated very high degrees of HIV protection in populations that took PrEP consistently. *Reduction in HIV incidence vs control. †Based on pill counts or the detection of study drug in plasma. From Kenneth E. Mayer, MD, in New York, New York, October 20, 2017

Is TDF/FTC PrEP Safe? Meta-analysis of randomized, placebo-controlled PrEP studies demonstrated that the risk of any AE or grade 3/4 AEs is not increased for TDF-based PrEP vs placebo[1] Reversible changes in creatinine, ↑ in older pts. Bone safety: iPrEx bone mineral density substudy[2,3] High-risk MSM/TGW who received TDF/FTC PO QD PrEP and had 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) Lost BMD during TDF/FTC use recovered following discontinuation AE, adverse event; BMD, bone mineral density; FTC, emtricitabine; MSM, men who have sex with men; PBO, placebo; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate; TGW, transgender women. A meta-analysis of data from randomized, placebo-controlled PrEP trials demonstrated that the risk of any adverse event or of high-grade adverse events was no different for TDF-based PrEP compared to placebo. Thus, PrEP did not increase the risk of adverse outcomes overall.   Several trials have assessed bone safety during PrEP treatment, including an iPrEx substudy. In high-risk men and transgender women who have sex with men who received daily TDF/FTC PrEP, there was a small net decrease in spine and total hip bone mineral density (BMD) vs placebo at 24 weeks. However, there was no difference in the fracture rate between the groups, and BMD loss that was associated with PrEP recovered once PrEP was discontinued. As previously discussed, PrEP users are expected to discontinue. In general, PrEP is not expected to be a lifelong medication. So while there appear to be changes in bone mineral density, they have not been clinically relevant, and bone mineral density is recovered when PrEP is discontinued. 1. Fonner VA, et al. AIDS. 2016;30:1973-1983. 2. Mulligan K, et al. Clin Infect Dis. 2015;61:57580. 3. Grant R, et al. CROI 2016. Abstract 48LB. From Kenneth E. Mayer, MD, in New York, New York, October 20, 2017

USPHS/CDC Guidelines on Prescribing PrEP Determine Eligibility (negative HIV test, at high-risk for HIV acquisition, renal function, screen/treat for STIs, screen/vaccinate for Hep B, HCV Ab; pregnancy test) Prescribe tenofovir-emtricitabine 1 tablet by mouth daily Provide condoms and risk-reduction counseling Monitor closely (q 2-3 mo: HIV test, risk assessment/counseling; q 6 mo: renal function, STI screen (q 3 months for some populations?) www.cdc.gov/hiv/pdf/PrEPguidelines2014.pdf CDC has issued and updated guidelines since the FDA approval of TDF-FTC for HIV prevention. From Kenneth E. Mayer, MD, in New York, New York, October 20, 2017

PrEP if serodiscordant partner has a suppressed viral load? PARTNER study 888 HIV discordant couples HIV+ partner VL < 200 39% MSM couples ~36,000 condomless sex acts No transmissions when HIV+ pts’ PVL BLD Opposites Attract 358 HIV discordant MSM couples >12,000 condomless anal acts No HIV transmissions when HIV+ pt. PVL BLD 3 pts infected by outside partner Rodger JAMA 2016; Bavington IAS 2017 From Kenneth E. Mayer, MD, in New York, New York, October 20, 2017

From Kenneth E. Mayer, MD, in New York, New York, October 20, 2017