1. Slide 1 of 9 From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA. IAS–USA Jeanne Marrazzo, MD, MPH Professor of Medicine University of Washington Seattle, Washington Update on Pre-Exposure Prophylaxis: Never a Dull Moment From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA.

2. Slide 2 of 9 From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA. What is PrEP, and Why Might it Work? Garcia-Lerma JG, et al. Trends Pharmacol Sci. 2010 Definition: Provision of chemopreventive agent at vulnerable site(s) prior to infection Rationale: Infection of healthy mucosa requires relatively large dose of virus (10-6 to 10-8 particles) In theory, the right drug could prevent founder population from establishing infection, but time is of the essence! Animal data is very supportive; stresses need for PEP component

3. Slide 3 of 9 From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA. Evidence for PrEP Efficacy with Tenofovir-Based Regimens, 2012* StudyPopulationNEfficacy (%) iPrEx Brazil, Ecuador, Peru, South Africa, Thailand, US Men Having Sex with Men 2499 44% Daily oral FTC/TDF TDF2 Study Botswana Young men & women 1200 62% Daily oral FTC/TDF Partners PrEP Study Kenya, Uganda Heterosexual couples 4758 67% daily oral TDF 75% daily oral FTC/TDF At time of FDA meeting Baeten J, Celum C. Current Opinion HIV AIDS, 2012

4. Slide 4 of 9 From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA. FDA Antiviral Drugs Advisory Committee Meeting, May 10, 2012 Recommended approval of daily TDF/FTC for HIV prevention in 3 groups: –MSM: 19-3 YES –HIV-uninfected partner in discordant couples: 19-2 YES –Other populations: 12:8 YES 16 July 2012

5. Slide 5 of 9 From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA. 0 10 20 30 40 50 60 70 80 90 100% Efficacy Effect size (95% CI) FTC/TDF for HIV discordant couples (Partners PrEP) 75% (55; 87) Oral FTC/TDF PrEP Studies FTC/TDF for MSM (iPrEx) 42% (15; 63) FTC/TDF for young Heterosexuals (TDF-2) 63% (22; 83) Wide confidence intervals outside of discordant couples, with lower limit <20% in iPrEx

6. Slide 6 of 9 From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA. 0 10 20 30 40 50 60 70 80 90 100% Efficacy Effect size (95% CI) FTC/TDF for HIV discordant couples (Partners PrEP) 75% (55; 87) Oral FTC/TDF PrEP Studies, 2012 FTC/TDF for MSM (iPrEx) 42% (15; 63) FTC/TDF for young heterosexuals (TDF-2) 63% (22; 83) FTC/TDF for women (FEM-PrEP) 6% (-69; 41)

7. Slide 7 of 9 From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA. Divergent PrEP trial results: Contributions of Adherence + Biology? Adherence PrEP Efficacy Biology* Low genital drug levels (pK/pD) Inflammation, STI Acute HIV (high VL in partner) Disrupted vaginal microbiome Slide adapted from J. Baeten Behavior Frequency of anal vs. vaginal intercourse Vaginal hygiene practices * These factors may make PrEP efficacy more sensitive to imperfect adherence

8. Slide 8 of 9 From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA. HIV Incidence in CAPRISA 004 No K65R resistance mutations among seroconverters Abdool Karim, Q, et al. Science. 2010;329:1168-1174.

9. Slide 9 of 9 From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA. Candidate Drugs in PrEP Pipeline NNRTIs: Dapivirine intravaginal ring Effectiveness trials for dapivirine ring under way (MTN, IPM) Entry inhibitors: Maraviroc with NRTI or NNRTI Oral maraviroc +/- FTC/TDF (HPTN 069) Maraviroc & dapivirine vaginal ring (IPM, MTN) NNRTIs: Rilpivirine (TMC 278), long-acting injectable Once monthly injections; in phase I safety studies in UK Integrase strand transfer inhibitors Macaque & humanized mice protected with topical & oral raltegravir (Dobard CROI 30; Neff PLoS ONE 2010); macaques protected with parenteral long-acting agent (GSK744) (Andrews CROI 2013) NRTIs: Tenofovir intravaginal ring (Smith CROI 2013) Phase IIB Phase II Phase I Animal Studies