1. ART Initiation: PrEP and Treatment-naïve Patients Clinical Instructor, Harvard Medical School Director of Research, CRI New England Vice Chair, INSIGHT Scientific Steering Committee Boston, USA Calvin Cohen, MD, MSc

2. Disclosures Grants/Research Support: Gilead, Viiv, Merck, Janssen, BMS Advisory Boards: Gilead, Viiv, Merck, Janssen, BMS, Splicos, Oncolys Speakers Bureau: none Stock Shareholder: none Other Support: Expert Testimony - Gilead

3. When to Start? The SMART Study: Predictors of Clinical Illness/Death For every 100-cell increase in CD4: – 22% decreased risk (CI 13%-30%) Risk of OI/death after controlling for CD4: Age – per decade: 1.6 (1.3-1.8) SMART Study Group. J Infect Dis. 2008:197:1145-1155. Most recent viral loadHR for OI/Death <400 c/mL vs 401-10,0002.3 (1.1-4.9) 10,0004.1 (1.8-9.3)

4. The START Study: Design Fully enrolled Dec. 2013 Hypothesis: early ART reduces rate of primary endpoint by 28.8% – 43% for AIDS events, 24% for non-AIDS events www.clinicaltrials.gov Accessed Feb 04, 2014 Early ART group Initiate ART immediately following randomization n=2,300 Early ART group Initiate ART immediately following randomization n=2,300 Deferred ART group Defer ART until the CD4 count declines to <350 cells/mm 3 or AIDS develops n=2,300 Deferred ART group Defer ART until the CD4 count declines to <350 cells/mm 3 or AIDS develops n=2,300 ART-naïve HIV-infected individuals Confirmed CD4 count >500 cells/mm 3 ART-naïve HIV-infected individuals Confirmed CD4 count >500 cells/mm 3

5. CD4 Count (cells/mm 3 ) AIDS or HIV-related Symptoms<350350-500>500 United States DHHS (2014) Yes IAS-USA (2012)Yes British HIV Association (2013)Yes ConsiderDefer European AIDS Society (2013)Yes Consider WHO (2013)Yes Defer When to Start ART: Global Consensus and Diversity DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May, 2014. IAS-USA. Thompson MA, et al. JAMA. 2012;308:387-402. EACS. Available at: http://www.europeanaidsclinicalsociety.org. Version 7.0 October 2013. BHIVA. Available at: www.bhiva.org. WHO. Available at: http://www.who.int/publications/guidelines/hiv_aids/en/index.html.

6. n=1,763 HIV-positive patients in relationship with HIV-negative partner 97% Heterosexual CD4 350-550 n=877 Delayed HAART until CD4<250 (or AIDS) n=886 immediate HAART Randomized, Placebo-controlled Efficacy and Safety Study 13 Sites in Africa, Asia, Americas HPTN 052: Treatment as Prevention Study stopped 4 years early by DSMB (May 2011) n=1 transmission n=27 transmissions 96% risk reduction Available at: http://www.hptn.org/web%20documents/PressReleases/HPTN052PressReleaseFINAL5_12_118am.pdf Accessed May 12, 2011. All received ongoing safe sex education/condoms

7. PrEP Efficacy and the iPrEx Study: HIV Dx by Group and Drug Detection Grant R, et al. N Engl J Med. 2010;30:2587-2599. Group Drug detection HIV infectionsIncidence PlaceboNo643.86 FTC/TDF No334.04 Yes30.35 Relative rate reduction by use of FTC/TDF 91%

8. iPrEx: Intracellular Tenofovir Drug Levels and HIV Infection Drug levels measured for all active arm participants in iPrEX Model estimated HIV incidence Drug levels compared to those in STRAND – PK study of oral TDF in 23 HIV volunteers Anderson PL, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 31LB. Model estimates for HIV risk reduction (95% CI) 2 doses/wk76% (56% - 96%) 4 doses/wk96% (90% - >99%) 7 doses/wk99% (96% - >99%)

9. Summary of Investigational ARVs for PrEP MechanismDosing route Dosing frequency Current stage Maraviroc CCR5 antagonist oralonce dailyPhase 2 enrolling Rilpivirine-LANNRTIinjectable, IMonce monthly Phase 1 pilot; Phase 2 planned DapivirineNNRTIringmonthlyPhase 3 enrolling Ibalizumab CD4 attachment inhibitor injectable, SConce weeklyPhase 1 pilot ‘744-LAP integrase inhibitor injectable, IMonce quarterly Phase 1 pilot; Phase 2 enrolling Gulick R. 7th IAS Conference on Pathogenesis, Treatment, and Prevention, Kuala Lumpur, Malaysia, June 30 – July 3, 2013, Abs MOBS0204.

10. US DHHS Guidelines April 2014: Seven Preferred Regimens DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013. DHHS. Available at: http://aidsinfo.nih.gov/contentfiles/AdultARV_INSTIRecommendations.pdf. Update October 30,2013. NNRTIEfavirenz 1 /emtricitabine 2 /tenofovir DF 3 PIAtazanavir 4 + ritonavir + emtricitabine 2 /tenofovir DF 3 Darunavir + ritonavir (qd) + emtricitabine 2 /tenofovir DF 3 INSTIRaltegravir + emtricitabine 2 /tenofovir DF 3 Elvitegravir/cobicistat/emtricitabine/tenofovir DF 5 Dolutegravir + abacavir/lamivudine 6 Dolutegravir + emtricitabine/tenofovir DF INSTI: Integrase strand transfer inhibitors. 1 Efavirenz should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception. 2 Lamivudine may substitute for emtricitabine or visa versa. 3 Tenofovir DF should be used with caution in patients with renal insufficiency. 4 Atazanavir + RTV should not be used in patients who require >20 mg omeprazole equivalent/day. 5 Patients with creatinine clearance >70 mL/min. 6 Patients who are HLA-B*5701 negative.

11. US DHHS Guidelines May 2014: Ten Recommended Regimens NNRTIEfavirenz 1 /emtricitabine 2 /tenofovir DF 3 PIAtazanavir 4 + ritonavir + emtricitabine 2 /tenofovir DF 3 Darunavir + ritonavir (qd) + emtricitabine 2 /tenofovir DF 3 INSTIRaltegravir + emtricitabine 2 /tenofovir DF 3 Elvitegravir/cobicistat/emtricitabine/tenofovir DF 5 Dolutegravir + abacavir/lamivudine 6 Dolutegravir + emtricitabine/tenofovir DF Additional options if the VL < 5 log: Efavirenz + abacavir/lamivudine 6 Atazanavir + ritonavir + abacavir/lamivudine 6 Rilpivirine / tenofovir DF / emtricitabine (if CD4 count > 200/mm 3 ) INSTI: Integrase strand transfer inhibitors. 1 Efavirenz should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception. 2 Lamivudine may substitute for emtricitabine or visa versa. 3 Tenofovir DF should be used with caution in patients with renal insufficiency. 4 Atazanavir + RTV should not be used in patients who require >20 mg omeprazole equivalent/day. 5 Patients with creatinine clearance >70 mL/min. 6 Patients who are HLA-B*5701 negative. DHHS. Available at: http://aidsinfo.nih.gov/contentfiles/AdultARV_INSTIRecommendations.pdf. Update May 2014

12. Current EACS Guidelines: Ten Initial Recommended Regimens One from A & one from B ABRemarks Recommended NNRTI EFV RPV ABC/3TC or TDF/FTC EFV/TDF/FTC coformulated RPV/TDF/FTC coformulated RPV only for VL<5 log Ritonavir- boosted PI ATV/r DRV/r ATV/r: 300/100 mg QD DRV/r: 800/100 mg QD Integrase Inhibitor RAL RAL: 400 mg BID Caution: ABC in those with high CVD risk and persons with a VL>5 log

13. WHO 2013 Guidelines: What to Start First-line ART Adults and adolescents (including pregnant women, TB coinfection and HBV coinfection) Preferred (FDC) regimen(s) TDF + 3TC (or FTC) + EFV Alternative regimens AZT + 3TC + EFV (or NVP) TDF + 3TC (or FTC) + NVP Special situations ABC + 3TC + EFV (or NVP) AZT (or ABC) + 3TC + LPV/r (or ATV/r)

14. How Do We Choose from Among These Options? Drug characteristics: – Twice-daily vs once-daily dosing – Food requirements – Number of pills per day (range 1-3)  Role of coformulation vs multi-tablet regimens – Pharmacologic “forgiveness” for missed doses – Barrier to resistance if viremic – Potential for drug-drug interactions – Duration of experience

15. How Do We Choose from Among These Options? Patient characteristics: – Risk of pretreatment virus resistance – Risk of adverse events  Rate, type, strength of evidence of adverse events – Other medical comorbidities  CV, diabetes, renal, bone, psychological, etc. – Cost, access, and payment factors Other criteria you use?

16. Nonnucleoside RTIs EFV/TDF/FTC RPV/TDF/FTC Nonnucleoside RTIs EFV/TDF/FTC RPV/TDF/FTC ARV Development: More FDCs & STRs Protease Inhibitors ATV/COBI ATV/RTV DRV/COBI DRV/COBI/FTC/TAF Protease Inhibitors ATV/COBI ATV/RTV DRV/COBI DRV/COBI/FTC/TAF Integrase Inhibitors EVG/COBI/FTC/TDF EVG/COBI/FTC/TAF DTG/ABC/3TC DTG/RPV Integrase Inhibitors EVG/COBI/FTC/TDF EVG/COBI/FTC/TAF DTG/ABC/3TC DTG/RPV FDC – Fixed dose combinations; STR – Single tablet regimens

17. Summary and Conclusions When to Start – What to do until the START study results – No controversy about treatment for prevention Which Regimen to Choose – Matching drug attributes to patient needs The increasing support for PrEP – How best do we implement this