ART Initiation: PrEP and Treatment-naïve Patients

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

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.

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 ART-naïve HIV-infected individuals Confirmed CD4 count >500 cells/mm3 Early ART group Initiate ART immediately following randomization n=2,300 Deferred ART group Defer ART until the CD4 countdeclines to <350 cells/mm3 or AIDS develops n=2,300 www.clinicaltrials.gov Accessed Feb 04, 2014

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

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.

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.

9. Summary of Investigational ARVs for PrEP 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 INSTI: Integrase strand transfer inhibitors. 1Efavirenz should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception. 2Lamivudine may substitute for emtricitabine or visa versa. 3Tenofovir DF should be used with caution in patients with renal insufficiency. 4Atazanavir + RTV should not be used in patients who require >20 mg omeprazole equivalent/day. 5Patients with creatinine clearance >70 mL/min. 6Patients who are HLA-B*5701 negative. 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.

11. US DHHS Guidelines May 2014: Ten Recommended Regimens INSTI: Integrase strand transfer inhibitors. 1Efavirenz should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception. 2Lamivudine may substitute for emtricitabine or visa versa. 3Tenofovir DF should be used with caution in patients with renal insufficiency. 4Atazanavir + RTV should not be used in patients who require >20 mg omeprazole equivalent/day. 5Patients with creatinine clearance >70 mL/min. 6Patients 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 Caution: ABC in those with high CVD risk and persons with a VL>5 log

13. WHO 2013 Guidelines: What to Start

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 coformulationvs 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. ARV Development: More FDCs & STRs • Nonnucleoside RTIs • EFV/TDF/FTC • RPV/TDF/FTC • 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 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