2. Hit Hard, Hit Early: When to Treat and With What? Brian G. Gazzard, MD, Moderator Julio Montaner, MD Calvin J. Cohen, MD, MS

3. Faculty Disclosure Brian G. Gazzard, MD No real or apparent conflicts of interest to report. Julio Montaner, MD Research grants, advisory boards, speakers bureaus: Abbott, Argos Therapeutics, Bioject Inc, Boehringer Ingelheim, Bristol- Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hoffmann-La Roche, Janssen-Ortho, Merck Frosst, Panacos, Pfizer, Schering Serono Inc. TheraTechnolgies, Tibotec (J&J), Trimeris Calvin J. Cohen, MD Consulting fees, fees for non-CME services, contracted research: Abbott, Bristol-Myers Squibb, Gilead Sciences, Merck, Pfizer, Tibotec

4. Hit Hard, Hit Early: When to Treat and With What? Brian G. Gazzard, MA, MD, FRCP Consultant Physician and Research Director, HIV/GUM Chelsea & Westminster Hospital London, UK

5. Cumulative Mortality Estimates Calculated Using Extended Kaplan-Meier Survival Estimates CD4 >500 & defer HAART (n=6539) CD4 >500 & initiate HAART (n=2616) Years After 1996 0.00 0.05 0.10 0.15 0.20 0246810 Kitahata M et al. 16th CROI; 2009; Montreal. Abstract 71.

6. CD4 Threshold (cells/mm 3 ) 0.5 1 2 4 Hazard Ratio 0 100 200 300 400 500 Note that successive comparisons are not statistically independent Sterne J et al. 16 th CROI; 2009; Montreal. Oral Abstract 72LB. Hazard Ratios for AIDS or Death, Adjusted for Lead Times and Unseen Events

7. Assume you are HIV positive and have a CD4 count of 500 cc/mL. You have two options. Which would you choose? 1. $10,000 in the bank annually earning compound interest until your CD4 count is 350 cc/mL 2. Start ART immediately

8. Hit Early? At what CD4 cell count would you start for the benefit of the patient?

9. STARTMRK: Percent of Patients With HIV RNA <50 Copies/mL (95% CI) (Non-Completer = Failure) 281279281279281279278280 282 281282280281 Raltegravir 400 mg bid a Efavirenz 600 mg qhs a Number of Contributing Patients Weeks Percent of Patients 0248121624324048 0 20 40 60 80 100 82% Noninferiority P Value <.001 86% a In combination with tenofovir/emtricitabine. Lennox J et al. 48 th ICAAC–46 th IDSA; 2008; Washington, DC. Abstract H-896a.

10. MERIT-ES Re-analysis: Kaplan-Meier Plot of Time to Virologic Failure (≥50 Copies/mL) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0100200300400500600 700 Only patients with an R5 screening result by enhanced Trofile assay are included. Nonresponders (failure, rebound, discontinuation) were censored. MVC + ZDV /3TC EFV + ZDV /3TC Survival Estimate Days Heera J et al. 5 th IAS; 2009; Capetown. Abstract TUAB 103. 3TC, lamivudine; EFV, efavirenz; MVC, maraviroc; ZDV, zidovudine.

11. Time to Virologic Failure (Plasma HIV RNA >200 log 10 copies/mL) No shorter time to undetectable viral load, but significantly shorter time to virologic failure. Consistent for other HIV RNA thresholds 0.00 0.25 0.50 0.75 1.00 97 939189 ZDV/ABC + TDF/FTC 105 104103102ATV/r + TDF/FTC 111 109 108EFV/TDF/FTC Number at risk 0412243648 Weeks EFV/TDF/FTC ATV/r + TDF/FTC ZDV/ABC + TDF/FTC ArmHRP EFV/TDF/FTC1 ATV/r + TDF/FTC0.880.840 ZDV + ABC + TDF/FTC3.300.012* ABC, abacavir; ATV/r, ritonavir-boosted atazanavir; EFV, efavirenz; FTC, emtricitabine; TDF, tenofovir; ZDV, zidovudine. Cooper D. 5 th IAS; 2009; Capetown. Abstract LBPEB09.

12. Hit hard? What agent would you start with? Why would you no longer start with efavirenz?