1. When to Start

2. Data Presentation

3. DHHS and IAS-USA: Recommendations for Initiation of ART in Naïve Patients Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008; Hammer SM, et al. JAMA 2008;300:555-570. Clinical Category CD4 Cell Count (cells/mm 3 ) Viral Load (copies/mL) 2008 DHHS Guidelines 2008 IAS-USA Guidelines AIDS-defining illness or severe symptoms Any value Treat Asymptomatic <200Any value Treat 200 to 350Any value Treat >350 >100,000 Generally defer treatment >350 <100,000 Generally defer treatment Pregnant women Any value Treat HIV-associated nephropathy Any value Treat HIV/HBV coinfection when HBV treatment is indicated Any value Treat Consider treatment

4. ACTG 5164: Early vs. Deferred ART with Acute OIs Assessment of optimal timing of ART in pts with acute OI (N=285) 92% Tx-naïve; median CD4+ 29 cells/mm 3 and HIV RNA 5.07 log 10 c/ml OIs with effective antimicrobial therapy only PCP (63%), bacterial infections, cryptococcal disease, MAC, toxoplasmosis TB excluded Zolopa A, et al. 15th CROI; Boston, MA (2008); Abst. 142. -14 Study day 02284284224 48 wks Enrollment Deferred Arm Start ART Opportunistic Infection Treatment Starts Immediate Arm Start ART Recommended Start window

5. A5164: Results Through 48 Weeks Number of Patients with Death or AIDS Progression By Time of ART Start At 48 weeks, no difference in virologic suppression, IRIS (7.6%) or need for ART changes Zolopa A, et al. 15th CROI; Boston, MA (2008); Abst. 142; Grant P, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 775. DeferredImmediate P=0.035

6. The SAPiT Trial: Starting Antiretroviral Therapy in TB Open-Label Randomized Trial; HIV+ pts with active TB (N=642) Randomized to one of 3 arms: Arm 1: ART initiated during intensive phase of TB treatment Arm 2: ART initiated after intensive phase of TB treatment Arm 3: ART initiated after TB treatment completed - Sequential Tx IRIS: Integrated 12.1% vs. Sequential 3.8% Sept 2008: DSMB stopped sequential arm Integrated Tx Abdool Karim S, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 36a. Months After Randomization Survival 1.00 0.90 0.70 0.80 0.95 0.85 0.75 0123456789101112131415161718192021222324 Post –TB Treatment Continuation Phase of TB treatment Intensive Phase of TB treatment Sequential Arm Integrated Arm Kaplan-Meier Survival Curve P=0.003

7. Cautionary Note: ART and Cryptococcal Meningitis (Zimbabwe) Immediate vs. delayed (10 weeks) ART in Cryptococcal Meningitis (N=54) Tx: Fluconazole 800 mg daily and d4T/3TC/NVP No use of amphotericin nor management of raised intracranial pressure Mortality: 87% immediate vs. 37% delayed (P=0.002) Most deaths in immediate ART group occurred within the first month, possibly due to IRIS Fluconazole-NVP drug interaction postulated Comparison of Kaplan-Meier Survival Estimates by Treatment Group 1.00 0.75 0.00 0.25 0200400600800 0.50 Time to Death (days) P=0.028 Delayed Early Survival Makadzange A, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 36cLB.

8. NA-ACCORD: Improved Survival When ART is Started with ≥350 CD4 North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) Regional collaboration of 22 HIV research cohorts from United States and Canada Study of HIV+ patients with: CD4 count 351-500 cells/mm 3 Active follow-up between 1996 and 2006 Outcome: All-cause mortality Groups compared from same CD4 count level: Immediate treatment: Initiate ART within 1.5 yrs after 1st CD4 count between 351-500 cells/mm 3 Deferred treatment: Do not initiate ART in this time frame Patient data censored if treatment not initiated within the 1.5 year interval after the target CD4 count for ART initiation Kitahata M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896b

9. NA-ACCORD: Baseline Characteristics Initiate HAART (n=2,473) Defer HAART (n=5,901) Follow up person-years8,35816,636 Males (%)8375 Median Age (years)4038 White (%)3938 Median CD4 count cells/mm 3 421432 Median log 10 HIV RNA copies/mL4.34.1 Hepatitis C virus infection (%)2734 History of Injection Drug Use (%)1621 Kitahata M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896b

10. NA-ACCORD: Results Relative Hazard (RH)* 95% Confidence Interval P-value Deferral of HAART at 351-500 cells/mm 3 1.71.4, 2.1<0.001 Female Sex1.10.9, 1.50.290 Older Age (per 10 years)1.61.5, 1.8<0.001 Baseline CD4 count (per 100 cells/mm 3 ) 0.90.7, 1.00.083 HIV RNA was not an independent predictor of mortality Rate of virologic suppression (<500 c/ml) similar between groups Kitahata M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896b * Stratified by Cohort and Year

11. NA-ACCORD: Improved Survival When ART is Started When CD4 Count ≥500 cells/mm 3 ARV-naïve; CD4 count >500 cells/mm 3, no prior H/O AIDS-defining illness, follow-up between 1996 and 2006 All-cause mortality compared between immediate vs. deferred ART Immediate Group: Start ART with > 500 cells/mm 3 Deferred Group: Start ART within 1.5 years of CD4 <500 Statistical analysis adjusted for baseline population differences Kitahata M, et al. 16th CROI, Montreal, Canada, 2009. Abst. 71. 0.00 0.05 0.10 0.15 0.20 0246810 Years after 1996 Relative Hazard of Deferral 1.6 (1.3,1.9; p<0.001) Defer HAART > 500 CD4 cells (N=6,539) Initiate HAART > 500 CD4 cells (N= 2,616) Mortality

12. SMART Naïve/Off Treatment Sub-study: Clinical Outcomes of (re-)Starting ARVs Emery S, et al. JID 2008; 197: 1133–1144. Serious non-AIDS Hazard Ratio = 7.05 (95% CI: 1.58-31.5) p=0.01 Months Cum. Probability (X100) No. at Risk Deferred ART Immediate ART 25 20 15 10 5 0 04812162024283236 228 249 189 210 159 180 128 145 96 125 73 106 59 80 36 58 27 44 24 36 Opportunistic disease (fatal and non-fatal) Hazard Ratio = 4.40 (95%.CI: 1.23-15.8) p=0.02 Months No. at Risk 25 20 15 10 5 0 04812162024283236 228 249 192 210 162 179 130 144 95 124 73 104 58 80 37 58 26 44 21 35 Opportunistic disease and death Deferred ART Immediate ART Hazard Ratio = 4.38 (95%.CI: 1.45-13.2) p=0.009 Months Cum. Probability (X100) No. at Risk Deferred ART Immediate ART 25 20 15 10 5 0 04812162024283236 228 249 192 210 162 179 130 144 95 124 73 104 58 80 37 58 26 44 21 35 Months No. at Risk 25 20 15 10 5 0 04812162024283236 228 249 188 210 157 179 125 144 90 124 69 104 55 79 33 57 24 43 20 35 Hazard Ratio = 5.08 (95% CI: 1.91-13.5) p=0.001 Composite endpoint

13. SMART: Influence of CD4+ Count and Treatment on Clinical Event Rate * per 100 person years Last CD4+ cell count (cells/mL) < 250 250-349350-499> 500 Overall Continuous ART Event Rate * 10.46.71.80.01.3 Intermittent ART Event Rate * 16.09.27.63.17.0 Emery S, et al. JID 2008; 197: 1133–1144.

14. Antiretroviral Therapy Cohort Collaboration (ART-CC) Collaboration of HIV cohort studies to estimate risk of deferring ART at different CD4 Count levels ARV-naïve patients (N=24,444) starting ART after 1997 with <550 cells/mm 3 Patients with H/O AIDS or IDU excluded Rates of AIDS and death with immediate vs. deferred ART compared in adjacent CD4 ranges of 100 cells/mm 3 Adjusted for lead-time and unseen events in final analysis Sterne J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 72LB.

15. ART-CC: When Should ART be Started? Hazard ratios for AIDS or death, adjusted for lead time/unseen events Delaying ART to <350 (but not <375) cells/mm 3 is associated with an increased risk of AIDS or death ComparisonHazard Ratio (95% CI) 276-375 vs 376-4751.19 (0.96 to 1.47) 251-350 vs 351-4501.28 (1.04 to 1.57) 226-325 vs 326-4251.21 (1.01 to 1.46) Sterne J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 72LB. 4 Hazard Ratio for AIDS or Death 2.5 1 5004003002001000 CD4 Threshold (cells/mm 3 )

16. Observational Studies Can Be Wrong Numerous epidemiological studies demonstrated women on hormone replacement therapy (HRT) had decrease in risk of coronary heart disease (CHD) These studies led HCPs to recommend HRT as protection against CHD Controlled trials demonstrated HRT caused small, but significant, increase in CHD risk Re-analysis of epidemiological studies showed women on HRT more likely to be from socio-economic groups with better than average diet and exercise HRT use and decreased CHD risk were coincident effects of a common cause, rather than cause and effect 1 Lawlor DA, et al. Intl J Epidemiol 2004;33:464-467.

17. Improved CD4 Recovery When Starting with Higher CD4 Count CD4-count increases on sustained suppressive (<400 c/mL) ARV treatment (n=655) by baseline count >350 cells/mm 3 : CD4 counts return to near-normal levels ≤350 cells/mm 3 : CD4 counts significantly increased but plateau after 4 years below normal range Differences in CD4 counts associated with differences in morbidity and mortality Median CD4 Counts Over 6 Years Stratified by Baseline CD4 Count Moore RD, Keruly JC. Clin Infect Dis 2007;44:441-446. 900 800 700 600 500 400 300 200 100 0 0123456 Years After Starting HAART CD4 Count (cells/mm 3 ) <200201–350>350

18. Lower Risk of Triple-Class Failure when Starting at Higher CD4 Large collaborative European cohort assessed risk factors for triple-class virologic failure (TCVF): All pts starting ART with 2 NRTIs + NNRTI or boosted PI (N=45,977) 980 developed TCVF Risk factors for TCVF: Non-MSM Younger age Higher HIV RNA Lower CD4 *Adjusted for all factors in the model Lodwick R, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 585. Adjusted * hazard ratios for TCVF by baseline CD4 and VL after starting ART 0.11 Lower risk of TCVF Greater risk of TCVF Baseline CD4 count (cells/mm 3 ) Baseline viral load (log 10 copies/ml) 0-49 50-199 200-349 350-499 500- Unknown 0-3.9 4.0-4.4 4.5-4.9 5.0-5.4 5.5-5.9 6.0- Unknown

19. Treatment as Prevention: Rwanda Study to evaluate effect of ART on HIV transmission among HIV serodiscordant couples (N=2,993) ART only if clinically indicated Negative partner tested q3 months Sexual risk assessed by Self report Sperm on vaginal smear Pregnancy Combined variable using any of above Sullivan P, et al. 16th CROI, Montreal, Canada, 2009. Abst. 52bLB.

20. Treatment as Prevention: Results Sexual risk behaviors lower in those on ART (19% vs. 25%, P<0.05) Both ART and change in behavior independently reduced HIV transmission ARV Status CY Observation No. Linked Infections Infection Rate (C-Y) Infection Rate Ratio (95% CI) Not on ARV5,0621713.4/100--- On ARV54740.7/1000.21 (0.08, 0.59) On ARV – conservative* 54761.0/1000.32 (0.14, 0.73) * Includes 2 partners who seroconverted in the same 3-month interval when the HIV-infected partner initiated ARVs 2,993 couples were followed for a median of 512 daysHIV-free Survival of HIV-negative partners, by ARV status of HIV+ Partner 05001000150020002500 0.0 0.2 0.4 0.6 0.8 1.0 Survival Probability Days Off ARV On ARV Censored Logrank P<.0001 Sullivan P, et al. 16th CROI, Montreal, Canada, 2009. Abst. 52bLB.

21. Starting Earlier is Cost-Effective Markov modeling using Johns Hopkins HIV database Beginning ARV treatment at CD4+ >350 cells/mm 3 vs. 200-350 cells/mm 3 results in an incremental cost per QALY gained of $31,226 Starting ARV therapy at >350 cells/mm 3 is more cost-effective than: Coronary bypass Hemodialysis Screening mammograms Mauskopf J, et al. JAIDS. 2005;39:562-569. HAART Initiation (cells/mm 3 ) Incremental Lifetime Cost Cost per Life-year gained Cost per QALY Gained >350 vs. 200-350$19,074$25,567$31,226 200-350 vs. <200$28,066$22,064$25,806 QALY=Quality Adjusted Life Year

22. When to Start Debate/Discussion