1. Julio Montaner MD, FRCPC, FCCP Director, BC-Centre for Excellence on HIV/AIDS Professor of Medicine and Chair, AIDS Research Providence Health Care - University of British Columbia President, International AIDS Society When to Start?

2. Integrating HIV Prevention and Treatment from Slogans to Impact J Salomon 1 *, D Hogan 1, J Stover 2, K Stanecki 3, NWalker 3-4, P Ghys 3, B Schwartländer 5 PLoS Medicine, http://www.plosmedicine.org January 2005, Volume 2, Issue 1, e16

3. HIV prevalence Montaner et al, Lancet 2006 Number of infections prevented Treat all Treat 30% Cost of treatment Treat all Treat 30% The Power of HAART: Demographic Model

4. V D Lima, et al JID July 1st 2008

5. CD4 200/mm3 Adh <40% CD4 200/mm3 Adh 40 - 80% CD4 200/mm3 Adh 80 - 95% CD4 200/mm3 Adh 95 - 100% CD4 350/mm3 Adh <40% CD4 350/mm3 Adh 40 - 80% CD4 350/mm3 Adh 80 - 95% CD4 350/mm3 Adh 95 - 100% 50% 75% 90% 100% 50% 75% 90% 100% 50% 75% 90% 100% 50% 75% 90% 100% 50% 75% 90% 100% 50% 75% 90% 100% 50% 75% 90% 100% 50% 75% 90% 100% V D Lima, et al JID July 1st 2008

6. Expected Impact of an Increase in HAART Coverage from current 50 to 75% of Medically Eligible on New HIV Infections in BC V D Lima, et al JID July 1st 2008

7. Net benefit is an economic measure that incorporates survival and QoL 1 Quality adjusted life year (QALY) valued at $50K * All Values discounted at 3% per year, using 2005 CDN$ 10/22/2008 - Provisional Transmission model Incremental net benefit (Millions of CDN $) over 30 years Baseline = Status Quo Scenario I = Incremental Benefit going from Baseline to 50% coverage with Expanded Eligibility (n=761) Scenario II = Added Incremental Benefit going from Scenario I to 75% coverage Expanded Eligibility (n=1187) Scenario I Scenario II K Johnston et al, in progress, 2009

8. And now back to When to Start…

9. AIDS Death Rate in British Columbia Eric Druyts, et al. BC-CfE, in preparation, 2009

10. HAART: Safety

11. Survival on HAART by CD4 count Hogg et al. JAMA 2001 Wood et al. AIDS 2003

12. Continuous HAART Time ContInt PVLU/DInt CD4HighOK Cost++++ Deaths00 OI/Ca00 Non-ADI Events +++ Toxicity + QoL++++

13. Continuous vs Intermittent HAART Time ContInt PVLU/DInt CD4HighOK Cost++++ Deaths00 OI/Ca00 Non-ADI Events +++ Toxicity + QoL++++

14. Continuous vs Intermittent HAART Time Q: Could Intermittent HAART preserve clinical benefit and minimize ADEs/Cost?

15. SMART: Endpoints Primary and Major Secondary End Points * Hazard Ratio for Drug Conservation Group vs. Viral Suppression Group (95% CI) End Point Drug Conservation Group (N=2720) Viral Suppression Group (N=2752) P Value No. of Participants with Events Event Rate (per 100 Pers-Yr) No. of Participants with Event Event Rate (per 100 Pers-Yr) Primary end point1203.3471.32.6 (1.9-3.7)<0.001 Death from any cause551.5300.81.8 (1.2-2.9)0.007 Opportunistic disease Serious130.420.16.6 (1.5-29.1)0.01 Non-serious631.7180.53.6 (2.1-6.1)<0.001 Major cardiovascular, renal, or hepatic disease 651.8391.11.7 (1.1-2.5)0.009 Fatal or nonfatal cardiovascular disease 481.3310.81.6 (1.0-2.5)0.05 Fatal or nonfatal renal disease 90.220.14.5 (1.0-20.9)0.05 Fatal or nonfatal liver disease 100.370.21.4 (0.6-3.8)0.46 Grade 4 event1735.01484.21.2 (1.0-1.5)0.13 Grade 4 event or death from any cause 2055.91644.71.3 (1.0-1.6)0.03

16. SMART: Endpoints Primary and Major Secondary End Points * Hazard Ratio for Drug Conservation Group vs. Viral Suppression Group (95% CI) End Point Drug Conservation Group (N=2720) Viral Suppression Group (N=2752) P Value No. of Participants with Events Event Rate (per 100 Pers-Yr) No. of Participants with Event Event Rate (per 100 Pers-Yr) Primary end point1203.3471.32.6 (1.9-3.7)<0.001 Death from any cause551.5300.81.8 (1.2-2.9)0.007 Opportunistic disease Serious130.420.16.6 (1.5-29.1)0.01 Non-serious631.7180.53.6 (2.1-6.1)<0.001 Major cardiovascular, renal, or hepatic disease 651.8391.11.7 (1.1-2.5)0.009 Fatal or nonfatal cardiovascular disease 481.3310.81.6 (1.0-2.5)0.05 Fatal or nonfatal renal disease 90.220.14.5 (1.0-20.9)0.05 Fatal or nonfatal liver disease 100.370.21.4 (0.6-3.8)0.46 Grade 4 event1735.01484.21.2 (1.0-1.5)0.13 Grade 4 event or death from any cause 2055.91644.71.3 (1.0-1.6)0.03

17. SMART: Endpoints Primary and Major Secondary End Points * Hazard Ratio for Drug Conservation Group vs. Viral Suppression Group (95% CI) End Point Drug Conservation Group (N=2720) Viral Suppression Group (N=2752) P Value No. of Participants with Events Event Rate (per 100 Pers-Yr) No. of Participants with Event Event Rate (per 100 Pers-Yr) Primary end point1203.3471.32.6 (1.9-3.7)<0.001 Death from any cause551.5300.81.8 (1.2-2.9)0.007 Opportunistic disease Serious130.420.16.6 (1.5-29.1)0.01 Non-serious631.7180.53.6 (2.1-6.1)<0.001 Major cardiovascular, renal, or hepatic disease 651.8391.11.7 (1.1-2.5)0.009 Fatal or nonfatal cardiovascular disease 481.3310.81.6 (1.0-2.5)0.05 Fatal or nonfatal renal disease 90.220.14.5 (1.0-20.9)0.05 Fatal or nonfatal liver disease 100.370.21.4 (0.6-3.8)0.46 Grade 4 event1735.01484.21.2 (1.0-1.5)0.13 Grade 4 event or death from any cause 2055.91644.71.3 (1.0-1.6)0.03 Of 85 deaths in SMART, only 7 (8%) were from ADIs

18. Emery S, et al. IAS 2007. Abst WEPEB018 Virologic Suppression Strategy Continuous HAART (n = 249 not receiving ART at Bsl) Treatment Interruption Strategy Deferred HAART until CD4+ count < 250/mm³; discontinue therapy when CD4+ cell count > 350/mm³ (n = 228 not receiving ART at Bsl) CD4 > 350/mm³ Antiretroviral naive (n = 249) or not on ART for ≥ 6 mos (n = 228) (N = 477) Mean follow-up: 16 months Study halted early SMART: Immediate vs Deferred HAART

19. Opportunistic Disease/Death Opportunistic Disease Alone Serious non ADI/non-OD-Death OD/Serious non ADI & All Cause Death SMART: Immediate vs Deferred HAART Emery S, et al. IAS 2007. Abst WEPEB018

20. SMART: Summary  Continued HAART better than Intermittent HAART –Survival –AIDS and non AIDS events –Adverse effects –Quality of life –Differences remained when HAART was re-started  What is driving the excess morbidity and mortality?

21. SMART: Consequences of Stopping HAART Change in D-Dimer (µg/mL) From Baseline to 1 Month Month 1 HIV-1 RNA Level (copies/mL) 0 0.2 0.3 D-Dimer (µg/mL) > 50,00010,000- 50,000 401- 10,000 ≤ 400 0.28 0.11 0.40 0 0.1 P =.0005 for trend Change in IL-6 (pg/ml) From Baseline to 1 Month Kuller L, et al. CROI 2008. Abstract 139. Modified from Kuller LH, et al. (2008). PLoS Med 5(10): e203doi:10.1371/journal.pmed.0050203

22. Kuller L, et al. CROI 2008. Abstract 139. Modified from Kuller LH, et al. (2008). PLoS Med 5(10): e203doi:10.1371/journal.pmed.0050203 Risk of Death Associated with Biomarker Levels at Entry Risk of Death Associated with Latest Biomarker Level Risk of Death Associated with Change in Biomarker Levels SMART: Risk of Death and Biomarkers

23. New Evidence ICAAC/IDSA 2008 & CROI 2009

24.  NA-ACCORD, established in 2006, includes 22 HIV cohorts –Analysis includes patients with CD4 count 351-500/mm 3 at study visit between 1996-2006  Compared outcomes based on Rx according to –Immediate treatment: initiated HAART within 1.5 years of first CD4 count in 351-500/mm 3 range –Deferred treatment: did not initiate HAART within 1.5 years of first CD4 count in 351-500/mm 3 range. Included patients who did not initiate treatment after reaching CD4 count < 350 l/mm 3  Primary outcome: death from any cause Kitahata MM, et al. ICAAC/IDSA 2008. Abstract H-896b. Survival Benefit With Earlier vs Deferred HAART

25. Kitahata MM, et al. ICAAC/IDSA 2008. Abstract H-896b.  Increased relative hazard of death with deferral of HAART remained unchanged when adjusted for IDU or for HCV co-infection, which were both independent predictors of mortality Parameter Associated With Risk of Death Relative Hazard (95% CI) Older age (per 10 yrs) BL CD4+ cell count (per 100 cells/mm 3 increase) 1.6 1.02.50.1 Deferral of HAART until < 350 cells/mm 3 (vs starting at 350-500 cells/mm 3 ) Female sex 0.9 1.7 1.1 P Value <.001.290 <.001.083

26. M Kitahata for CROI 2009

27. Hazard ratios for AIDS or death, adjusted for lead times and unseen events 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) ART Cohort Collaboration Jonathan A C Sterne CROI, 2009

28. When to Start ARTA Policy Evaluation While Awaiting Trial Results: South Africa Walensky et al CROI 2009 Abstract 596b Used a published mathematical model of HIV-infection in South Africa to simulate co-trimoxazole prophylaxis plus 3 alternative ART initiation strategies: No ART (for comparison only) ART at CD4 <250/μL or severe opportunistic disease (OD) ART at CD4 <350/μL or severe OD Projected 5-year morbidity, mortality, and costs, in a South African cohort of HIV-infected persons with mean age 33 years. Natural history and healthcare utilization data derived from the Cape Town AIDS Cohort. Assumed 2 sequential ART regimens (NNRTI-based followed by PI-based), with published 48-week viral suppression rates of 84% and 71%, and per person annual costs of $288 and $564.

29. When to Start ARTA Policy Evaluation While Awaiting Trial Results: South Africa Walensky et al CROI 2009 Abstract 596b Over a 5-year, 4.7 million HIV + South Africans will become eligible to start ART in the CD4 250 to 350/μL window. Assuming all eligible patients present for care and that ART is equally effective in the CD4 250 to 350/μL range, initiation of ART at <350/μL compared to <250/μL would result in fewer total OD (730,272 vs 951,370) and fewer total deaths (244,249 vs 497,059). Starting at <350/μL would also lead to additional (discounted) treatment costs of $1.4 billion over the next 5 years. As long as the probability that the trial will confirm a survival benefit to earlier ART is judged to be greater than 17%, a policy of initiating ART at CD4 <350/μL is cost-effective and should be used over the next 5 years. Conclusions: Earlier ART initiation in South Africa will reduce morbidity and mortality substantially, and will be cost-effective. In anticipation of trial results, treatment guidelines should be liberalized to allow for earlier ART initiation (CD4<350/μL).

30. Summary - HIV is a chronic inflammatory disease - Inflammation: important driver of non-AIDS events - heart, liver, kidney, etc - malignancies - Inflammation: important driver of CD4 decline - ADIs at a late stage of the disease

31. Summary - HIV is a chronic inflammatory disease - Inflammation: important driver of non-AIDS events - heart, liver, kidney, etc - malignancies - Inflammation: important driver of CD4 decline - ADIs at a late stage of the disease

32. Summary - HIV is a chronic inflammatory disease - Inflammation: important driver of non-AIDS events - heart, liver, kidney, etc - malignancies - Inflammation: important driver of CD4 decline - ADIs at a late stage of the disease

33. When to Start Antiretroviral Therapy MeasureRecommendationComments Symptomatic HIV diseaseTherapy recommended Asymptomatic HIV disease CD4 <350/µLTherapy recommended Recommendation strengthened since 2006 CD4 >350/µLTherapy should be considered and decision individualized Correlates of faster HIV disease progression:  High viral load (>100,000 RNA copies/mL)  Rapidly declining CD4 (>100/µL per year) Coexistent conditions influenced by uncontrolled viremia:  Presence of, or high risk for, cardiovascular disease  Active HBV or HCV  HIV-associated nephropathy Examples Antiretroviral Treatment of Adult HIV Infection 2008 Recommendations of the IAS-USA Hammer SM; Eron JJ, Jr.; Reiss P; Schooley RT; Thompson MA; Walmsley S; Cahn P; Fischl MA; Gatell JM; Hirsch MS; Jacobsen DM; Montaner JSG; Richman DD; Yeni P; Volberding PA. JAMA. 2008; 300 (5) 555-570

34. 164 187 102 181 200 192 87 239 163 97 134 179 97 100 125 123 86 122 103 53 157206 95 72  Review of data from 2003-2005 from 176 sites in 42 countries (N = 33,008)  Since 2000, CD4+ cell count at initiation in developed countries stable at approximately 150-200 cells/mm 3, increasing in sub-Saharan Africa from 50-100 cells/mm 3 When to Start: The Real World Egger M, et al. CROI 2007. Abstract 62.

35. DTES BC HA1 HA2 HA4 HA5 AIDS Death Rate in British Columbia HA3 Eric Druyts, et al. BC-CfE, in preparation, 2009

36. AIDS Death Rate in British Columbia Eric Druyts, et al. BC-CfE, in preparation, 2009

37. Expanded HAART Coverage: an Aid to HIV Prevention Montaner et al, Lancet, IAS, Toronto, 2006

38. Expected Impact of an Increase in HAART Coverage from current 50% of Medically Eligible to 75% on New HIV Infections in BC V D Lima, et al JID July 1st 2008

39. Net benefit is an economic measure that incorporates survival and QoL 1 Quality adjusted life year (QALY) valued at $50K * All Values discounted at 3% per year, using 2005 CDN$ Transmission model Incremental net benefit (Millions of CDN $) over 30 years Baseline = Status Quo Scenario I = Incremental Benefit going from Baseline to 50% coverage with Expanded Eligibility (n=761) Scenario II = Added Incremental Benefit going from Scenario I to 75% coverage Expanded Eligibility (n=1187) Scenario I Scenario II K Johnston et al, in progress, 2009

40. When to Start HAART? A matter of Perspective years Viral Load CD4 Count

41. When to Start HAART? A matter of Perspective years Viral Load CD4 Count

42. When to Start HAART? A matter of Perspective years Viral Load CD4 Count

43. When to Start HAART? A matter of Perspective years Viral Load CD4 Count

44. AIDS Nov 27th 2008, The Economist Deploying the drugs used to treat AIDS may be the way to limit its spread Illustration by Peter Schrank

45. Acknowledgements P. Cahn J.J. Eron M. A. Fischl J. M. Gatell S.M. Hammer M. S. Hirsch D. M. Jacobsen P. Reiss D. D. Richman R.T. Schooley M.A. Thompson P. A. Volberding S. Walmsley P. Yeni L. Akagi A. Alimente A. Anis R. Barrios J. Bishop G. Bondy K. Buchanan D. Burge I. Day J. Forbes S. Guillemi R. Harrigan M. Harris S. Smith R.S. Hogg E. Lun W. A. McLeod D. Money V. Montessori P. Philips N. Pick N. Press P. M. Sestak D. Shahvarani C. Sherlock G. Tsang M. Tyndall W. O’Briain

46. In partnership with Dira Sengwe 5 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 19 - 22 July 2009 Abstratct Submission Deadline 25th February 2009

47. Thank You