1. Strategies forAntiretroviral Therapy:When to Start, How to Finish Michael S. Saag, MDProfessor of MedicineThe University of Alabama at Birmingham The International AIDS Society–USA

2. M Saag, UAB

4. Latently Infected CD4+ Lymphocytes HIV Infected Cells HIV virions Antiretroviral Rx Uninfected Activated CD4+ Lymphocytes Uninfected Resting CD4+ Lymphocytes M Saag, UAB

6. At steady state, when an actively producing cell dies, it is replaced by how many newly infected cells? One Twenty-five One hundred One thousand It depends on the viral load [Default] [MC Any] [MC All]

7. M Saag, UAB

8. VL = 100,000

9. VL < 50

16. Goals of Antiretroviral Therapy Prevent Clinical Progression Prevent Resistance

19. NEJM, 1993

20. Impact of Replication on Resistance Likelihood of Resistance High Degree of Suppression

21. Case 1 30 yo white man Diagnosed on routine insurance examination PMHx remarkable for HTN, diet controlled No medications Understands treatment issues and wants to begin therapy if you think it is appropriate

22. If his viral load is 30,000 c/ml, at which CD4 count would you recommend starting therapy? 750 cells / ul 500 cells / ul 350 cells / ul 300 cells / ul 250 cells / ul ≤ 200 cells / ul Would observe Would treat at any CD4 count [Default] [MC Any] [MC All]

23. When To Start Treatment? – Summary of Current Guidelines symptoms

24. CD4 Count at Initiation of ARV 2003-2005 Egger M, 14th CROI; 2007; Abstract 62.

25. Which of the following convinces you MOST to start therapy earlier in course of HIV infection? Cohort Study Results (NA-ACCORD / ART-CC Consequences of unchecked viral replication (Inflammation / Harm) Improved tolerability / convenience of newer ARV regimens Treatment reduces transmission of HIV Cost Savings I have my own personal reasons! [Default] [MC Any] [MC All]

27. A Randomized Clinical Trial of Early Versus Standard Antiretroviral Therapy for HIV-infected Patients with a CD4 T Cell Count of 200 – 350 cells/ml (CIPRAHT001) Daniel Fitzgerald, MD The GHESKIO Centers, Haiti Weill Cornell Medical College, USA

28. Baseline Characteristics

29. Clinical Endpoints

31. Case 1 30 yo white man Diagnosed on routine insurance examination PMHx remarkable for HTN, diet controlled No medications Understands treatment issues and wants to begin therapy if you think it is appropriate VL is 30,000 c/mL CD4 is 650 cells/ul

32. If his viral load is 30,000 c/ml, and his CD4 count is 650 cells/ul, at what age would you recommend starting therapy? 20 yrs 30 yrs 40 yrs 50 yrs 60 yrs 70 yrs Would treat at any age Would not treat [Default] [MC Any] [MC All]

33. Relative Time on Treatment… 40 years on Rx CD4 650/ul 35 years on Rx 5 years CD4 500/ul 30 35 40 45 50 55 60 65 70 AGE (years)

35. Consequences of unchecked viral replication (Inflammation / Harm)

36. Improved tolerability / convenience of newer ARV regimens

37. Treatment reduces transmission of HIV

38. Cost Savings

40. So ….what is the harm?(Pick the most compelling reason) Destruction of lymphoid tissue Inflammation Increased Cardiovascular events Increased incidence of certain malignancies Increased ‘aging’ Accelerated cognitive decline Another reason [Default] [MC Any] [MC All]

41. Question 1 – Cognitive Differences Detected? * * Lower scores reflect better function. Trails A - Sig. Dif. for Age and HIV Trails B – Sig. Dif. For HIV

42. Question 1 – Cognitive Differences Detected? * Higher scores reflect better function. Finger Tapping - Sig. Dif. for HIV

43. Question 2 – Differences in TIADLs in Older and Younger Adults with and without HIV? * * Lower scores reflects better function. Age, HIV, and AgeXHIV effects observed.

44. Question 2 – Differences in TIADLs in Older and Younger Adults with and without HIV? * * Lower scores reflects better function. Age, HIV, and AgeXHIV effects observed for Total Score.

46. Consequences of unchecked viral replication (Inflammation / Harm)

47. Improved tolerability / convenience of newer ARV regimens

48. Treatment reduces transmission of HIV

49. Cost Savings

51. 1st Line ARV Therapy: 2003- 2007 McKinnell, et al, AIDS Pt Care & STDs, 2010

52. Does treating HIV lead to reduced transmission of HIV? Yes No Depends on the sexual practices! [Default] [MC Any] [MC All]

53. Most New Infections Transmitted by Persons who Do Not Know Their Status account for… ~25% Unaware of Infection ~54% New Infections ~75% Aware of Infection ~46% of New Infections Source: G. Marks et al. AIDS 2006

54. <400 <400 <400 >50 000 >50 000 >50 000 400-3499 400-3499 400-3499 3500-9999 3500-9999 3500-9999 10 000-49 999 10 000-49 999 10 000-49 999 TNT: Based on the association of viral load and HIV transmission risk 30 Female-to-Male Transmission Male-to-Female Transmission All subjects 25 20 15 Transmission rate per 100 Person-Years 10 5 0 Viral load (HIV-1 RNA copies/mL) and HIV transmission Quinn TC, et al.NEJM 2000; also Fideli U, et al. AIDS Res Hum Retrovir 2001

56. Consequences of unchecked viral replication (Inflammation / Harm)

57. Improved tolerability / convenience of newer ARV regimens

58. Treatment reduces transmission of HIV

59. Cost Savings

62. Consequences of unchecked viral replication (Inflammation / Harm)

63. Improved tolerability / convenience of newer ARV regimens

64. Treatment reduces transmission of HIV

65. Cost Savings

67. Case 1 30 yo white man Diagnosed on routine insurance examination PMHx remarkable for HTN, diet controlled No medications Understands treatment issues and wants to begin therapy if you think it is appropriate

68. If his viral load is 30,000 c/ml, at which CD4 count would you recommend starting therapy? 750 cells / ul 500 cells / ul 350 cells / ul 300 cells / ul 250 cells / ul ≤ 200 cells / ul Would observe Would treat at any CD4 count [Default] [MC Any] [MC All]

69. START (Strategic Timing of ART) Study INSIGHT Network: multinational Study population: adults with CD4 >500 Study treatment: Immediate ART CD4 <350 Study endpoints: Serious AIDS-defining illness, non-AIDS illness, death Sample size: N=900 (pilot for feasibility) N=4000 (definitive) Duration: ~6 yrs. http://insight.ccbr.umn.edu/official_documents/START/protocol_documents/START_ProtocolSynopsis.pdf

70. CD4 Count at Initiation of ARV 2003-2005 Egger M, 14th CROI; 2007; Abstract 62.

71. Which of the following convinces you MOST to start therapy earlier in course of HIV infection? Cohort Study Results (NA-ACCORD / ART-CC) Consequences of unchecked viral replication (inflammation / harm) Improved tolerability / convenience of newer ARV regimens Treatment reduces transmission of HIV Cost savings I have my own personal reasons! [Default] [MC Any] [MC All]

72. Case 1 30 yo White Male Diagnosed on routine insurance examination PMHx remarkable for HTN, diet controlled No medications Understands treatment issues and wants to begin therapy if you think it is appropriate

73. If his viral load is 30,000 c/ml, at which CD4 count would you recommend starting therapy? 750 cells / ul 500 cells / ul 350 cells / ul 300 cells / ul 250 cells / ul ≤200 cells / ul Would observe Would treat at any CD4 count [Default] [MC Any] [MC All]

74. END of SESSION 1