1. Adherence in TLC+: The Sticky Wicket Michael S. Saag, MD Center for AIDS Research University of Alabama at Birmingham USA

2. One Mans Journey to Adherence: Michael S. Saag, MD Center for AIDS Research University of Alabama at Birmingham USA Lessons from a Career Path in HIV Research

3. Disclosures Grant Support / Consulting Ardea Avexa Boehringer-Ingelheim Bristol-Myers Squibb Gilead Sciences GlaxoSmithKline /ViiV Merck Pain Therapeutics Pfizer / ViiV Progenics Tibotec / Virco Tobria

4. Translational Research

5. M Saag, UAB

6. Piatak, et al, Science, 1993

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

11. At steady state, when an actively producing cell dies, it is replaced by how many newly infected cells? 1.One 2.Twenty – Five 3.One Hundred 4.One Thousand 5.It depends on the viral load

12. M Saag, UAB

13. VL = 100,000

14. VL < 50

23. Clinical Trials

24. Slide #24 How Did We Get Here? Sequential exposure to effective monotherapy in a population of largely adherent, aggressively treated patients created a cohort of individuals with highly-resistant HIV 1996 1997 1998 1999 2000 ZDV NVP 3TC EFV LPV ddI SQVRTV ABC TDF d4T IDVNFV

25. Slide #25 New HAART Era After years of sequential monotherapy many patients with MDR are now entering a period where more than one new medication may be readily available 2004 2005 2006 2007 2008 2009 T20 TPVDRV Maraviroc, Raltegravir Etravirine

26. Slide #26 1009090 % RESPONSE 0 607070 80 1010 2020 3030 4040 5050 Bartlett, JA, et al Abst # 586 CROI 2005

27. Outcomes Research

28. MEDICAL INFORMATICS The FUTURE:

31. 8 Year Survival in HAART Era Updated from Chen, et al, 8 th CROI, 2001

32. CD4 Count at HAART Initiation Median CD4 % CD4 < 200 1996115 62.8% 1997180 53.8% 1998221 47.8% 1999212 49.3% 2000197 50.1% 2001277 39.5% 2002210 48.8% 2003220 47.2% 2004207 49.1% Median CD4 % CD4 < 200 2005278 39.6% 2006300 35.4% 2007296 35.2% 2008310 29.4%

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

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

35. Lancet 2009; 373:48-57 2009 WHO model

36. Slide #36 Test and Treat 21% of HIV-infected individuals in the U.S. are undiagnosed Role in reducing HIV transmission Campsmith M et al. MMWR 2008;57:1073-76, Gardner et al. AIDS 2005;19:423-431, Marks et al. AIDS 2006;20: 1447-50, Fleming et al. 9th CROI 2002, abstract 11, Metsch et al. Clin Infect Dis 2008;47:577-584, Cohen at al. Ann Intern Med 2007;146:591-601, Diffenbach & Fauci. JAMA 2009;301:2380-82 …dont forget Engagement

37. Slide #37 Test and Treat 24-44% fail to enter care w/in 6 mos. 33% with known HIV NOT in regular care 21% of HIV-infected individuals in the U.S. are undiagnosed Role in reducing HIV transmission Campsmith M et al. MMWR 2008;57:1073-76, Gardner et al. AIDS 2005;19:423-431, Marks et al. AIDS 2006;20: 1447-50, Fleming et al. 9th CROI 2002, abstract 11, Metsch et al. Clin Infect Dis 2008;47:577-584, Cohen at al. Ann Intern Med 2007;146:591-601, Diffenbach & Fauci. JAMA 2009;301:2380-82 …dont forget Engagement

38. Slide #38 Celebrate Make a plan Identify a Need Name It Empower Others Join You to Emerge Challenges New Client- Oriented New Patient Navigation to Encourage Connection to Treatment Project CONNECT

39. Slide #39 CONNECT: Program Evaluation Time PeriodNo ShowUnadjusted OR (95%CI) Adjusted OR (95%CI) a Pre-CONNECT (n=522) Post-CONNECT (n=361) 30.7% 17.7% 1.0 0.48 (0.35-0.68) 1.0 0.54 (0.38-0.76) a Multivariable model controls for age, race, sex, insurance, location of residence and time from call to scheduled visit. Wylie et al. 4 th International Conference on HIV Treatment Adherence 2009

40. Slide #40 Mugavero, Davila, Nevin & Giordano; 4th International Conference on HIV Treatment Adherence 2009 Missed Visits Appt. Adherence Visit Constancy Gap in Care HRSA HAB Measure Patient AYes; 180%100%NoYes Patient BYes; 433%50%Yes Patient CNo; 0100%75%NoYes Patient DYes; 167%25%YesNo

41. Slide #41 Missed Visits and Mortality CharacteristicHR (95%CI) a Missed visit in 1 st year2.90 (1.28- 6.56) Age (HR per 10 years)1.58 (1.12-2.22) CD4 count <200 cells/mm 3 2.70 (1.00-7.30) Log 10 plasma HIV RNA1.02 (0.75-1.39) ART started in 1 st year0.64 (0.25-1.62) a Cox proportional hazards (PH) analysis also adjusts for sex, insurance, race/ethnicity, depression, anxiety, alcohol abuse, and substance abuse. Mugavero et al. Clin Infect Dis 2009;48:248-56

42. Slide #42 Retention in Care: Challenge to Survival Giordano et al. Clin Infect Dis 2007;44:1493-1499 Quarters w/ visit (Visit Constancy) N (%) of Sample Adjusted HR (95%CI) for Mortality 41685 (64%)1.0 (Referent) 3479 (18%)1.41 (1.10-1.82) 2286 (11%)1.68 (1.24-2.26) 1169 (7%)1.94 (1.36-2.76)

43. Slide #43 Expanding the Spectrum of Adherence Mugavero. Top HIV Med 2008;16:156-61.

44. Slide #44 Expanding the Spectrum of Adherence Mugavero. Top HIV Med 2008;16:156-61.

45. Slide #45 Expanded spectrum of HIV adherence Engagement in care includes distinct steps: Linkage, Retention and Re-engagement Engagement in care vital for HIV treatment success at individual & population level Early missed visits may identify patients at risk for poor long-term health outcomes Engagement worse in groups bearing a disproportionate burden of US HIV epidemic Summary

46. Slide #46 Incorporate adherence to care counseling into patient encounters as a matter of routine Evaluate no show phenomenon at the clinic level & revise new patient orientation Develop partnerships with local HIV testing, clinical & supportive service providers Integrate HIV testing and linkage activities Coordinate activities around retention and re-engagement for shared patients What Can We Do?

47. Slide #47 Thanks UAB 1917 Clinic Cohort supported by UAB CFAR (P30AI27767), CNICS (R24AI067039), and the Mary Fisher CARE Fund; MJM supported by NIMH (K23MH082641) & CDC