Adherence in TLC+: The Sticky Wicket Michael S. Saag, MD Center for AIDS Research University of Alabama at Birmingham USA One Man’s Journey to Adherence: Lessons from a Career Path in HIV Research Michael S. Saag, MD Center for AIDS Research University of Alabama at Birmingham USA Disclosures Grant Support / Consulting • • • • • • Ardea Avexa Boehringer-Ingelheim Bristol-Myers Squibb Gilead Sciences GlaxoSmithKline /ViiV • Merck • • • • • Pain Therapeutics Pfizer / ViiV Progenics Tibotec / Virco Tobria Translational Research M Saag, UAB Piatak, et al, Science, 1993 106 105 104 Viral Load 103 102 101 T1/2 = 1.1 days 0 2 4 6 Weeks 8 10 12 Latently Infected CD4+ Lymphocytes 103 104 HIV virions 102 Viral Load 105 106 HIV Infected Cells 101 T1/2 = 1.1 days 0 2 4 6 Weeks 8 10 12 Antiretroviral Rx Uninfected Activated CD4+ Lymphocytes M Saag, UAB Uninfected Resting CD4+ Lymphocytes RNA+ cells in Lymph node vs RNA in Plasma Plasma Viral Load (copies/ml) 10000000 1000000 100000 10000 1000 100 <50 10 0.1 1 10 100 1000 HIV RNA+ cells/106 LN cells 10000 At steady state, when an actively producing cell dies, it is replaced by how many newly infected cells? 1. 2. 3. 4. 5. One Twenty – Five One Hundred One Thousand It depends on the viral load M Saag, UAB VL = 100,000 VL < 50 106 105 104 Viral Load 103 102 101 T1/2 = 1.1 days 0 2 4 6 Weeks 8 10 12 Clinical Trials 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 ZDV NVP 3TC ddI SQV RTV d4T IDV 1996 2000 EFV ABC LPV TDF NFV 1997 1998 1999 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 T20 2004 2009 TPV 2005 DRV Maraviroc, Raltegravir Etravirine 2006 2007 2008 Slide #26 0 1 0 2 0 3 4 60 5 0 % RESPONSE 0 0 7 0 80 9 0 100 Bartlett, JA, et al Abst # 586 CROI 2005 Outcomes Research The FUTURE: MEDICAL INFORMATICS 8 Year Survival in HAART Era Updated from Chen, et al, 8th CROI, 2001 CD4 Count at HAART Initiation 1996 1997 1998 1999 2000 2001 2002 2003 2004 Median CD4 % CD4 < 200 115 180 221 212 197 277 210 220 207 62.8% 53.8% 47.8% 49.3% 50.1% 39.5% 48.8% 47.2% 49.1% 2005 2006 2007 2008 Median CD4 % CD4 < 200 278 300 296 310 39.6% 35.4% 35.2% 29.4% Most New Infections Transmitted by Persons who Do Not Know Their Status ~25% Unaware of Infection account for… ~75% Aware of Infection Source: G. Marks et al. AIDS 2006 ~54% New Infections ~46% of New Infections 30 Female-to-Male Transmission Male-to-Female Transmission All subjects 25 20 15 10 >50 000 10 000-49 999 3500-9999 400-3499 <400 >50 000 10 000-49 999 3500-9999 400-3499 <400 >50 000 10 000-49 999 3500-9999 0 400-3499 5 <400 Transmission rate per 100 Person-Years TNT: Based on the association of viral load and HIV transmission risk 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 2009 WHO model Lancet 2009; 373:48-57 Slide #36 Test and Treat…don’t forget Engagement 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 Slide #37 Test and Treat…don’t forget Engagement 33% with known HIV NOT in regular care 24-44% fail to enter care w/in 6 mos. 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 Slide #38 Project CONNECT ClientOriented New Patient Navigation to Encourage Connection to Treatment New Identify a Challenges Need Emerge Name It Make a plan Empower Others to Join You Celebrate Slide #39 CONNECT: Program Evaluation Time Period “No Show” Unadjusted OR (95%CI) Adjusted OR (95%CI)a Pre-CONNECT (n=522) 30.7% 1.0 1.0 Post-CONNECT (n=361) 17.7% 0.48 (0.35-0.68) 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. 4th International Conference on HIV Treatment Adherence 2009 Slide #40 Missed Visits Appt. Visit Gap in Adherence Constancy Care HRSA HAB Measure Patient A Yes; 1 80% 100% No Yes Patient B Yes; 4 33% 50% Yes Yes Patient C No; 0 100% 75% No Yes Patient D Yes; 1 67% 25% Yes No Mugavero, Davila, Nevin & Giordano; 4th International Conference on HIV Treatment Adherence 2009 Slide #41 Missed Visits and Mortality Characteristic HR (95%CI)a Missed visit in 1st year Age (HR per 10 years) CD4 count <200 cells/mm3 Log10 plasma HIV RNA 2.90 (1.28- 6.56) 1.58 (1.12-2.22) 2.70 (1.00-7.30) 1.02 (0.75-1.39) ART started in 1st year 0.64 (0.25-1.62) Cox proportional hazards (PH) analysis also adjusts for sex, insurance, race/ethnicity, depression, anxiety, alcohol abuse, and substance abuse. a Mugavero et al. Clin Infect Dis 2009;48:248-56 Slide #42 Retention in Care: Challenge to Survival Quarters w/ visit (Visit Constancy) N (%) of Sample Adjusted HR (95%CI) for Mortality 4 1685 (64%) 1.0 (Referent) 3 479 (18%) 1.41 (1.10-1.82) 2 286 (11%) 1.68 (1.24-2.26) 1 169 (7%) 1.94 (1.36-2.76) Giordano et al. Clin Infect Dis 2007;44:1493-1499 Slide #43 Expanding the Spectrum of Adherence % of Sample 40 30 20 10 0 <50 50-59 60-69 70-79 80-89 90-99 Appo intment Adherence (%) Mugavero. Top HIV Med 2008;16:156-61. 100 Slide #44 % with VL<50c/mL Expanding the Spectrum of Adherence 100 80 60 40 20 0 <50 50-59 60-69 70-79 80-89 90-99 Appo intment Adherence (%) Mugavero. Top HIV Med 2008;16:156-61. 100 Slide #45 Summary 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 Slide #46 What Can We Do? 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 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