1. Adherence Interventions to Improve HIV Treatment Outcomes David R Bangsberg Massachusetts General Hospital Center for Global Health Harvard Medical School Harvard Initiative for Global Health June, 2010

2. Outline Adherence goals Simple stuff to improve adherence RCT intervention summary RCT intervention highlights Cost effectiveness of ART adherence interventions Future directions in adherence interventions

3. MEMS Adherence and Viral Suppression Paterson DL, et al. Ann Intern Med. 2000;133:21-30.  

4. NNRTI Lead to Better Viral Suppression (<400 copies/ml) than Unboosted PIs at Moderate Electronic Medication Monitor Adherence n=65 p=0.01 Bangsberg CID 2006 : 43:939-41

5. Stopping drugs with different half lives 0244836 12 Time (hours) Drug concentration Zone of potential replication IC 90 IC 50 Last Dose Day 1 Day 2 MONOTHERAPY S. Taylor et al. 11th CROI Abs 131

6. NNRTI Resistance and Treatment Discontinuation Parienti et al CID 2004:38:1311-6 No. patients at Risk ≤1 drug holiday52473830194 >= 2 drug holidays1917131061

7. The Risk of Virologic Failure Decreases with Duration of Continuous Viral Suppression in 221 Suppressed Patients M. Rosenblum et al PLOS One 2009

8. Adherence Goals Goals –Prevent HIV-related mortality –Prevent evolution of drug resistance Sustain adherence above 70% Prevent treatment interruptions on NNRTI based therapy –Adherence is important all the time, but especially important after initiating treatment

9. Outline Adherence goals Simple stuff to improve adherence RCT intervention summary RCT intervention highlights Cost effectiveness of ART adherence interventions Future directions in adherence interventions

10. Pill box organizers improve adherence and reduce viral load ML Petersen et al Clin Infect Dis. 2007 Oct 1;45(7):908-15 MSM Estimator Difference in % Adherence 95% CIDifference in Log VL 95% CIOR VL<400 95% CI G-Comp 4.5% (2.0, 7.0) -0.34 (0.08, 0.60) 1.81 (1.25, 2.62) IPTW 4.1% (0.0, 8.3) -0.37 (0.05, 0.69) 1.91 (1.27, 2.90) Double Robust 4.1% (1.1, 7.1) -0.36 (0.09, 0.63) 1.91 (1.27, 2.90) 4% better adherence 1.9 odds better viral suppression $5.00/pill box: extremely cost-effective intervention Should be standard-of-care

11. A single tablet regimen is associated with higher adherence and viral suppression than multiple tablet regimens in homeless and marginally housed individuals. Bangsberg et al CROI 2010 Unannounced pill count adherenceProportion VL<400 c/ml

12. Outline Adherence goals Simple stuff to improve adherence RCT intervention summary RCT intervention highlights Cost effectiveness of ART adherence interventions Future directions in adherence interventions

13. RCT Adherence Interventions Meta-analyses/Systematic reviews J Simoni et al JAIDS 2006 Dec 1;43 Suppl 1:S23-35 Amico et al JAIDS 2006 41:285-297 Simoni, Amico et al Curr HIV/AIDS Rep (2010) 7:44–51

14. 95% Adherence at First Follow-up J Simoni et al JAIDS 2006 Dec 1;43 Suppl 1:S23-35 Study Intervention Control OR (95% CI) (n/N) (n/N) DiIorio 8/8 6/99.29 (3.15, 27.35) Knobel 46/60 58/1102.95 (2.32, 3.76) Margolin 23/3712/32 2.74 (1.03, 7.28) Weber 21/31 12/272.42 (0.78, 7.52) Safren-life 16/30 8/262.30 (1.42, 3.74) Remien 30/86 18/952.30 (1.82, 2.90) Rathbun 6/16 4/171.94 (1.16, 3.25) Pradier 75/64 62/701.92 (1.56, 2.36) Tuldra 37/40 35/651.76 (1.05, 2.95) Murphy 14/1711/141.27 (0.69, 2.35) Andrade 14/32 12/321.25 (0.44, 3.53) Rawlings 15/5118/571.13 (0.88, 1.46) Samet 33/53 40/650.96 (0.74, 1.24) Goujard 86/101 73/85 0.94 (0.71, 1.25) Jones 40/92 40/820.79 (0.43, 1.43) Rigsby 4/15 4/12 0.75 (0.43, 1.33) Safren-pager 1/34 1/360.62 (.02, 19.33) Rotheram 15/19 12/13 0.30 (0.14, 0.67) Overall 484/786 426/847 1.50 (1.16,1.94) 0.010.101.0010.00 100.00 OR=1.5 (1.16-1.94)

15. Study Intervention Control OR (95% CI) (n/N) (n/N) Rathbun 16/16 12/17 13.48 (4.81, 37.79) Smith 7/115/13 2.90 (1.64, 5.14) Tuldra 22/28 17/26 2.03 (1.33, 3.07) Knobel 39/60 60/110 1.55 (1.24, 1.94) Pradier 79/123 65/121 1.51 (1.27, 1.81) Goujard 49/77 37/62 1.21 (0.96, 1.54) Rawlings 53/66 43/54 1.13 (0.88, 1.46) Remien 37/86 39/95 1.09 (0.89, 1.33) Samet 19/31 24/38 0.96 (0.69, 1.34) Andrade 10/29 11/29 0.86 (0.60, 1.25) Rigsby 3/15 3/12 0.84 (0.44, 1.58) Margolin 11/25 11/20 0.64 (0.43, 0.97) Weber 27/29 23/24 0.58 (0.25, 1.35) Rotheram 4/9 2/3 0.52 (0.21, 1.29) Overall 376/605 352/642 1.25 (.99, 1.59) Undetectable VL Post-Intervention J Simoni et al JAIDS 2006 Dec 1;43 Suppl 1:S23-35 OR 1.25 (.99-1.59)

16. Efficacy of Antiretroviral Therapy Adherence Interventions: A Research Synthesis of Trials, 1996 to 2004 Amico et al JAIDS 2006 41:285-297 Intervention effect stronger for studies that selected for incomplete adherence

17. Simoni and Amico Synthesis Interactive, open-ended, and multidisciplinary –pharmacist, case manager, physician, family/partner –education, behavioral skills, motivation/cognition expectations, reminders Multiple sessions Greatest effect in the least adherent Doesn’t last much beyond the intervention More recent interventions may be less likely to find virologic benefit

18. Outline Adherence goals Simple stuff to improve adherence RCT intervention summary RCT intervention highlights Cost effectiveness of ART adherence interventions Future directions in adherence interventions

19. 92.8% 88.9% Interventions Prevent a Decline in Adherence Cognitive behavior intervention on adherence to ARV therapy Weber et al Antiviral Therapy 2004:9:85

20. Couple-focused support to improve HIV medication adherence: a randomized controlled trial Remien et al AIDS 2005:19:807-814 Serodiscordant couple >6 months 2 week MEMS adherence monitor screen –Eligible if <80% adherence Four 45-60 minutes sessions –Structured discussion and education about adherence to identify barriers –Problem solving to overcome barriers –Couple communication exercises to optimize partner support MEMS Adherence and VL over 6 months

21. Proportion Adherent at 3 Levels Couple-focused support to improve HIV medication adherence: a randomized controlled trial Remien et al AIDS 2005:19:807-814

22. ACTG 731: A Multi-site Randomized Controlled Trial of Weekly Nursing Telephone Support to Improve ARV Adherence Reynolds et al JAIDS 2008 Content: –Patient-centered—elicits patient perspective and addresses patient’s biological, social and cultural realities Mode: –Fits clinical environment of care –Provides “safety feature” in context of home –Suitable to persons with lower levels of literacy –Takes advantage of training of nurses who are widely available in different clinic settings

23. ACTG 731. Nurse-Delivered Telephone Intervention A better overall treatment effect was observed in the treated (telephone group) (p = 0.023) in comparison with standard care Reynolds et al., JAIDS, 2008

24. Home Visits to Improve Adherence to Highly Active Antiretroviral Therapy: A Randomized Controlled Trial Williams et al JAIDS 2006:42:314-321 RCT community based home visits vs standard care –Paulo Freire: True learning occurs through dialogue and participation among equals –24 home visits over 12 months: identify concerns, individuals, social factors –Outcome: MEMS adherence and HIV VL

25. Home Visits to Improve Adherence to Highly Active Antiretroviral Therapy: A Randomized Controlled Trial Williams et al JAIDS 2006:42:314-321 Proportion MEMS Adherence >90% No difference in VL or CD4 between groups (54 vs 52% ND)

26. Cognitive Behavioral Therapy For Improving Adherence and Depression Safren et al Health Psychology in Press 2 Arm, cross-over design comparing 12 sessions of CBT-AD to a single session of adherence counseling Participants: 45 randomized, 42 completers with DSM-IV diagnosable depression CBT-AD resulted in improved adherence (MEMS) and depression at three months, and maintains were gained at 6 and 12 months. ITT ANCOVA, F(1,42) = 21.94, p<.0001, Effect size (Cohen d) = 1.0 Three-month (acute) outcome depicted above Pattern of results similar ITT and completer analyses

27. Directly Assisted Antiretroviral Therapy Not effective for “all-comers” (Wohl CID 2006, Ford Lancet 2009) Effective in active drug users and methadone maintenance (Macalino AIDS 2007, Altice CID 2007, Lucas CID 2004) Does not last beyond intervention Exit strategy and relapse remain a challenge

28. Outline Adherence goals Simple stuff to improve adherence RCT intervention summary RCT intervention highlights Cost effectiveness of ART adherence interventions Future directions in adherence interventions

29. Adherence Interventions are Cost Effective Goldie et al AJM 2003

30. Outline Adherence goals Simple stuff to improve adherence RCT intervention summary RCT intervention highlights Cost effectiveness of ART adherence interventions Future directions in adherence interventions

31. Duration of MEMS Defined Treatment Interruption and Probability of NNRTI Resistance Parienti and Bangsberg PLOS One 2008 + Controls O Cases Estimated 95% confidence interval Longer interval of treatment discontinuation in days Estimated probability of viral control

32. Real-time Adherence Monitoring Bangsberg and Deeks Annal Int Med 2010

33. Adherence Intervention Summary Goals of adherence are changing –>80% and no sustained interruptions –Preventing the decline in adherence Most effective interventions: educational, motivational, open-ended, interactive sessions to identify barriers and develop behavioral skills Intensive interventions for high risk patients Real-time monitoring: reactive response to proactive prevention of treatment resistant failure