1. Addressing adherence challenges – what does the evidence say? Dr Catherine Orrell Desmond Tutu HIV Foundation November 2013

2. What is adherence and why is adhering important? Which adherence interventions have been shown to work in resource limited settings? What tools can we use in our clinic that might improve adherence? Overview…

3. Why is adherence important? Antiretroviral therapy options are limited. First-line (usually NNRTI-based): easier to take; reduced adverse effects and cheaper (R95/month). Second-line (usually protease inhibitor-based): increases both tablet burden and dosing times; less well tolerated; more expensive. (R338/month)  genotyping, salvage So…maintaining people on first-line is crucial to programmatic success; minimising and delaying impact of resistance…

4. What is adherence? There are two main components: 1)Adherence to daily treatment  All tablets taken At the correct time 2)Adherence to care  No treatment interruptions Retention in care

5. Bell-shaped adherence and resistance curve Increasing probability of selecting mutation Increasing Adherence Inadequate Drug Pressure To Select Resistant Virus Drug Pressure Selects Resistant Virus Complete Viral Suppression

6. Barriers to Adherence in sub-Saharan Africa – ETOH/substance use – Depression – Memory – Side effects – Pill burden/dosing frequency – Adolescence – Transportation to clinic – Food security – Stigma – Stock-outs and substitutions – Unfriendly service Mill PLoS 2006, Oyugyi AIDS 2007, Tuller AIDS Beh 2010, Weiser JAIDS 2003; McCurdy CROI 2010, Nachega AIDS 2008, JAIDS 20090

7. Adherence interventions can be successful Orrell, Antiviral therapy 2007 Need two consecutive viral loads >1000 copies/ml for failure. Use the first >1000 copies/ml reading to intervene…

8. What works in RLS? Africa is better than developed world at adherence. (Mills, JAMA 2006 – meta-analysis) Review of recent literature - studies with comparator arms (case-control or randomised) and an adherence or biological marker as an outcome. 27 studies from resource-limited settings identified by early 2012. Bärnighausen, Lancet ID 2011 Thompson, Annals 2012

9. Quality of Body of Evidence Interpretation Excellent (I) RCT evidence without important limitations Overwhelming evidence from observational studies High (II) RCT evidence with important limitations Strong evidence from observational studies Medium (III) RCT evidence with critical limitations Observational study evidence without important limitations Low (IV) Observational study evidence with important or critical limitations Quality of the body of evidence

10. Strength of Recommendations Strength of Recommendation Strong (A) Almost all patients should receive the recommended course of action. Moderate (B)Most patients should receive the recommended course of action. However, other choices may be appropriate for some patients. Optional (C)There may be consideration for this recommendation on the basis of individual patient circumstances. Not recommended routinely.

11. What works in RLS Peer-driven group pre-treatment education benefits adherence in the first 12-18 months of ART. (BIII) No consistent method (by whom, how many sessions, how long) but all improve adherence. Peer support may improve adherence in the first 12- 18 months of ART. (BIII) 3 studies, also used DOTS – benefit in terms of adherence, but not biological outcomes

12. What works in RLS Monthly food supplementation packages improve early adherence to first-line antiretroviral therapy and are recommended. (BII) Two studies showed substantial improvement in adherence by objective adherence measures (pharmacy return, pill counts) in the first 6 or 12 months on ART.

13. What works in RLS Electronic adherence reminder devices, including mobile phone text messages, coupled with clinic contact may be effective tools to improve adherence in resource poor settings and are recommended where feasible. (AI) 4 randomised studies from Africa showed 12-13% adherence benefit in ART-naïve adults. Varying length (8 weeks to one year); most with feedback. 1 RCT: alarm only showed no benefit

14. What works in RLS Shifting the care for people on ART from doctors to nurses and peer counselors does not have a negative impact on adherence or biological outcome. Are now 3 randomised studies confirming this…

15. Develop your adherence toolkit: Medication factors - Service / provider factors – Patient factors -

16. Quality of Body of Evidence Interpretation Excellent (I) RCT evidence without important limitations Overwhelming evidence from observational studies High (II) RCT evidence with important limitations Strong evidence from observational studies Medium (III) RCT evidence with critical limitations Observational study evidence without important limitations Low (IV) Observational study evidence with important or critical limitations Quality of the body of evidence

17. Strength of Recommendations Strength of Recommendation Strong (A) Almost all patients should receive the recommended course of action. Moderate (B)Most patients should receive the recommended course of action. However, other choices may be appropriate for some patients. Optional (C)There may be consideration for this recommendation on the basis of individual patient circumstances. Not recommended routinely.

18. Among regimens of similar efficacy and tolerability, once-daily regimens are recommended for treatment-naive patients beginning ART (II B). Simplify where possible… Among regimens of equal efficacy and safety, fixed- dose combinations are recommended to decrease pill burden (III B). Medication factors:

19. Explain things! Individual one-on-one ART education is recommended (II A). Providing one-on-one adherence support to patients through 1 or more adherence counseling approaches is recommended (II A). Group education and group counseling are recommended; (II C). Multidisciplinary education and counseling intervention approaches are recommended (III B). Offering peer support may be considered (III C). Provider factors:

20. Measure adherence!! Self-reported adherence should be obtained routinely in all patients (II A) Pharmacy refill data are recommended for adherence monitoring when medication refills are not automatically sent to patients (II B) The following are not routinely recommended, but can be useful: – Drug concentrations in biological samples (III C) – Pill counts performed by staff or patients (III C) – Electronic Drug Monitors for clinical use (I C) Provider factors:

21. Remind people to take meds! Reminder devices and use of communication technologies with an interactive component are recommended (I B). Notice if a visit is missed… Provider factors:

22. Pillboxes: simple and effective intervention and should be widely used – improves adherence by ~4.5% (drop VL 0.35 log) Best for intermittent non-adherence (80-90%). Not enough of a reinforcement for those with very poor adherence. Pill box of more benefit than changing to once a day therapy. (Petersen, CID 2007) Reminder devices:

23. Wisepill: South African invention. Allows real-time adherence monitoring by GPRS. Useful in TB and HIV. ?for second-line ?replace viral load monitoring Could be developed for R120-200 per annum (and purchase costs). Reminder devices:

24. Wisepill report:

25. Use the viral load! WHO recommends VL monitoring with other adherence measures. Raised viral load indicates a risk of failure, so DO something! 56-68% can re-suppress with an adherence intervention. Provider factors:

26. Adherence interventions are successful StudyYearnInterventionOutcome Berki- Benhaddad 200615Personal adh supportAve decrease VL by 2.3 log Calmy200723 2 Counseling, pill boxes, support group, treatment partner 77% achieved VL<400 DeFino200445Counseling, pill boxes, alarm reminders, repeat education… Ave decrease VL by 0.6 log Khan201340Structured adh counseling, including families 78% achieved resuppression Orrell200743Pill box, dosing diaries, counseling, home visit 54% achieved resuppression Parker201320 0 Intensive adh counseling48% achieved resuppression Pirkle2009561 month mDAART, weekly f/u visits36% decreased VL by >1 log Wilson200940Counseling and education90% resuppression Bonner, JAIDs 2013

27. Be flexible! Appointments? Out of hours? … and be kind. Provider factors:

28. Support those at risk: Pregnant women (initiate in MOU; care with transition) The poor… Children and adolescents (pill-swallowing training; adolescent friendly services) Mentally ill (including alcohol and depression - screen for and treat!) Patient factors:

29. Summary Treatment preparedness and ongoing adherence monitoring and support is key Particular groups are at risk of poor adherence. Goal is to minimise resistance… We can do a lot with what we have already.

30. Approaches to managing adherence Annals of Internal Medicine, 2012

31. Acknowledgements Melanie Thompson and IAPAC guideline team Dr Jean Nachega for some slides Desmond Tutu HIV Centre team