Addressing adherence challenges – what does the evidence say?

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

2. Overview… • 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?

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: • Adherence to daily treatment All tablets takenAt the correct time • Adherence to care No treatment interruptionsRetention in care

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

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. Kaplan-Meier failure estimate for time to first, then second consecutive HIV RNA level > 1000 copies/ml. 0.25 0.25 First HIV RNA > 1000 copies/ml Plus Second consecutive HIV RNA > 1000 copies/ml 0.20 0.20 0.15 0.15 Proportion of patients on program 0.10 0.10 0.05 0.05 0.00 0.00 0 0 4 4 20 20 24 24 28 28 32 32 36 36 8 8 12 12 16 16 Duration on Treatment (months) 929 641 421 328 229 162 127 86 51 Patients at Risk of starting Second Line therapy Adherence interventions can be successful Need two consecutive viral loads >1000 copies/ml for failure. Use the first >1000 copies/ml reading to intervene… Orrell, Antiviral therapy 2007

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 the body of evidence

10. Strength of Recommendations

11. 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 What works in RLS

12. 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. What works in RLS

13. 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 What works in RLS

14. 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… What works in RLS

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

16. Quality of the body of evidence

17. Strength of Recommendations

18. Medication factors: • Among regimens of similar efficacy and tolerability, once-daily regimensare 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).

19. Provider factors: 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 counselingare recommended; (II C). • Multidisciplinary education and counselingintervention approaches are recommended (III B). • Offering peer support may be considered (III C).

20. Provider factors: 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)

21. Provider factors: 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…

22. Reminder devices: • 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)

23. Reminder devices: • 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).

24. Wisepill report:

25. Provider factors: 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.

26. Adherence interventions are successful Bonner, JAIDs 2013

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

28. Patient factors: 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!)

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