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Impact of Electronic Drug Impact of Electronic Drug Monitoring Feedback on Adherence Monitoring Feedback on Adherence

to Antiretroviral Therapyto Antiretroviral Therapy

April 6, 2009April 6, 2009

Lora SabinLora SabinCenter for International Health Center for International Health

and Developmentand Development

Boston UniversityBoston University

China Adherence For Life (AFL) China Adherence For Life (AFL) study collaboratorsstudy collaborators

Boston University SPHBoston University SPH• Lora Sabin, MA, PhDLora Sabin, MA, PhD• Christopher J. Gill, MS, MDChristopher J. Gill, MS, MD• Mary B. DeSilva, MS, ScDMary B. DeSilva, MS, ScD• Davidson H. Hamer, MDDavidson H. Hamer, MD

Tufts-New England Medical Tufts-New England Medical CenterCenter

• Ira Wilson, MS MDIra Wilson, MS MD

Funding provided by: USAID, WHO/Beijing, US CDCFunding provided by: USAID, WHO/Beijing, US CDCAdditional acknowledgments: Additional acknowledgments:

Don Thea, Jon Simon, Deirdre Pierotti, Mini Singh, Anna Knapp, James Chen, Wan-Don Thea, Jon Simon, Deirdre Pierotti, Mini Singh, Anna Knapp, James Chen, Wan-ju Wu, Guo Jianhua, Matt Bobo, Ahmar Hashmi, and Jordan Tuchman ju Wu, Guo Jianhua, Matt Bobo, Ahmar Hashmi, and Jordan Tuchman

Ditan Hospital, BeijingDitan Hospital, Beijing• Xu Keyi, MDXu Keyi, MD

Dali Second People’s Dali Second People’s Hospital, DaliHospital, Dali

• Zhang Jianbo, MDZhang Jianbo, MD

Horizon Research Group, Horizon Research Group, BeijingBeijing

• Yuan Yue, MA, PhDYuan Yue, MA, PhD• Fan Wen, MAFan Wen, MA• Li Tao, MALi Tao, MA

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BackgroundBackground

• China is rapidly scaling up ART, but treatment China is rapidly scaling up ART, but treatment programs are at an early stage:programs are at an early stage:• Little is known about levels of adherence, Little is known about levels of adherence,

particularly among IDUs and former IDUsparticularly among IDUs and former IDUs• Little is understood about how to improve Little is understood about how to improve

adherenceadherence• Drug resistance is rising, and there are fears about Drug resistance is rising, and there are fears about

the cost and availability of 2the cost and availability of 2ndnd and 3 and 3rdrd line regimens line regimens

• As in other countries, there is an urgent need As in other countries, there is an urgent need for interventions that are effective in improving for interventions that are effective in improving adherence among HIV-positive patientsadherence among HIV-positive patients

The relationship between ART adherence The relationship between ART adherence and HIV outcomes was deduced using and HIV outcomes was deduced using

electronic drug monitors (EDM)electronic drug monitors (EDM)

• EDM pill bottles have an EDM pill bottles have an embedded microchip in the embedded microchip in the capcap

– Time/date stamps each Time/date stamps each bottle openingbottle opening

– Surrogate marker for Surrogate marker for adherence adherence

• Comparative studies show Comparative studies show that EDM are by far the that EDM are by far the best measure of adherence best measure of adherence available. available.

STUDY QUESTION:STUDY QUESTION:

Can we improve adherence Can we improve adherence to ART using Electronic to ART using Electronic

Drug Monitor (EDM) Drug Monitor (EDM) feedback?feedback?

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Overview of AFLOverview of AFL

(Control)

Continued passive observation

(Intervention)

Active EDM feedback

Adherence observed prospectively via EDM,

relationship between barriers and actual adherence, clinical

outcomes measured

Phase I6 months

Phase II6 months

Phase III6 months

Qualitative investigations on what patients/doctors in Dali

view as key barriers to adherence

Randomized controlled trial to determine effectiveness of EDM

feedback strategy

N=80Patients enrolled

N=68Patients randomized

Study siteStudy site, Dali, Yunnan Province, Dali, Yunnan Province

Yunnan province

Dali

Study populationStudy population

• HIV epidemic driven by injectable drug useHIV epidemic driven by injectable drug use

• Lesser contribution from commercial sex Lesser contribution from commercial sex workwork

• Minimal spread into larger populationMinimal spread into larger population

AFL Study objectivesAFL Study objectives

1.1. Primary ObjectivePrimary Objective To determine effect of EDM feedback on adherence To determine effect of EDM feedback on adherence ratesrates

2.2. Secondary ObjectivesSecondary Objectives To determine effect of EDM feedback on CD4-cell counts To determine effect of EDM feedback on CD4-cell counts and undetectable viral loads (UDVL)and undetectable viral loads (UDVL)

The study was powered to detect a 15% difference in The study was powered to detect a 15% difference in adherence rates, as assessed by EDMadherence rates, as assessed by EDM

Randomization ProcedureRandomization Procedure

• Block stratified randomization Block stratified randomization • At end of Phase I, patients stratified by ‘high’ or At end of Phase I, patients stratified by ‘high’ or

‘low’ adherence ‘low’ adherence • ≥≥95% = ‘high adherence’95% = ‘high adherence’

• <95% = ‘low adherence’<95% = ‘low adherence’

• Based on average adherence during the 5 months prior Based on average adherence during the 5 months prior to randomizationto randomization

• Equal numbers of patients allocated from within Equal numbers of patients allocated from within each adherence stratumeach adherence stratum

• Ensured balanced allocation at start of interventionEnsured balanced allocation at start of intervention

What happened in intervention What happened in intervention group?group?

• EDM dataEDM data reviewed at each monthly study visit reviewed at each monthly study visit• Patients with <95% adherence Patients with <95% adherence by EDM in previous monthby EDM in previous month

flagged for “additional adherence counseling”flagged for “additional adherence counseling”

• EDM report given to doctor and patient at each visitEDM report given to doctor and patient at each visit• % doses taken% doses taken

• % on time% on time

• Histogram readoutHistogram readout

• Additional counseling had no fixed script Additional counseling had no fixed script • involved a conversation between doctor and patient in involved a conversation between doctor and patient in

which doctor asked about problems or challenges, which doctor asked about problems or challenges, referring to EDM print-outreferring to EDM print-out

What happened in control group?What happened in control group?

• Self-report dataSelf-report data reviewed at each monthly visit reviewed at each monthly visit• EDM data EDM data notnot provided to doctor/patient provided to doctor/patient

• Patients with <95% adherence Patients with <95% adherence by self report in by self report in previous monthprevious month flagged for “additional adherence flagged for “additional adherence counseling” counseling” • Like intervention arm, additional counseling involved a Like intervention arm, additional counseling involved a

conversation in which doctor asked about problems or conversation in which doctor asked about problems or challenges faced, challenges faced, referring to patient’s self-reportreferring to patient’s self-report

Definition of Primary Outcome Definition of Primary Outcome MetricMetric

Composite EDM measure includes proportion taken and timing of

doses:

# doses taken +/- 1 hour of scheduled time

# prescribed doses

Clinical measuresClinical measures

• CD4-cell count• Undetectable Viral load (UDVL)

(Using RT PCR: <400 copies/ml = “undetectable”

RESULTSRESULTS

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Patient Characteristics at randomization (Mo. 6)Patient Characteristics at randomization (Mo. 6)

* Statistically significant at the p<0.01 level

Characteristic Number (%) Mean (SD) Number (%) Mean (SD)

Gender Male 25 (74) 25 (74) Female 9 (26) 9 (26)

Age (Mean, SD) 36.1 (8.3) 35.1 (8.0)

Education* Elementary 7 (21) 13 (38) Junior high 17 (50) 20 (59) Senior high/technical school 10 (29) 1 (3)

Marital status Single 15 (44) 16 (47) Married 19 (56) 18 (53)

Ethnic background Han Chinese 18 (53) 15 (44) Bai 14 (41) 17 (50) Other 2 (6) 2 (6)

Household size 4.2 (1.5) 4.5 (1.4)

Employment status Currently employed 10 (31) 12 (37) Currently unemployed 22 (69) 20 (63)

ControlIntervention

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Patient Characteristics at randomization (Mo. 6)Patient Characteristics at randomization (Mo. 6)

** basis for block randomization procedure

Characteristic Number (%) Mean (SD) Number (%) Mean (SD)

Heroin use in previous 3 mos Yes 4 (12) 5 (15) No 30 (88) 29 (85)

Depression (Beck's, continuous) 9.8 (3.6) 10.2 (4.0)

Depression (Beck's, binary) Yes 6 (18) 10 (30) No 27 (82) 23 (70)

CD4, Month 6 (continuous) 297 (145) 357 (196)

UDVL, Month 6 (yes) 30 (88.2) 28 (87.5)

Mean adherence, Months 0-5**

High (>= 95%) 16 (47) 17 (50) Low (<95%) 18 (53) 17 (50)

Intervention Control

*p<0.05 ** p<0.01At Month 6, no significant differences between intervention and control groups

At Month 12, large increase in adherence in intervention arm; no significant increase in control arm.

Point Adherence at Months 6 and 12Point Adherence at Months 6 and 12

** p<0.01At Month 6, no significant differences between intervention and control groups (in Months 1-6 adherence)

Large increase in adherence in Months 7-12 in intervention arm; no significant increase in control arm.

Mean adherence over time, periods 1 and 2Mean adherence over time, periods 1 and 2

Achievement of mean adherence Achievement of mean adherence ≥95% throughout Months 7-12≥95% throughout Months 7-12

InterventionInterventionn/N (%)n/N (%)

ControlControln/N (%)n/N (%)

23/31 (74)23/31 (74) 11/33 (33)11/33 (33)

RR = 2.23RR = 2.23(95% CI 1.3-3.8)(95% CI 1.3-3.8)

***p=0.001

Composite Adherence by group and timeComposite Adherence by group and time

50%

55%

60%

65%

70%

75%

80%

85%

90%

95%

100%

1 2 3 4 5 6 7 8 9 10 11 12

Month

Ad

he

ren

ce

Low adherers, intervention group

Low adherers, control group

High adherers, intervention group

High adherers, control group

Clinical outcomes: Changes in CD4-cell Clinical outcomes: Changes in CD4-cell counts between months 6 and 12counts between months 6 and 12

InterventionInterventionNo. (%)No. (%)

ControlControlNo. (%)No. (%)

Proportion with CD4 Proportion with CD4 increase, months 6-increase, months 6-1212

22/3122/31(71%)(71%)

15/3115/31(48%)(48%)

RR 1.5 (1.0-2.2) RR 1.5 (1.0-2.2) p=0.072p=0.072

Mean change in CD4 Mean change in CD4 (x1000 cells/ml)(x1000 cells/ml)

+ 90+ 90 - 9- 9

p=0.020p=0.020

Note: regarding UDVL: little change from Month 6

Patient-level EDM view: Patient-level EDM view: A near perfect patient profileA near perfect patient profile

Patient-level EDM view: Patient-level EDM view: A patient with poor adherence A patient with poor adherence

Patient-level EDM view: Patient-level EDM view: A patient with improved adherence A patient with improved adherence

6 months

Pre-intervention phase

Intervention phase

Main FindingsMain Findings• EDM feedback improved ART adherenceEDM feedback improved ART adherence

• Adherence rise was prompt and sustainedAdherence rise was prompt and sustained• Intervention arm: adherence improved Intervention arm: adherence improved

• Control arm: adherence stayed steady with a falling trendControl arm: adherence stayed steady with a falling trend

• Effect seen in both Month 6 v. Month 12 point comparisons and in Effect seen in both Month 6 v. Month 12 point comparisons and in pre-intervention v intervention phase comparisonspre-intervention v intervention phase comparisons

• Patients more likely to achieve ≥95% adherencePatients more likely to achieve ≥95% adherence

• EDM feedback improved clinical outcomesEDM feedback improved clinical outcomes• CD4-cell counts rose significantlyCD4-cell counts rose significantly

• Trend towards higher proportion of rising CD4s among Trend towards higher proportion of rising CD4s among intervention armintervention arm

• EDM feedback is a promising intervention – it warrants EDM feedback is a promising intervention – it warrants further evaluation in other populationsfurther evaluation in other populations

Thank you for Thank you for your attentionyour attention

Any Any questions?questions?