Adherence Interventions to Improve HIV Treatment Outcomes

David R Bangsberg

Massachusetts General Hospital Center for Global HealthHarvard Medical School

Harvard Initiative for Global HealthJune, 2010

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

MEMS Adherence and Viral Suppression

Paterson DL, et al. Ann Intern Med. 2000;133:21-30.

19%

29% 33%

45%

78%

0%

20%

40%

60%

80%

100%

<70 70-80 80-90 90-95 95

% Adherent

% P

atie

nts

wit

h

vira

l lo

ad <

400

cop

ies/

ml

NNRTI Lead to Better Viral Suppression (<400 copies/ml) than Unboosted PIs at Moderate Electronic

Medication Monitor Adherencen=65

23%33%

67%

83%

33%

100%

86%75%

0%

20%

40%

60%

80%

100%

120%

0-53 54-73 74-93 94-100

Adherence

Per

cent

VL

<40

0 co

pies

/ml

PINNRTI

p=0.01

Bangsberg CID 2006:43:939-41

Stopping drugs with different half lives

0 24 483612

Time (hours)

Dru

g c

on

cen

trat

ion

Zone of potential replication

IC90

IC50

Last Dose

Day 1Day 1 Day 2Day 2

MONOTHERAPY

S. Taylor et al. 11th CROI Abs 131

NNRTI Resistance and Treatment DiscontinuationParienti et al CID 2004:38:1311-6

No. patients at Risk≤1 drug holiday 52 47 38 30 19 4>= 2 drug holidays 19 17 13 10 6 1

The Risk of Virologic Failure Decreases with Duration of Continuous Viral Suppression in 221 Suppressed Patients

M. Rosenblum et al PLOS One 2009

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

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

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% CI Difference in Log VL

95% CI OR 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

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

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1 2 3 4 5 6

Month

Me

an

Ah

ere

nc

e

FDC EFV/TDF/FTC NNRTI PI RPI

0

10

20

30

40

50

60

70

80

90

100

'0-49' '50-<75' '75-<80' '80-<90' '90-100'

Adherence Category

Pro

po

rtio

n V

L<

50

FDC EFV/TDF/FTCF r-PI

Unannounced pill count adherence Proportion VL<400 c/ml

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

RCT Adherence InterventionsMeta-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

95% Adherence at First Follow-upJ 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 6/9 9.29 (3.15, 27.35)

Knobel 46/60 58/110 2.95 (2.32, 3.76)

Margolin 23/37 12/32 2.74 (1.03, 7.28)

Weber 21/31 12/27 2.42 (0.78, 7.52)

Safren-life 16/30 8/26 2.30 (1.42, 3.74)

Remien 30/86 18/95 2.30 (1.82, 2.90)

Rathbun 6/16 4/17 1.94 (1.16, 3.25)

Pradier 75/64 62/70 1.92 (1.56, 2.36)

Tuldra 37/40 35/65 1.76 (1.05, 2.95)

Murphy 14/17 11/14 1.27 (0.69, 2.35)

Andrade 14/32 12/32 1.25 (0.44, 3.53)

Rawlings 15/51 18/57 1.13 (0.88, 1.46)

Samet 33/53 40/65 0.96 (0.74, 1.24)

Goujard 86/101 73/85 0.94 (0.71, 1.25)

Jones 40/92 40/82 0.79 (0.43, 1.43)

Rigsby 4/15 4/12 0.75 (0.43, 1.33)

Safren-pager 1/34 1/36 0.62 (.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)

0.01 0.10 1.00 10.00 100.00

OR=1.5 (1.16-1.94)

Study Intervention Control OR (95% CI) (n/N) (n/N)

Rathbun 16/16 12/17 13.48 (4.81, 37.79)

Smith 7/11 5/13 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)0.10 1.00 10.00 100.000.10 1.00 10.00 100.00

Undetectable VL Post-InterventionJ Simoni et al JAIDS 2006 Dec 1;43 Suppl 1:S23-35

OR 1.25 (.99-1.59)

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

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

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

0-1 2-3 4-6 7-9 10-120-1 2-3 4-6 7-9 10-1280

85

90

95

100

ControlIntervention

Dailydose

Months

Mea

n (

SE

M)

wee

kly

adh

eren

ce (

%)

92.8%

88.9%

Interventions Prevent a Decline in AdherenceCognitive behavior intervention on adherence to ARV therapy

Weber et al Antiviral Therapy 2004:9:85

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

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

ACTG 731: A Multi-site Randomized Controlled Trial of Weekly Nursing Telephone

Support to Improve ARV AdherenceReynolds 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

4 16 32 48 6495

96

97

98

99

100Control GroupIntervention Group

Figure 2: Mean (+/- SE) Adherence by Treatment Group

P= 0.023

Study Week

Per

cen

t se

lf-r

epo

rted

ad

her

ence

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

Home Visits to Improve Adherence to Highly Active Antiretroviral Therapy: A Randomized

Controlled TrialWilliams 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

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)

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.

MEMS outcomes, LECF

0

25

50

75

100

BASELINE T2

CBT ETAU

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

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

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

Adherence Interventions are Cost EffectiveGoldie et al AJM 2003

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

Duration of MEMS Defined Treatment Interruption and Probability of NNRTI Resistance

Parienti and Bangsberg PLOS One 2008

+ ControlsO Cases Estimated 95% confidence interval

Longer interval of treatment discontinuation in days

Est

ima

ted

pro

babi

lity

of v

iral c

ontr

ol

Real-time Adherence MonitoringBangsberg and Deeks Annal Int Med 2010

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