Sustained Benefit from a Longterm Antiretroviral AR Adherence Intervention: Results of a Large Rando

1
Sustained Benefit from a Long-term Antiretroviral
(AR) Adherence Intervention Results of a Large
Randomized Clinical Trial CPCRA 062
Adherence Strategies Using a Medication Manager
and an Electronic Medication Reminder System
for HIV-Infected Patients Receiving HAART

• Sharon Mannheimer, Edward Morse, John Matts,
  Laurie Andrews, Carol Miller, Barry Schmetter and
  Gerald Friedland for the Terry Beirn Community
  Program for Clinical Research on AIDS (CPCRA)
• Late Breakers Track B, Abstract LbOrB15

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Background

• AR adherence associated with many benefits
• Better virologic outcome
• Better immunologic outcome
• Less progression of HIV disease
• Fewer hospitalizations
• Better quality of life
• Lower mortality
• Suboptimal adherence common
• Very few interventions to improve adherence have
  been studied in randomized controlled trials

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Presentation today will focus on

• Primary Results of CPCRA 062
• 928 participants co-enrolled from CPCRA FIRST
  protocol (CPCRA 058), an AR trial for AR-naïve
  persons with HIV FIRST participants randomized
  to
• PI-based regimen
• NNRTI-based regimen
• or
• PI NNRTI-based regimen
• Enrollment November 1999 through January 2002
• Follow-up through June 2003
• CPCRA Community Programs for Clinical Research
  on AIDS, an NIAID-funded HIV clinical trials
  network

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Purpose

• To evaluate the effects of
• two adherence interventions
• Medication Manager
• Electronic medication reminder

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Medication Manager Intervention

• Based on Information-Motivation-Behavioral
  Skills theoretical model
• Medication Manager is a trained research staff
  member who provided tailored adherence support
• Comprehensive standardized baseline assessment
• Individualized adherence support plans
• Contact w/ pts. weekly for 4 weeks, then at least
  monthly
• Observe pillbox use
• Standardized follow-up assessments every 4 months
• Fischer JD, et al. Heath Psychol
  199413238-50

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Electronic Medication Reminder Intervention

• ALR A Little Reminder
• (Timely Devices Incorporated Edmonton, Alberta)

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Study Endpoints

• Primary
• Time to first virologic failure defined as
• first plasma HIV RNA level gt 2,000 copies/mL
  occurring at or after the 4-month follow-up visit
• Secondary
• Percent of patients with HIV RNA lt 50 copies
• Change in CD4 count
• Self-reported AR adherence
• Based on original definition of virologic
  failure in CPCRA FIRST study
• Using validated CPCRA 7-day recall Adherence
  Self-report instrument

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Design and Enrollment
Cluster Randomization Number of Clusters (Number
of Patients)
No MM
MM
No ALR
9 (222)
10 (256)
10 (254)
9 (196)
ALR
2 x 2 Factorial design
MM vs. no MM
and ALR vs. no
ALR MM Medication Manager ALR
Electronic reminder device
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Statistical Considerations

• Sample Size of 948 powered to detect 15
  difference in virologic failure (first HIV RNA gt
  2000) between primary comparison groups
• Primary endpoint analyzed by life table analysis
  taking into account the clustering
• Secondary endpoints analyzed by repeated measures
  analysis
• Intent-to-treat analysis
• Power of at least 0.80 and a 0.05 two-sided
  level of significance

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Baseline CharacteristicsN 928

• Age, mean yrs. 38
• Female 22
• Nonwhite 75
• Prior AIDS 38
• Prior IV drug use 15
• CD4 lymphocyte count,median cells/mm3
  155
• Log HIV RNA, median
  5.2

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Results
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Primary Endpoint Time to First HIV RNA gt2000
Copies/mL at or after 4-Month Visit

Event Rate per 100 person years
P-value for interaction 0.51 MM
Medication Manager ALR Electronic reminder
device
13
Medication Manager Effect Primary Endpoint Time
to First HIV RNA gt2000 Copies/mL at or after
4-Month Visit
p0.13
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Medication Manager Effect on HIV RNA Percent of
Patients with HIV RNA lt50 copies/mL
P 0.09
MM No MM
0 20 40 60 80 100
Percent
1 4 8 12 16 20 24 28 32 36
Months from Randomization
15
Medication Manager Effect on CD4 Change in Mean
CD4 ( 2 SE) from Baseline
p0.01
Months from Randomization
16
Medication Manager Effect on Adherence Percent
of Patients Reporting 100 Adherence
p lt0.001
Months from Randomization
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Summary of ResultsMedication Manager Effect
P-value
Relative Risk

• Primary EndpointTime to first HIV-RNA gt2,000
  0.87 (favor MM) 0.13 copies/mL at or after
  4-Month visit
• Secondary Endpoints HIV-RNA lt 50 copies/mL
  1.13 (favor MM) 0.09
• Patients reporting 100 1.42 (favor
  MM) lt0.001 adherence
• CD4, mean change from 22.5 (favor
  MM) 0.01 baseline (cells/mm3)

Odds Ratio
Difference
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ALR Results
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ALR Effect Primary Endpoint Time to First HIV
RNA gt2000 copies/mL at or after 4-Month Visit
p0.02
20
ALR Effect on HIV RNA Percent of Patients with
HIV RNA lt50 copies/mL
P 0.73
ALR No ALR
0 20 40 60 80 100
Percent
1 4 8 12 16 20 24 28 32 36
Months from Randomization
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ALR Effect on CD4 Change in Mean CD4 ( 2 SE)
from Baseline
p 0.77
22
ALR Effect on Adherence Percent of Patients
Reporting 100 Adherence
p 0.26
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Summary of Results ALR Effect
P-value
Relative Risk

• Primary EndpointTime to first HIV-RNA gt2,000
  1.25 (favor No ALR) 0.02 copies/mL at or after
  4-Month visit
• Secondary Endpoints HIV-RNA lt 50 copies/mL
  1.03 (no difference) 0.73
• patients reporting 100 0.90 (no
  difference) 0.25 adherence
• CD4, mean change from -2.6 (no
  difference) 0.77 baseline (cells/mm3)

Odds Ratio
Difference
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Summary

• Medication Manager associated with
• Trend toward lower risk of virologic failure (13
  lower)
• Greater CD4 cell increase (overall 23 cells)
• Improved self-reported adherence
• Sustained benefit over time
• No benefit associated with ALR

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Conclusions

• The CPCRA Adherence study is the largest
  randomized controlled trial of adherence
  interventions in persons with HIV
• Medication Manager use was associated with
  improved outcomes among antiretroviral-naïve
  patients initiating therapy
• No benefit was seen with the electronic reminder
• The study results support the use of this
  standardized medication manager intervention to
  promote antiretroviral adherence

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Acknowledgements

• CPCRA 062 participants
• CPCRA 062 team members
• Sharon Mannheimer, Co-Chair
• Edward Morse, Co-Chair
• Laurie Andrews
• Lynn Besch
• Barbara Brizz
• Judith Brooks
• Linda Budan
• Carroll Child
• Noreen Choudhry
• Marjorie Dehlinger
• Elaine Ferguson
• Gerald Friedland
• Johnnie Jenkins Patricia Simon-Morse
• John Matts Marie Sioud
• Carol Miller Bentley Sweeton
• Nancy Reilly Ellen Tedaldi

CPCRA 058 (FIRST) team Rodger D. MacArthur,
Chair CPCRA Statistical Center John Matts Carol
Miller Glenn Bartsch Grace Peng Li Chen Ying
Xiang CPCRA Operations Center Caron Lee Barry
Schmetter CPCRA sites staff
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Medication Managers

• Antonio Alexander
• Philip Andrew
• Cristina Baroni
• Dale E. Britt
• Susan P. Caras
• Carol S. Clark
• Rosetta Contreras
• Kimberly L. Cosby-McCargo
• Richard Cratty
• Pierre-Cedric B. Crouch
• Leith Daley
• Brenda Devarie
• Patricia W. Dodson
• Eileen Dolce
• Jairo Eraso
• Martha Farrough
• Deborah Goraj

• Pamela Gorman
• Carol Graeber
• Lynne E. Green
• Kerry Griscti
• Martha L. Howe
• Maria Tadea Insignares
• Karen Lambert Jones
• Michael Jones
• Karen L. Kaufmann
• Nancy Kimmel
• Karen Loveless
• Robert Manning
• Norma Martinez
• Lillian Mercado
• Mark Miller
• Dolores Milnes
• Jorge Camilo Mora
• Frances Moran

• Paula Pell
• Sue Peterson
• Kevin Pierson
• Jonathan Prevost
• Lena Richardson-Wells
• James Robinson
• Marlana Robinson
• Victoria Rudzik
• Helen May Seedhom
• Sandy Sheble-Hall
• Paulette Dawn Slowinski
• Diane States
• Suzanne M. Sweek
• Candace L. Tobin
• Dominick P. Varsalone
• Luz Marina Vasco
• Vicky W. Watson
• Julia Weise