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 LbOrB15C•P•C•R•A

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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:

(1) Medication Manager

(2) 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 1994;13:238-50

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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 > 2,000 copies/mL occurring at or after the 4-month follow-up visit

Secondary

• Percent of patients with HIV RNA < 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

2 x 2 Factorial design: MM vs. no MM and ALR™ vs. no ALR™

MM = Medication Manager

ALR™ = Electronic reminder device

No MM MM

No ALR™

ALR™

9 (222)

10 (254)

10 (256)

9 (196)

Cluster Randomization Number of Clusters (Number of Patients)

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Statistical Considerations

• Sample Size of 948 powered* to detect 15% difference in virologic failure (first HIV RNA > 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 EndpointTime to First HIV RNA >2000 Copies/mL at or after 4-Month Visit

P-value for interaction = 0.51

MM = Medication Manager

ALR™ = Electronic reminder device

No MM MM

No ALR™

ALR™

30.4

41.6

28.2

33.3

Event Rate per 100 person years

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Medication Manager Effect Primary Endpoint:

Time to First HIV RNA >2000 Copies/mL at or after 4-Month Visit

p=0.13MMNo MM

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Medication Manager Effect on HIV RNA:Percent of Patients with HIV RNA <50 copies/mL

P = 0.09MMNo MM

1 4 8 12 16 20 24 28 32 36

020

4060

8010

0

420 418 404 396 392 346 280 196 146 100445 444 427 406 387 361 299 239 183 117

No. of Patients:MM:

No MM:

Months from Randomization

Per

cen

t

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Medication Manager Effect on CD4:Change in Mean CD4 (± 2 SE) from Baseline

p=0.01

Months from Randomization

MMNo MM

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Medication Manager Effect on Adherence:Percent of Patients Reporting 100% Adherence

Months from Randomization

p <0.001

MMNo MM

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Summary of ResultsMedication Manager Effect

Primary EndpointTime to first HIV-RNA >2,000 0.87 (favor MM) 0.13 copies/mL at or after 4-Month visit

Secondary Endpoints% HIV-RNA < 50 copies/mL 1.13 (favor MM) 0.09

% Patients reporting 100% 1.42 (favor MM) <0.001 adherence

CD4, mean change from 22.5 (favor MM) 0.01 baseline (cells/mm3)

P-valueRelative Risk

Odds Ratio

Difference

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ALR Results

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ALR Effect: Primary EndpointTime to First HIV RNA >2000 copies/mL at or after 4-Month Visit

p=0.02ALRNo ALR

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ALR Effect on HIV RNA:Percent of Patients with HIV RNA <50 copies/mL

P = 0.73ALRNo ALR

1 4 8 12 16 20 24 28 32 36

020

4060

8010

0

412 410 399 379 369 339 276 212 155 98453 452 432 423 410 368 303 223 174 119

No. of Patients:MM:

No MM:

Months from Randomization

Per

cen

t

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ALR Effect on CD4:Change in Mean CD4 (± 2 SE) from Baseline

p = 0.77ALRNo ALR

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ALR Effect on Adherence:Percent of Patients Reporting 100% Adherence

p = 0.26

ALRNo ALR

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Summary of Results ALR Effect

Primary EndpointTime to first HIV-RNA >2,000 1.25 (favor No ALR) 0.02 copies/mL at or after 4-Month visit

Secondary Endpoints% HIV-RNA < 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)

P-valueRelative Risk

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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CPCRA 062 participants

CPCRA 062 team membersSharon Mannheimer, Co-ChairEdward Morse, Co-ChairLaurie Andrews Lynn BeschBarbara BrizzJudith BrooksLinda BudanCarroll ChildNoreen ChoudhryMarjorie Dehlinger Elaine FergusonGerald FriedlandJohnnie Jenkins Patricia Simon-MorseJohn Matts Marie SioudCarol Miller Bentley SweetonNancy Reilly Ellen TedaldiBarry Schmetter Robert Vallier

CPCRA 058 (FIRST) team Rodger D. MacArthur, Chair

CPCRA Statistical CenterJohn MattsCarol MillerGlenn BartschGrace PengLi ChenYing Xiang

CPCRA Operations CenterCaron LeeBarry Schmetter

CPCRA sites & staff

Acknowledgements

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