The Measurement of Antiretroviral Adherence in HIV

Sharon Mannheimer, MD

Harlem Hospital / Columbia University

Treatment Adherence Services Quality Learning Network meeting

May 3, 2007

Overview

• Background on Adherence in HIV

• Adherence Measurement

• CASE Adherence Index

• Other Self-Report Measures

Importance of Adherence

Nonadherence associated with:

• Virologic failure

• Worse immunologic (CD4) outcomes

• Higher Hospitalization rates

• OIs / HIV disease progression

• Increased Mortality• Resistance (at some adherence levels)

Survival vs. Adherence

Progression to death among 847 initially ART-naïve HIV+ subjects with >12 mos. follow-up; adherence > 75% (circles) vs. adherence <75% (squares). Hogg, et al. AIDS 2002,16:1051-8.

How much adherence is enough?

Adherence to Antiretroviral Therapy and Virologic Failure

Paterson, Annals of Internal Medicine, 2000

0

20

40

60

80

100

% with virologic

failure

Adherence (by MEMS) significantly associated with virologic failure (P<0.001)

Adherence, %>95 90-94.9 80-89.9 70-79.9 <70

21.7

54.6

66.771.4

82.1

Adherence MeasurementAdherence Measurement

– No “gold standard”– Many methods are impractical in clinical

settings– Simple measures predictive of HIV

outcomes would be valuable

Classification of Adherence Measures:

• Direct

or

• Indirect

Direct Measures of Adherence:

• direct observation

• measuring levels of the drug in body fluids (“Therapeutic Drug Monitoring”)

• biologic markers

• monitoring clinic attendance

Indirect Measures of Adherence:

• self-report

• provider assessment

• electronic monitoring devices (MEMS)

• pill count

• medication refill rate (pharmacy)

• monitoring for an expected therapeutic outcome

Direct vs. Indirect Measures:

• In general, direct measures are more objective and yield more reliable assessments of adherence

• each method has limitations

Problems with direct measures:• Direct observation: usually not practical

• Therapeutic drug monitoring: costly, inconvenient, not widely available, reflects recent adherence only

• Biologic marker (e.g. HIV viral load): may not correlate 100% with adherence, factors other than adherence could effect marker

• Clinic attendance: does not necessarily correlate with medication adherence

Problems with indirect measures:• Self report: can overestimate adherence• Provider assessment: physicians poor at

predicting adherent behavior• Electronic monitoring devices (e.g. MEMS

caps): costly, bulky, for only 1 drug, measures only opening, interferes with pillbox use, inaccuracies can occur with improper use (e.g., pocketing doses)

• Pill count: ”pill dumping,” patient can forget to bring bottles, does not assess timing

• Refill rate: only practical if patients use same pharmacy, not 100% correlation

Benefits of Self-Report

• Easy to administer• Inexpensive• May reveal reasons for missed doses• Self-report of nonadherence very

reliable• Adherence measured by self-report

correlates with HIV laboratory and clinical outcomes

Self-Report Methods

• No gold standard• AACTG 3- or 4-day self-report format widely

used– Day-by-day, dose-by-dose recall of each ART

med. Over prior 3 or 4 days

• Other simpler formats available:– CPCRA 7-day self-report– Visual Analog Scale– CASE Adherence Index

The Case Adherence Index QuestionnaireThe Case Adherence Index QuestionnairePlease ask each question and circle the corresponding number next to the answer, then add up the numbers circled to calculate Index score.1. How often do you feel that you have difficulty taking your HIV medications on time? By “on time” we mean no more than two hours before or two hours after the time your doctor told you to take it. 4      Never

3      Rarely 2      Most of the time 1 All of the time

2. On average, how many days PER WEEK would you say that you missed at least one dose of your HIV medications?

1      Everyday2      4-6 days/week3      2-3 days/week4      Once a week5      Less than once a week6      Never

3.When was the last time you missed at least one dose of you HIV medications?

1      Within the past week2      1-2 weeks ago3      3-4 weeks ago4      Between 1 and 3 months ago5      More than 3 months ago6      Never

INDEX SCORE: ______ (> 10 = good adherence, < 10 = poor adherence)

Development of CASE Index

• Developed during a large Health Resources and Services Administration (HRSA)-funded evaluation study (1999-2003) of 12 US adherence support programs– Special Projects of National Significance (SPNS)

• Cross-site evaluation coordinated by the New York Academy of Medicine’s (NYAM) Center for Adherence Support Evaluation (CASE)

CASE Cross-Site Evaluation

• CASE insured uniform data collection:– Standardized core data elements– Uniform Instrument– Central interviewer and chart abstractor training– Uniform measurement periods

• Adherence questions:– Individual questions about adherence behavior – AACTG 3-day self-report

Adherence Intervention & Evaluation SitesAdherence Intervention & Evaluation Sites

Health Services Center, Inc., Hobson City, ALHealth Services Center, Inc., Hobson City, AL Chase Brexton Health Services, Inc., Baltimore, MDChase Brexton Health Services, Inc., Baltimore, MD Dimock Community Health Center, Roxbury, MADimock Community Health Center, Roxbury, MA Harlem Hospital Center, New York, NYHarlem Hospital Center, New York, NY Helena Hatch Special Care Center, Washington University, Helena Hatch Special Care Center, Washington University,

St. Louis, MOSt. Louis, MO Johns Hopkins University School of Medicine, Baltimore, Johns Hopkins University School of Medicine, Baltimore,

MDMD Mission Neighborhood Health Center, San Francisco, CAMission Neighborhood Health Center, San Francisco, CA Multnomah County Health Department, Portland, ORMultnomah County Health Department, Portland, OR SUNY Downstate Medical Center, Brooklyn, NYSUNY Downstate Medical Center, Brooklyn, NY St. Luke's Roosevelt Hospital Center, New York, NYSt. Luke's Roosevelt Hospital Center, New York, NY North Broward Hospital District, Ft. Lauderdale, FLNorth Broward Hospital District, Ft. Lauderdale, FL Urban Health Study, San Francisco, CAUrban Health Study, San Francisco, CA

Participants in Adherence Analysis

• 1,154 participants in HRSA/SPNS cross-site study: – enrolled between July 1, 2000 and July 1, 2003

• 524 cases included in adherence analyses:– Had at least 1 follow-up

– On ART at baseline and follow-up– had corresponding CD4 and HIV RNA data at the

first 3-month follow-up

Participant Characteristics%

Gender

Male 65

Female 34

Transgender 1

Race/Ethnicity

African American 66

Latino 5

White 26

Education

Not high school graduate 41

High school graduate or GED 36

Some college/technical school 23

Mean age, years 40.13 (SD = 8.6)

Participant Characteristics - 2%

Self-reported HIV risk behavior

Men reporting sex with men (MSM) 29

Injecting drug use 16

MSM and injected drugs 2

Heterosexual contact 45

Heterosexual contact and injected drugs

3

Blood transfusion, blood components, or tissue

3

Other 2

Mean CD4 count, cells/mm3(SD) 256 (251)

Median CD4 count, cells/mm3 193

Mean log10 HIV RNA level (SD) 3.99 (1.35)

Analysis of HRSA/SPNS Cross-Site Adherence Data:

Development of the CASE Index

• Principal component analysis performed:– Responses to 3 adherence questions

explained 69% of total variation in adherence, higher than any other combination of questions

– Responses to each of the 3 CASE questions carried approximately equal importance

Mannheimer, et al. AIDS Care 2006;18:853-861.

The Case Adherence IndexThe Case Adherence Index

3 adherence questions:– 1. Frequency of “difficulty taking HIV medication on

time (no more than two hours before or two hours after the time your doctor told you to take it)” –

• Response options: Never, Rarely, Most of the time, or All of the time

– 2. frequency of “average number of days per week at least one dose of HIV medications was missed”

• Response options: Everyday, 4-6 days per week, 2-3 days per week, Once a week, Less than once a week, or Never

– 3. “Last time missed at least one dose of HIV medications”

• Response options: Within the past week, 1-2 weeks ago, 3-4 weeks ago, 1 to 3 months ago, More than 3 months ago, or Never

The Case Adherence Index – The Case Adherence Index – Statistics / ScoringStatistics / Scoring

• Responses coded: – For #1 (reverse coded) - possible range of 1 to 4

points – For #2 and #3 - possible range of 1 to 6 points

• Composite score obtained by adding responses: – Range 3 to 16 – Higher scores indicate better adherence

The Case Adherence Index QuestionnaireThe Case Adherence Index QuestionnairePlease ask each question and circle the corresponding number next to the answer, then add up the numbers circled to calculate Index score.1. How often do you feel that you have difficulty taking your HIV medications on time? By “on time” we mean no more than two hours before or two hours after the time your doctor told you to take it. 4      Never

3      Rarely 2      Most of the time 1 All of the time

2. On average, how many days PER WEEK would you say that you missed at least one dose of your HIV medications?

1      Everyday2      4-6 days/week3      2-3 days/week4      Once a week5      Less than once a week6      Never

3.When was the last time you missed at least one dose of you HIV medications?

1      Within the past week2      1-2 weeks ago3      3-4 weeks ago4      Between 1 and 3 months ago5      More than 3 months ago6      Never

INDEX SCORE: ______ (> 10 = good adherence, < 10 = poor adherence)

CASE Index Compared to CASE Index Compared to AACTG 3-day Self ReportAACTG 3-day Self Report

• CASE Index’s sensitivity and specificity relative to 3-day self-report at cut-off of ≥ 95% was calculated

• Based on the analysis, CASE Index was recoded as a dichotomy where: – CASE Index scores > 10 indicated high adherence– CASE Index scores ≤ 10 indicated low adherence

Sensitivity and Specificity of CASE Adherence Index

vs. 3-day recall adherence self-report

CASE Index Score Sensitivity (%) Specificity (%)

5 99.28 8.00

6 98.32 18.00

7 96.64 30.00

8 92.57 52.00

9 84.65 77.00

1010 74.1074.10 99.0099.0011 62.83 99.00

12 55.64 100.00

13 48.20 100.00

14 38.61 100.00

15 25.42 100.00

CASE Index Concurrent Validity CASE Index Concurrent Validity with 3-day Self Reportwith 3-day Self Report

• Logistic regression showed strong correlation:– Odds of 3-day self-report > 95% was at least 60 times more

for patients with a CASE Index score > 10 compared to those with a CASE Index score ≤ 10 (p < 0.001) across four serial cross-section follow-up periods (3, 6, 9 and 12 months after enrollment)

• Receiver Operating Characteristic Curves (ROC) showed a very strong association between 3-day self-report at 95% and CASE Adherence Index Scores (>10 vs. < 10) across the four measurement quarters

Mannheimer, et al. AIDS Care 2006;18:853-861.

Relationships between Relationships between Self-reported Adherence Measures and HIV RNASelf-reported Adherence Measures and HIV RNA

• CASE Adherence Index was strongly associated with:– a 1 log decrease in HIV RNA levels (p ≤ 0.05)– achieving HIV RNA < 400 copies/ml (p ≤ 0.05)

• Association between 3-day self-report with HIV RNA was not as strong: – significance for a 1-log decrease from baseline

HIV only at 6-month follow-up – significance for HIV < 400 copies/ml also only at

6-month follow-up

Relationship between Self-reported Adherence Relationship between Self-reported Adherence and HIV RNAand HIV RNA

Adherence Measure Comparison

HIV RNAMeasure

Odds ratio estimates

3 Months 6 Months 9 Months 12 Months

3-Day Self-Report

> 95%vs. ≤

95%

1-log Decrease

1.23 2.26** 1.53 1.16

HIV RNA < 400

0.97 2.30** 1.66* 1.23

CASEAdherence

Index

> 10vs. ≤ 10

1-log Decrease

1.52* 1.90** 1.76** 2.13**

HIV RNA < 400

1.60** 1.68** 1.87** 1.60*

Note: * p < 0.10 ** p < 0.05

Relationships between Relationships between Self-reported Adherence Measures Self-reported Adherence Measures

and CD4 Land CD4 Lymphocyte Counts Counts

• A significant relationship between CASE Adherence Index and changes in CD4 lymphocyte counts from baseline only at 12 months

• There were no observed relationships between changes in CD4 and 3-day self-report

Limitations of HRSA/SPNS dataLimitations of HRSA/SPNS data• Only 524 of 1,154 individuals in local sites’

adherence programs were included in adherence analyses

• ART Naive and ART experienced but not currently receiving ART were excluded from the analyses

• High attrition rates• Social desirability of self-report• Adherence instruments administered in same

interview• Only self-reported adherence

CASE Index SummaryCASE Index Summary

• a new measure of self-reported ART adherence

• easy to administer and score

• high degree of sensitivity and specificity with the 3-day self-report (concurrent validity)

• a better predictor of HIV RNA changes over time than 3-day self-report

Other Self-Report Methods

• AACTG 3- or 4- day recall

• CPCRA 7-day recall

• Visual Analog Scale

AACTG 3-day recall

CPCRA 7-day recall

Virologic Outcome by Adherence*in two CPCRA Antiretroviral Trials

Mannheimer, et al. CID 2002

0

10

20

30

40

50

60

70

80

100%

80-99%

0-79%

% HIV RNA <50 copies/ml

) (n=922) (n=699) (n=531)Month 1 (n=1074)

Month 4 Month 8 Month 12

P < 0.005 for difference between categories at months 4,8,12*by adherence self-report C•P•C•R•A

Immunologic Outcome by Adherence*in two CPCRA Antiretroviral Trials

Mannheimer, et al. CID 2002

10

30

50

70

90

110

130

150

170

190

100%

80-99%

0-79%

Change in CD4 (cells/mm3) from baseline

(n=1074) (n=922) (n=699) (n=531)Month 1 Month 4 Month 8 Month 12

P < 0.05 for difference between categories at months 4,8,12 *by adherence self-report C•P•C•R•A

Visual Analog Scale

“Put a cross on the line below at the point showing your best guess about how much medication you have taken in the last month.

We would be surprised if this was 100% for most people, e.g. 0% means you have taken no medication; 50% means you have taken half your medication; 100% means you have taken every single dose of medication.”

_______________________________________________0 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Walsh AIDS 2002, 16:269-277; Oyugi JAIDS 2004;36:1100–1102

Summary

• Adherence critical for successful HIV treatment

• Many methods available for measuring adherence

• CASE Index – easy to administer and score – correlates with HIV RNA outcomes