The Measurement of Antiretroviral Adherence in HIV

1. The Measurement of Antiretroviral Adherence in HIV Sharon Mannheimer, MD Harlem Hospital / Columbia University Treatment Adherence Services Quality Learning Network meeting May 3, 2007

2. Overview • Background on Adherence in HIV • Adherence Measurement • CASE Adherence Index • Other Self-Report Measures

3. 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)

4. 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.

5. How much adherence is enough?

6. Adherence to Antiretroviral Therapy and Virologic FailurePaterson, Annals of Internal Medicine, 2000 82.1 71.4 66.7 54.6 21.7 >95 90-94.9 80-89.9 70-79.9 <70 Adherence, % Adherence (by MEMS) significantly associated with virologic failure (P<0.001)

7. Adherence Measurement • No “gold standard” • Many methods are impractical in clinical settings • Simple measures predictive of HIV outcomes would be valuable

8. Classification of Adherence Measures: • Direct or • Indirect

9. Direct Measures of Adherence: • direct observation • measuring levels of the drug in body fluids (“Therapeutic Drug Monitoring”) • biologic markers • monitoring clinic attendance

10. Indirect Measures of Adherence: • self-report • provider assessment • electronic monitoring devices (MEMS) • pill count • medication refill rate (pharmacy) • monitoring for an expected therapeutic outcome

11. Direct vs. Indirect Measures: • In general, direct measures are more objective and yield more reliable assessments of adherence • each method has limitations

12. 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

13. 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

14. 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

15. 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

16. The Case Adherence Index Questionnaire Please 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. 4Never 3Rarely 2Most 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? 1Everyday 24-6 days/week 32-3 days/week 4Once a week 5Less than once a week 6Never • When was the last time you missed at least one dose of you HIV medications? 1Within the past week 21-2 weeks ago 33-4 weeks ago 4Between 1 and 3 months ago 5More than 3 months ago 6Never INDEX SCORE: ______(> 10 = good adherence, < 10 = poor adherence)

17. 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)

18. 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

19. Adherence Intervention & Evaluation Sites Health Services Center, Inc., Hobson City, AL Chase Brexton Health Services, Inc., Baltimore, MD Dimock Community Health Center, Roxbury, MA Harlem Hospital Center, New York, NY Helena Hatch Special Care Center, Washington University, St. Louis, MO Johns Hopkins University School of Medicine, Baltimore, MD Mission Neighborhood Health Center, San Francisco, CA Multnomah County Health Department, Portland, OR SUNY Downstate Medical Center, Brooklyn, NY St. Luke's Roosevelt Hospital Center, New York, NY North Broward Hospital District, Ft. Lauderdale, FL Urban Health Study, San Francisco, CA

20. 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

21. Participant Characteristics

22. Participant Characteristics - 2

23. 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.

24. The 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

25. The Case Adherence Index – Statistics / 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

26. The Case Adherence Index Questionnaire Please 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. 4Never 3Rarely 2Most 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? 1Everyday 24-6 days/week 32-3 days/week 4Once a week 5Less than once a week 6Never • When was the last time you missed at least one dose of you HIV medications? 1Within the past week 21-2 weeks ago 33-4 weeks ago 4Between 1 and 3 months ago 5More than 3 months ago 6Never INDEX SCORE: ______(> 10 = good adherence, < 10 = poor adherence)

27. CASE Index Compared to AACTG 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

28. Sensitivity and Specificity of CASE Adherence Index vs. 3-day recall adherence self-report

29. CASE Index Concurrent Validity with 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.

30. Relationships between Self-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

31. Relationship between Self-reported Adherence and HIV RNA

32. Relationships between Self-reported Adherence Measures and CD4 Lymphocyte 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

33. Limitations 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

34. CASE 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

35. Other Self-Report Methods • AACTG 3- or 4- day recall • CPCRA 7-day recall • Visual Analog Scale

36. AACTG 3-day recall

37. CPCRA 7-day recall

38. Virologic Outcome by Adherence*in two CPCRA Antiretroviral TrialsMannheimer, et al. CID 2002 % HIV RNA <50 copies /ml Month 4 Month 12 Month 8 Month 1(n=1074) (n=699) ) (n=922) (n=531) P < 0.005 for difference between categories at months 4,8,12 *by adherence self-reportC•P•C•R•A

39. Immunologic Outcome by Adherence*in two CPCRA Antiretroviral TrialsMannheimer, et al. CID 2002 Change in CD4 (cells/mm3) from baseline Month 1 Month 4 Month 8 Month 12 (n=1074) (n=922) (n=699) (n=531) P < 0.05 for difference between categories at months 4,8,12 *by adherence self-reportC•P•C•R•A

40. 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

41. 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