Penn
Infectious Diseases
CCEB
Robert Gross, MD MSCE
Associate Professor of
Medicine (ID) and Epidemiology
University of Pennsylvania
Perelman School of Medicine

• Most research on adherence
• Entry and retention have emerged as highly important
– Less data available on “how to”
– More local logistics come into play
• Overarching message
– “Monitoring provides key data on which patients need interventions ”

• Entry into care shortly after dx associated with survival
• Monitoring challenge
– Multiple sources of data (e.g., dedicated testing sites, clinics)
– Responsible parties need to be identified and logistics arranged

• Retention has multiple benefits
– Decreased morbidity/mortality
– Decreased community viral load
• Various metrics used
– Visit adherence, gaps in care, visits per time frame
• Logistics easier than for entry
– Use medical records and admin data
– May require integration of sources

• 45 y.o. HIV infected man
– Philadelphia VAMC
– Serial monoRx in 90s, then HAART
– Excellent adherence, but multiple resistance mutations acquired
– CD4=0 (0%) x 3 years
• New regimen
– DRV/r in combination therapy
– HIV-1 RNA <50 c/ml
, CD4~300 cells/mm 3

• Follow-up visit
– HIV-1 RNA<50 copies/ml
– Queried re: adherence as always
– Had stopped meds entirely for 3 wks!
– New onset depression
– Depression/non-adherence overcome
– Resumed adherence and no subsequent virologic failure

• Can detect impending failure
– Irrespective of viral load monitoring
(e.g., Bisson G, Gross R et al. PLoS
Med 2008)
• Intervention before failure
• Same principles likely for entry and retention in care

False Security of RNA Suppression
• ATH02 study
– Observational
– EFV-based regimen
– HIV-1 RNA<75 copies/ml
– Monitored RNA monthly
– MEMS for adherence monitoring
– Follow until breakthrough or 1 year
Gross R et al, HIV Clinical Trials, 2008

Timing of Adherence and Outcome
Adherence interval without time shift time
Adherence interval with time shift time shift event or censor date

Time Shift
Prior to
Event Date
VL<1000 n=109
VL>1000 n=7 p value
0 days
30 days
60 days
90 days
96% (83-100%)
96% (86-100%)
96% (87-100%)
95% (86-100%)
38% (12-100%)
63% (24-100%)
71% (42-96%)
57% (51-72%)
0.03
0.08
0.04
0.008

• Assess adherence each visit
– Self-report
– Pharmacy refill data (MPR)
– Do not recommend microelectronic monitors at this time
– Do not recommend drug concentrations at this time
– Do not recommend routine pill counts

• Must use non-judgmental tone
– Preamble admitting perfect adherence unrealistic, but desired
– Allow for honesty
• Specify time period of recall
• Multiple potential tools
– Choice of tool site specific

• ACTG questionnaire
– How many doses missed yesterday,
1, 2, and 3 days before
– How many doses missed over w/e?
– When last dose missed?
• Visual Analog Scale
– Ask ~how many doses taken over past month
– Place X on graduated line

• Specify period of interest
– Past 1, 2, 3 months for example
– Cannot be shorter than length of days supply
– Too long may be irrelevant data
• Ensure full data capture
– If centralized pharmacy: simple
– If multiple commercial pharmacies: logistically challenging, but feasible

Time
First fill Second fill Third fill Fourth fill
First interval Second interval Third interval
(
Adherence metric:
Σ interval days supply)
/
(4 th fill date-1 st fill date)
Grossberg R et al, J Clin Epi 2004

• Variable association with outcome
– Some drugs strongly associated
– Different pts on different drugs
– Variability across drugs limits programmatic utility
• Logistical limitations
– Need for specimens (blood, hair)
– Need for sophisticated lab
– Turnaround time
– Cost

• Weak association with outcome
– Yet commonly used
– Demanding of staff time
• Other value
– Limits dispensing expensive drug if supply not used
– Can add information to pharmacy refill data

• Strongly associated with outcome
– Can provide objective feedback
– Useful in intervention
– Granular view of dose timing and daily taking
• Logistical limitations
– Cumbersome
– Inconvenient (cannot pocket doses)
– Cost

• Monitor entry in care
– Collate sources of data
– Establish responsibilities for linkage
• Monitor retention
– Track clinic administrative records
• Monitor adherence
– Self-report or refill records
– Other techniques need refinement or replacement