Adherence in
TLC+: The Sticky
Wicket
Michael S. Saag, MD
Center for AIDS Research
University of Alabama at Birmingham
USA
One Man’s Journey to
Adherence:
Lessons from a Career
Path in HIV Research
Michael S. Saag, MD
Center for AIDS Research
University of Alabama at Birmingham
USA
Disclosures
Grant Support / Consulting
•
•
•
•
•
•
Ardea
Avexa
Boehringer-Ingelheim
Bristol-Myers Squibb
Gilead Sciences
GlaxoSmithKline
/ViiV
• Merck
•
•
•
•
•
Pain Therapeutics
Pfizer / ViiV
Progenics
Tibotec / Virco
Tobria
Translational Research
M Saag, UAB
Piatak, et al, Science, 1993
106
105
104
Viral Load
103
102
101
T1/2 = 1.1 days
0
2
4
6
Weeks
8
10
12
Latently Infected
CD4+ Lymphocytes
103
104
HIV virions
102
Viral Load
105
106
HIV Infected
Cells
101
T1/2 = 1.1 days
0
2
4
6
Weeks
8
10
12
Antiretroviral Rx
Uninfected Activated
CD4+ Lymphocytes
M Saag, UAB
Uninfected Resting
CD4+ Lymphocytes
RNA+ cells in Lymph node vs RNA in Plasma
Plasma Viral Load (copies/ml)
10000000
1000000
100000
10000
1000
100
<50
10
0.1
1
10
100
1000
HIV RNA+ cells/106 LN cells
10000
At steady state, when an actively
producing cell dies, it is replaced by how
many newly infected cells?
1.
2.
3.
4.
5.
One
Twenty – Five
One Hundred
One Thousand
It depends on the viral load
M Saag, UAB
VL =
100,000
VL < 50
106
105
104
Viral Load
103
102
101
T1/2 = 1.1 days
0
2
4
6
Weeks
8
10
12
Clinical Trials
Slide #24
How Did We Get Here?
Sequential exposure to effective “monotherapy” in
a population of largely adherent, aggressively
treated patients created a cohort of individuals with
highly-resistant HIV
ZDV NVP 3TC
ddI SQV RTV
d4T
IDV
1996
2000
EFV
ABC
LPV
TDF
NFV
1997
1998
1999
Slide #25
New HAART Era
After years of sequential “monotherapy” many
patients with MDR are now entering a period where
more than one new medication may be readily
available
T20
2004
2009
TPV
2005
DRV
Maraviroc, Raltegravir
Etravirine
2006
2007
2008
Slide
#26
0
1
0
2
0
3
4
60
5
0 % RESPONSE
0
0
7
0
80 9
0
100
Bartlett, JA, et al
Abst # 586 CROI
2005
Outcomes Research
The FUTURE:
MEDICAL
INFORMATICS
8 Year Survival in HAART Era
Updated from Chen, et al, 8th CROI, 2001
CD4 Count at HAART Initiation
1996
1997
1998
1999
2000
2001
2002
2003
2004
Median
CD4
% CD4
< 200
115
180
221
212
197
277
210
220
207
62.8%
53.8%
47.8%
49.3%
50.1%
39.5%
48.8%
47.2%
49.1%
2005
2006
2007
2008
Median
CD4
% CD4
< 200
278
300
296
310
39.6%
35.4%
35.2%
29.4%
Most New Infections Transmitted by
Persons who Do Not Know Their Status
~25%
Unaware
of
Infection
account for…
~75%
Aware
of
Infection
Source: G. Marks et al. AIDS 2006
~54%
New
Infections
~46%
of New
Infections
30
Female-to-Male
Transmission
Male-to-Female
Transmission
All subjects
25
20
15
10
>50 000
10 000-49 999
3500-9999
400-3499
<400
>50 000
10 000-49 999
3500-9999
400-3499
<400
>50 000
10 000-49 999
3500-9999
0
400-3499
5
<400
Transmission rate per 100 Person-Years
TNT: Based on the association of viral
load and HIV transmission risk
Viral load (HIV-1 RNA copies/ml) and HIV transmission
Quinn TC, et al. NEJM 2000; also Fideli U, et al. AIDS Res Hum Retrovir 2001
2009 WHO model
Lancet 2009; 373:48-57
Slide #36
Test and Treat…don’t forget Engagement
21% of HIV-infected
individuals in the U.S. are
undiagnosed
Role in reducing
HIV transmission
Campsmith M et al. MMWR 2008;57:1073-76, Gardner et al. AIDS 2005;19:423-431, Marks et al. AIDS 2006;20: 1447-50,
Fleming et al. 9th CROI 2002, abstract 11, Metsch et al. Clin Infect Dis 2008;47:577-584, Cohen at al. Ann Intern Med
2007;146:591-601, Diffenbach & Fauci. JAMA 2009;301:2380-82
Slide #37
Test and Treat…don’t forget Engagement
33% with known HIV
NOT in regular care
24-44% fail to enter
care w/in 6 mos.
21% of HIV-infected
individuals in the U.S. are
undiagnosed
Role in reducing
HIV transmission
Campsmith M et al. MMWR 2008;57:1073-76, Gardner et al. AIDS 2005;19:423-431, Marks et al. AIDS 2006;20: 1447-50,
Fleming et al. 9th CROI 2002, abstract 11, Metsch et al. Clin Infect Dis 2008;47:577-584, Cohen at al. Ann Intern Med
2007;146:591-601, Diffenbach & Fauci. JAMA 2009;301:2380-82
Slide #38
Project CONNECT
ClientOriented
New Patient
Navigation to
Encourage
Connection to
Treatment
New
Identify a
Challenges
Need
Emerge
Name It
Make a plan
Empower
Others
to
Join You
Celebrate
Slide #39
CONNECT: Program Evaluation
Time Period
“No Show”
Unadjusted OR
(95%CI)
Adjusted
OR (95%CI)a
Pre-CONNECT (n=522)
30.7%
1.0
1.0
Post-CONNECT (n=361)
17.7%
0.48 (0.35-0.68)
0.54 (0.38-0.76)
a
Multivariable model controls for age, race, sex, insurance, location of residence and
time from call to scheduled visit.
Wylie et al. 4th International Conference on HIV Treatment Adherence 2009
Slide #40
Missed
Visits
Appt.
Visit
Gap in
Adherence Constancy Care
HRSA HAB
Measure
Patient A
Yes; 1
80%
100%
No
Yes
Patient B
Yes; 4
33%
50%
Yes
Yes
Patient C
No; 0
100%
75%
No
Yes
Patient D
Yes; 1
67%
25%
Yes
No
Mugavero, Davila, Nevin & Giordano; 4th International Conference on HIV Treatment Adherence 2009
Slide #41
Missed Visits and Mortality
Characteristic
HR (95%CI)a
Missed visit in 1st year
Age (HR per 10 years)
CD4 count <200 cells/mm3
Log10 plasma HIV RNA
2.90 (1.28- 6.56)
1.58 (1.12-2.22)
2.70 (1.00-7.30)
1.02 (0.75-1.39)
ART started in 1st year
0.64 (0.25-1.62)
Cox proportional hazards (PH) analysis also adjusts for sex, insurance,
race/ethnicity, depression, anxiety, alcohol abuse, and substance abuse.
a
Mugavero et al. Clin Infect Dis 2009;48:248-56
Slide #42
Retention in Care: Challenge to Survival
Quarters w/ visit
(Visit Constancy)
N (%)
of Sample
Adjusted HR (95%CI)
for Mortality
4
1685 (64%)
1.0 (Referent)
3
479 (18%)
1.41 (1.10-1.82)
2
286 (11%)
1.68 (1.24-2.26)
1
169 (7%)
1.94 (1.36-2.76)
Giordano et al. Clin Infect Dis 2007;44:1493-1499
Slide #43
Expanding the Spectrum of Adherence
% of Sample
40
30
20
10
0
<50
50-59
60-69
70-79
80-89
90-99
Appo intment Adherence (%)
Mugavero. Top HIV Med 2008;16:156-61.
100
Slide #44
% with VL<50c/mL
Expanding the Spectrum of Adherence
100
80
60
40
20
0
<50
50-59
60-69
70-79
80-89
90-99
Appo intment Adherence (%)
Mugavero. Top HIV Med 2008;16:156-61.
100
Slide #45
Summary
 Expanded spectrum of HIV adherence
 Engagement in care includes distinct steps:
Linkage, Retention and Re-engagement
 Engagement in care vital for HIV treatment
success at individual & population level
 Early missed visits may identify patients at
risk for poor long-term health outcomes
 Engagement worse in groups bearing a
disproportionate burden of US HIV epidemic
Slide #46
What Can We Do?
 Incorporate adherence to care counseling into
patient encounters as a matter of routine
 Evaluate “no show” phenomenon at the clinic
level & revise new patient orientation
 Develop partnerships with local HIV testing,
clinical & supportive service providers
 Integrate HIV testing and linkage activities
 Coordinate activities around retention and
re-engagement for shared patients
Slide #47
Thanks
UAB 1917 Clinic Cohort supported by UAB CFAR (P30AI27767), CNICS (R24AI067039),
and the Mary Fisher CARE Fund; MJM supported by NIMH (K23MH082641) & CDC