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:

Michael S. Saag, MD

Center for AIDS Research

University of Alabama at Birmingham

USA

Lessons from a Career Path in HIV Research

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

Viral Load

101

102

103

104

105

106

0 2 4 6 8 10 12

Weeks

T1/2 = 1.1 days

HIV Infected Cells

Uninfected Resting CD4+ Lymphocytes

Uninfected Activated CD4+ Lymphocytes

Antiretroviral Rx

Latently Infected

CD4+ Lymphocytes

HIV virions

M Saag, UAB

Viral Load

101

102

103

104

105

106

0 2 4 6 8 10 12

Weeks

T1/2 = 1.1 days

RNA+ cells in Lymph node vs RNA in Plasma

HIV RNA+ cells/106 LN cells0.1 1 10 100 1000 10000

Plasma Viral Load (copies/ml)

10

100

1000

10000

100000

1000000

10000000

<50

At steady state, when an actively producing cell dies, it is replaced by how

many newly infected cells?

1. One

2. Twenty – Five

3. One Hundred

4. One Thousand

5. It depends on the viral load

M Saag, UAB

VL = 100,000

VL < 50

Viral Load

101

102

103

104

105

106

0 2 4 6 8 10 12

Weeks

T1/2 = 1.1 days

Clinical Trials

Slide #24

How Did We Get Here?How Did We Get Here?How Did We Get Here?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

1996 1997 1998 19992000

ZDV NVP 3TC EFV LPV

ddI SQV RTV ABC TDF

d4T IDV NFV

Slide #25

New HAART EraNew HAART EraNew HAART EraNew 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

2004 2005 2006 2007 2008 2009

T20 TPV DRV Maraviroc, Raltegravir Etravirine

Slide #26

10090% RESPONSE

0 60 70

8010

20

30

40

50 Bartlett, JA, et al

Abst # 586 CROI 2005

Outcomes Research

MEDICAL INFORMATICS

The FUTURE:

8 Year Survival in HAART Era8 Year Survival in HAART Era

Updated from Chen, et al, 8th CROI, 2001

CD4 Count at HAART InitiationCD4 Count at HAART Initiation

Median Median CD4CD4

% CD4 % CD4 < 200< 200

19961996 115 62.8%

19971997 180 53.8%

19981998 221 47.8%

19991999 212 49.3%

20002000 197 50.1%

20012001 277 39.5%

20022002 210 48.8%

20032003 220 47.2%

20042004 207 49.1%

Median Median CD4CD4

% CD4 % CD4 < 200< 200

20052005 278 39.6%

20062006 300 35.4%

20072007 296 35.2%

20082008 310 29.4%

Most New Infections Transmitted by Persons who Do Not Know Their Status

~25% Unaware

of Infection

~75% Aware

of Infection

account for…

~54% New

Infections

~46% of New

Infections

Source: G. Marks et al. AIDS 2006

TNT: Based on the association of viral load and HIV transmission risk

0

5

10

15

20

25

30

Viral load (HIV-1 RNA copies/ml) and HIV transmission

Tra

nsm

issi

on

rat

e p

er 1

00 P

erso

n-Y

ears

<40

0

400

-349

9

350

0-99

99

10 0

00-4

9 99

9

>50

000

Quinn TC, et al. NEJM 2000; also Fideli U, et al. AIDS Res Hum Retrovir 2001

<40

0

400

-349

9

350

0-99

99

10 0

00-4

9 99

9

>50

000

<40

0

400

-349

9

350

0-99

99

10 0

00-4

9 99

9

>50

000

All subjectsMale-to-FemaleTransmission

Female-to-MaleTransmission

Lancet 2009; 373:48-57

2009 WHO model

Slide #36

Test and TreatTest and Treat

21% of HIV-infected individuals in the U.S.

are undiagnosedRole in reducing

HIV transmissionCampsmith 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

……don’t forget don’t forget EngagementEngagement

Slide #37

Test and TreatTest and Treat

24-44% fail to enter care w/in 6

mos.

33% with known HIV NOT in regular care

21% of HIV-infected individuals in the U.S.

are undiagnosedRole in reducing

HIV transmissionCampsmith 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

……don’t forget don’t forget EngagementEngagement

Slide #38

Celebrate

Make a plan

Identify a Need

Name It

Empower Others

Join You

to

Emerge

ChallengesNew

Client-OrientedNew PatientNavigation

toEncourageConnection

toTreatment

Project CONNECTProject CONNECT

Slide #39

CONNECT: Program EvaluationCONNECT: Program Evaluation

Time Period “No Show”

Unadjusted OR (95%CI)

Adjusted OR (95%CI)a

Pre-CONNECT (n=522)

Post-CONNECT (n=361)

30.7%

17.7%

1.0

0.48 (0.35-0.68)

1.0

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

Mugavero, Davila, Nevin & Giordano; 4th International Conference on HIV Treatment Adherence 2009

Missed Visits

Appt. Adherence

Visit Constancy

Gap in 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

Slide #41

Missed Visits and MortalityMissed Visits and Mortality

Characteristic HR (95%CI)a

Missed visit in 1st year 2.90 (1.28- 6.56)

Age (HR per 10 years) 1.58 (1.12-2.22)

CD4 count <200 cells/mm3

2.70 (1.00-7.30)

Log10 plasma HIV RNA 1.02 (0.75-1.39)

ART started in 1st year 0.64 (0.25-1.62)

a Cox proportional hazards (PH) analysis also adjusts for sex, insurance, race/ethnicity, depression, anxiety, alcohol abuse, and substance abuse.

Mugavero et al. Clin Infect Dis 2009;48:248-56

Slide #42

Retention in Care: Challenge to Retention in Care: Challenge to SurvivalSurvival

Giordano et al. Clin Infect Dis 2007;44:1493-1499

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)

Slide #43

Expanding the Spectrum of Expanding the Spectrum of AdherenceAdherence

0

10

20

30

40

<50 50-59 60-69 70-79 80-89 90-99 100

Appointment Adherence (%)

% o

f S

am

ple

Mugavero. Top HIV Med 2008;16:156-61.

Slide #44

Expanding the Spectrum of Expanding the Spectrum of AdherenceAdherence

0

20

40

60

80

100

<50 50-59 60-69 70-79 80-89 90-99 100

Appointment Adherence (%)

% w

ith V

L<50c/m

L

Mugavero. Top HIV Med 2008;16:156-61.

Slide #45

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

SummarySummary

Slide #46

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

What Can We Do?What Can We Do?

Slide #47

ThanksThanks

UAB 1917 Clinic Cohort supported by UAB CFAR (P30AI27767), CNICS (R24AI067039), and the Mary Fisher CARE Fund; MJM supported by NIMH (K23MH082641) & CDC