ADHERENCE: THE ACHILLES HEEL OF CLINICAL TRIALS

David Bangsberg, MD, MPH

DirectorMassachusetts General Hospital Center for Global Health

ProfessorHarvard Medical School

ProfessorHarvard School of Public Health

Visiting ProfessorMbarara University of Science and Technology

March, 2014

ACKNOWLEDGEMENTS Jessica Haberer Steve Safren Alex Tsai Christina Psaros Ingrid Katz Elizabeth Garrett-Mayer

PREP: A CASE STUDY Adherence and heterogeneity  Determinants of PrEP Adherence Measuring adherence to guide interpretation

of efficacy vs effectiveness Post hoc analysis to estimate efficacy

conditioned on adherence Adherence intervention to improve efficacy

estimates 

HETEROGENEITY OF PRE-EXPOSURE PROPHYLAXIS RESULTS

Study Population N Results

iPrEx MSM 2499 44% efficacy FTC/TDF

TDF2 StudyYoung men and

women 1200 62% efficacy FTC/TDF

Partners PrEP Study

Heterosexual couples

475867% efficacy TDF

75% efficacy FTC/TDF

FEM-PrEP Women 2021 6% efficacy FTC/TDF

VOICE Women3021

(oral arms)No efficacy TDF

FTC/TDF ongoing

Bangkok Tenofovir Study

IDUs 2400 TDF ongoing

SOURCES OF HETEROGENEITY Drop-out Cross-over Adherence Other health-related behaviors related to

adherence

ADHERENCE AND EFFICACY IN PREP TRIALS

% of blood samples with tenofovir

detected

HIV protection efficacy in

randomized comparison

Partners PrEPFTC/TDF arm

81% 75%

TDF2 79% 62%

iPrEx 51% 44%

FEM-PrEP 26% 6%

Donnell et al CROI 2012 Grant et al N Engl J Med 2010Van Damme et al CROI 2012Paxton et al FDA 2012

PREP: A CASE STUDY

Adherence and heterogeneity  Determinants of PrEP Adherence Measuring adherence to guide interpretation

of efficacy vs effectiveness Post hoc analysis to estimate efficacy

conditioned on adherence Adherence intervention to improve efficacy

estimates 

PREP adherence is opportunity to

mitigate tensionand strengthen

relationship

“Discordance dilemma”

Excellent PrEP Adherence Explained by Relationship Dynamics (Ware et al JAIDS 2012)

PrEP Resolves Tension in a Committed HIV Discordant Sexual Relationship

PREP adherence is opportunity to

mitigate tensionand strengthen

relationship

“Discordance dilemma”

Excellent PrEP Adherence Explained by Relationship Dynamics (Ware et al JAIDS 2012)

PrEP Resolves Tension in a Committed HIV Discordant Sexual Relationship

Love

PREP adherence is opportunity to

mitigate tensionand strengthen

relationship

“Discordance dilemma”

Excellent PrEP Adherence Explained by Relationship Dynamics (Ware et al JAIDS 2012)

PrEP Resolves Tension in a Committed HIV Discordant Sexual Relationship

Discord and

Distrust

PREP ADHERENCE DURING RELATIONSHIP DISCORD AND DISTRUST

Courtesy of Fran Priddy IAVI

WOMEN’S EXPERIENCES WITH ORAL AND VAGINAL PRE-EXPOSURE PROPHYLAXIS:

THE VOICE-C QUALITATIVE STUDY IN JOHANNESBURG, SOUTH AFRICA (ARIANE VAN DER STRATEN ET AL PLOS ONE

2014)

Qualitative interview of 102 VOICE participants. ambivalence toward research preserving a healthy status managing social relationships

PREP: A CASE STUDY Adherence and heterogeneity  Determinants of PrEP Adherence Measuring adherence to guide interpretation

of efficacy vs effectiveness Post hoc analysis to estimate efficacy

conditioned on adherence Adherence intervention to improve efficacy

estimates 

MEASURING ADHERENCE Patient report

Longer intervals (Lu AIDS and Beh 2008) Rating scales (Lu AIDS and Beh 2008; Deschampes AIDS Pt Care STD

2008) Pill counts

Clinic (Donnell AIDS and Beh 2013) Unanounced at home (Bangsberg AIDS 2000) Unannouned via telephone (Kalichman JGIM 2007)

Drug level Blood (Liechty AIDS 2004) Hair (Liu PLoS One 2014)

Pharmacy refill (Grossberg J Clin Epi 2004) Electronic

Flash memory/MEMS (Paterson Ann Int Med 2000) Real-time wireless (Haberer AIDS and Beh 2011)

PREP: A CASE STUDY Adherence and heterogeneity  Determinants of PrEP Adherence Measuring adherence to guide interpretation

of efficacy vs effectiveness Post hoc analysis to estimate efficacy

conditioned on adherence Adherence intervention to improve efficacy

estimates 

HIGH LEVEL OF PROTECTION WHEN TENOFOVIR IS DETECTED IN BLOOD

% with tenofovir detected

Protectionp-value

(detected vs not

detected)

iPrEx 51% 92% <0.001

Partners PrEPFTC/TDF arm

81% 90% 0.002

Donnell et al CROI 2012 Abstract 30Grant et al N Engl J Med 2010

ADHERENCE TO ANTIRETROVIRAL PROPHYLAXIS FOR HIV

PREVENTION: A SUBSTUDY COHORT WITHIN A CLINICAL TRIAL OF

SERODISCORDANT COUPLES IN EAST AFRICA(HABERER ET AL PLOS MED 2013)

3 Site substudy of Partners PrEP Study: RCT of TNF/FTC, TNF, placebo 1,147 HIV serodiscordant couples in Kenya and

Uganda Adherence measures

unannounced home-based pill counts electronic pill bottle monitoring.

Intensified counseling for unannounced pill count adherence < 80%.

53% male, median age: 34 yr , and median partnership duration: 8.5 years.

ADHERENCE TO ANTIRETROVIRAL PROPHYLAXIS FOR HIV

PREVENTION: A SUBSTUDY COHORT WITHIN A CLINICAL TRIAL OF SERODISCORDANT COUPLES

IN EAST AFRICA(HABERER ET AL PLOS MED 2013)

Unannounced Pill Count

MEMS Clinic Pill Count Self Report

N Mean (SD)

Median (IQR)

Mean (SD)

Median (IQR)

Mean (SD)

Median (IQR)

Mean (SD)

Median (IQR)

Overall 1,03997.6(6.3)

99.1(96.9-100)

86.9(16.4)

92.1(85.9-94.2)

96.6(6.7)

98.8(96-99.8)

98.2(3.8)

99.4(98-100)

By gender

Female 49098.2(5.1)

99.3(97.5-100)

89.6(12.4)

92.9(88.4-94.6)

97.4(6.1)

99.1(97-100)

98.4(3.9)

99.5(98.3-100)

Male 54997.1(7.2)

98.8(96.2-100)

84.6(19)

91.2(83.5-93.6)

95.9(7.2)

98.4(95.5-99.6)

97.9(3.8)

99.2(97.6-100)

PREP EFFICACY HIV-1 infections

14 in 404 participants on placebo (333 person-years)

0 infections in 750 participants on active drug (616 person-years)

PrEP efficacy within the sub-study was 100% (95% CI 87-100%)

IMPACT OF PARTIAL ADHERENCE IN RANDOMIZED CONTROLLED TRIALS

(WEISS ET AL EMERG THEMES EPIDEMIOL 2008)

Fem Prep Adherence:

21%Efficacy: 6%

IPrex Adherence: 51%

Efficacy: 44%

TDF2 Adherence: 79%

Efficacy: 62%

Partners PrEP Substudy

Adherence: 96%Efficacy: 100%

VoiceAdherence:

25%Efficacy: 4%

IMPACT OF PARTIAL ADHERENCE IN RANDOMIZED CONTROLLED TRIALS

(WEISS ET AL EMERG THEMES EPIDEMIOL 2008)

Fem Prep Adherence:

21%Efficacy: 6%

IPrex Adherence: 51%

Efficacy: 44%

Partners PrEP Substudy

Adherence: 96%Efficacy: 100%

IMPACT OF PARTIAL ADHERENCE IN RANDOMIZED CONTROLLED TRIALS

(WEISS ET AL EMERG THEMES EPIDEMIOL 2008)

VoiceAdherence:

25%Efficacy: 4%

TDF2 Adherence: 79%

Efficacy: 62%

PREP: A CASE STUDY Adherence and heterogeneity  Determinants of PrEP Adherence Measuring adherence to guide interpretation

of efficacy vs effectiveness Post hoc analysis to estimate efficacy

conditioned on adherence Adherence interventions to improve efficacy

estimates 

PreEP Adherence Intervention Design(Psaros and Safren IAPAC 2013)

Based on Lifesteps, an ART treatment adherence intervention (Safren et al., 1997; 2001; 2007) targeted to HIV-negative participants with low (<80%) unannounced pill count adherence

Counseling occurs in two phases: (1) with individual on PrEP (2) with their HIV infected partner (optional) Number of sessions tailored to needs of participants

(minimum of 1) Median number of sessions completed = 10 (IQR

5, 16) Median length of sessions:

Session one: 40 minutes (IQR 30,50) Session length decreased to median of 20

minutes (IQR 15,30) by session four.

Component Description and Goals

Educational and informational

Opportunities for counselor to gather relevant information (e.g., history of the relationship with the HIV-positive partner), provide information about PrEP (e.g., dispel myths about PrEP, explain why adherence is important), and orient the participant to the counseling.

Motivational interviewing Reviewing the pros and cons of achieving high levels of adherence to PrEP. Motivation viewed as dynamic and attempted to resolve any ambivalence about adherence, thus moving participants to a higher level of readiness to adhere. Potential cons were addressed later in the session as part of the problem-solving protocol.

Problem solving Involved identifying barriers to PrEP adherence and generating solutions to each identified barrier. Counselors also encouraged to use rehearsal strategies when relevant (e.g., setting cell phone reminders in session, practicing asking for help with adherence).

Couples session Optional (but encouraged), and allowed counselors to address any concerns of the HIV-positive partner around PrEP use, address any relational barriers to adherence, and generate a plan for the HIV-positive partner to support the HIV-negative partner’s PrEP adherence.

Follow-up sessions Optional and provided at the discretion of the counselors. Followed a similar format whereby the prior session content was reviewed, the success of the adherence plan was evaluated and adjusted as necessary, and new barriers to adherence were addressed as needed.

INTERVENTION CONTENT

INTERVENTION RESULTS 168 (14.6%) of participants triggered the

intervention due to <80% unannounced pill count adherence Counseling occurs in two phases: 9 were ineligible for follow-up analysis

Of remaining 159: 154 (91.7%) received at least one intervention

session 46 (94.8%) had adequate MEMS data to examine

adherence following the intervention.

Supplemental content figure I. Participant flow

Enrolled in ancillary adherence study prior to July 10, 2011

(N= 1,147)

Triggered intervention

(N= 168)

Did not trigger intervention

(N= 979)

Did not receive at least one intervention session

(N= 5)

Triggered but ineligible for follow-up analysis*

(N=9)

Received at least one intervention session

(N= 154)

Adequate MEMS data for analysis**

(N= 146)

Completed 2-4 sessions

(N= 25)

Completed >4 sessions

(N= 127)

Completed only one session

(N= 2)

•Taken off drug due to exit from study (N=1), seroconversion (N=1), or triggering immediately before unblinding of the placebo arm during the parent trial (N=7)

•**Had MEMS data available for the trigger interval, the interval between the trigger and intervention (minimum of 3 days), and following the first intervention session.

Mean crude and predicted adherence by months since the first intervention session(Psaros and Safren IAPAC 2013)

CONCLUSIONS Edward Koop

Drugs don’t work if people don’t take them

CONCLUSIONS Edward Koop

Drugs don’t work if people don’t take them Corollary

It’s as important to find out if people will take a drug as it is to find out if it works

CONCLUSIONS Edward Koop

Drugs don’t work if people don’t take them Corollary

It’s as important to find out if people will take a drug as it is to find out if it works

Phase II adherence behavior finding studies

CONCLUSIONS Edward Koop

Drugs don’t work if people don’t take them Corollary

It’s as important to find out if people will take a drug as it is to find out if it works

Phase II adherence behavior finding studies More attention to evidence based

approaches to monitoring and supporting adherence to improve efficacy estimates