Upload
miranda-hampton
View
220
Download
0
Tags:
Embed Size (px)
Citation preview
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