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Adherence to ARV Treatment and Prevention to End AIDS
David Bangsberg, MD, MPH
Director Massachusetts General Hospital Center for Global Health
Associate Professor
Harvard Medical School
Visiting Professor Mbarara University of Science and Technology
November, 2011
Antiretroviral therapy in Africa Warren Stevens, Steve Kaye, Tumani Corrah BMJ 2004;328:280-282
[In sub-Saharan Africa]….the potential short term gains from reducing individual morbidity and
mortality may be far outweighed by the potential for the long term spread of drug resistance…. In Africa, a higher proportion of patients are likely to fall into
the category of potential poor adherers unless resource intensive adherence programmes are
available.
Bell-shaped Adherence and Resistance Curve
Incr
easi
ng p
roba
bilit
y of
sel
ectin
g m
utat
ion
Increasing Adherence
Inadequate
Drug Pressure To Select Resistant
Virus
Drug Pressure Selects
Resistant Virus
Resistance Risk by Adherence and Regimen Class
Bangsberg et al J. Antimicrob Chem; 2002 53(5):696-9.
A Single Tablet Regimen is Associated with Higher Adherence and Viral Suppression than Multiple Tablet
Regimens in Homeless and Marginally Housed Individuals.
Bangsberg et al AIDS 2010
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FDC EFV/TDF/FTC NNRTI PI RPI
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'0-49' '50-<75' '75-<80' '80-<90' '90-100'
Adherence Category
Prop
ortio
n VL
<50
FDC EFV/TDF/FTCF r-PI
Unannounced pill count adherence STR 86% vs other 73% p=0.001
Proportion VL<400 c/ml STR 69% vs other 47% p=0.034
Meta-Analysis of Barriers to Adherence in Africa and North
America Mills et al JAMA 2006:296:679-690
• Systematic review of adherence – 28,689 patients in 228 studies
• North America • Brazil, Uganda, Cote d’Ivoire, South Africa,
Malawi, Bostwana, Costa Rica, Romania
Resource-Rich Country 54.7% (95CI: 48.0-61.3%)
Resource-Poor Country 77.1% (95CI:67.3%-85.6%)
A Social Model of Adherence for sub-Saharan Africa Ware et al PLoS Medicine 2009
Improving Health
Resource Scarcity
Resource Scarcity
Improving Health
A Social Model of Adherence for sub-Saharan Africa Ware et al PLoS Medicine 2009
Resource Scarcity
Resource Scarcity
Adherence fulfills
responsibility to helpers and
preserve relationships as a resource
Relationships
as resources to overcome economic
obstacles to adherence
Social Capital
Improving Health
A Social Model of Adherence for sub-Saharan Africa Ware et al PLoS Medicine 2009
Resource Scarcity
Resource Scarcity
Adherence fulfills
responsibility to helpers and
preserve relationships as a resource
Relationships
as resources to overcome economic
obstacles to adherence
Social Capital
Improving Health
A Social Model of Adherence for sub-Saharan Africa Ware et al PLoS Medicine 2009
Resource Scarcity
Resource Scarcity
Adherence fulfills
responsibility to helpers and
preserve relationships as a resource
Relationships
as resources to overcome economic
obstacles to adherence
Social Capital
Improving Health
A Social Model of Adherence for sub-Saharan Africa Ware et al PLoS Medicine 2009
Modest Decline in Adherence Over Time in Uganda
Byakika-Tusiime et al. AIDS Behavior 2009
• 177 participants on ART for 2-42 months • Unannounced pill count adherence 98.3% • Declinining adherence:
– Each month 0.93 odds of sustaining >95% adherence (p = .003)
Structural and Economic Barriers to Adherence
• Transportation • Tuller et al AIDS and Beh 2009 • Hardon et al AIDS Care 2007 • Rosen et al S.African Med J 2007
• Food insecurity • Tsai et al Soc Sci Med 2011 • Weiser et al AIDS 2011 • Weiser PLoS One 2010 • Tuller et al PLoS One 2010 • Miller el al Aids and Behavior 2010 • Weiser JAIDS 2009
Frequency and Duration of Treatment Interruptions >48hrs over 24 weeks
Oyugi et al AIDS 2007
Interruptions > 48 hours 199 interruptions 62 people (64%)
Mean # interruptions/person 2.0 ±2.9 (S.D) Mean duration (days) for those who have interruptions
11.5 ±9.2 (S.D)
Interruptions account for 90% of all missed doses
Duration of MEMS Defined Treatment Interruption and Probability of NNRTI Virologic Failure
Parienti et al PLoS One 2008 n=72
+ Controls O Cases Estimated 95% confidence interval
Longer interval of treatment discontinuation in days
Est
imat
ed p
roba
bilit
y of
vira
l con
trol
Real-time Adherence Monitoring Haberer et al AIDS and Behavior 2010
Wisepill Adherence Monitor www.wisepill.com
Real-time Adherence Monitoring Haberer et al AIDS and Behavior 2010
Real-time Adherence Monitoring Haberer et al AIDS and Behavior 2010
Weekly Short Message Service
Reminders Improve Adherence in Kenya
Pop-Eleches et al. AIDS 2011 “This is your reminder”
N=431 Weekly Daily Control
Proportion >90% MEMS adherent
63% p= .01
50% p= .92
47%
Lester et al. Lancet 2010 “How are you?”
N=528 SMS Control p Self-reported adherence >95%
62% 50% .006
Viral suppression <400 copies/ml
57% 48% .04
Treatment as Prevention
• Dose response: HIV RNA-transmission Quinn et al NEJM 2000
• Comprehensive HIV testing and treatment may bring Ro <1 Granich et al Lancet 2009
• ART 92% reduction in transmission Donnell et al Lancet 2010
• ART 96% reduction in transmission Cohen NEJM 2012
Treatment as Prevention Challenges
• Can we get everyone tested, treated, and retained? – Geng Jama 2008, Gardner CID 2011; Bassett JAIDS 2009, AIDS
2010; Katz AIDS 2010; Rosen PLoS Med 2011
• Will healthy people adhere as well as ill people?
• Will adherence be sustained? – Tusiime AIDS Beh 2009
• Can health systems expand access under fiscal constraints – Geng PLoS One 2011
At Front Lines, AIDS War Is Falling Apart Donald McNeil Jr, May 9, 2010
Dinavance Kamukama, 28, front right, with her cousins in Kampala, Uganda. She is on a waiting list for AIDS medication.
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Freq
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01apr2009 01jul2009 01oct2009 01jan2010 01apr2010
PEPFAR Global Fund-MOH FTF
Weekly Number of Patients Starting ART by Stakeholder
Diminishing Availability of Publicly Funded Slots for Antiretroviral Initiation Among ART-eligible HIV-infected
Patients in Uganda Geng et al PLoS One 2010
Decrease in Multinational Funding Slots Delays Time to ART Start
Geng et al PLoS One 2010
Pre-exposure Prophylaxis: ARV in HIV negatives to Prevent HIV
Acquisition
• Partners 62-73% reduction • TDF2 63% reduction • Caprisa 004 39% reduction • IPREX 44% reduction • Fem-PREP 0% reduction • Voice MTN-003 0% reduction
(oral tenofovir)
CAPRISA 004: Adherence is critical for efficacy against HIV
• High (>80% gel adherence) n=336 (38%) 54% efficacy • Intermediate (50-80% adherence) n=181 (20%) 38% efficacy • Low (<50% gel adherence) n=367 (42%) 28% efficacy
Abdool Karim et al, Science 2010
HIV Biomedical Prevention Studies Study Population Adherence Diaphragm and gel High risk women 49% self report
West Africa TNF Female sex workers 60% clinic pill count
Tanzania Acyclovir High-risk women 50% took 90%
Caprisa High-risk women 72% applicator count
IPREX MSM <50% detectable drug level
Fem-PREP/Voice High-risk women Unknown
Partners in Prevention Acyclovir
Stable discordant couples
80% reported >90%
Partners PREP Stable discordant couples
95-100% electronic monitoring and unannounced pill count
PREP adherence is opportunity to
mitigate tension and strengthen
relationship
“Discordance dilemma”
Excellent Adherence PrEP Adherence Explained by Relationship Dynamics Ware et al IAPAC 2011
PrEP Resolves Tension in a Committed HIV Discordant Sexual Relationship
PREP adherence is opportunity to
mitigate tension and strengthen
relationship
“Discordance dilemma”
Excellent Adherence PrEP Adherence Explained by Relationship Dynamics Ware et al IAPAC 2011
PrEP Resolves Tension in a Committed HIV Discordant Sexual Relationship
Love
PREP nonadherence
becomes mechanism to
express discord
PREP is a reminder of “discordance
dilemma” in setting of mistrust or threat to
the relationship
Corollary: Relationship Discord Threatens PrEP Adherence
Ware et al (IAPAC2010) PrEP Can Create Tension in a Previously Committed HIV
Discordant Sexual Relationship
Discord and
Distrust
PrEP Adherence During Relationship Discord and Distrust
Courtesy of Fran Priddy IAVI
Africans “don’t know what Western time is,”and “do not know what you are talking about,” when asked to take drugs at specific times.
Andrew Natsios USAID Administrator
How to Take ARVs on Time in Rural Uganda Without a Watch: John’s Adherence Story
Maier et al PLOS 2006
• No education • Works as a farmer. • Lives with his brother, sister-in-law, and three
nieces in a three room mud-walled house without electricity.
• Owns a lantern, bed, sofa, bike, and a radio, but no watch.
• HIV in April 2005 and started generic D4T/3TC/NVP (Triomune) after disseminated herpes zoster and Kaposi’s sarcoma
• CD4 count of 151
Electronic medication monitor record of time of bottle openings for am and pm doses.
Adherence
• 90% of doses within 10 minutes of 7:20 • 90% of doses within 17 minutes of 7:20
pm • Overall adherence 98.9%
John’s Adherence: 0-9 and 10-18 months
Initial MEMS assessment (August 2005 to April 2006 (9 months))
Subsequent MEMS assessment (May 2006 to January 2007 (9 months))
Conclusions • Adherence-resistance relationships are regimen specific and
dynamic; patterns matter
• Simpler and more potent regimens associated with favorable outcomes
• ARV adherence in sub-Saharan Africa is excellent
• Fragile balance of social capital to overcome routine structural and economic barriers to care.
• Return of treatment ARV waitlists will have an unpredictable impact on adherence
• ARV prevention will depend on adherence in a poorly understood context
Andrew Moss, PhD UCSF
Tom Coates, PhD UCLA
Bruce Walker, MD MGH/Harvard
Jessica Haberer, MD, MS MGH/Harvard
Peter Hunt, MD Jeff Martin, MD
UCSF UCSF
Conrad Muzoora, MMED Mbarara University of Science and Technology
Anna Baylor, MD MGH
Steven Deeks, MD UCSF
Mwbesa Bwana, MD Mbarara University of Science and Technology
Isaac Kigorzi, MD Mbarara University of Science and Technology
Norma Ware, PhD Harvard Medical School
Richard Harrigan, PhD University of British Columbia
Lloyd Marshall Wisepill, Cape Town
Acknowledgements
Funding Mark and Lisa Schwartz Foundation
NIMH RO-1 54907; Michael Stirratt, PhD and Chris Gordon, PhD
