Adherence and Resistance to HIV Antiretroviral Therapy
David Bangsberg, MD, MPH
Massachusetts General HospitalHarvard Medical School
Harvard Initiative for Global Health
February, 2009
Will “widespread, unregulated access to antiretroviral drugs in sub-Saharan Africa, lead to the rapid emergence of drug resistant viral strains, spelling doom for the individual, curtailing future treatment options, and [leading] to transmission of resistant virus?”
“Preventing antiretroviral anarchy in sub-Saharan Africa” Harries et al Lancet 2001; 358:410-4.
Bell-shaped Adherence and Resistance CurveIn
crea
sing
pro
babi
lity
of s
elec
ting
mut
atio
n
Increasing Adherence
Inadequate Drug Pressure
To Select Resistant Virus
Drug PressureSelects
Resistant Virus
Complete Viral Suppression
Adherence and Prospective Accumulation of Drug Resistance Mutations in The REACH
Cohort
>1mo HAART 6 mo HAART
Genotype #1VL>50 copies
Genotype #2VL >50 copies
>3 mo pill count
Outcome: # IAS-USA primary or secondary drug resistant mutations at Genotype #2 not present at Genotype #1
>7 mo HAART w/o change in regimen
Bangsberg et al AIDS 2003:17:1325
New Drug Resistance Mutations Over 6 Months in by Adherence Quintile in Viremic Patients
REACH Cohort n=57
00.20.40.60.8
11.21.41.61.8
Adherence Quintile
0-41% 42-57% 58-78% 79-91% 92-100%
p=0.0002
#New
DR
M
Bangsberg et al AIDS 2003:17:1325
Proportion VL>50 copies/ml by Adherence QuintileREACH Cohort n=148
00.10.20.30.40.50.60.70.80.9
1
Adherence Quintile
0-41% 42-57% 58-78% 79-91% 92-100%
p=<0.0001
Pro
port
ion
VL
>50
Bangsberg et al AIDS 2003:17:1325
Resistance Risk by Adherence and Regimen Class
Bangsberg et al J. Antimicrob Chem; 2002 53(5):696-9.
5%
30%
46%
65%
0%
48%
71%60%
0%
20%
40%
60%
80%
100%
0-49% 50-74% 75-95% >=95%
pi rpi
Ritonavir Boosted PIs Lead to Better Viral Suppression at Moderate Adherence LevelsViral Suppression <50 copies/ml for RTV Boosted and Unboosted PI
N=46 N=67 N=83 n=71
Bangsberg et al Int Conference on Adherence to HIV Treatment 2007
P=0.04
Resistance Risk by Adherence and Regimen Class
Bangsberg et al J. Antimicrob Chem; 2002 53(5):696-9.
Why NNRTI Might Have A Different Adherence-Resistance Relationship
• NNRTI potent and exert high selective pressure• NNRTI act distant to the active site – little impact
on fitness• NNRTI resistance seen with single dose therapy
NNRTI Lead to Better Viral Suppression (<400 copies/ml) than Unboosted PIs at Moderate
Electronic Medication Monitor Adherencen=65
23%33%
67%
83%
33%
100%
86%75%
0%
20%
40%
60%
80%
100%
120%
0-53 54-73 74-93 94-100
Adherence
Per
cent
VL
<40
0 co
pies
/ml
PINNRTI
p=0.01
Bangsberg CID 2006:43:939-41
Prevalence of NNRTI Resistance by AdherenceBangsberg AIDS 2006 20:223-232
0102030405060708090
100
0-53% 54-79% 80-94% 95-100%Adherence Quartile
% R
esist
ant
p=0.03
N=54
Resistance Risk by Adherence and Regimen Class
Bangsberg et al J. Antimicrob Chem; 2002 53(5):696-9.
Subjects selecting for viral mutations (NN = any mutation; PI = 1 major or 3 minor)
0
1
2
3
4
5
6
< 75% 75-95% > 95%
NN PI boosted PI
Adherence
%
Percent of patients selecting for mutations at by adherence level
Maggiolo et al HIV Clin Trials. 2007 Sep-Oct;8(5):282-92.
Resistance Risk by Adherence and Regimen Class
Bangsberg et al J. Antimicrob Chem; 2002 53(5):696-9.
Patient Plasma
Replicative Capacity
Purify Viral RNA AAAA
AAAAAAAA
RT-PCR
HIV PR and RTSequences
Transfection
Pool of Patient-DerivedRecombinant Viruses Containing Luciferase
+
Luciferase
+
PR-RT
Luciferase
A-MLV env
Luciferase Activity (Replication) of Sensitive “Wild-Type” Virus Decreases at Higher Drug Levels
100
1,000
10,000
100,000
1,000,000
10,000,000
1 10 100 1,000Drug concentration, nM
Lu
cife
rase
0
WT Control (NL4-3)
Replication of Sensitive vs. Resistant Virus
Drug concentration, nM
100
1,000
10,000
100,000
1,000,000
10,000,000
1 10 100 1,000
Lu
cife
rase
0
WT Control (NL4-3)
Resistant (pt-derived)
Res
ista
nt:
WT
rat
io0.01
0.1
1
10
100
0 1 10 100 1,000
Drug concentration(nM)
Resistant virus favored
Resistance:WT >1
Wildtype virus favoredResistance:WT <1
Sensitive HIV is More Fit than Resistant HIV at Lower Drug Concentrations and Becomes Less Fit at Higher Drug Concentration
100
1,000
10,000
100,000
1,000,000
10,000,000
1 10 100 1,000
Lu
cife
rase
0
WT Control (NL4-3)
Resistant (pt-derived pol)
Low RC
High RC
Resistant : Wildtype Replication RatioComparing Resistant Subject IsolatesWith Sensitive Reference Strain
Bangsberg et al AIDS 2006 20:223-232
Methods
Derive average resistant/WT fitness curve
Convert adherence adjusted predicted in vivo concentrations to comparable in vitro concentrations
0.001 0.01 0.1 1 100.1
1
10
100
1000
10000 1 3 10 30 100
Adherence (%)
Res
ista
nt/
Ref
eren
ceEfavirenz
0.001 0.01 0.1 1 100.1
1
10
100
1000
10000 Adherence (%)1 3 10 30 100
Res
ista
nt/
Ref
eren
ce
Nevirapine
0.001 0.01 0.1 1 100.1
1
10
100
1000
10000
1 3 10 30 100
Adherence (%)
Drug Concentration(protein adjusted, mg/L)
Res
ista
nt/
Ref
eren
ce
Nelfinavir
Bangsberg et al. AIDS 2006; 20:223-231
Level of adherence above which the resistant virus is more fit than the wild-type virus is ~ 2% for efavirenz and nevirapine and ~ 85% for nelfinavir
0.001 0.01 0.1 1 100.1
1
10
100
1000
10000 1 3 10 30 100
Adherence (%)
Res
ista
nt/
Ref
eren
ceEfavirenz
0.001 0.01 0.1 1 100.1
1
10
100
1000
10000 Adherence (%)1 3 10 30 100
Res
ista
nt/
Ref
eren
ce
Nevirapine
0.001 0.01 0.1 1 100.1
1
10
100
1000
10000
1 3 10 30 100
Adherence (%)
Drug Concentration(protein adjusted, mg/L)
Res
ista
nt/
Ref
eren
ce
Nelfinavir
Bangsberg et al. AIDS 2006; 20:223-231
Impact of initial
mutations on resistance
Impact of initial
mutations on fitness (no
drug)
Resistance at low
adherence?
NNRTIs ++++ ↓ Yes
PI + ↓↓ No
3TC ++++ ↓↓ Yes
TNF, ZDV, ddI, ABC
+ ↓↓ No
T20 ++++ ↓↓ Yes
Integrase ++++ ↓↓ Possibly
Maraviroc, R5 inhibitors
? ? ?
Simple Stuff to Improve Adherence
• Medication Errors
• Pill Boxes
• Case management
Pill Identification TestParienti et al. JAMA 2001;285:412.
P<.001; OR, 3.7, 95% CI = 1.9-7.2
Computer-Assisted Self-Interviewing (CASI)
• Advantages of CASI– Privacy may improve
disclosure – Visual ARV recognition– Standardizes adherence
assessment– Not personnel intensive– Could be administered in
waiting room or at home via the web
Bangsberg et al. AIDS Care 2002:14:3-15
• Purposes of CASI– Determine patient’s understanding of medication regimen– Determine patient’s adherence over 3-day period
http://www.edermpda.com/hivadheredemo
Audio CASI Adherence Measurement
Proportion VL < 500 by Patient Reported Adherence
65%
38%
0%20%40%
60%80%
100%
Adherent(>=80%)
Non-Adherent(<80%)
% <
500
cop
ies
• 114 patient-provider pairs
• 18% of patients misunderstood regimen
• Providers missed 74% of non-adherent patients
Bangsberg et al. AIDS Care 2002:14:3-15
Pill Box Organizers are Associated with Improved HIV Antiretroviral Adherence and Viral Suppression: A
Marginal Structural Model Analysis ML Petersen, Y Wang, MJ van der Laan, D Guzman, E Riley, DR Bangsberg
Clin Infect Dis. 2007 Oct 1;45(7):908-15
• Objective: Estimate the effect of pill box organizer (Mediset) use for a given month on adherence to ART and viral load the same month
• REACH Cohort: – Recruited from San Francisco homeless shelters, free meal programs
and low-income single-room-occupancy hotels
– Adherence assessed using unannounced pill count
• Study sample:– 237 individuals followed for 3170 person-months
– March 1998 - September 2005
– Majority non-white men
– High proportion injection drug users
Results: Pill box organizers improve adherence and reduce viral load
MSM Estimator
Difference in % Adherence
95% CI Difference in Log VL
95% CI OR VL<400
95% CI
G-Comp 4.5% (2.0, 7.0) -0.34 (0.08, 0.60) 1.81 (1.25, 2.62)
IPTW 4.1% (0.0, 8.3) -0.37 (0.05, 0.69) 1.91 (1.27, 2.90)
Double Robust 4.1% (1.1, 7.1) -0.36 (0.09, 0.63) 1.91 (1.27, 2.90)
• 4% better adherence• 1.9 odds better viral suppression• $5.00/pill box: extremely cost-effective intervention• Should be standard-of-care
ML Petersen, Y Wang, MJ van der Laan, D Guzman2, E Riley, DR BangsbergClin Infect Dis. 2007 Oct 1;45(7):908-15
Routine Case Management in HIV+ Homeless and Marginally Housed
Kushel and Bangsberg CID 2006 Jul 15;43(2):234-42.
Outcomeadjusted odds
ratio
95% confidence
interval
Sustained Primary Care 4.0 1.2 – 14.0
No Hospitalization 2.7 1.2 – 5.8
No ER Visit 2.3 1.3 – 4.1
HIV Viral RNA <400 2.1 1.1 – 3.9
Increasing CD4 2.5 1.3 – 4.6
Simple Stuff Summary
• Ask patients to construct their regimen– Pictures are better than words
• Give patients a pill box organizer
• Send patients to a good case manager
Meta-analysis of HIV Adherence Interventions J Simoni et al JAIDS 2006 Dec 1;43 Suppl 1:S23-35
•19 studies reported between 1998-2005-Published since 2003 74%
•Studies conducted in the -U.S. 74% -Spain 11%-France 11%-Switzerland 5%
•Study sites-Outpatient HIV primary care clinics 84%
Intervention CharacteristicsJ Simoni et al JAIDS 2006 Dec 1;43 Suppl 1:S23-35
n (%)Intervention provided by:
Health care provider 8 (47%)Pharmacist 2 (12%)Counselor 5 (29%)
Median RangeNumber of intervention sessions 4 1 – 54
Duration of each session 1 hr 45 min–2.5 hrs
Intervention duration (days) 70 1 day – 1 yr
Post Intervention follow-up (k=16) 56 days 14 days-1 yr
Intervention Components J Simoni et al JAIDS 2006 Dec 1;43 Suppl 1:S23-35
HAART information 79%(One-way didactic provision of information about HIV, HAART, and the prescribed regimen)
Cognitive strategies 79% (Two-way discussion involving patient-specific information addressing cognitions such as motivations and expectations)
Behavioral strategies 84% (Such as providing external rewards or two-way discussion involving patient-specific information addressing behaviors such as plans or coping or cue-dosing)
External reminders 32%(Such as pagers, diaries, or calendars)
95% Adherence at First Follow-upJ Simoni et al JAIDS 2006 Dec 1;43 Suppl 1:S23-35
Study Intervention Control OR (95% CI) (n/N) (n/N)
DiIorio 8/8 6/9 9.29 (3.15, 27.35)
Knobel 46/60 58/110 2.95 (2.32, 3.76)
Margolin 23/37 12/32 2.74 (1.03, 7.28)
Weber 21/31 12/27 2.42 (0.78, 7.52)
Safren-life 16/30 8/26 2.30 (1.42, 3.74)
Remien 30/86 18/95 2.30 (1.82, 2.90)
Rathbun 6/16 4/17 1.94 (1.16, 3.25)
Pradier 75/64 62/70 1.92 (1.56, 2.36)
Tuldra 37/40 35/65 1.76 (1.05, 2.95)
Murphy 14/17 11/14 1.27 (0.69, 2.35)
Andrade 14/32 12/32 1.25 (0.44, 3.53)
Rawlings 15/51 18/57 1.13 (0.88, 1.46)
Samet 33/53 40/65 0.96 (0.74, 1.24)
Goujard 86/101 73/85 0.94 (0.71, 1.25)
Jones 40/92 40/82 0.79 (0.43, 1.43)
Rigsby 4/15 4/12 0.75 (0.43, 1.33)
Safren-pager 1/34 1/36 0.62 (.02, 19.33)
Rotheram 15/19 12/13 0.30 (0.14, 0.67)
Overall 484/786 426/847 1.50 (1.16,1.94)
0.01 0.10 1.00 10.00 100.00
OR=1.5 (1.16-1.94)
Study Intervention Control OR (95% CI) (n/N) (n/N)
Rathbun 16/16 12/17 13.48 (4.81, 37.79)
Smith 7/11 5/13 2.90 (1.64, 5.14)
Tuldra 22/28 17/26 2.03 (1.33, 3.07)
Knobel 39/60 60/110 1.55 (1.24, 1.94)
Pradier 79/123 65/121 1.51 (1.27, 1.81)
Goujard 49/77 37/62 1.21 (0.96, 1.54)
Rawlings 53/66 43/54 1.13 (0.88, 1.46)
Remien 37/86 39/95 1.09 (0.89, 1.33)
Samet 19/31 24/38 0.96 (0.69, 1.34)
Andrade 10/29 11/29 0.86 (0.60, 1.25)
Rigsby 3/15 3/12 0.84 (0.44, 1.58)
Margolin 11/25 11/20 0.64 (0.43, 0.97)
Weber 27/29 23/24 0.58 (0.25, 1.35)
Rotheram 4/9 2/3 0.52 (0.21, 1.29)
Overall 376/605 352/642 1.25 (.99, 1.59)0.10 1.00 10.00 100.000.10 1.00 10.00 100.00
Undetectable VL Post-InterventionJ Simoni et al JAIDS 2006 Dec 1;43 Suppl 1:S23-35
OR 1.25 (.99-1.59)
Correlates of Successful InterventionsJ Simoni et al JAIDS 2006 Dec 1;43 Suppl 1:S23-35
• >7 day recall period
• Didactic component
• Interactive discussion of cognition, expectations, and motivation
• Conducted outside of US
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.
Adherence to HIV Therapy in the Industrialized North
San FranciscoBangsberg AIDS 2000
67%
Pittsburgh Paterson Annals Int Med 2000
74%
Los AngelesLiu Annals Int Med 2001
63%
New York City Arnsten CID 2001
57%
HartfordMcNabb CID 2001
53%
Philadelphia Gross AIDS 2001
79%
Mbarara, Uganda
Adherence in Patients Purchasing Generic D4T/3TC/NVP in Uganda
N=36
MEMS Unannounced Pill Count
Self Report
93%
(SD 16%)
92%
(SD 16%)
94%
(SD 16%)
Oyugi et al JAIDS 2004 36:1100-1102
Meta-Analysis of Barriers to Adherence in Africa and North America
Mills and Bangsberg 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 Summary54.7% (95CI: 48.0-61.3%)
Resource-Poor Country Summary77.1% (95CI:67.3%-85.6%)
UARTO Adherence Over 12 Months on Free ARV Therapy n=274Bangsberg et al CROI 2008
0102030405060708090
100
3 months 6 months 9 months 12 months
Pill Count MEMS Self Report
A Social Model of Adherence for sub-Saharan AfricaWare and Bangsberg PLoS Medicine 2009
Improving Health
ResourceScarcity
ResourceScarcity
Improving Health
A Social Model of Adherence for sub-Saharan AfricaWare and Bangsberg PLoS Medicine 2009
ResourceScarcity
ResourceScarcity
Adherencefulfills
responsibility to helpers and
preserverelationshipsas a resource
Relationshipsas resources to
overcome economic
obstacles to adherence
Social Capital
Improving Health
A Social Model of Adherence for sub-Saharan AfricaWare and Bangsberg PLoS Medicine 2009
ResourceScarcity
ResourceScarcity
Adherencefulfills
responsibility to helpers and
preserverelationshipsas a resource
Relationshipsas resources to
overcome economic
obstacles to adherence
Social Capital
Improving Health
A Social Model of Adherence for sub-Saharan AfricaWare and Bangsberg PLoS Medicine 2009
ResourceScarcity
ResourceScarcity
Adherencefulfills
responsibility to helpers and
preserverelationshipsas a resource
Relationshipsas resources to
overcome economic
obstacles to adherence
Social Capital
Improving Health
A Social Model of Adherence for sub-Saharan AfricaWare and Bangsberg PLoS Medicine 2009
Social Structural:Patterns of Inequality,
e.g., stigma,gender inequality
Adherencefulfills
responsibility to helpers and
preserverelationshipsas a resource
Relationshipsas resources to
overcome economic
obstacles to adherence
Social Capital
Infrastructural:Few treatment sites
Distance to careCost/Availability of
Transportation
Cultural:Religious Beliefs
Respect for AuthorityImportance of
having children
Individual:HIV knowledge
Med side effectsCognitive function
Mental healthAlcohol Use
ResourceScarcity
ResourceScarcity
Improving Health
A Social Model of Adherence for sub-Saharan AfricaWare and Bangsberg PLoS Medicine 2009
D4T/3TC/Nevirapine17 USD per month
Triomune
Stopping drugs with different half lives
0 24 483612
Time (hours)
Dru
g c
on
cen
trat
ion
Zone of potential replication
IC90
IC50
Last Dose
Day 1Day 1 Day 2Day 2
MONOTHERAPY
S. Taylor et al. 11th CROI Abs 131
NNRTI Resistance and Treatment DiscontinuationParienti et al CID 2004:38:1311-6
No. patients at Risk≤1 drug holiday 52 47 38 30 19 4>= 2 drug holidays 19 17 13 10 6 1
Frequency and Duration of Treatment Interruptions >48hrs over 24 weeks on Self-pay ART
Oyugi and Bangsberg 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)
Frequency and Duration of Treatment Interruptions >48hrs over 24 weeks on Self-pay ART
Oyugi and Bangsberg 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)
Correlates: Financial difficulty securing ARVs and pharmacy stockouts
Frequency and Duration of Treatment Interruptions >48hrs over 24 weeks on Self-pay ART
Oyugi and Bangsberg 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)
Correlates: Financial difficulty securing ARVs and pharmacy stockouts
90% of all missed doses occur during an interruption
MEMS-Defined 48 Hour Treatment Interruptions Predict Resistance to Self-pay
ART in UgandaOyugi and Bangsberg AIDS 2007
Resistant
Interruption >48 hours
Yes 8/32 (63%)
No 0/56 (0%)
P=0.04
Duration of MEMS Defined Treatment Interruption and Probability of NNRTI ResistanceParienti and Bangsberg PLoS One 2008
n=72
+ ControlsO Cases Estimated 95% confidence interval
Longer interval of treatment discontinuation in days
Est
ima
ted
pro
babi
lity
of v
iral c
ontr
ol
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 StoryMaier, Mwebesa, Emenyonu, Pepper, Bangsberg
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))
Summary
• Most resistance has occurred in highly adherent patients on partially suppressive regimens
• Potent regimens reduce resistance at all levels of adherence
• NNRTI resistance: low adherence and treatment discontinuation
• Internationally: stable drug supply and distribution
Summary
• Most resistance has occurred in highly adherent patients on partially suppressive regimens
• Potent regimens reduce resistance at all levels of adherence
• NNRTI resistance: low adherence and treatment discontinuation
• Internationally: stable drug supply and distribution
Summary
• Most resistance has occurred in highly adherent patients on partially suppressive regimens
• Potent regimens reduce resistance at all levels of adherence
• NNRTI resistance: low adherence and treatment discontinuation
• Internationally: stable drug supply and distribution
Summary
• Most resistance has occurred in highly adherent patients on partially suppressive regimens
• Potent regimens reduce resistance at all levels of adherence
• NNRTI resistance: low adherence and treatment discontinuation
• Internationally: stable drug supply and distribution
Andrew Moss, PhD UCSF Epi/Biostat
Ed Acosta
Huyen Cao, MD
Univ of Alabama
Ca Sate Health Department
Tom Coates, PhD
Edwin Charlebois, MPH, PhD
UCLA
UCSF EPI Center
Barry Bredt, PhD UCSF Center for AIDS Prevention
Richard Clark, MPH UCSF Epi/Biostat
Steven Deeks, MD UCSF Positive Health Program
Nneka Emenyonu
Robert Grant, MD, MPH
UCSF Epi Center
UCSF Gladstone Institute
Norma Ware, PhD
Gwen Hammer, PhD
Rick Hecht, MD
Harvard Medical School
UCSF EPI Center
UCSF Positive Health Program
Mark Holodniy, MD Palo Alto VA
Jeff Martin, MD
Neil Parkin, PhD
Jennifer Free
Travis Porco, PhD
UCSF Epidemiology
Monogram Bioscience
UCSF Epi Center
SF Department of Public Health
Irene Andia, MMed Mbarara University
Elise Riley, PhD UCSF EPI Center
Neil Parkin, PhD Virologic
Richard Harrigan, PhD University of British Columbia
Andrew Zolopa, MD Stanford Positive Care Program
Funding: NIMH, NIAAA, The Doris Duke Charitable Foundation, Bill and Melinda Gates Foundation, University-Wide AIDS Research Program, UCSF Center for AIDS Research