Adherence and Resistance to HIV Antiretroviral Therapy David Bangsberg, MD, MPH Massachusetts General Hospital Harvard Medical School Harvard Initiative

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


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


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



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



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.



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

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


ResourceScarcity

ResourceScarcity

Adherencefulfills

responsibility to helpers and

preserverelationshipsas a resource

Relationshipsas resources to

overcome economic

obstacles to adherence

Social Capital

Improving Health


ResourceScarcity

ResourceScarcity

Adherencefulfills




overcome economic


Social Capital

Improving Health


ResourceScarcity

ResourceScarcity

Adherencefulfills




overcome economic


Social Capital

Improving Health


Social Structural:Patterns of Inequality,

e.g., stigma,gender inequality

Adherencefulfills




overcome economic


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


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)





11.5 ±9.2 (S.D)

Correlates: Financial difficulty securing ARVs and pharmacy stockouts





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





Summary





Summary





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

Documents

Adherence and Resistance to HIV Antiretroviral Therapy David Bangsberg, MD, MPH Massachusetts General Hospital Harvard Medical School Harvard Initiative