international perspectives of adherence and resistance to hiv antiretroviral therapy · 2019. 9....

International Perspectives of Adherence and Resistance to HIV Antiretroviral Therapy

David Bangsberg, MD, MPH

Massachusetts General HospitalHarvard Medical School

Harvard Initiative for Global Health

October, 2008

Bell-shaped Adherence and Resistance CurveIn

crea

sing

pro

babi

lity

of se

lect

ing

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 Quintile0-41% 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 Quintile0-41% 42-57% 58-78% 79-91% 92-100%

p=<0.0001

Prop

ortio

n V

L>50


Resistance Risk by Adherence and Regimen Class

0 20 40 60 80 100

Percent AdherenceSingle PI

Res

istan

ce R

isk

NNRTI

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


0 20 40 60 80 100

Percent AdherenceSingle PI Boosted PI

Res

istan

ce R

isk


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

23.3 23.5

5.3 3.410.3

5.6 1.6 20

5

10

15

20

25

<=75 76-85 86-95 >95

Self-reported Adherence and Virological Failure

Adherence: Patient report of % daily doses taken at the right time

Maggiolo F et al. CID 2005;40:158–163.

Failu

re ra

te

PI-based

NNRTI-based

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

Perc

ent V

L<4

00 c

opie

s/m

l

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

esis

tant p=0.03

N=54


0 20 40 60 80 100

Percent AdherenceSingle PI Boosted PI

Res

istan

ce R

isk

NNRTI


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.


0 20 40 60 80 100

Percent AdherenceSingle PI

Res

istan

ce R

isk

NNRTI


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

Luci

fera

se

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

Luci

fera

se

0

WT Control (NL4-3)Resistant (pt-derived)

Res

ista

nt:W

T ra

tio0.01

0.1

1

10

100

0 1 10 100 1,000Drug 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

Luci

fera

se

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 100Adherence (%)

Res

ista

nt/R

efer

ence

Efavirenz

0.001 0.01 0.1 1 100.1

1

10

100

1000

10000 Adherence (%)1 3 10 30 100

Res

ista

nt/R

efer

ence

Nevirapine

0.001 0.01 0.1 1 100.1

1

10

100

1000

10000

1 3 10 30 100Adherence (%)

Drug Concentration(protein adjusted, mg/L)

Res

ista

nt/R

efer

ence

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 100Adherence (%)

Res

ista

nt/R

efer

ence

Efavirenz

0.001 0.01 0.1 1 100.1

1

10

100

1000

10000 Adherence (%)1 3 10 30 100

Res

ista

nt/R

efer

ence

Nevirapine

0.001 0.01 0.1 1 100.1

1

10

100

1000

10000

1 3 10 30 100Adherence (%)

Drug Concentration(protein adjusted, mg/L)

Res

ista

nt/R

efer

ence

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

? ? ?

Antiretroviral therapy in AfricaWarren 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%)

Adherence Declines Over Time in A Resource-Limited SettingOyugi and Bangsberg AIDS 2007:21:965-971

Measure Mean (SD) Mean (SD) 0-12 Week 13-24 Week 3-day SR 0.93 ± 0.179 0.91 ± 0.216 P=0.04 30-day VAS 0.95 ± 0.101 0.90 ± 0.175 P=0.008 PC 0.90 ± 0.164 0.87 ± 0.197 P=0.002 MEMS 0.91 ± 0.152 0.82 ± 0.271 P<0.001 VL ≤400 71 (71/88) 80.7%70 (70/86) 81.4% NS

N=97

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

Socioeconomic Ladder

San Francisco Africa

A Social Model of Adherence for sub-Saharan AfricaWare and Bangsberg International HIV Adherence Conference 2008

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


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 knowledgeMed side effects

Cognitive functionMental healthAlcohol Use

ResourceScarcity

ResourceScarcity

Improving Health


D4T/3TC/Nevirapine17 USD per month

Triomune

Stopping drugs with different half lives

0 24 483612Time (hours)

Dru

g co

ncen

trat

ion

Zone of potential replicationIC90

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

Estimated95% confidence interval

Longer interval of treatment discontinuation in days

Est

imat

ed p

roba

bilit

y of

vira

l con

trol

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 monthsInitial 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

Andrew Moss, PhD UCSF Epi/Biostat

Ed AcostaHuyen Cao, MD

Univ of AlabamaCa Sate Health Department

Tom Coates, PhDEdwin Charlebois, MPH, PhD

UCLAUCSF EPI Center

Barry Bredt, PhD UCSF Center for AIDS Prevention

Richard Clark, MPH UCSF Epi/Biostat

Steven Deeks, MD UCSF Positive Health Program

Nneka EmenyonuRobert Grant, MD, MPH

UCSF Epi CenterUCSF Gladstone Institute

Norma Ware, PhDGwen Hammer, PhDRick Hecht, MD

Harvard Medical SchoolUCSF EPI CenterUCSF Positive Health Program

Mark Holodniy, MD Palo Alto VA

Jeff Martin, MDNeil Parkin, PhDJennifer FreeTravis Porco, PhD

UCSF EpidemiologyMonogram BioscienceUCSF Epi CenterSF 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

Harvard Global Health Scholars Program

David Bangsberg, MD, MPHJason Harlow, MA, MPH

CDC, 2006

PubMed – HIV, 2008 (n=100)

Balanced Leadership: Resource-rich Resource-poorMentorship: Junior Apprentice Senior MentorKnowledge: Discover Deliver

Harvard Global Health ScholarTri-axial Framework

Program

• Didactic Training in research methods• Leadership training in international research• Individualized mentored research program

Application Process

• Announcement: July 2010• Deadline September: 2010• First Cohort: January, 2011

international perspectives of adherence and resistance to hiv antiretroviral therapy · 2019. 9....

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