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Global HIV Resistance: The Implications of Transmission
Deenan Pillay, MD, PhD
Professor of Virology
Royal Free & University College Medical School
University College London
London, UK
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Disclosures
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Structure of Talk
• Basis of resistance
• Resistance in treated: prevalence and predictors
• Resistance in untreated: prevalence, risk groups, persistence, minority populations and consequences
• Potential for resistance in developing world
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Replication Cycle of HIV
DS dna COMPLEX
reversetranscriptase
inhibitors
proteaseinhibitors
integrase inhibitors
HIV entry inhibitors
maturation inhibitor
fusion inhibitor
chemokine receptor
inhibitors
CD4 attachment inhibitors
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The Biological Basis of HIV Drug Resistance
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Question:Drug resistance emerges during antiretroviral therapy
Because the drug interacts with the virus to cause resistance mutations
Because pre-existing variants of virus preferentially replicate in the presence of drug
Regardless of the level of viral suppression achieved
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Virological Response to Antiretroviral Therapy
105
104
103
102
101
100
10-1
10-2
10-3
Cop
ies/
mL
Therapy
Suppression
Virological rebound
assay limit of detection
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Selective Pressure of Therapy V
iral l
oad
Time
Drug-susceptible quasispecies
Drug-resistant quasispecies
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Selective Pressure of Therapy
Treatment begins
Vira
l loa
d
Time
Drug-susceptible quasispecies
Drug-resistant quasispecies
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Selection of resistant quasispecies
Selective Pressure of Therapy
Incomplete suppression• Inadequate potency• Inadequate drug levels• Inadequate adherence• Pre-existing resistance
Vira
l loa
d
Time
Treatment begins Drug-susceptible quasispecies
Drug-resistant quasispecies
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Resistance Accumulates
Susceptible Resistant
Mutations
Fold Change
Determine clinical relevance for each drug
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How Much Resistance in ARV Treated Individuals?
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Pillay et al. JID 2005;192:967-73.
Prevalence of Resistance as a Proportion of Treated Patients
0
5
10
15
20
1998 1999 2000 2001 2002 2003 2004 2005
Prevalence of Resistance
>/=1 classes >/=2 classes 3 classes
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Predictors of Resistance in ARV-treated Patients
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Prevalence of Triple-class Drug Failure Over Calendar Time
0
5
10
15
20
Calendar year
Mocroft et al. JID 2004;190:1947–56.
Follow-up (n)554 1482 1814 1944 1988 2029 2028 140 514 716 860 958 1174 12120 10 68 163 241 282 315 0 0 10 21 33 38 58
Triple-class treatment failure (n)
Treatment experienced at start of HAART
Treatment naïve at start of HAART
1/97 1/98 1/99 1/00 1/01 1/02 1/03 1/97 1/98 1/99 1/00 1/01 1/02 1/03
Prevalence (%)
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Cumulative Risk of Triple-class Virologic Failure (incl boosted PIs) in 10,603 Patients
PI failure = boosted PIs; TCF = triple class failure
Phillips et al. CROI 2007. Abst 532.
2 4 6 8 10
Extensive failure of:
Nucleosides 4% 9% 15% 21% 28%
PIs 2% 4% 8% 11% 16%
NNRTI 13% 20% 26% 31% 35%
TCF 2% 5% 9% 13% 20%
Extensive TCF 0% 1% 3% 5% 8%
Years from start of ART (≥3 drugs)
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Resistance in Treated Individuals is…
• Decreasing since initiation of triple therapy
• Low in those using RTV boosted PIs
• Managed by new drugs within existing classes and new classes
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Transmission of Resistance
• ARV treated individuals living longer
• Incident infections continue to increase worldwide
• Transmitted resistance well recognised in countries with wide ARV coverage
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Transmission of Resistance in Europe (17 countries)
Route of Infection p-value OR CI
IDU 6.8% 6/88 0.35 0.65 0.27 1.58
Origin / infect. in HPC 5.2% 10/193 0.046 0.49 0.24 0.99
Heterosexual 12.0% 30/246 0.38 1.24 0.76 2.02
MSM (reference) 10.0% 47/467 1.00
Origin / infect. in HPC* 5.2% 10/193 0.046 0.49 0.24 0.99
Wensing et al. JID 2005;192:958-66.
n=989; 22% recent infections*HPC = high prevalence countries
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In resource rich world, transmitted resistance appears to be stabilising or even reducing
UK Collaborative Group on HIV Drug Resistance.AIDS 2007;21:1035-9.
Chronic infection
Acute infection
14
12
10
8
6
4
2
0
1997 1998 1999 2000 2001 2002 2003 2004 2005
Year of sample
Sam
ples
with
IA
S m
utat
ion(
s) (
%)
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Persistence of Transmitted Resistance in Primary HIV Infection
n=9Persistent resistance
n=2Reversion to wild type
n=14Persistent resistance
n=2Reversion to wild type
Variable persistence according to mutations: TAMs persist, K103N persists, PI persist, MDR persist
n=11Primary resistance
US; F/U median 9 months
n=16Primary resistance
UK; F/U up to 3 years
Little et al. 11th CROI 2004, San Francisco, CA. Abs 36LB.
Pao et al. JAIDS 2004;37:1570-3.
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In resource rich world...
• Rates of transmitted resistance stabilising or reducing
• Transmitted resistant species persist prior to initiating treatment, and represents a risk for onward transmission
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Implications of ARV Rollout in Resource Poor World for
Resistance
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Implications of HAART Without Virological Monitoring: Therapy Failure?
Increasing Resistance
Treatment onset Virological failure (>1000c/mL)
Clinical failure (AIDS events)
VL 1000
Months Years
CD4 count
VL
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Resistance Following First-line ART
Country
Mostcommon
ARTregimen
Otherdrugs
%failure
%resistance
Mostcommonmutation
Othersmutations
Abstract number
South Africad4T + 3TC+ NNRTI
LPV/r AZTddI
2% 68%M184V
43%
NRTI (TAMs);NNRTI
PI (M46I, G48V,
I54V, V82A, L90M)
661
Malid4T + 3TC
+ NVPNone 23% 50%
M184V100%
NNRTI 662
BotswanaAZT + ddI +
NNRTId4T 3TC
NA 78%NNRTI 74%
NRTI (TAMs)52%
664
CROI 2007
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DART TRIAL ZDV/3TC/TDF (n=300)
MutationWeek 24(n=24)
Week 48(n=41*)
M184V 15 (62%) 32 (78%)K65R 3 (12%) 6 (15%)M41L 7 (29%) 17 41%)D67NG 9 (38%) 23 (56%)K70R 8 (33%) 23 (56%)L210W 0 (0%) 3 (7%)T215FY 7 (29%) 17 (41%)K219QEN 1 (4%) 9 (22%)Total TAMs: 0
1–34–6
10 (42%)13 (54%)
1 (4%)
11 (27%)18 (44%)12 (39%)
TAM Group** I II
I and II
5 (36%)4 (11%)5 (36%)
2 (7%)11 (37%)17 (57%)
Pillay et al. CROI 2007. Abstr. 642.
Prevalence of mutations at 24 and 48 weeks in absence of virological monitoring
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Summary
• Resistance develops following failure of therapy
• Resistance can be transmitted
• Improvements in ARV use reduces emergence and transmission of resistance
• Extensive resistance may develop in absence of monitoring of ARV use
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Question:Risk of resistance is increased by:
Mono and/or dual therapy prior to HAART
Use of ritonavir boosted PIs
Initiation of HAART at CD4 counts >200/L