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
Disclosures
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
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
The Biological Basis of HIV Drug Resistance
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
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
Selective Pressure of Therapy V
iral l
oad
Time
Drug-susceptible quasispecies
Drug-resistant quasispecies
Selective Pressure of Therapy
Treatment begins
Vira
l loa
d
Time
Drug-susceptible quasispecies
Drug-resistant quasispecies
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
Resistance Accumulates
Susceptible Resistant
Mutations
Fold Change
Determine clinical relevance for each drug
How Much Resistance in ARV Treated Individuals?
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
Predictors of Resistance in ARV-treated Patients
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 (%)
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)
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
Transmission of Resistance
• ARV treated individuals living longer
• Incident infections continue to increase worldwide
• Transmitted resistance well recognised in countries with wide ARV coverage
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
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) (
%)
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.
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
Implications of ARV Rollout in Resource Poor World for
Resistance
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
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
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
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
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