antiretroviral drug resistance anna maria geretti ucl medical school & royal free hampstead...
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Antiretroviral Drug Resistance
Anna Maria GerettiUCL Medical School &
Royal Free Hampstead Medical School, London
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Drug-related factors•Potency•PK properties•Genetic barrier
Host-related factors•Adherence•Tolerability•Immunity•Genetics
Drug pressure
Emergence and evolution
of drug resistance
Virus-related factors•Viral load•Drug susceptibility•Fitness
Persistent virus replication during HAART
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Attachment Fusion Release of RNA
Reverse transcription Integration Transcription
Maturation and budding
Assembly
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Characteristics of HIV-1 infection
1. High virus replication rate (109-1010 virus particles / day)
2. Rapid virus clearance (T½ cells producing virus: <1 day; T½ free virus in plasma: a few hrs)
3. Virus latency (1:106 resting CD4 T cells)
4. Chronic immune activation and inflammation
5. CD4 T-cell depletion (108-109 cells lost daily)
6. Progressive immune deficient state
7. Continuous virus genetic evolution
Wong 1997; Chun 1997; Siliciano 2003; Strain 2003; Han 2007
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Mechanisms of HIV genetic evolution1. RT-driven mutagenesis
– Rate: ~1 wrong incorporation per genome round– All possible point mutations generated daily
2. APOBEC-driven mutagenesis– Deamination of cytosine residues in nascent DNA– GA hypermutation
3. Recombination– Rate: 7-30 per genome round– Hybrid virus progeny produced from different strains
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Dominant quasispecies
Escape from pressure
Preserved fitness
rapid turnover rapid adaptation
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Consequences of HIV genetic variability
At the population level
Continuous emergence of new variants
At the patient level
Escape from immune pressure
Escape from drug pressure
Increased fitness and pathogenicity
Challenge for diagnostic and monitoring assays
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Emergence and evolution of resistance
Increasing number of mutations Accumulation of mutations on the same viral genome Initially reduced viral fitness Compensatory changes restore fitness
Evolution Emergence
Single mutant Double mutant Triple mutant
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Key principles of resistance
Drug-resistant mutants are selected (not created) by drug pressure if virological suppression is incomplete
Ongoing virus replication under drug pressure leads to the evolution of resistance and cross-resistance
Resistant mutants often display reduced fitness but compensatory changes emerge over time that partially restore virus fitness
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Plasma HIV RNAViral gene (e.g., RT)
PCR
Sequencing Mutations
RT M184V
Methionine Valine
@ codon 184 of RT
ATG / AUG GTG / GUG
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Detection of resistant mutants
0.001
0.01
0.1
1
10
100
Detected by ultrasensitive methods
Mu
tatio
n F
requ
enc
yDetected by routine methods
Natural background
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Low-frequency resistance in the FIRST study
Mutations Resistance test P
Standard
UDS
NNRTI 7% 15% <0.001
NRTI 6% 14% <0.001
PI 2% 5% 0.03
Any 14% 28% <0.001
N=258
Risk of failure of first-line NNRTI-based ART in patients with NNRTI resistance
Bulk resistance: HR 12.4 [3.4-45.1]
UDS resistance: HR 2.5 [1.2-5.4]
Siemen, JID 2009USD = Ultra deep sequencing
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Drug pressureResistant
Wild-type
20-3
0%
Limit of detection
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Key principles of resistance
Once drug pressure is removed, resistant mutants are outgrown by fitter wild-type virus and become undetectable by routine tests
Resistance test results obtained after therapy is discontinued are not reliable
Resistant mutants persist at low frequency in plasma and are “archived” in latently infected cells
Resistance is long-lasting
Resistance test results must be interpreted in the context of the patient’s treatment history
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Wild-type Resistant
Ms S., 35 yr Δ HIV+ Dec 1997
10
1000
100000
Dec-97 Jun-98 Dec-98 Jun-99 Dec-99 Jun-00 Dec-00 Jun-01 Dec-01 Jun-02 Dec-02
d4T 3TC NVP
d4T 3TC NVP
VL
<50
M184V
Y181C
M184V
Y181C
M184V = 3TC, FTC
Y181C = NNRTIs
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Drug pressure
Transmission
Transmitted drug resistance
Stable after transmissionGradual reversion over time, sometimes incompletePersistence at low frequency in plasmaPersistence in latently infected cells
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Genetic barrier
Key concepts
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Genetic barrier to resistance
Defined by:
Number of mutations required to compromise activity
Impact of each mutation on drug susceptibility
Interactions between mutations
Fitness cost of resistance
Drug concentration
Resistant
Wild-type
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Genetic barrier – A simplified overview
Class ARVs Genetic barrier
NRTIs
ZDV/3TC, d4T/3TC ++
ABC/3TC, TDF/3TC +
TDF/FTC ++
NNRTIsEFV, NVP, ETV, RPV +
ETV, RPV +/++
PIs Boosted +++/++++
Fusion inhibitors T20 +
CCR5 antagonists MVC ++ (for R5 virus)
Integrase inhibitors RAL, ELV +
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Common NRTI resistance patterns
NRTIs Mutations ZDV d4T ABC ddI TDF 3TC FTC
ZDV 3TC
d4T 3TC
M184V
TAMs
+ TAMs
d4T 3TCTDF 3TCTDF FTC
M184V
K65R
ABC 3TC
M184V
L74V
K65R Y115F
TAMs = thymidine analogue mutations: M41L, D67N, K70R, L210W, T215Y/F, L219Q/E
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Resistance with first-line HAART
Study ART wk Tests
K65R L74V M184V TAMs 3rd drug
GS903 n=299 TDF 3TC EFV 48 29 24% 0 41% 0 EFVR 55%
GS934 n=244 TDF FTC EFV 96 14 0 0 14% 0 EFVR 71%
GS934 n=243 ZDV 3TC EFV 96 29 0 0 31% 3% EFVR 62%
CNA30021 n=770 ABC 3TC EFV 48 38 3% 21% 47% 0 EFVR 58%
ABT418 n=190 TDF FTC LPV/r 96 23 0 0 17% 0 PIR 0
SOLO n=190 ABC 3TC FPV/r 48 32 0 0 12% 0 PIR 0
ARTEMIS n=343 TDF FTC DRV/r 96 31 0 0 6% 0 PIR 0
STARTMRK n=281 TDF FTC RAL 96 13 0 0 38% 0 RALR 33%
Margot, HIV Med 2006; Margot, JAIDS 2009; Moyle, JAIDS 2005; Molina, IAC 2004; Gathe, AIDS 2004; Mills, AIDS 2009; Lennox, Lamcet 2009.
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1st and 2nd generation NNRTIs
Nevirapine Efavirenz Etravirine
Major resistance mutationsL100I, K101E/PK103N/SV106A/ME138K, V179FY181C/I/V, Y188L/H/C, G190A/S/EF227C, M230L, K238T
Rilpivirine
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Activity of ETV with a strong backboneDUET studies: OBR (with DRV/r) + ETV or Placebo
0 2 4 8 12 16 20 24 32 40 48
40%
p<0.0001*Res
pond
ers
(%)
± 95
% C
I
100
90
80
70
60
50
40
30
20
10
0
Time (weeks)
Patients with VL <50 copies/ml at wk 48 (ITT-TLOVR)
ETV + OBR (n=599)
Placebo + OBR (n=604)
61%
Katlama, AIDS 2009
ART-experienced patients with documented NNRTI and PI resistance
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Activity of ETV with a weak backboneStudy TMC125-C227: 2 NRTIs + ETV or PI
Ruxrungtham, HIV Med 2008
ART-experienced, PI-naive patients with documented NNRTI resistance
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The genetic barrier of PIs in vitro
De Meyer, Antimicrob Agents Chemother 2005;De Meyer, IHDRW 2006
Time (days)
Incr
ease
i n P
I se l
e cti
on
c o
nce
nt r
a tio
n
0
50
100
150
200
250
300
350
400
450
0 100 300 500 700 900 1100
DRV (R41T, K70E)
RTV (G16E, M46I, V82F, I84V)
SQV (G48V, A71V, G73S, I84V, L90M)
NFV (L10F, D30N, R41K, K45I, M46I, V77I, I84V, N88D)
APV (L10F, V32I, L33F, M46I, I47V, I50V)LPV (L10F, L23I, M46I, I50V, I54V, L63P, V82A)
TPV (L33V, M46L, V82T)ATV (L10F, V32I, M46I, I62V, A71V, I84V, N88S)
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Hypersusceptibility
Key concepts
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Mechanisms of NRTI resistance: Primer unblocking
T215Y-mediated resistance
Hydrolytic removal of the chain-terminating NRTI enables DNA synthesis to resume
The pyrophosphate donor in most cells is ATP
M184V antagonizes the process
3TC partially restores susceptibility to ZDV,d4T and TDF in the presence of TAMs
3TC antagonizes the emergence of TAMs P P P
P
PP
P
P
PP
P
PP
P
P
P
Gotte, J Virol 2000
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Residual activity
Key concepts
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Res
po
nse
Resistance
Lower cut-off = Level of resistance beyond which response begins to fall off
Upper cut-off = Level of resistance beyond which clinical response is lost
Zone of intermediate response
Resistance as a continuum
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Partial treatment interruption in patients with resistance reveals residual activity
NRTI PI NNRTI T20–0.5
0.0
0.5
1.0
Discontinued treatment class
Change in plasma
viral load
Week 2 change in VL
Deeks, CROI 2005
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Key principles of resistance
Resistance moves along a continuum and increasing numbers of mutations lead to progressive loss of responses
Residual activity is possible despite the presence of extensive resistance (best evidence for the NRTIs)
Resistance carries a fitness cost that reduces viral replication
Antagonistic effects between mutations can have beneficial effects
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Clinical implications for patients with treatment failure
The likelihood of drug-resistance depends upon the drug, the regimen and the level of adherence
When selecting a new regimen, aim for at least 2 fully active drugs
Avoid functional monotherapy with drugs that have a low genetic barrier
If options are limited, exploit residual activity and hypersusceptibility effects – continue the NRTIs rather than stopping therapy
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Thank you