PPT Rusconi "Le multiresistenze dell'HIV/AIDS"

Le Multiresistenze dell’HIV/AIDS
Stefano Rusconi
Divisione Clinicizzata di Malattie Infettive
DIBIC “Luigi Sacco”
Università degli Studi di Milano
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Milano,
Palazzo
delle
Stelline,
22
marzo
2014

Resistance
to
an8viral
drugs

•  The
(in)ability
of
the
virus
to
replicate
in
the
presence
of
an6retroviral
drugs

•  Caused
by
changes
in
relevant
part
of
the
virus
genome
(muta6ons)

2

The
emergence
of
resistance
is
the
inevitable
consequence
of
incomplete
suppression

of
HIV
(HBV/HCV)
replica8on
by
the
current
an8retroviral
drugs,

and
is
a
major
limita8on
of
an8viral
therapy

Viral
escape

•  The
ability
of
a
virus
to
escape
an6viral
pressure
depends
also
upon
the

characteris6cs
of
drugs

•  Gene6c
barrier:
the
number
of
muta6ons
required
by
the
virus
to
develop
a
fully

resistant
virus

–  Low
gene8c
barrier:
drugs
whose
eﬃcacy
is
lost
with
a
single
muta6on

–  High
gene8c
barrier:
drugs
whose
eﬃcacy
is
lost
only
aAer
the
sequen6al

appearance
and
selec6on
of
a
substan6al
number
of
muta6ons

3

Dinamica virale e resistenza farmacologica
Pressione
farmacologica
Tempo
Virus “selvaggio”
(sensibile al
farmaco)
Virus “mutante”
(resistente al
farmaco)
viremia

Utilizzo (combinato) di antiretrovirali anti HIV-1
Pressione farmaco A
Tempo
Viremia
Pressione farmaco B
Pressione farmaco C ...
“Functionally disabled HIV”

Selec8on
-‐>
Resistance

A
single
muta8on
preexis8ng
therapy,
selected
under
an8viral

pressure:
an
easy
and
rapid
phenomenon

Inconsistent
an8viral
pressure
Viral
load

Time

Wt

Res.
variant

For
instance
NNRTI
(K103N)

(gene6c
barrier=1)

6

Selec8on
+
Genera8on
-‐>
Resistance

A
muta8on
preexis8ng
therapy,
conferring
only
marginal

resistance,
selected
under
an8viral
pressure...

Selec8on

Viral
load/
frequency

Time

Wt

Single
mut.

Double
mut.

…
a
long-‐term
phenomenon

For
instance,
ritonavir-‐boosted
PIs

7

Selec8on

Viral
load/
frequency

Time

Wt

Single
mut.

Double
mut.

Resist.mut.

For
instance,
ritonavir-‐boosted
PIs

Evolu8on
toward
high
resistance
and
high
ﬁtness

Selec8on
+
Evolu8on

A
muta8on
preexis8ng
therapy,
conferring
marginal
resistance,

selected
under
an8viral
pressure,
followed
by
the
genera8on
of

further
muta8ons
while
con8nuing
an8viral
therapy

8

Selec8on

Viral
load/
frequency

Time

Wt

Single
mut.
Double
mut.

Resist.
mut.

For
instance
boosted
PI

Evolu8on
toward
high
resistance
and
high
ﬁtness

Events
that
require
a
long-‐term
failing
treatment

to
occur

Triple/quadruple
mutant

Selec8on
+
Genera8on
-‐>
Resistance

A
muta8on
preexis8ng
therapy,
conferring
marginal
resistance,

selected
under
an8viral
pressure,
followed
by
the
genera8on
of

further
muta8ons
while
con8nuing
an8viral
therapy

9

Drug
Resistance
in
Europe
during
1997-‐2012
(EuroSIDA)

A.
Schultze
et
al.,
EACS
2013

The RAM prevalence significantly varied
according to the viremia levels
P <0.001 (Chi-squared test for trend)
54

72

76

87

78

66

0

20

40

60

80

100

Prevalenceofsampleswith
atleast1MRM(%)
Viremia
ranges
(copies/mL)
N
samples

3,726

374

270

227

1,060

1,173

622

Fabeni et al., V ICAR 2013

Viremia ranks
(copies/mL)
Overview of 11,986 genotypic requests from clinical samples with different
viremia ranks over the years.
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Overall (N=11,986) Naive (N=4,711) Experienced
(N=7,275)
>100,000
10,000-100,000
1,000-10,000
500-1,000
200-500
50-200
In experienced patients 1,115 (15.3%) samples had viremia
values ≤500 copies/mL
Fabeni et al., 8° EHDRW 2013, V ICAR 2013

15
Methods
WHO – list 20091
Group 0
Patients with no detected
mutation
(used as a reference group)
Patients having
at least one mutation
Group 1
show no drug resistance to their
prescribed drug (classified as
‘susceptible’ or as
‘potential low level resistance’)
Group 2
resistant to at least one
of their prescribed drugs
(classified as ‘Low-level resistance‘,
‘Intermediate' or as ‘High level resistance‘)
Stanford2
version 6.0.5
•  Virologic endpoint:
–  time to first of two consecutive viral load>500 copies/mL
after six months of therapy
•  Definition TDR (two steps):
1Bennett PlosOne 2009, 2Liu CID 2006
EuroCoord-CHAIN: L. Wittkop et al., Lancet Infect Dis. Feb 28, 2011

16
Virological failure according to TDR
In adjusted analysis*:
Ø  Patients with resistance to ≥1 drug:
- significant higher risk of VF
compared to patients without
mutations
- HR: 3.3 (2.5; 4.4) P<10-4
Ø  patients receiving a fully active cART
and patients with no mutation:
- risk of VF was not significantly
different
- HR: 1.4 (0.9; 2.3) P=0.17
Time after start of therapy (month)
% VF
6 7 8 10 11 129
0
5
10
15
20
25
*All models stratified by cohort ; multivariable models ajusted for: Gender, age, pre-treatment viral load and
CD4 count, year of treatment start, previous AIDS diagnosis, subtype, HIV transmission risk group, origin

17
Impact of TDR according to treatment strata
0.1
1
10
No TDR TDR and
fully-
active
cART
TDR and
resistant
No TDR TDR and
fully-
active
cART
TDR and
resistant
No TDR TDR and
fully-
active
cART
TDR and
resistant
ALL 2NRTI+1NNRTI 2NRTI+1PI/rtv
HR*
TDR
and
fully
active
TDR
and
fully
active
TDR
and
fully
active
TDR
and
resistant
TDR
and
resistant
TDR
and
resistant
No TDR No TDR No TDR
ALL 2NRTIs + 1NNRTI 2NRTIs + PI/rtv
*All models stratified by cohort ; multivariable models ajusted for: Gender, age, pre-treatment viral load and CD4 count, year of
treatment start, previous AIDS diagnosis, subtype, HIV transmission risk group, origin

Impact
of
Minority
Drug
Resistant
and
X4
variants
in

Naive
Pa6ents
Star6ng
ART
with
<100
CD4/mm3

M.
Casadellà
et
al.,

CROI
2014,
abs
602

Primary
resistance
to
integrase

inhibitors
in
Europe
(Spread)

M.
Casadellà
et
al.,

CROI
2014,
abs
580

Impact
of
RAL/EVG
selected

muta6ons
on
DTG
cross-‐resistance

Pa6ent
viruses
containing
Q148H/K/R
muta8ons
displayed
reduced
DTG

suscep8bility
with
a
median
fold
change
in
IC50
(FC)=4.6
(range
1.7
to
96.0).

Q148K
viruses
that
emerge
less
frequently
than
Q148H/R
variants
exhibited
larger

reduc6ons
in
DTG
suscep6bility
compared
to
Q148H/R
viruses.

All
pa6ent
viruses
contained
one
or
more
addi6onal
IN
muta6ons
with
G140

subs6tu6ons
occurring
most
frequently
followed
by
E138
subs6tu6ons.
Based
on

the
analysis
of
a
panel
of
SDMs,
a
single
muta6on
at
posi6on
148
did
not
reduce

DTG
suscep6bility
(DTG
FC=0.5
to
0.7).
However,
the
addi8on
of
a
second

muta8on
at
posi8on
140
conferred
measurable
reduc8ons
in
DTG
suscep8bility

(FC=2.2
to
58).
The
further
introduc6on
of
addi6onal
muta6ons
at
posi6ons
74,

92,
97
and
138
conferred
incremental
reduc6ons
in
DTG
suscep6bility.
Q148K

SDMs
containing
addi8onal
muta8ons
displayed
larger
reduc8ons
in
DTG

suscep8bility
than
corresponding
Q148H/R
SDMs.

W.
Huang
et
al.,
CROI
2014,
abs
595

Clin
Microbiol
Infect.
2013
Jan
4.
doi:
10.1111/1469-‐0691.12100.

Weeks
24201612840
Oneminussurvival
1,0
0,8
0,6
0,4
0,2
0,0
1.50+
1-1.49
<1
GSS
Figure
1a.
Time
to
ﬁrst
undetectable
HIV-‐RNA
by
GSS

Clin
Microbiol
Infect.
2013
Jan
4.
doi:
10.1111/1469-‐0691.12100.

Weeks
24201612840
Oneminussurvival
1,0
0,8
0,6
0,4
0,2
0,0
1.50+
1-1.49
<1
Weighted GSS
Figure
1b.
Time
to
ﬁrst
undetectable
HIV-‐RNA
by
weighted
GSS

Clin
Microbiol
Infect.
2013
Jan
4.
doi:
10.1111/1469-‐0691.12100.

0,1
1
10
100
GSS GSS 1-1.5 GSS >1.5 Weighted
GSS
Weighted
GSS 1-1.5
Weighted
GSS >1.5
LogScale
Factors
associated
with
virological
response
at
six
months

according
to
mul8variate
analysis
(AOR)

Clin
Microbiol
Infect.
2013
Jan
4.
doi:
10.1111/1469-‐0691.12100.

Detec8on
of
NNRTI
resistance
muta8ons

ager
interrup8ng
NNRTI-‐based
regimens

V.
Cambiano
et
al.,

CROI
2014,
abs
593

•Among
the
208
individuals
with
a
resistance
test

performed
aAer
stopping
suppressive
NNRTI-‐based

ART
(see
characteris6cs
in
table
1),
12%
(n=25,
95%

CI:
8%-‐17%)
had
≥1
NNRTI
resistance
muta8on

detected
at
the
ﬁrst
resistance
test
following
ART

treatment
interrup8on.

•In
those
with
at
least
1
NNRTI
resistance
muta8on

detected
the
median
8me
between
TI
and
the

resistance
test
was
12
months
(IQR:
3-‐20
months).

Detec8on
of
NNRTI
resistance
muta8ons

ager
interrup8ng
NNRTI-‐based
regimens

V.
Cambiano
et
al.,

CROI
2014,
abs
593

Decay Rate of Archived HIV-1 Drug Resistance
Mutations

J.
De
La
Cruz
et
al.,
CROI
2014,
abs
604

Prevalence
of
Minority
Resistant
Variants
to
ETR,

DRV
and
RAL
at
Baseline
in
the
ANRS
139
TRIO

Trial

C.
Charpen6er
et
al.,
CROI
2014,
abs
605

P.
Di
Vincenzo,
S.
Rusconi
et
al.,
HIV
Medicine
(2010)
11,
530–534

Prevalence
of
muta8ons
and
determinants
of
genotypic

resistance
to
etravirine
(TMC125)
in
a
large
Italian
resistance

database
(ARCA)

Determinants
of
genotypic
resistance
[Tibotec
(TBT)
score
0–2
or
>2]
to
TMC125

<
0.001

0.015

0.005

<
0.001

0.964

0.004

<
0.001

<
0.001

0.002

0.665

<
0.001

0.369

0.207

Category
TBT
score
0-‐2
TBT
score
>2
AOR
95%CI
p

This
mul8variate
analysis
was
conducted
with
the
endpoint
of
having
a
TBT
score
4
2.

Values
in
the
TBT
score
columns
are
n
(%),
with
the
excep8on
of
mean
(median)
for
age.
AOR
for
age
is
for
each
addi8onal
10
years.

*Reference
category.

AOR,
adjusted
odds
ra8o;
CI,
conﬁdence
interval;
ND,
not
determined;
EFV,
efavirenz;
NVP,
nevirapine;
PI,
protease
inhibitor;
T20,
enfuvir8de.

P.
Di
Vincenzo,
S.
Rusconi
et
al.,
HIV
Medicine
(2010)
11,
530–534

TMC125
Control
0
–1
–2
–3
Changeinlogviralload(mean)
Weeks
0
4 8 12 16
59 56 46 36 2959n (TMC125) =
57 55 49 33 2957n (control) =
Initial 1.3 log decline in viral load was not sustained past 8
weeks, possibly affected by limited activity of the
background regimen.
TMC125-C227: Change in viral load (observed)
B. Woodfall et al., HIV8, Glasgow Nov 12-16, 2008. Abstract PL5.6

l  A large number of NRTI
resistance-associated
mutations were noted in
this first line failure
population
l  Many NRTIs were
recycled in this study
l  TMC125 group
l  37% recycled one,
9% two
l  Control group
l  35% recycled one,
12% two
IAS-USANRTIresistanceassociatedmutations
(%)
90
80
70
60
50
40
30
20
10
0
TMC125 Control
100
0 1 2 3 4 5 6 7
Group
16.9
10.2
15.3
20.3
28.8
8.8
10.5
22.8
38.6
10.5
6.8
1.7
7.0
Baseline NRTI mutations
B. Woodfall et al., HIV8, Glasgow Nov 12-16, 2008. Abstract PL5.6
1.8

Low-‐Frequency
HIV-‐1
Drug
Resistance
Muta8ons

and
Risk
of
NNRTI-‐Based
An8retroviral
Treatment
Failure

A
Systema8c
Review
and
Pooled
Analysis

Systema6c
Review
and
Baseline

Characteris6cs

10
studies
with
985
pa6ents

were
iden6ﬁed
as
mee6ng
the

inclusion
and
exclusion
criteria.

The
median
CD4
cell
count
was

229
cells/mm3
and
mean

plasma
HIV-‐1
RNA
level
was
5.0

log10
copies/mL.

All
studies
evaluated
the

presence
of
NNRTI
muta6ons

K103N,
Y181C
(N=435)
and
NRTI

muta6ons
M184V
(N=228)
and

K65R
(N=163).

Li
et
al
JAMA
2011

• 
Minority
drug-‐resistant
variants
were
found
in
14%
(117/808).

Baseline Parameter Odds Ratio (95% CI)
P-Value
Χ2 - test
K103N >= 2,000 copies/mL
K103N detectable and < 2,000
copies/mL
47.4 (5.2, 429.2)
1.19 (0.15, 9.71)
0.0006
0.8703
BL HIV RNA >100,000 0.98 (0.51, 1.88) 0.9471
BL CD4 >=200 0.60 (0.31, 1,16) 0.1282
Treatment arm 0.75 (0.40, 1.41) 0.3695
• Multivariate logistic regression to predict risk of VF with predictors treated as categorical variables
•  16 of 476 (3.4%) evaluable participants had low-level K103N at baseline by
AS-PCR (0.8-15%).
• K103N >2% was also predictive of VF with Odds Ratio = 25.5 and P = 0.0002
Svarovskaia
et
al
XVIII
Inter
HIV
Drug
Resist

2009

Goodman
et
al
AIDS
2011

The presence of K103N mutant virus in plasma above 2000
copies/ml prior to therapy in treatment-naive individuals
correlated with increased risk of virologic failure of
efavirenz-containing triple-drug regimens

Prevalence of etravirine (ETR)-RAMs at NNRTI
failure and predictors of resistance to ETR in a
large Italian resistance database (ARCA)
S.
Rusconi
et
al.,
Clin
Microbiol
Infect
2013

Adjusted risk of triple class
virologic failure after the
start of cART
Lodwick R, for COHERE, 16th CROI; Montreal (CA), 2009

Boosted-PIs are associated with lower risk of
HIV resistance at any level of adherence
Lima VD et al, JID 2008
*Plasma viral load log
* *

Differential Presence of Selected Drug Resistance
in Patient Populations
70.7
66.1
61.3
37.2
70
10.1
61.5
23.7
0
10
20
30
40
50
60
70
80
Long-term treated patients (n=380) PHI (Untreated n=59)
Prevalence(%)
TAMs
NNMs
M184V
PRAMs
D Turner et al, J AIDS 37, 1627ff, 2004

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