3. 0
2
4
6
8
10
12
14
1997-‐1999
2000-‐2002
2003-‐2005
2006-‐2008
2009-‐2010
2011-‐2013
Incidence
of
death
by
cause
and
calendar
period
Cardio-‐cerebro-‐vascular
Drug
abuse
Hepa>c
HIV
related
Non
HIV
related
infec>ons
Non-‐AIDS
malignancies
(excluded
HCC)
Other
Suicide
Unknown
for
2013,
10
months
ICONA:
update
2013
4. 54,1
46,1
32,7
39,3
29,6
31,0
13,5
24,3
21,8
16,7
33,8
10,3
20,3
9,9
13,6
9,5
8,5
6,9
0
3,3
5,5
11,9
8,5
19,0
6,8
5,9
10,0
9,5
4,2
13,8
2,0
2,6
4,5
8,3
7,0
5,2
2,7
2,6
3,6
2,4
4,2
8,6
0,7
2,6
3,6
2,4
4,2
3,4
0
2,6
4,5
0
0
1,7
0%
10%
20%
30%
40%
50%
60%
1997-‐1999
n=148
2000-‐2002
n=152
2003-‐2005
n=110
2011-‐2013
n=84
2006-‐2008
n=71
2009-‐2010
n=58
Causes
of
death
according
to
calendar
period
of
death
HIV
related
HepaEc
Other
Non-‐AIDS
malignancies
(excluded
HCC)
Unknown
Cardio-‐cerebro-‐vascular
Suicide
Non
HIV
related
infecEons
Drug
abuse
for
2013,
10
months
ICONA:
update
2013
6. Persions
with
HIV
are
not
fully
immune
reconsEtuted
unEl
the
CD4
count
increases
to>750
cells/uL.
CID
2013
7.
8. JAIDS
Feb
2014
In
conclusion,
this
study
shows
that
within
the
HIV
infected
popula>on
the
propor>on
of
subjects
that
has
achieved
a
sa>sfactory
immune
recovery
has
increased
over
>me.
As
a
consequence,
a
higher
propor>on
of
pa>ents
approaches
life
expectancy
of
the
general
popula>on.
9. Strategie
validate
per
ocmizzare
il
recupero
immunologico
in
soggec
a
rischio
di
risposta
immunologica
subocmale
17. Lessons
from
anE-‐TB
therapy
• INH 300 mg/die
• Rifampicin 600 mg/die
• Pyrazinamide 25 mg/kg/die
• (Ethambutol 15-25 mg/kg/die)
• INH 300 mg/die
• Rifampicin 600 mg/die
Why
a
combina>on
therapy?
1. Preven>on
of
selec>on
of
resistance
18. How drug resistance arises. Richman DD. Scientific American, July 1998.
How Drug-resistance Arises
When HIV replication is not completely blocked
• Sub-optimal therapy regimens eg monotherapy at initial stage
• Adherence problems
• Pharmacokinetic problems: poor drug absorption, inadequate dosing or drug-
drug interactions
These conditions can allow drug-resistant virus, already present in the population to
dominate
19. Less
(than
3)
Drug
Regimens
Ra>onale
Less
than
3
drugs
could
be
sufficient
to
maintain
viral
suppression
in
stable
pa>ents
(data
are
more
conflic>ng
in
naive)
Clinical
needs
Extensive-‐
resistance
and/or
toxicity
related
to
NRTIs
Preserva>on
of
future
therapu>cal
op>ons
Cost
saving
20. Among
pts
with
moderate
adherence
(80%
-‐
95%)
probability
of
VF
was
0.85
aner
12-‐months
suppression
and
0.08
aner
72-‐months
suppression
21. In
pazien>
seleziona>:
§ senza
storia
di
fallimento
virologico,
§ con
viremia
non
rilevabile
(<
50
copie/mL)
da
almeno
6
mesi,
§ buon
recupero
immunologico
e
nadir
dei
CD4+
>
100
cellule/μL,
§ non
anemici,
§ in
trapamento
con
IP
e
senza
mutazioni
di
resistenza
agli
IP
determinata
prima
dell’inizio
del
trapamento
an>retrovirale,
lo
switch
a
monoterapia
con
LPV/r
BID
o
DRV/r
QD
può
rappresentare
un’opzione
accepabile
in
un
contesto
di
ocmizzazione
della
terapia.
CRITERI
DI
SELEZIONE
DEI
PAZIENTI
CANDIDATI
A
MONOTERAPIA
(linee
guida
italiane
2013)
22. Dynamics
of
cellular
HIV-‐1
DNA
levels
over
144
weeks
of
darunavir/ritonavir
monotherapy
versus
triple
therapy
in
the
MONET
trial.
Gerec
AM,
Arribas
JR,
Lathouwers
E,
Foster
GM,
Yakoob
R,
Kinloch
S,
Hill
A,
van
Deln
Y,
Moecklinghoff
C.
§ In
this
substudy
of
the
MONET
trial,
HIV-‐1
DNA
levels
remained
stable
during
144
weeks
of
either
DRV/r
monotherapy
or
triple
therapy
with
DRV/r
+
2
NRTIs.
§ In
both
treatment
arms,
baseline
HIV-‐1
DNA
levels
were
predicted
by
the
nadir
CD4
cell
count
and
predic>ve
of
plasma
HIV-‐1
RNA
detec>on
during
follow-‐up.
23. Early
treatment
facilitated
the
achievement
of
undetectable
levels
of
plasma
viremia
and
cellular
HIV
DNA
and
a
beper
recovery
of
CD4
lymphocytes.
HIV
DNA
levels
before
and
during
highly
ac>ve
an>retroviral
therapy
may
be
used
as
a
new
tool
for
monitoring
treatment
efficacy
24. Lessons
from
anE-‐TB
therapy
• INH 300 mg/die
• Rifampicin 600 mg/die
• Pyrazinamide 25 mg/kg/die
• (Ethambutol 15-25 mg/kg/die)
• INH 300 mg/die
• Rifampicin 600 mg/die
Why
a
combina>on
therapy?
1. Preven>on
of
selec>on
of
resistance
2. Differen>al
papern
of
compartmentaliza>on
and
ac>vity
of
an>-‐TB
drugs
25. Hypothetical model of TB chemoterapy
0 1 2 3 4 5 6
A
B
C
Bactericidal
acEvity
and
sterilizing
effect
A = rapidly multiplying (extracell) INH>>SM>RIF>EMB
B = slowly multiplying (acid) PZA>>RIF>INH
C = sporadically multiplying (caseum) RIF>>INH
Rifampin
is
the
only
drug
ac>ve
on
dormant
bacilli
in
caseum,
allowing
cure
of
TB
and
preven>on
of
relapses
27. Ac>va>on
of
the
Latent
Viral
Reservoir
“Shock
and
Kill”
Key steps and assumptions of the induction and clearance approach:
n Activate viral replication by reversing latency,
n HIV RNA synthesis è viral protein production è release of HIV
particles,
n Killing of the infected cell by the virus cytopathic effect or the
patient’s immune system or both,
n Inhibition of released infectious virus by ART.
Deeks
SG.
Nature
2012;487:439-‐40.
HAART
must
block
majority
of
new
infec>on
events.
Are
ARVs
available
in
all
the
compartments
where
they
are
needed?