1. Clinica
e
terapia
dell’infezione
da
HIV
Stefano
Bonora
Università
di
Torino

2. Outline
La
clinica
dell’HIV
oggi
Le
lezioni
della
terapia
an>tubercolare

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

5. 9,0
10,3
12,6
7,7
7,3
8,8
13,8
17,6
12,6
14,1
12,9
14,4
16,2
16,6
19,4
19,7
18,3
20,0
22,1
18,6
19,2
22,3
25,1
22,7
38,9
36,8
36,2
36,2
36,4
34,2
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
1997-­‐1999
n=3986
2000-­‐2002
n=1395
2003-­‐2005
n=588
2006-­‐2008
n=795
2009-­‐2010
n=1132
2011-­‐2013
n=2468
CD4
count
strata
at
enrolment
according
to
calendar
period
CD4
-­‐
<=50
CD4
-­‐
51-­‐200
CD4
-­‐
201-­‐350
CD4
-­‐
351-­‐500
CD4
-­‐
>500
0,3
1,7
1,6
1,6
1,9
2,5
9,1
5,7
4,9
2,7
3,3
3,1
47,9
42,1
38,1
43,8
39,0
37,4
19,4
22,5
26,7
24,1
26,4
24,0
23,4
27,9
28,6
27,8
29,4
32,9
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
1997-­‐1999
n=3904
2000-­‐2002
n=1378
2003-­‐2005
n=569
2006-­‐2008
n=772
2009-­‐2010
n=1106
2011-­‐2013
n=2404
HIV
RNA
strata
at
enrolment
according
to
calendar
period
VL
-­‐
<=50
VL
-­‐
51-­‐500
VL
-­‐
501-­‐30.000
VL
-­‐
30.001-­‐100.000
VL
-­‐
>100.000
for
2013,
10
months
/mm3
/mm3
/mm3
/mm3
/mm3
cps/mL
cps/mL
cps/mL
cps/mL
cps/mL
ICONA:
update
2013

6. Persions
with
HIV
are
not
fully
immune
reconsEtuted
unEl
the
CD4
count
increases
to>750
cells/uL.
CID
2013

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

10. Linee
guida
italiane
HIV
2013

11. The
end
of
AIDS:
HIV
infec>on
as
a
chronic
disease
Steven
G
Deeks,
Sharon
R
Lewin,
Diane
V
Havlir
Lancet
nov
2013

12. Prevalence
of
different
non-­‐AIDS
related
co-­‐morbidiEes
at
different
age
strata
in
naive
paEents
0,3
0,8
1,1
0,4
1,1
2,9
0,6
1,7
5,1
0
0,3
0,7
0,1
0,4
1,4
3,2
15,1
0,5
1,2
2,9
0%
2%
4%
6%
8%
10%
12%
14%
16%
<=50
(N=8411)
51-­‐60
(N=1031)
>60
(N=272)
naive
Cerebrovascular
Diabetes
Hypertension
Myocardial
infarc>on
Lipodystrophy
eGFR
<60
ICONA:
update
2013

13. CID
2011

14. Crothers
K,
CROI
2014,
poster
774

15. Linee
guida
italiane
HIV
2013
Terapia
HIV:
29
pagine
Management
comorbidità:
24
pagine

16. Linee
guida
italiane
HIV
2013

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

26. Poten>al
Strategies
for
Eradica>ng
HIV
Chun
TW
and
Fauci
AS.
AIDS
2012;26:1261-­‐68.

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?

28.
Grazie