trattamento arv nel cirrotico roma, istituto superiore sanità 15-16 dicembre 2010 renato maserati...
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Trattamento ARV nel cirrotico
Roma, Istituto Superiore Sanità15-16 dicembre 2010
Renato MASERATIFondazione “IRCCS San Matteo”Pavia
A) Overall-Mortality
Observation time[days]]
500040003000200010000
Cu
mu
lati
ve s
urv
ival
1,1
,9
,7
,5
,3
P<0.0001
Patients with HAART
Patients with ART
untreated Patients
6000
Patients under observation:HAART-group: 93 79 33 - - - ART-group: 55 46 30 15 9 1Untreated-group: 137 94 49 37 32 27
6000500040003000200010000
1,1
,9
,7
,5
,3
B) Liver-related-Mortality
P<0.018
Patients with HAART
Patients with ART untreated Patients
Overall and Liver-related Mortality - effect of HAART
Qurishi N et al. Lancet, 2004
Cu
mu
lati
ve s
urv
ival
Observation time[days]]
Patients under observation:HAART-group: 93 79 33 - - - ART-group: 55 46 30 15 9 1Untreated-group: 137 94 49 37 32 27
Mortalità cumulativa da causa epatica dopo il primo episodio di scompenso in pazienti
HIV+
Bruno R. CROI 2006Bruno R. et al JAIDS 2007
HAART attenuates liver fibrosis in patients with HIV/HCV co-infection: fact or fiction?
1 HCV mono2No therapy/NRTI3HAART4NRTI to HAART
Verna S, JAC 2006
HIV & Hepatic Stellate Cells: implications for fibrosis in HIV/HCV co-infected patients
Friedman SL and Arthur, Science and Medicine 2002; Tuyama AC, et al., Hepatology 2010; 52: 612-622.
Activated HSC with fibrosisNormal liver
Human Hepatic Stellate Cells, HIV and Liver Fibrosis
• HSCs are permissive to HIV infection in vitro
• Human HSCs support HIV entry and gene expression
• HIV promotes HSC collagen I expression and secretion of MCP-1
…but• Quiescent HSCs are not infectable by HIV
Tuyama AC, et al, Hepatology 2010
Best option for the initial treatment of patients with liver disease:
• Good safety profile • No increase insulin resistance• No increase of bilirubin (no modification of Child Pugh score)• No major changes in Pk parameters
Reduced risk of ART-induced hepatotoxicity after HCV clearance
Labarga P et al. JID 2007;196:670–6
0 25 50 75 100 125 150
Follow-up (months)
8943
3825
115
74
64
34
01
Number of patientsNo:Yes:
0
20
40
60
80
100
Cu
mu
lati
ve i
nci
den
ceo
f h
epat
ic e
ven
ts (
%) Sustained HCV clearance
NoYes
Log Rank: 14.01 (p <0.001)
NASH (steatosi epatica non alcoolica)
INSULINRESISTANCE
(Visceralobesity)
FFA Insulin (Type 2)diabetes
STEATOSIS
Benignsteatosis
Cytokines
Oxydative stress
NASH
FIBROSISCIRRHOSIS
Concentrazione di ARV e grado di fibrosi
HCV/HIV+
F4
HCV/HIV+
F0-F3
HIV+
Indinavir
p= 0.50
294
(66-256)
229
(41-334)
328
(11-837)
Lopinavir
p= 0.09
1867
(368-10565)
3869
(2689-7503)
5990
(2939-10939)
Efavirenz
p= 0.07
4750
(3456-6045)
3583
(1405-8036)
1494
(1147-5935)
Nevirapina
p= 0.09
7045
(4864-9860)
4492
(3376-9585)
3954
(1903-17058)
Dominguez S, et al 2004; JAC 2010
•Concentrazioni di valle mediane espresse in ng/mL (range)•p calcolato tramite Mann-Whitney Test
Risk Factors for Decompensation: Multivariate Analysis
• Didanosine exposure, cirrhosis, and elevated bilirubin
• significantly associated with hepatic decompensation (10%)
Bani-Sadr F, et al. Clin Infect Dis. 2005;41:1806-1809.
Factor
Odds Ratio (95% Confidence
Interval) P ValueDidanosine exposure 8.8 (1.2-102.3) .02METAVIR fibrosis classification of cirrhosis
8.8 (1.2-104.2) .02
Elevated bilirubin level 7.9 (1.08-93.30) .03
Abacavir and SVR
Mira JA, et al. J Antimicrob Chemother 2008; 62(6): 1365–1373
ABC
ABV-MP
Adenylosuccinatesynthase-lyase
RBV
RBV-MPCBV-MP
Adenylate kinase
Guanylate kinase
RBV-DPCBV-DP
Nucleoside diphospho-kinase
RBV-TPCBV-TP
p=0.02p=0.02 p=0.03p=0.03 p=0.4p=0.4
Transaminase Transaminase elevations were more elevations were more common in coinfected common in coinfected subjects compared to subjects compared to subjects without subjects without coinfection.“coinfection.“
Comparison of adverse Comparison of adverse events is difficult due events is difficult due to the limited number to the limited number of coinfected subjects; of coinfected subjects; however, no apparent however, no apparent differences in differences in tolerability were noted tolerability were noted between HBV and HCV between HBV and HCV negative and negative and coinfected subjects.coinfected subjects.
D Norris, IAS 2007 MOPEB059.
KLEAN Study:Treatment-Emergent Grade 3-4 Lab Abnormalities
ARTEMIS 96-week comparison of liver tolerability of OD DRV/r vs LPV/r
Fatkenheuer G, et al. 12° EACS, Cologne 2009
Parameter, n (%) DRV/r (n=343) LPV/r (n=346) p value
Any liver-related AE 8 (2.3) 15 (4.3) 0.2024
Increased ALT 5 (1.5) 10 (2.9) 0.2975
Increased AST 4 (1.2) 7 (2.0) 0.5456
Grade 2–4 at least possibly treatment-related liver-related AEs (in ≥1% of patients in either treatment group).
Probability of remaining free of grade 3 or 4 hepatotoxicity in patients who begin treatment
with nevirapine (NVP) or efavirenz (EFZ).
Martin Carbonero L, et al. HIV Clin Trials 2003
SENSE: Liver Enzyme Elevations
ALT AST Alk Phos
Per
cent
age
of p
atie
nts
Marks S, IAS 2010 Vienna
ARVs IN PATIENTS WITH HEPATIC IMPAIRMENT : PI
LEVEL OF HEPATIC IMPAIRMENTLEVEL OF HEPATIC IMPAIRMENT
DRUGDRUG MILDMILD
CTP < 9CTP < 9
ADVANCEDADVANCED
CTP CTP > > 99
ATAZANAVIRATAZANAVIR YESYES
DOSE ADJUST.DOSE ADJUST.
CTP 7-9 300 QDCTP 7-9 300 QD
NOT RECOMMENDEDNOT RECOMMENDED
DARUNAVIRDARUNAVIR NO DOSAGE NO DOSAGE ADJUSTMENTADJUSTMENT
NOT RECOMMENDEDNOT RECOMMENDED
FOSAMPRENAVIFOSAMPRENAVIRR
YESYES
DOSE ADJUST.DOSE ADJUST.
CTP 6-9 700 mg BID CTP 6-9 700 mg BID
NOT RECOMMENDEDNOT RECOMMENDED
LOPINAVIRLOPINAVIR YESYES USE WITH CAUTIONUSE WITH CAUTION
TIPRANAVIRTIPRANAVIR USE WITH CAUTIONUSE WITH CAUTION NOT RECOMMENDEDNOT RECOMMENDED
HEPATIC IMPAIRMENT
DRUG MILD ADVANCED
NVP USE WITH CAUTION
NO
EFV USE WITH CAUTION
USE WITH CAUTION
ETV NO DOSAGE ADJUSTMENT
NOT EVALUATED
MRV CONCENTRATION INCREASED
RALTEGRAVIR NO DOSAGE ADJUSTMENT
ARVs IN PATIENTS WITH HEPATIC IMPAIRMENT : OTHER 3rd DRUG
Terapia ARV nel paziente cirrotico Take Home Messages
• Nessun farmaco (combo di farmaci) ARV è libero da tossicità, inclusi i più recenti!
• L’eradicazione di HCV migliora il profilo degli ARVs
• Importanza del controllo dei cofattori / confondenti
• Attenzione alla farmacocinetica (interazioni!)