Trattamento ARV nel cirrotico

Roma, Istituto Superiore Sanità15-16 dicembre 2010

Renato MASERATIFondazione “IRCCS San Matteo”Pavia

A) Overall-Mortality

Observation time[days]]

500040003000200010000

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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

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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

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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!)