Workshop 5: Il coinfetto Moderatori: G. Angarano, V. Vullo Discussant: A. Cerioli Quando e come...
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Transcript of Workshop 5: Il coinfetto Moderatori: G. Angarano, V. Vullo Discussant: A. Cerioli Quando e come...
Workshop 5: “Il coinfetto”Moderatori: G. Angarano, V. VulloDiscussant: A. Cerioli
Quando e come cominciareP. Nasta
0
10
20
30
40
50
60
10 20 30 40
Years after infection
F3F4
In the Natural History of Chronic Hepatitis In the Natural History of Chronic Hepatitis Fibrosis is a Non-Linear processFibrosis is a Non-Linear process
ESLD
From M Pinzani
HIV
BMS CONFIDENTIAL: For internal use only. Not for distribution.
IAS 07
• Bonn cohort (1990-2002)– 285 HIV/HCV coinfected
patients
• Liver-related mortality rates per 100 person-years
– HAART: 0.45– ART: 0.69– No therapy: 1.70
• Predictors for liver-related mortality
– No HAART– Low CD4 cell count– Increasing age
Qurishi N, et al. Lancet. 2003:362:1708-1713.
DaysDays
Overall MortalityOverall Mortality
Cu
mu
lati
ve S
urv
ival
Cu
mu
lati
ve S
urv
ival
0 1000 2000 3000 4000 5000 60000 1000 2000 3000 4000 5000 6000
ARTART
HAART*HAART*
DaysDays
Liver-Related MortalityLiver-Related Mortality
Cu
mu
lati
ve S
urv
ival
Cu
mu
lati
ve S
urv
ival
0 1000 2000 3000 4000 5000 60000 1000 2000 3000 4000 5000 6000
HAART*HAART*
No therapyNo therapy
ARTART
No therapyNo therapy
**PP=0.018=0.018
**PP<0.001<0.001
Impact of ART on Overall Liver Mortalityin HIV/HCV-Coinfected Patients
Impact of ART on Overall Liver Mortalityin HIV/HCV-Coinfected Patients
Impact of 3TC on the risk of liver-related death in HBs-Ag/HIV+ individuals
Study of impact of ART with 3TC on the risk of liver-related death
Inter-cohort analysis (12 Europe, 1 Canada) Results2041 patients, 758 (37%) IVDUsMedian follow-up of 48 months
(range 2–91)217 died; 57 liver related
ConclusionsUse of 3TC associated with a 23%
decreased risk of liver-related death over 4 years
Lamivudine withdrawal associated with an increased risk of LR death AOR 11.59 (95% CI:6.17-21.75, p=0.0001) vs continuous Tx
Puoti M, Puoti M, Antiviral Therapy 2006Antiviral Therapy 2006
Association with other NRTI studied as ‘control
group’33
3 p=0.003
p=0.0001
p=0.0001
p=0.004p=0.97
p=0.84
0.1
1
10
100
3TC- HAART
year+
DLD Pre-
HAART
CD4+ per 100+cells
Age per 10+years
ddI- HAART
year+
d4T- HAART
year+
Factors independently associated with the risk of liver-Factors independently associated with the risk of liver-related death from fitting a Poisson regression modelrelated death from fitting a Poisson regression model
Antiretroviral therapy should also be initiated regardless
of CD4 count in patients with the following conditions: pregnancy
(AI), HIV associated nephropaty (AII), and hepatitis B virus (HBV)
co-infection when treatment of HBV is indicated (AIII)
CD4:350-500Treatment recommended in hepatitis C
co-infection, hepatitis B coinfection requiring therapy, HIV associated nephropaty or other specific organ
deficiencyCD4>500
Treatment can be offered if presence of >1 of the above
co-morbid conditions
When to start HAART therapy in HIV/virus hepatitis co-infected persons
Raccomandazioni DHHS & EACS & Italia
When to start HAART therapy in HIV/virus hepatitis co-infected persons
Raccomandazioni DHHS & EACS & Italia
-Start HAART early (Cd4 350-500)-Avoid ddI-D4T and AZT should be avoided -Antiretroviral therapy should be promptly withdrawn in case of:•Lactic acidosis •Hypersensitivity reaction •LEE > 10 NV•Janduice •Liver decompesation
How to treat HIV How to treat HIV when HCV treatment is startedwhen HCV treatment is startedGuidelines recommendation Guidelines recommendation
How to treat HIV How to treat HIV when HCV treatment is startedwhen HCV treatment is startedGuidelines recommendation Guidelines recommendation
When deciding to treat HCV, the choice of anti-HIV therapy should be agreed in association with an experienced HIV physician ABC may reduce RBV level
Didanosine is contraindicated
AZT and d4T should be avoided
1 Vispo E Antiviral Ther 2008; 2 Laufer N Antiviral Ther 2008;3 Mira J J Antimicrob Chemother 2008; 4 Amorosa KV Antiviral Ther 2010; 5 Rodriguez-Novoa S AIDS 2008; 6 Moreno A Antivir Therapy 2004; 7 Mauss S AIDS 2004; 8 Bani-Sadr F JAIDS 2005; 9 Quereda C JAIDS 2008; 10 Ballestreros Antivir Ther 2004; 12 Bani-Sadr F J Viral Hepat 2008; 13 Nunez M J Viral Hepat 2008; 14 Mira JA Antiviral Ther 2008
How to treat HIV How to treat HIV when HCV treatment is started when HCV treatment is started DDrug-drug interactionrug-drug interaction
How to treat HIV How to treat HIV when HCV treatment is started when HCV treatment is started DDrug-drug interactionrug-drug interaction
Effetto tempo dipendente della HAARTsulla fibrosi epatica?
•Immuno-restoration •HIV suppression • Metabolic toxicity
• Liver enzyme elevation
Years HIV-RNA
CD4
HAART
Rockstroh et al. The Lancet 20023.3 & 3.9 aa
Brau et al. J Hepatol 20073.6 aa
Barreiro P CROI 20086.8 aaMerchante N Gut 20095 aa
Long term HAART toxicity and liver fibrosis progression
Long term HAART toxicity and liver fibrosis progression
• “Inflamm-aging”
CCR5 is required for hepatic fibrogenesis and in CCR5 -/- fibrosis is lower than in wild type.
WTCCR5-/-
Ekiro S et al. J Clin Invest . 2009; 119:1858-70
WT CCR 5 -/-
WT CCR5 -/-
Macrophage infiltration is lower in CCR5 -/-
Role of CCR5 in fibrogenesis
HSCs proliferation and migration are largely mediated by CCR5.
CCR5 contributed to ≈ 70% of rhRANTES-induced signaling events and appears to be the major the receptor for RANTES in HSCs.
Gut 2009;58:1654–1660.
Our data indicate that higher HCV RNA levels are associated with the presence of IR in CHC patientsIR was positively correlated with body mass index, triglyceride, HCV-RNA and ALT leveland negatively correlate with adiponectine.
Liver disease progression and HAART Liver disease progression and HAART related factorsrelated factors
Liver disease progression and HAART Liver disease progression and HAART related factorsrelated factors
Livelli di AST si associano alla sopravvivenza nei pazienti HIV
Justice et al. XIV IAC 2002; poster 1058
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.650 500 1000 1500 2000
Tempo (gg))
P < 0.001
AST < 0.5 ULN
AST 0.5–2 ULN
AST 2 ULN
VACS 3 (n = 773 patients) e CHORUS (n = 4,946)
Sop
ravv
iven
za
HCV Pipeline
Phase 1 Phase 3Phase 2
Protease Inhibitors
PolymeraseInhibitors
• Boceprevir (MSD)• Telaprevir
(Vertex/J&J)
Novel MOAs
• ABT-333 (Abbott)• ABT-450 (Abbott/Enanta)• AVL-181 (Avila)• PHX1766 (Phenomix)• VX-813 (Vertex)
Nucleoside• IDX184 (Idenix)• MK-0608 (MSD)• PSI-7851 (Pharmasset)Non-Nucleoside• ANA598 (Anadys)• BILB 1941 (Boehringer)• MK-3281 (MSD)• VCH-222, 759, 916 (ViroChem)
• ANA773 (Anadys)• Bavituximab (Peregrine)• BMS-790052 (BMS) • JTK-652 (PRA) • NOV-205 (Novelos)• SCY-635 (Scynexis)
• BI 201335 (Boehringer)• ITMN-191 (InterMune/Roche)• MK-7009 (MSD)• SCH 900518 (MSD)• TMC435 (Medivir/Tibotec)
• A-831 (Arrow/AZ)• Celgosivir (Migenix) • Debio-025 (DebioPharm)• GI-5005 (GlobeImmune)• GS 9450 (Gilead)• ITX5061 (iTherX)• NIM811 (Novartis)• SCV-07 (SciClone)
MOAs, mechanisms of action.
Nucleoside• R7128 (Pharmassest/Roche)Non-Nucleoside• Filibuvir (Pfizer)• GS 9190 (Gilead)
• Nitazoxanide (Romark)
HAARTAnd
New Anti HCV
Drugs
Interactions
ConclusioneLa co-infezione con virus epatite C è la più grave co-morbidità nelle persone HIV
positive
L’immunoricostituzione è essenziale per ridurre la progressione della malattia di fegato
Nel lungo tempo la tossicità epatica e metabolica di alcuni farmaci antiretrovirali, e la condizione di immonoattivazione cronica potrebbero incrementare i processi fibrogenetici
La scelta di una terapia antiretrovirale ottimale nel soggetto co-infetto potrebbe essere la prima, e nei soggetti non eleggibili all’interferone, l’unica possibilità per rallentare la progressione della malattia di fegato