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