1. Workshop 5: Il coinfetto Moderatori: G. Angarano, V. Vullo Discussant: A. Cerioli Quando e come cominciare P. Nasta

2. Guidelines and Clinical Expertise: the Italian Algorithm to build the future with the patients Roma, Istituto Superiore Sanità 15-16 dicembre 2010 Conference Chairmen: Mauro Moroni - Vincenzo Vullo

3. 0 10 20 30 40 50 60 10 20 30 40 Years after infection F3 F4 In the Natural History of Chronic Hepatitis Fibrosis is a Non-Linear process ESLD From M Pinzani HIV

4. 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. Days Overall Mortality Cumulative Survival 0 1000 2000 3000 4000 5000 6000 ART HAART* Days Liver-Related Mortality Cumulative Survival 0 1000 2000 3000 4000 5000 6000 HAART* No therapy ART *P=0.018 *P<0.001 Impact of ART on Overall Liver Mortality in HIV/HCV-Coinfected Patients

5. 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) Results 2041 patients, 758 (37%) IVDUs Median follow-up of 48 months (range 2–91) 217 died; 57 liver related Conclusions Use 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, Antiviral Therapy 2006 Association with other NRTI studied as control group 33 3 p=0.003 p=0.0001 p=0.004 p=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- related death from fitting a Poisson regression model

6. 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) CD4:350-500 Treatment recommended in hepatitis C co-infection, hepatitis B coinfection requiring therapy, HIV associated nephropaty or other specific organ deficiency CD4>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

7. -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 when HCV treatment is started Guidelines recommendation How to treat HIV when HCV treatment is started 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

8. 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 when HCV treatment is started Drug-drug interaction How to treat HIV when HCV treatment is started Drug-drug interaction

10. Effetto tempo dipendente della HAART sulla fibrosi epatica? Immuno-restoration HIV suppression Metabolic toxicity Liver enzyme elevation Years HIV-RNA CD4 HAART Rockstroh et al. The Lancet 2002 3.3 & 3.9 aa Brau et al. J Hepatol 2007 3.6 aa Barreiro P CROI 2008 6.8 aa Merchante N Gut 2009 5 aa Long term HAART toxicity and liver fibrosis progression Inflamm-aging

11. Fast liver damage progression in HIV/HCV coinfected patients in spite of effective HAART Macias J et al, Abs 659, IAS 2010 Age 44(42-46) Male 360(80%) TD 376(84%) Alchool > 50g/day 50(14%) CDC C 150(30%) CD4 cell 444(287-654) ART 435(97%) Undetectable 324(74%) G 1-4 346(77%) ALT 63 IU/ml(40-104) LS 6,9 KpA(5,6-9.6) LS Reduction >20% No change LS Increase >20% 17% 46% 37% % of pts In spite of effective HAART, liver fibrosis progresses in a significant proportion of HIV/HCV-coinfected patients over a short period of time BASELINE (N 449) FU 18-24 months

12. CCR5 is required for hepatic fibrogenesis and in CCR5 -/- fibrosis is lower than in wild type. WT CCR5-/- Ekiro S et al. J Clin Invest. 2009; 119:1858-70 WTCCR 5 -/- WTCCR5 -/- 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.

13. Gut 2009;58:1654–1660.

14. Our data indicate that higher HCV RNA levels are associated with the presence of IR in CHC patients IR was positively correlated with body mass index, triglyceride, HCV-RNA and ALT level and negatively correlate with adiponectine.

15. genotype 1-4 correlation coefficient r^2= 0,9; p<0,0001 genotype 2-3 correlation coefficient r^2 0,6= p<0,0006 correlation coefficient r^2= 0,93 ; p<0,0001 HOMA score is associated with Hepatitis C Viremia (Hsui SC et al. 2010) N 107 pts HIV/HCV who started PegIFN/RBV, 49,5% G 1,HOMA IR 3,2(+2,9), Cirrhosis 33% Nasta P et al. ICAR 2010 (#91) Nasta P er al, CROI submitted Nasta P et al, ICAAC 2010, ABS H 1673 … and with Liver Stiffness (N Merchante et al, 2010

16. Liver disease progression and HAART related factors

17. 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 0.65 0500100015002000 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) Sopravvivenza

19. HCV Pipeline Phase 1Phase 3Phase 2 Protease Inhibitors Polymerase Inhibitors 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)

20. HAART And New Anti HCV Drugs Interactions

21. Conclusione La co-infezione con virus epatite C è la più grave co-morbidità nelle persone HIV positive Limmunoricostituzione 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 allinterferone, lunica possibilità per rallentare la progressione della malattia di fegato