1. Trattamento ARV nel cirrotico Roma, Istituto Superiore Sanità 15-16 dicembre 2010 Renato MASERATI Fondazione IRCCS San Matteo Pavia

2. A) Overall-Mortality Observation time[days]] 500040003000200010000 Cumulative survival 1,1,9,7,5,3 P<0.0001 Patients with HAART Patients with ART untreated Patients 6000 Patients under observation: HAART-group:937933--- ART-group:5546301591 Untreated-group: 1379449373227 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 Cumulative survival Observation time[days]] Patients under observation: HAART-group:937933--- ART-group:5546301591 Untreated-group: 1379449373227

3. Mortalità cumulativa da causa epatica dopo il primo episodio di scompenso in pazienti HIV+ Bruno R. CROI 2006 Bruno R. et al JAIDS 2007

4. HAART attenuates liver fibrosis in patients with HIV/HCV co-infection: fact or fiction? 1 HCV mono 2No therapy/NRTI 3HAART 4NRTI to HAART Verna S, JAC 2006

5. 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

6. 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

7. 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

8. Reduced risk of ART-induced hepatotoxicity after HCV clearance Labarga P et al. JID 2007;196:670–6 0255075100125150 Follow-up (months) 89 43 38 25 11 5 7474 6464 3434 0101 Number of patients No: Yes: 0 20 40 60 80 100 Cumulative incidence of hepatic events (%) Sustained HCV clearance No Yes Log Rank: 14.01 (p <0.001)

9. NASH (steatosi epatica non alcoolica) INSULIN RESISTANCE (Visceral obesity) FFAInsulin(Type 2) diabetes STEATOSIS Benign steatosis Cytokines Oxydative stress NASH FIBROSIS CIRRHOSIS

10. 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

11. 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 Value Didanosine exposure8.8 (1.2-102.3).02 METAVIR fibrosis classification of cirrhosis 8.8 (1.2-104.2).02 Elevated bilirubin level7.9 (1.08-93.30).03

12. Abacavir and SVR Mira JA, et al. J Antimicrob Chemother 2008; 62(6): 1365–1373 ABC ABV-MP Adenylosuccinate synthase-lyase RBV RBV-MPCBV-MP Adenylate kinase Guanylate kinase RBV-DPCBV-DP Nucleoside diphospho-kinase RBV-TPCBV-TP p=0.02p=0.03p=0.4

13. Transaminase elevations were more common in coinfected subjects compared to subjects without coinfection. Comparison of adverse events is difficult due to the limited number of coinfected subjects; however, no apparent differences in tolerability were noted between HBV and HCV negative and coinfected subjects. D Norris, IAS 2007 MOPEB059. KLEAN Study: Treatment-Emergent Grade 3-4 Lab Abnormalities

14. 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 AST4 (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).

15. 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

16. SENSE: Liver Enzyme Elevations ALTASTAlk Phos Percentage of patients Marks S, IAS 2010 Vienna

18. ARVs IN PATIENTS WITH HEPATIC IMPAIRMENT : PI LEVEL OF HEPATIC IMPAIRMENT DRUGMILD CTP < 9 ADVANCED CTP > 9 ATAZANAVIRYES DOSE ADJUST. CTP 7-9 300 QD NOT RECOMMENDED DARUNAVIR NO DOSAGE ADJUSTMENT NOT RECOMMENDED FOSAMPRENAVI R YES DOSE ADJUST. CTP 6-9 700 mg BID NOT RECOMMENDED LOPINAVIRYES USE WITH CAUTION TIPRANAVIR NOT RECOMMENDED

19. HEPATIC IMPAIRMENT DRUG MILDADVANCED NVPUSE WITH CAUTION NO EFVUSE WITH CAUTION ETVNO DOSAGE ADJUSTMENT NOT EVALUATED MRVCONCENTRATION INCREASED RALTEGRAVIRNO DOSAGE ADJUSTMENT ARVs IN PATIENTS WITH HEPATIC IMPAIRMENT : OTHER 3 rd DRUG

20. Terapia ARV nel paziente cirrotico Take Home Messages Nessun farmaco (combo di farmaci) ARV è libero da tossicità, inclusi i più recenti! Leradicazione di HCV migliora il profilo degli ARVs Importanza del controllo dei cofattori / confondenti Attenzione alla farmacocinetica (interazioni!)