1. Tavola Rotonda Le tossicità d'organo in HIV Fegato: overview P. Nasta Clinica di Malattie Infettive e Tropicali, Azienda Ospedaliera Spedali Civili di Brescia Discussione Conduce: M. Puoti S.C. Malattie Infettive, A.O. Ospedale Niguarda, Ca Granda, Milano

2. Progressione di APRI SCORE e FIB 4 in pazienti mono-infetti HIV Mendeni ICAR 2010

3. Effetto tempo dipendente della HAART sulla fibrosi epatica? Immuno-restoration HIV suppression 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

4. -Liver elevation enzyme -Metabolic toxicity and NAFLD -Immunoactivation and chronic inflammation - DAA and HAT HAART related factors and liver fibrosis progression HAART related factors and liver fibrosis progression

5. Adverse events to antiretrovirals in the Swiss HIV Cohort Study: effect on mortality and treatment modication. (Keiser O et al.Antivir Ther 2007; 12:1157–116.) Elevated serum alanine aminotransferase and gamma-glutamyltransferase and mortality in the United States popu lation. (Ruhl CE et al.Gastroenterology 2009; 136:477–485). ALT elevation was associated with deaths from liver disease (HR, 8.2; 95% CI, 2.1-31.9) During a median follow up of 5.9 years, laboratory AEs were associated with higher mortality (HR 1.3; 95% CI, 1.2-1.5; P < 0.001)

6. 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

7. 2365 pts 9972 person-years Age 38 yrs, 66% male, CD4 426, 56% on ART Chronic ALT elevation : 16% 3,9 cases per 100 p/y (IC 95%1,3-4,3) Related factors at multivariate analysis IRR (IC95%) HIV-RNA 100.000 c/ml 2,2 (1,45-3,42) BMI (25-29,9)1,56 (1,245-1,96) BMI > 30 1,70 (1,16-2,51) Alcohol abuse1,04 (1,00-1,08) - NRTI or PI exposure did not remain statistical significant after adjustment for exposure to stavudine - treatment outcome and mortality did not differ in groups with or without ALT elevation (CID 2010;50:502-11)

10. NNRTI: informazioni prescrittive Association between HLA to DRB1*0103 HLA to B*5801 and hepatotoxicity in patients who initiated NVP containing regimen : South Africa (Phillips E et al. CROI 2011 #949) HLA-DRB1*0102 an allele closely related to HLA-DRB1*0101 was associated with hepatotoxicity in South african initiating NVP containing regimen

11. PI: informazioni prescrittive

12. HCV positive 37/194 (19,1%) N of pts with LEE HCV negative: 10/42 (7%) Patients free by LEE (any grade) Long Rank 13,0( p 0,0003) days Probability to be free by LEE in HCV positive ( n 194) vs HCV negative ( n 143) patients treated with RAL ( Brescia n 377) OR 3,1 (1,4-6,4) p0,001 RALTEGRAVIR

13. All causalities and severities, n (%) Unadjusted for duration of exposure OBT alone N=207* MVC QD + OBT N=408* MVC BID + OBT N=421* AST: Grade 3 >5.0 to 10.0 ULN Grade 4 >10.0 x ULN TOTAL (grade 3/4) 6 (2.9) 0 6 (2.9) 11 (2.7) 3 (0.7) 14 (3.4) 13 (3.1) 6 (1.4) 19 (4.5) ALT: Grade 3 >5.0 to 10.0 ULN Grade 4 >10.0 x ULN TOTAL (grade 3/4) 6 (2.9) 1 (0.5) 7 (3.4) 14 (3.4) 2 (0.5) 16 (3.9) 6 (1.4) 4 (1.0) 10 (2.4) Total bilirubin: Grade 3 >2.5 to 5.0 x ULN Grade 4 >5.0 x ULN TOTAL (grade 3/4) 8 (3.9) 3 (1.5) 11 (5.3) 29 (7.1) 4 (1.0) 33 (8.1) 21 (5.0) 3 (0.7) 24 (5.7) * Patients with at least one on-drug follow-up assessment van der Ryst E, et al. 4th IAS 2007; Poster WEPEB115LB MOTIVATE 1 and 2 – Week 24 ARLI:inibitori dellentry-Maraviroc MARAVIROC: Hepatic tolerability

14. -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

15. ABC co administration does not interfere with the suppresisve activity of RBV in an HCV replicon system (Van de Eynde E et al. CROI 2011; #963) In a subgenomic replicon system the antiviral effect of RBV was not modified by the addition of ABC, 3TC or TDF

18. -Liver elevation enzyme -Metabolic toxicity and NAFLD -Immunoactivation and chronic inflammation - DAA and HAT HAART related factors and liver fibrosis progression HAART related factors and liver fibrosis progression

20. P=0.006 P=NS P=0.01 Liver-related (2.8% vs.0.2%, P.04) Cardiovascular diseases (15.5% vs. 7.5%, P.04). Long-term follow-up of patients with NAFLD Ekstedt et al., Hepatology 2006;44:865

21. Nonalcoholic Fatty Liver Disease (NAFLD) among HIV-Infected Persons ( Crum-Cianflon N. et al.JAIDS 2009;50:464-473 ) Sixty-seven (31%) of 216 patients had NAFLD based on ultrasound evaluation. among those with NAFLD, Mild 60%, Moderate 28%, Severe/ Marked 12%. Variables associated at multivariate analysis: waist circumference OR 2.1 per 10 cm, p<0.001 elevated triglycerides OR 1.2 per 100 mg/dl, p=0.03 and lower HDL levels OR 0.7, p=0.03

22. LEPTIN RESISTIN VISFATIN ADIPONECTIN Adipokines and liver fibrosis

23. Leptin and hepatic stellate cells, the effectors of liver wound healing Leptin TIMP-1Proliferation ERK PI3K/Akt SurvivalChemokines NF- B VEGF HIF-1 Type I Collagen H 2 O 2 Jak-Stat ERK p38 MAPK AP-1 H 2 O 2 Jak-Stat ERK p38 MAPK ERK PI3K/Akt Marra, J Hepatol 2007;46:12 2007

24. clinicaloptions.com/hiv Implications of New Data on Complications Associated With ARV Regimens Patogenesi del danno metabolico da PI - Alterata funzione di SREBP 1 e 2 e PPAR e PPAR - Produzione delle VLDL - Lipoprotein lipasi (LPL) VLDL circolanti (pieno di TGD) - della captazione dei TGD nel tex adiposo (lipodistrofia) - GLUT 4, recettori IRS1 FAA circolanti e zuccheri Depositi di FAA in tex ectopici ( fegato, m scheletrico) IR e leptino resistenza LEPTINA, INSULINA

25. clinicaloptions.com/hiv Implications of New Data on Complications Associated With ARV Regimens (CID 2010;50:502-11)

26. Gut 2009;58:1654–1660.

27. 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.

28. 600 patients: 500 HCV and 100 HBV positive IR is a specific feature of CHC, associated with genotype 1 and 4 and HCV RNA level. Significant fibrosis is associated with IR independent from steatosis

29. 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

30. Triglyceride level is associated with HCV RNA There is a linear correlation between trglyceride plasma level and HCV-RNA N 107 pts HIV/HCV who started PegIFN/RBV 49,5% G 1 Cirrhosis 33% Median TRG level 125 (82-181)mg/dl, TRG>150 mg/dl 34,5% Nasta P Correlation coeficient r^2 0,7 p 0,006

31. LDL level as prognostic tool of liver diseases progression in HIV/HCV coinfection (M Habayeb et al. CROI 2011, # 925) Low LDL was significantly associated with the degree of liver disaease measured with APRI overall and among those without fibrosis at baseline. HCV may utilize the LDL receptor to enter in the hepatocyte and co-opt the very LDL secretion pathway for virion maturation and secretion. They may cause disruption of Lipoprotein metabolism Low LDL levels may serve as biomarker of intra-hepatic HCV replication

32. Liver disease progression and HAART related factors

33. -Liver elevation enzyme -Metabolic toxicity and NAFLD -Immunoactivation and chronic inflammation - DAA and HAT HAART related factors and liver fibrosis progression HAART related factors and liver fibrosis progression

34. Activation of KC and inflammatory cells Toll-like Pattern recognition receptors LPS LTA PGN Paik et al., Hepatology 2003;37:1043 Brun et al., AJP-GI 2005 289: G571 Seki et al. Nat Med 2007 Hepatic stellate cells MCP-1 TLR4 TLR2 PGRP-L CD14 PGRP-S TGF-

35. Microbial translocation and immunoactivation in HIV/virus hepatitis co-infection - 55 HIV/HBV coinfected pts from Thailand and 20 uninfected control Markers of microbial translocation and immunoactivation studied before and after initiation of anti HBV containing HAART, LPS, sCD14, and CXCL10 are elevated in HIV/HBV coinfected compared with uninfected control and the levels return to normal following HBV effective HAART. No significant association between LPS and liver disease severity, Persistent elevation of CCL2 on HAART may potentially play a role in ongoing diseases progression (M Crane, CROI 2011; #937)

36. Plasma soluble sCD14 levels are associated with severity of liver diseases and predict clinical outcome in HBV and HCV infection ( Sandler N et al, CROI 2011; #939) - 16 minimal fibrosis HBV or HCV-HIV co-infected -68 with cirrhosis HBV or HCV-HIV co-infected -40 uninfected control -Analysis: I-FABP(Intestinal fatty acid binding protein: marker of enterocyte death), LPS, sCD14 and IL6 Low platlets count (consistent with portal hypertension) were associated with high I-FABP sCD14 was higher in pts with severe fibrosis and predicted the disease progression Successful HAART induce reduction of IL6 and I-FABP, but not of sCD14 and LPS, suggesting reduction in enterocyte death and IL6 production occur more quickly than reduction of MT and monocyte activation LPS ng/mlsCD14 (x106 pg/ml)I-FABP*(pg/ml)IL-6(pg/ml) Healthy20,41,71200,0 HBV HCV 38,5 p=0,17 29,3 1,85 p=0,05 2,08 211,0 p= 0,04 303,1 4,4 p=0,02 8,5 NO Fibrosis Cirrhosis 31,5 p=0,41 34,8 1,74 p=0,01 2,06 138,5 p=0,39 212,1 6,7 p=0,62 7,3 No Progression Progression 35,2 p=0,42 35,6 1,81 p=0,0009 2,22 164,7 p=0,74 223,3 6,2 p=0,94 7,5

37. -Liver elevation enzyme -Metabolic toxicity and NAFLD -Immunoactivation and chronic inflammation - DAA and HAT HAART related factors and liver fibrosis progression HAART related factors and liver fibrosis progression

39. 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)

40. HAART And New Anti HCV Drugs Interactions

41. Discussion Strong association between liver-related mortality and elevated ALT levels in general population (Ruhul CE et al.,Gastroenterology 2009). and in HIV infected population without chronic viral hepatitis (Keiser O et al.Antivir Ther 2007). Prolonged exposure to stavudine and zidovudine were associated with chronic ALT elevation (Kovari H et al. CID 2010) The main causes of chronic liver disease in HIV-infected patients without hepatitis B and C co- infections are alcohol consumption, non- alcoholic fatty liver disease (NAFLD) and antiretroviral drugs. (Kovari H et al CID 2010) Immunoactivation due to microbial translocation may contribute to the liver fibrosis progression despite an effective HAART (Sandler N et al, CROI 2011; #939 )