1. 1 Management of anti retroviral treatment in patients with cirrhosis Dominique Salmon Cochin Hospital June 23, 2006

2. 2 Background Beneficial impact of ARV on liver disease morbidity and mortality Hepatotoxicity more frequent in severe liver disease ARV clearance impaired in patients with severe liver disease Correlation between toxicity and plasma concentrations for some ARV => Specificity of ARV use in cirrhosis

3. 3 Qurishi N et al, Lancet 2003 Time (days) 500040003000200010000 Survival 1.1 0.9 0.7 0.5 0.3 p < 0,0001 Patients on HAART Patients on HAART Patients on ARV Patients on ARV Non treated patients 6000 500040003000200010000 1.1 0.9 0.7 0.5 0.3 p < 0,018 Patients on HAART Patients on HAART Patients onARV Patients onARV Non treated patients Non treated patients Survial Time (days) HAART937933--- ARV5546301591 Non treated 1379449373227 Patients followed HAART937933--- ARV5546301591 Non treated 1379449373227 Patients followed Beneficial effect of HAART on hepatic mortality Global mortalityHepatic mortality

4. 4 Negative impact Beneficial impact Short term hepatotoxicity Steatosis Fibrosis Decrease of hepatic ;;; mortality Impact of antiretroviral agents (ARV) on liver disease

5. 5 Hepatotoxicity is frequent in patients with cirrhosis Intrinsec hepatotoxicity Impaired hepatic metabolism Risk of hepatic decompensation Increased toxicity Other organ toxicity

6. 6 Aranzabal L, Clin Infect Dis, 2005; 40:588 15% 38% 6% 11% 17% 19% 0 10 20 30 40 F1/F2F1/F2F3/F4F1/F2 Incidence (%) F1/F2 OverallNNRTI Non NNRTI Correlation between liver fibrosis and HAART related-hepatotoxicity F3/F4 F3/F4 107 HCV co-infected patients who underwent liver biopsy Hepatotoxicity defined as ALT X 5N or > 3.5 X baseline F3/F4

7. 7 Imperiale et al. HIV6, 2002; poster 150 ALT/AST > 5N in 2 198 patients treated between 1997 et 2001 18.00 16.00 14.00 12.00 10.00 8.00 6.00 4.00 2.00 0.00 Relative Risk 3TCSTV 3TC- ZDV ddIABVNVPEFVNFVSQVRTVIDVAPV Age>60 CD4 + >350 HBV/HCV HCV/HBV Age >60 2357NRTIs NNRTIs PIs Patients characteristics Incidence of hepatotoxicity in TARGET cohort

8. 8 Steatosis and HIV/HCV co-infection Frequent : - 40 to 67 % of the patients - Severe in 7 % - Microvesicular - Macrovesicular Sulkowsky, AIDS, 2005; BaniSadr, AIDS 2006; Castéra et al., Lemoine et al., Marks et al, Agarwal et al, AASLD, 2004

9. 9 Risk factors of steatosis in HIV/HCV co-infection BMI Genotype 3 Caucasian race Fibrosis score Hyperglycemia/insulin resistance Lipodystrophy D4T use Cumulative time on PI (1) Castera, 2004; (2) Sulkowski, 2005; (3) Bani-Sadr, 2006 Role of HAART

10. 10 Depletion of hepatic mtDNA with D-nucleosides (ddI, D4T, ddC) 47% decrease of mtADN in patients with « D-drugs » (n=35) versus « non D-drugs » (n=34) (p<0.0001) Walker U., Hepatology, 2004;39:311-317

11. 11 Pharmacokinetics of ARV in cirrhotic patients

12. 12 Impaired hepatic metabolism in cirrhosis  protein synthesis =>  increase of free form  hepatic metabolism (CYP 450, UGP..)  hepatic flow =>  decrease hepatic clearance  Increase of C max, AUC

13. 13 Protease inhibitors

14. 14 Examination of NFV PK profile: plasma conc. Regazzi ME et al. 4 th International Workshop on the Clinical Pharmacology of HIV Therapy, 2003; abstract 14 0 2 4 6 8 10 12 024681012 Time after drug administration (hours) NFV plasma conc. (mcg/ml) HCV- HCV- HCV+ HCV+ HCV+/cirrhosis HCV+/cirrhosis n = 14 n = 29 n = 50

15. 15 Lopinavir Total and Unbound AUC12, Individual and Mean ± SD, Study Day 14 Total LPV Unbound LPV Arribas et al.; EACS 2003, #F2/6

16. 16 Veronese et al. AAC2000 Relationship between amprenavir AUC and Child-Pugh score. No subjects with a Child- Pugh score of >12 were enrolled; therefore, extrapolation of results to subjects with higher Child-Pugh scores should be made with caution. 80000 70000 60000 50000 40000 30000 20000 10000 0 -202468101214 Child-Pugh score at screening AUC 0 →∞ (h.ng/mL) Healthy subjects Subjects with moderate cirrhosis Subjects with severe cirrhosis y=3267 x + 9790 r 2 =0.5884 p=0.0001 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ● Single-dose pharmacokinetics of amprenavir in subjects with normal or impaired hepatic function

17. 17 Normal hepatic function 1,200 mg BID Child-Pugh scores 5 - 8 450 mg BID Child-Pugh scores 9 - 14 300 mg BID Veronese et al. AAC2000 Single-dose pharmacokinetics of amprenavir in subjects with normal or impaired hepatic function

18. 18 NNRTI

19. 19 NNRTI plasma concentrations in cirrhotic patients : HEPADOSE Cross sectional prospective study NVP and EFV Cmin measurement Median C min (ng/mL)HIV HIV-HCV p NVP (N : 3400-6000)39545331.12 n=13n=11 EFV (N : 1100-3000)14943583.04 n=8n=12

20. 20 Nevirapine plasma concentrations in cirrhotic patients : NEVADOSE Med NVP Cmin (ng/mL) 4033 7045.04 (95%CI) NVP > 6000 ng/mL (% pts) 27% 66%.03 HIV and HIV/HCV patients receiving NVP Fibrotest° at time of NVP Cmin measurement Med NVP Cmin (ng/mL) Fibrosis stageF0-F3F4 n= 27n= 8

21. 21 NRTI = few datas

22. 22 Only AZT and abacavir are > 50% metabolized by hepatic enzymes such as UGP % renalT 1/2intracell (h) excretion ABC< 5 % 3 ddI50 % 15-20 FTC80 % 39 3TC80 % 10-15 d4T80 % 3-5 ddC80 % 4-8 ZDV20 % 3-5 TDF80 % > 60

23. 23 Zidovudine pharmacokinetics in patients with liver cirrhosis Clearances ml/min CloClfgzdv Healthy 2562 ± 813 1540 ± 540 Cirrhosis 686 ± 243** 236 ± 73** Clo-ml/min/kg Child-Pugh scores 0 10 20 30 40 50 60 70 H678910111213 Cirrhosishealthy Taburet et al., CPT 1990 ; 47 : 731

24. 24 Abacavir pharmacokinetics in patients with liver cirrhosis Single oral dose of 600 mg abacavir 9 HIV+ subjects with mild cirrhosis (Child Pugh score 5-6) were compared to 9 controls 89%  in abacavir AUC 59%  in abacavir T1/2 (p<0.0001) => Dose reduction to 150mg/d recommended in patients with cirrhosis Raffi et al, ICAAC,2004

25. 25 Tenofovir Pharmacokinetics in Hepatic Impairment No significant alteration in subjects with moderate or severe hepatic impairment Consistent with its low protein binding and elimination as unchanged drug in urine Kearney B, et al. 11 th CROI. San Francisco 2004, #600. 012243648 1 10 100 1000 Unimpaired Controls Moderate Hepatic Impairment Severe Hepatic Impairment Time (hr) Tenofovir Concentrations (ng/mL) Mean +/- 95%CI INTI

26. 26 Peytavin, CROI, 2001 AE GI Nephro Cut Metab AE Gastrointestinal Nephrolithiasis Cutaneous Metabolic RTV/IDV (mg bid) 100/400 400/400 100/600 100/800 r 2 =0.47 r 2 =0.90 r 2 =0.99 r 2 =0.90 0 500 1000 1500 2000 010203040 Adverse Effects (%) IDV Cmin (ng/ml) Correlation between plasma Cmin and adverse events : indinavir

27. 27 Stop Efavirenz Severe CNS side-effect and high EFV plasma levels in a patient with cirrhosis Bickel M, 2006 53 yo female, HIV/HCV compensated cirrhosis, Mood disorders and severe depression 15 days after EFV initiation Range : 1-4  g/l

28. 28 However, Major intra and inter individual variability Genetic polymorphisms Compensatory mechanisms in severe liver disease

29. 29 Conclusion (1) ARV are beneficial in patients with cirrhosis Normal dosage can be initially prescribed in patients with moderate hepatic impairement Early TDM is warranted in patients with cirrhosis - for NNRTI, PI, AZT, abacavir…. - mainly if Child Pugh score > B

30. 30 Conclusion (2) How to prevent steatosis ? Select HAART regimen with safe metabolic avoid : D4T, ddI, triple NUC regimen Select PI such as atazanavir Treat metabolic disturbances Avoid high BMI Treat HCV and HBV

31. 31 Risk factors of steatosis in HIC/HCV co-infection odds ratio (OR) Castera, 2004Sulkowski, 2005Bani-Sadr, 2006 BMIX2.81.13 Hyperglycemia/in sulin resistance X2.8 LypodistropphyX D4T use Cumulative time on PI 3.4 1.2 Genotype 3X3.2 Caucasian race4.6 Fibrosis scoreX1.43

32. 32 Abacavir and Hepatic Impairment Mild hepatic impairment: the data is very limited; due to the potential increases in exposure in some patients, close monitoring is required. Moderate: No data are available in patients with moderate or severe hepatic impariment. Plasma concentrations are expected to substantially increase in these patients. Therefore the use of abacavir in patients with moderate hepatic impariment is not recommended unless judged necessary and requires close monitoring of these patients Severe: For patients with severe hepatic impairment, Ziagen is contraindicated. European SmPC: Ziagen INTI

33. 33 Métanalyse Da Silva et al. XV IAC 2004 11% 5% 9% 4% 13% 5% 0 2 4 6 8 10 12 14 16 18 B/C+B/C-B/C+B/C-B/C+B/C- Incidence (%) B/C+ ALT all pts Naive Non naive Lopinavir/r : higher prevalence of ALT elevation in B/C+ coinfection than in HIV monoinfection

34. 34 Boosted atazanavir : higher prevalence of ALT elevation in B/C+ coinfection * Comparators : EFV, NFV et LPV/r Sanne I et al.41st ICAAC,2001:abstract 2001. Squires K et al.42nd ICAAC,2002:abstract H-1076. Nieto-Cisneros L et al., 2nd IAS 2003:abstract117. Badaro et al.,2nd IAS,2003:abstract 118. ALAT > 5xULN (%) ATV/RTVComparators* Hep B/C (+)18/151 (11 %)11/106 (11 %) Hep B/C (-)20/873 (2 %)11/638 (2 %)

35. 35 1 - Impact of antiretroviral agents (ARV) on liver disease 2 - Pharmacokinetics of ARV in cirrhotic patients 3 - Correlation between high concentrations and toxicity

36. 36 LONG TERM HAART TOXICITY Protease inhibitors NRTI Macrovesicular steatosis Microvesicular Steatosis Fibrosis ? Insuline resistance Decrease glucose uptake Hyperlipemia Mitochondrialtoxicity