Management of anti retroviral treatment in patients with cirrhosis

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

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. Beneficial effect of HAART on hepatic mortality

4. Hepatotoxicity may be either acute such as with nevirapine and leading to fulminant heaptitis or chronic the mechnism of which is not uniform. But this may lead one the long terme to steatosis and fibrosis worsening (faill bro zis) Macro : ma (ouvrir et tirer ) ve zic ular Micro : Maill cro ve zic ular Hepatotoxicity may be either acute such as with nevirapine and leading to fulminant heaptitis or chronic the mechnism of which is not uniform. But this may lead one the long terme to steatosis and fibrosis worsening (faill bro zis) Macro : ma (ouvrir et tirer ) ve zic ular Micro : Maill cro ve zic ular

5. Hepatotoxicity may be either acute such as with nevirapine and leading to fulminant heaptitis or chronic the mechnism of which is not uniform. But this may lead one the long terme to steatosis and fibrosis worsening (faill bro zis) Macro : ma (ouvrir et tirer ) ve zic ular Micro : Maill cro ve zic ular Hepatotoxicity may be either acute such as with nevirapine and leading to fulminant heaptitis or chronic the mechnism of which is not uniform. But this may lead one the long terme to steatosis and fibrosis worsening (faill bro zis) Macro : ma (ouvrir et tirer ) ve zic ular Micro : Maill cro ve zic ular

6. Correlation between liver fibrosis and HAART related-hepatotoxicity

7. Incidence of hepatotoxicity in TARGET cohort The risk of hepatotoxicity as been well studied in different cohorts and concordant results have been published. The most hepatotoxic drugs are : Among PI: ritonavir full dose and amprenavir both NNRTI nevirapine and efavirenz and among NRTI ddi and stavudine All these sutdies also show that the risk of hepatotoxicity is increased in older patients and in those with hepatitis C or B co infectionThe risk of hepatotoxicity as been well studied in different cohorts and concordant results have been published. The most hepatotoxic drugs are : Among PI: ritonavir full dose and amprenavir both NNRTI nevirapine and efavirenz and among NRTI ddi and stavudine All these sutdies also show that the risk of hepatotoxicity is increased in older patients and in those with hepatitis C or B co infection

8. Steatosis and HIV/HCV co-infection Frequent : 40 to 67 % of the patients Severe in 7 % Microvesicular Macrovesicular

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

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)

11. Pharmacokinetics of ARV in cirrhotic patients

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. Protease inhibitors

14. Examination of NFV PK profile:plasma conc. As you can see here nelfinavir plasma levels were higher in HIV-HCV co-infected patients without cirrhosis (shown here in orange) than in HIV mono-infected patients (shown here in green) over 12 hours after dosing. In HIV-HCV patients with cirrhosis (shown here in yellow) an even greater increase in nelfinavir plasma levels was observed. As you can see here nelfinavir plasma levels were higher in HIV-HCV co-infected patients without cirrhosis (shown here in orange) than in HIV mono-infected patients (shown here in green) over 12 hours after dosing. In HIV-HCV patients with cirrhosis (shown here in yellow) an even greater increase in nelfinavir plasma levels was observed.

15. Lopinavir Total and Unbound AUC12, Individual and Mean ± SD, Study Day 14

16. Single-dose pharmacokinetics of amprenavirin subjects with normal or impairedhepatic function

17. Single-dose pharmacokinetics of amprenavirin subjects with normal or impairedhepatic function

18. NNRTI 

19. NNRTI plasma concentrations in cirrhotic patients : HEPADOSE Cross sectional prospective study NVP and EFV Cmin measurement

20. Nevirapine plasma concentrations in cirrhotic patients : NEVADOSE But interstingly when we compared twenty seven patients (both coinfected and hiv) the mild to moderate liver disease group to the eight patients with cirrhosis, we we observed a significant difference on NVP CMinand a significant higher percentage of patients with Cmin over the therapeutic expected concentrationsBut interstingly when we compared twenty seven patients (both coinfected and hiv) the mild to moderate liver disease group to the eight patients with cirrhosis, we we observed a significant difference on NVP CMinand a significant higher percentage of patients with Cmin over the therapeutic expected concentrations

21. NRTI = few datas

22. Only AZT and abacavir are > 50% metabolized by hepatic enzymes such as UGP % renal T1/2intracell (h) excretion ABC < 5 % 3 ddI 50 % 15-20 FTC 80 % 39 3TC 80 % 10-15 d4T 80 % 3-5 ddC 80 % 4-8 ZDV 20 % 3-5 TDF 80 % > 60 It is now well known, that in patients who failed previous antiretroviral therapy, efficacy of a new PI will depend on both plasma exposure and genotype. The aim of this study which was to evaluate the efficacy of fosamprenavir, the new amprenavir prodrug in PI experienced patients. I will present preliminary data up to 6 months of treatment. It is now well known, that in patients who failed previous antiretroviral therapy, efficacy of a new PI will depend on both plasma exposure and genotype. The aim of this study which was to evaluate the efficacy of fosamprenavir, the new amprenavir prodrug in PI experienced patients. I will present preliminary data up to 6 months of treatment.

23. Zidovudine pharmacokinetics in patients with liver cirrhosis Clearances ml/min Clo Clfgzdv Healthy 2562 ± 813 1540 ± 540 Cirrhosis 686 ± 243** 236 ± 73**

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

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

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

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. 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. Risk factors of steatosis in HIC/HCV co-infectionodds ratio (OR)

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.

33. Lopinavir/r : higher prevalence of ALT elevation in B/C+ coinfection than in HIV monoinfection

34. Boosted atazanavir : higher prevalence of ALT elevation in B/C+ coinfection * Comparators : EFV, NFV et LPV/r

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. Hepatotoxicity may be either acute such as with nevirapine and leading to fulminant heaptitis or chronic the mechnism of which is not uniform. But this may lead one the long terme to steatosis and fibrosis worsening (faill bro zis) Macro : ma (ouvrir et tirer ) ve zic ular Micro : Maill cro ve zic ular Hepatotoxicity may be either acute such as with nevirapine and leading to fulminant heaptitis or chronic the mechnism of which is not uniform. But this may lead one the long terme to steatosis and fibrosis worsening (faill bro zis) Macro : ma (ouvrir et tirer ) ve zic ular Micro : Maill cro ve zic ular