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
• gt Specificity of ARV use in cirrhosis

3
Beneficial effect of HAART on hepatic mortality
Global mortality
Hepatic mortality
1.1
1.1
Patients on HAART
Patients on HAART
0.9
0.9
Patients onARV
Survial
Survival
Non treated patients
0.7
0.7
p lt 0,0001
p lt 0,018
0.5
0.5
Patients on ARV
Non treated patients
0.3
0.3
5000
4000
3000
2000
1000
0
6000
6000
5000
4000
3000
2000
1000
0
Time (days)
Time (days)
Patients followed
Patients followed
Qurishi N et al, Lancet 2003
4
Impact of antiretroviral agents (ARV) on liver
disease
Beneficial impact
Negative impact
Decrease of hepatic mortality
Short term hepatotoxicity Steatosis
Fibrosis
5
Hepatotoxicity is frequent in patients with
cirrhosis
Intrinsec hepatotoxicity
Impaired hepatic metabolism
Increased toxicity
Risk of hepatic decompensation
Other organ toxicity
6
Correlation between liver fibrosis and HAART
related-hepatotoxicity

• 107 HCV co-infected patients who underwent
  liver biopsy
• Hepatotoxicity defined as ALT X 5N or gt 3.5 X
  baseline

38
40
30
F1/F2
Incidence ()
19
20
17
F3/F4
15
11
10
6
0
F3/F4
F1/F2
F1/F2
F3/F4
F1/F2
F3/F4
Overall
NNRTI
Non NNRTI
Aranzabal L, Clin Infect Dis, 2005 40588
7
Incidence of hepatotoxicity in TARGET cohort
Imperiale et al. HIV6, 2002 poster 150
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
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

Role of HAART
(1) Castera, 2004 (2) Sulkowski, 2005 (3)
Bani-Sadr, 2006
10
Depletion of hepatic mtDNA with D-nucleosides
(ddI, D4T, ddC)

• 47 decrease of mtADN in patients with
   D-drugs  (n35) versus  non D-drugs  (n34)
  (plt0.0001)

Walker U., Hepatology, 200439311-317
11
Pharmacokinetics of ARV in cirrhotic patients
12
Impaired hepatic metabolism in cirrhosis

• ? protein synthesis gt ? increase of free form
• ? hepatic metabolism (CYP 450, UGP..)
• ? hepatic flow gt ? decrease hepatic clearance
• ? Increase of C max, AUC

13
Protease inhibitors
14
Examination of NFV PK profileplasma conc.
12
HCV-
HCV
HCV/cirrhosis
10
8
n 14
NFV plasma conc. (mcg/ml)
6
4
n 29
2
n 50
0
0
2
4
6
8
10
12
Time after drug administration (hours)
Regazzi ME et al. 4th International Workshop on
the Clinical Pharmacology of HIV Therapy, 2003
abstract 14
15
Lopinavir Total and Unbound AUC12, Individual
and Mean SD, Study Day 14
Unbound LPV
Total LPV
Arribas et al. EACS 2003, F2/6
16
Single-dose pharmacokinetics of amprenavirin
subjects with normal or impairedhepatic function
80000
?
Healthy subjects
Relationship between amprenavir AUC and
Child-Pugh score. No subjects with a Child-Pugh
score of gt12 were enrolled therefore,
extrapolation of results to subjects with higher
Child-Pugh scores should be made with caution.
?
Subjects with moderate cirrhosis
70000
?
Subjects with severe cirrhosis
?
?
60000
50000
?
?
?
y3267 x 9790
?
AUC 0?8 (h.ng/mL)
40000
r20.5884
?
p0.0001
?
?
?
30000
?
?
?
?
?
20000
?
?
?
?
?
?
?
?
?
10000
?
?
?
?
0
-2
0
2
4
6
8
10
12
14
Child-Pugh score at screening
Veronese et al. AAC2000
17
Single-dose pharmacokinetics of amprenavirin
subjects with normal or impairedhepatic function
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
18
NNRTI
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) 3954 5331 .12
n13 n11 EFV (N
1100-3000) 1494 3583 .04
n8 n12
20
Nevirapine plasma concentrations in cirrhotic
patients NEVADOSE

• HIV and HIV/HCV patients receiving NVP
• Fibrotest at time of NVP Cmin measurement

Med NVP Cmin (ng/mL) Fibrosis
stage F0-F3 F4 n 27 n 8
Med NVP Cmin (ng/mL) 4033
7045 .04 (95CI)
NVP gt 6000 ng/mL ( pts) 27
66 .03
21
NRTI few datas
22
Only AZT and abacavir are gt 50 metabolized by
hepatic enzymes such as UGP

• renal T1/2intracell (h)
• excretion
• ABC lt 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 gt 60

23
Zidovudine pharmacokinetics in patients with
liver cirrhosis
Cirrhosis
healthy
70

• Clearances
• ml/min
• Clo Clfgzdv
• Healthy 2562 813 1540 540
• Cirrhosis 686 243 236 73

60
50
40
Clo-ml/min/kg
30
20
10
0
H
6
7
8
9
10
11
12
13
Child-Pugh scores
Taburet et al., CPT 1990 47 731
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 (plt0.0001)
• gt Dose reduction to 150mg/d recommended in
  patients with cirrhosis

Raffi et al, ICAAC,2004
25
Tenofovir Pharmacokinetics in Hepatic Impairment
INTI

• 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. 11th CROI. San Francisco 2004,
600.
26
Correlation between plasma Cmin and adverse
events indinavir
AE
AE
GI
Gastrointestinal
Nephro
Nephrolithiasis
Cut
Cutaneous
Metab
Metabolic
RTV/IDV (mg bid)
100/400
400/400
100/600
100/800
Peytavin, CROI, 2001
27
Severe CNS side-effect and high EFV plasma levels
in a patient with cirrhosis

• 53 yo female, HIV/HCV compensated cirrhosis,
• Mood disorders and severe depression 15 days
  after EFV initiation

Stop Efavirenz
Range 1-4 mg/l
Bickel M, 2006
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 gt 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
INTI

• 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
33
Lopinavir/r higher prevalence of ALT elevation
in B/C coinfection than in HIV monoinfection
18
16
13
14
11
12
9
10
B/C
Incidence ()
8
ALT
5
5
6
4
4
2
0
B/C
B/C-
B/C
B/C-
B/C
B/C-
all pts
Naive
Non naive
Métanalyse Da Silva et al. XV IAC 2004
34
Boosted atazanavir higher prevalence of ALT
elevation in B/C coinfection

• Comparators EFV, NFV et LPV/r

Sanne I et al.41st ICAAC,2001abstract
2001. Squires K et al.42nd ICAAC,2002abstract
H-1076. Nieto-Cisneros L et al., 2nd IAS
2003abstract117. Badaro et al.,2nd
IAS,2003abstract 118.
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
LONG TERM HAART TOXICITY
Protease inhibitors
NRTI
Insuline resistance Decrease glucose
uptake Hyperlipemia
Mitochondrial toxicity
Microvesicular Steatosis
Macrovesicular steatosis
Fibrosis ?