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 Qurishi N et al, Lancet 2003Qurishi N et al, Lancet 2003

Time (days)Time (days)

500040003000200010000

Su

rviv

al

Su

rviv

al

1.1

0.9

0.7

0.5

0.3

p < 0,0001p < 0,0001

Patients on HAARTPatients on HAART

Patients on ARVPatients on ARV

Non treated patientsNon treated patients

6000 6000500040003000200010000

1.1

0.9

0.7

0.5

0.3

p < 0,018p < 0,018

Patients on HAARTPatients on HAART

Patients onARVPatients onARV

Non treated patientsNon treated patientsSu

rvia

lS

urv

ial

Time (days)Time (days)

HAART 93 79 33 - - -

ARV 55 46 30 15 9 1

Non treated

137 94 49 37 32 27

Patients followedPatients followedHAART 93 79 33 - - -

ARV 55 46 30 15 9 1

Non treated

137 94 49 37 32 27

Patients followedPatients followed

Beneficial effect of HAART on hepatic mortality

Global mortality Hepatic mortality

4

Negative impactNegative impact

Beneficial impact

Short term hepatotoxicity Steatosis Fibrosis

Decrease of hepatic ;;;mortality

Impact of antiretroviral agents (ARV) on liver disease

5

Hepatotoxicity is frequent in Hepatotoxicity is frequent in patients with cirrhosispatients with cirrhosis

Intrinsec hepatotoxicity

Impaired hepatic metabolism

Risk of hepatic decompensation

Increased toxicity

Other organ toxicity

6 Aranzabal L, Clin Infect Dis, 2005; 40:588

15%15%

38%38%

6%6%11%11%

17%17%19%19%

00

1010

2020

3030

4040

F1/F2F1/F2 F1/F2F1/F2 F3/F4F3/F4 F1/F2F1/F2

Inci

den

ce (

%)

Inci

den

ce (

%)

F1/F2F1/F2

OverallOverall NNRTINNRTI Non NNRTINon NNRTI

Correlation between liver fibrosis and HAART related-hepatotoxicity

F3/F4F3/F4 F3/F4F3/F4

• 107 HCV co-infected patients who underwent liver biopsy

• Hepatotoxicity defined as ALT X 5N or > 3.5 X baseline

F3/F4F3/F4

7 Imperiale et al. HIV6, 2002; poster 150Imperiale et al. HIV6, 2002; poster 150

ALT/AST > 5N in 2 198 patients ALT/AST > 5N in 2 198 patients treated between 1997 et 2001treated between 1997 et 2001

18.0018.00

16.0016.00

14.0014.00

12.0012.00

10.0010.00

8.008.00

6.006.00

4.004.00

2.002.00

0.000.00

Rel

ativ

e R

isk

Rel

ativ

e R

isk

3TC3TC STVSTV 3TC-3TC-ZDVZDV

ddIddI ABVABV NVPNVP EFVEFV NFVNFV SQVSQV RTVRTV IDVIDV APVAPV Age>60Age>60 CD4CD4++>350>350HBV/HCVHBV/HCV

HCV/HBVHCV/HBVAge >60Age >60

23235757

NRTIsNRTIs NNRTIsNNRTIs PIsPIsPatientsPatients

characteristicscharacteristics

Incidence of hepatotoxicity in TARGET cohort

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, Sulkowsky, AIDS, 2005; BaniSadr, AIDS 2006; Castéra et al., Lemoine et al., Marks et al, Agarwal et al, AASLD, 2004AASLD, 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

(1) Castera, 2004; (2) Sulkowski, 2005; (3) Bani-Sadr, 2006

Role of HAART

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)

240240

200200

160160

120120

8080

4040

22VIH negVIH negVHC posVHC pos

1A1AVIH posVIH posVHC posVHC pos

HAART négHAART nég

1B1BVIH posVIH posVHC posVHC pos

D-drug négD-drug nég

1C1CVIH posVIH posVHC posVHC pos

D-drug posD-drug pos

ADNADNmt/ADNn ratiomt/ADNn ratio(1A=100 %)(1A=100 %)

d4T posd4T posddI posddI posddC posddC posd4T + ddI posd4T + ddI posLactate > ULNLactate > ULN

Walker U., Hepatology, 2004;39:311-317Walker U., Hepatology, 2004;39:311-317

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.

Regazzi ME Regazzi ME et alet al. . 44thth International Workshop on the International Workshop on the Clinical Pharmacology of HIV Therapy, Clinical Pharmacology of HIV Therapy, 2003; abstract 2003; abstract

1414

00

22

44

66

88

1010

1212

00 22 44 66 88 1010 1212Time after drug administration (hours)Time after drug administration (hours)

NF

V p

lasm

a co

nc.

(m

cg/m

l)N

FV

pla

sma

con

c. (

mcg

/ml)

HCV-HCV- HCV+HCV+ HCV+/cirrhosisHCV+/cirrhosis

n = 14n = 14

n = 29n = 29

n = 50n = 50

15

Lopinavir Total and Unbound AUC12, Individual and Mean ± SD,

Study Day 14L

op

inav

ir A

UC

12 ( g

•h/m

L)

0

50

100

150

200

250

Un

bo

un

d L

op

inav

ir A

UC

12 ( g

•hr/

mL

)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Control Mild+Moderate

Control

Mild HI

Moderate HI

Control Mild+ModerateTotal LPV Unbound LPV

Arribas et al.; EACS 2003, #F2/6

16 Veronese et al. AAC2000Veronese et al. AAC2000

Relationship between Relationship between amprenavir AUCamprenavir AUC

and and

Child-Pugh score. Child-Pugh score.

No subjects with a Child-No subjects with a Child-Pugh score of >12 were Pugh score of >12 were enrolled; therefore, enrolled; therefore, extrapolation of results to extrapolation of results to subjects with higher subjects with higher Child-Pugh scores Child-Pugh scores should be made with should be made with caution.caution.

8000080000

7000070000

6000060000

5000050000

4000040000

3000030000

2000020000

1000010000

00-2-2 00 22 44 66 88 1010 1212 1414

Child-Pugh score at screeningChild-Pugh score at screening

AU

C

AU

C 00 →

∞→

∞ (

h.ng

/mL)

(h.

ng/m

L)

Healthy subjects Healthy subjects Subjects with moderate cirrhosisSubjects with moderate cirrhosisSubjects with severe cirrhosisSubjects with severe cirrhosis

y=3267 x + 9790y=3267 x + 9790

rr22=0.5884=0.5884

p=0.0001p=0.0001

●●●●●●●●

●

●●●●

●●

●

●●

●

▲▲ ▲

▲▲▲

▲

▲

▲

▲▲

●

Single-dose pharmacokinetics of amprenavirin subjects with normal or impaired

hepatic function

17

Normal hepatic function Normal hepatic function 1,200 mg BID1,200 mg BID

Child-Pugh scores 5 - 8 Child-Pugh scores 5 - 8 450 mg BID450 mg BID

Child-Pugh scores 9 - 14 Child-Pugh scores 9 - 14 300 mg BID300 mg BID

Veronese et al. AAC2000Veronese et al. AAC2000

Single-dose pharmacokinetics of amprenavirin subjects with normal or impaired

hepatic function

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 n=13 n=11

EFV (N : 1100-3000) 1494 3583 .04

n=8 n=12

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 stage F0-F3 F4

n= 27 n= 8

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

23

Zidovudine pharmacokinetics in patients with liver cirrhosis

Clearances

ml/min

Clo Clfgzdv

Healthy 2562 ± 813 1540 ± 540

Cirrhosis 686 ± 243** 236 ± 73**

Clo

-ml/m

in/k

gC

lo-m

l/min

/kg

Child-Pugh scoresChild-Pugh scores

00

1010

2020

3030

4040

5050

6060

7070

HH 66 77 88 99 1010 1111 1212 1313

CirrhosisCirrhosis healthyhealthy

Taburet et al., CPT 1990 ; 47 : 731Taburet 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 (p<0.0001)

• => Dose reduction to 150mg/d recommended in patients with cirrhosis Raffi et al, ICAAC,2004Raffi et al, ICAAC,2004

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. 11th CROI. San Francisco 2004, #600.

0 12 24 36 481

10

100

1000

Unimpaired ControlsModerate Hepatic ImpairmentSevere Hepatic Impairment

Time (hr)

Ten

ofov

ir C

once

ntr

atio

ns

(ng/

mL)

Mean +/- 95%CI

INTIINTI

26 Peytavin, CROI, 2001Peytavin, CROI, 2001

AE

GI

Nephro

Cut

Metab

AE

Gastrointestinal

Nephrolithiasis

Cutaneous

Metabolic

RTV/IDV (mg bid)

100/400

400/400

100/600

100/800

r2 =0.47r2=0.90

r2 =0.99r2 =0.90

00

500500

10001000

15001500

20002000

00 1010 2020 3030 4040

Adverse Effects (%)Adverse Effects (%)

IDV

Cm

in (

ng

/ml)

IDV

Cm

in (

ng

/ml)

Correlation between plasma Cmin and adverse events : indinavir

27

0

10

20

30

40

50

60

janv-02 D 15 D 38 D47 D45 D60

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

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)

Castera, 2004 Sulkowski, 2005 Bani-Sadr , 2006

BMI X 2.8 1.13

Hyperglycemia/insulin resistance

X 2.8

Lypodistropphy X

D4T use

Cumulative time on PI

3.4

1.2

Genotype 3 X 3.2

Caucasian race 4.6

Fibrosis score X 1.43

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

INTIINTI

33 Métanalyse Da Silva et al. XV IAC 2004Métanalyse Da Silva et al. XV IAC 2004

11%11%

5%5%

9%9%

4%4%

13%13%

5%5%

00

2244

66

881010

1212

14141616

1818

B/C+B/C+ B/C-B/C- B/C+B/C+ B/C-B/C- B/C+B/C+ B/C-B/C-

Inci

den

ce (

%)

Inci

den

ce (

%)

B/C+B/C+

ALTALT

all ptsall pts NaiveNaive Non naiveNon naive

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

Sanne I et al.41st ICAAC,2001:abstract 2001.Sanne I et al.41st ICAAC,2001:abstract 2001.Squires K et al.42nd ICAAC,2002:abstract H-1076.Squires K et al.42nd ICAAC,2002:abstract H-1076.Nieto-Cisneros L et al., 2nd IAS 2003:abstract117.Nieto-Cisneros L et al., 2nd IAS 2003:abstract117.

Badaro et al.,2nd IAS,2003:abstract 118.Badaro et al.,2nd IAS,2003:abstract 118.

ALAT > 5xULN (%)

ATV/RTV Comparators*

Hep B/C (+) 18/151 (11 %) 11/106 (11 %)

Hep B/C (-) 20/873 (2 %) 11/638 (2 %)

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 TOXICITYLONG TERM HAART TOXICITY

Protease inhibitors

NRTI

Macrovesicular steatosis

MicrovesicularSteatosis

Fibrosis ?

Insuline resistance Insuline resistance

Decrease glucose Decrease glucose uptakeuptake

HyperlipemiaHyperlipemia

MitochondrialMitochondrialtoxicitytoxicity