Download Epatotossicità da farmaci antiretrovirali: ruolo della farmacocinetica

Epatotossicità da farmaci
antiretrovirali: ruolo della
farmacocinetica e
della patologia epatica sottostante
Raffaele Bruno
Università degli studi di Pavia
Liver injury in HIV-infected patients
Opportunistic diseases
HCV treatment
HIV treatment
NRTIs,
NNRTIs, PIs;
OI Rx
Immune
reconstitution
Fatty
Liver
Disease
Hepatitis
viruses
Alcohol abuse/IVDU
Preexisting diseases
Incidence/
100 persons
Liver toxicity is the most common severe
adverse event in the HAART era
Coinfection with hepatitis B or C associated with 4.15
(95% CI 2.26–7.60) hazard ratio of Grade 4 liver toxicity
Reisler RB, et al. J Acquir Immune Defic Syndr 2003;34:379–86
How is hepatotoxicity defined?
ALT or AST level
(number of times ULN)
Grade 4 toxicity
10
“Severe
hepatotoxicity”
Grade 3 toxicity
5
Grade 1 or 2 toxicity
ULN → 1
Normal
0
Hepatotoxicity spectrum
Fulminant Hepatitis - Hepatic Failure
Reversible Clinical Druginduced Liver Injury
Asymptomatic
>5x ULN ALT/AST
Asymptomatic
≤5x ULN ALT/AST
Background noise:
HCV/HBV/HIV alcohol,
infections,
medication
Liver Disease and Antiretroviral Therapy
- Patterns of liver injury
z
In case series of patients with HIV infection, the prevalence
of liver enzyme abnormalities is:
– 40%-70% for elevations in ALT,
– 20%-40% for elevated alkaline phosphatase,
– 0%-10% for increased bilirubin.
Bruno et. Al. Am J Gastroenterol 2002
Liver Disease and Antiretroviral Therapy
Patterns of Hepatic Injury
Cholestatic
Mixed
Hepatocellular
Alanine aminotransferase
(ALT)
+
++
+++
Aspartate aminotransferase
(AST)
+
++
+++
Alkaline phosphatase
+++
++
+
Gamma glutamyl transpeptidase
(GGT)
+++
++
+
Liver Disease and Antiretroviral Therapy
Probable Mechanisms of Antiretroviral-Induced Hepatotoxicity
Drug
Class
Mechanism
Manifestations
NRTIs
Impaired mitochondrial polymerase
gamma function
Lactic acidosis, steatosis
? Inhibition of retinoic binding protein
Hepatocellular injury,
steatosis
PIs
UDP-glucuronyl
NNRTIs
? Impaired
transferase competition
mitochondrial polymerase
gamma
? Immune-mediated hypersensitivity
Unconjugated
hyperbilirubinemia
Lactic acidosis, steatosis
Eosinophilic hepatic injury
NRTI-related hepatotoxicity
z Syndrome of mitochondrial toxicity
– Mitochondria have their own DNA (mtDNA) that encodes 13%
of mitochondrial proteins
– mtDNA is replicated by DNA polymerase γ
• Differs from nuclear DNA
z NRTIs inhibit DNA polymerase γ
– Mitochondrial dysfunction
– Cellular toxicity
z High-risk drugs
– Stavudine, didanosine, zalcitabine
z Low-risk drugs
– Abacavir, zidovudine, lamivudine, tenofovir
100
11
9
3.6
10
13
1
0.1
0.01
0.01
0.04
0.02
Martin JL, et al. Antimicrob Agents Chemother 1994;38:2743-9
FI
A
U
in
e
Za
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ci
ta
b
ne
an
os
i
id
D
St
av
id
in
e
ud
in
e
iv
La
m
ov
ud
in
e
Zi
d
ba
ca
vi
r
0.001
A
Relative Potency of Inhibition*
NRTIs: Inhibition of DNA polymerase γ
Effect of NRTIs on mtDNA Content in
Liver and Muscle Cells
B: Skeletal Muscle Cells
Relative mtDNA content (%)
A: HepG2 Liver Cells
140
120
3TC
Tenofovir
100
Abacavir
80
ZDV
60
d4T
40
20
ddC
A
140
Abacavir
120
Tenofovir
3TC
ZDV
100
80
60
d4T
40
ddI
20
0
ddC
ddI
B
0
0.1
1
10
100
1000
NRTI concentration (µmol/L)
0.1
1
10
100
1000
NRTI concentration (µmol/L)
Birkus G, et al. Antimicrob Agents Chemother. 2002;46:716-723
Mitochondria
Mitochondrion
Cell
z
Energy power-houses
z
Have their own DNA
z
Mitochondrial DNA is
replicated by a separate
enzyme to nuclear DNA
Polymerase γ
mtDNA
mtDNA
mtDNA encoded protein
function
mitochondrion
Polymerase γ
NRTI
nDNA encoded protein
mtDNA
dysfunction
Inhibition of Mitochondrial DNA Synthesis
Compound
IC50 (µ M)
IC50 (µ M)
mt DNA
virus
3TC
>200
0.7
ABC
>100
5.3
ZDV
>100
0.01
d4T
10
0.9
ddC
0.002
0.5
ddI
not determined
3.9
Kakuda et al Clin Ther 2000
Segregation of mitochondria during cell division
Normal
Mitochondria
Dysfunctional
Mitochondria
Threshold
70% mutant
80% mutant
DISEASE
60% mutant
NORMAL
Progenitor cell
showing heteroplasmy
of mitochondria
At cell division, each daughter
cell gets the same nDNA, but
varying mtDNA
40% mutant
NORMAL
100%
NORMAL
Mitochondrial dysfunction due to NRTIs
y Neuromuscular:
y polyneuropathy ddC, ddI, d4T
y myopathy ZDV, ddI
y cardiomyopathy ZDV, ddC, ddI
y Hepatic:
y steatosis, lactic acidosis ddI,d4T,ddC
y gastro-intestinal:
y pancreatitis ddI, d4T
y hematological:
y pancytopenias ZDV
y nephrological:
y prox. renal tubular dysfunction adefovir
y metabolic
y lipodystrophy d4T
Energy production in mitochondria
glucose
pyruvate + NADH
FFA
cytosol
triglycerides
Resp chain
Acetyl CoA
NADH
TCA
cycle
CO2 + H2O
NAD+
ketone bodies
NAD+
mitochondrion
Lactic acidosis
glucose
pyruvate + NADH
FFA
cytosol
lactate + NAD+
triglycerides
Resp chain
Acetyl CoA
NADH
TCA
cycle
CO2 + H2O
NAD+
ketone bodies
NAD+
mitochondrion
From Hyperlactatemia to Acidosis
Source: Medscape
NRTI-based liver toxicity:
Clinical presentation
z Non-specific symptoms
– Abdominal pain, vomiting, anorexia, pain (right
upper quadrant), weight loss
z Hepatomegaly
z Mixed cholestatic/hepatocellular pattern of liver
enzymes
z Evidence of extrahepatic mitochondrial toxicity
– Amylase/lipase, CPK, lactate, metabolic acidosis,
loss of bicarbonate
Falco et al. Clin Infect Dis 2002
HCV and NNRTI-associated hepatotoxicity
Sulkowski MS, et al. Hepatology 2002;35:182-9
Risk of mitochondrial toxicity: NRTI + RBV in
HIV/HCV-coinfected patients
z US FDA Reporting System of
Mitochondrial Toxicity
HIV/HCV patients treated with
IFN/RBV
Risk
RBV +
z 31 cases (58 adverse events)
suggestive of mitochondrial
toxicity
– Pancreatitis and/or
increased lipase (n=21)
– Lactic acidosis (n=20)
– Elevated LFTs (n=8)
– Hepatic steatosis (n=6)
– Elevated creatinine,
neuropathy, multiorgan
failure (n=1 each)
12.4
Didanosine
Didanosine +
stavudine
8.0
3.3
Stavudine
1.1
Abacavir
0.2
Lamivudine
0.06
Zidovudine
0.01
0.1
1.0
10
Odds Ratio (95% CI)
Fleischer R, et al. Clin Infect Dis 2004;38:e79-e80
100
Interactions between Mito and CYPs 450
CYPs
MITO
ROS
Lipid peroxidation
Fat deposits
Mitochondrial
disfunction
1
TNF- α
2
3
ROS
Lipid
Depletion of
Peroxidation
antioxidans
4
FAT
Vicious cycles involving ROS and Mitochondria
From ROS to steatohepatitis
fibrosis
ROS
Lipid peroxidation products
Cytokines
Cell killing
(IL-2, IFN-γ ,TNF-α, TGF-β, PDGF)
TGF-β
Activation
Apoptosis
Kupffer cell
Hepatocytes
Hepatic stellate cells
FIBROSIS
Some ARV Pharmacogenetic Variants
z Abacavir HSR (HLA-B*5701)white > black
z Efavirenz PK (CYP2B6)
z
z
z
z
black > white
Nevirapine LFTs (ABCB1) black > white
Atazanavir jaundice (UGT) white > black
Atazanavir PK (PXR?)
white > black
Nelfinavir (CYP2C19)
Asian > black, white
To date, every genetic variant that affects HIV
disease progression, ARV pharmacokinetics,
efficacy, or toxicity differs considerably in frequency
depending on geographic region of ancestry.
From DH Haas, MD, at San Francisco, CA: April 20, 2009, IAS–USA.
Associations Between Allelic Variants
and HIV Treatment Response
Drug
z Abacavir
Phenotype
Gene
Hypersensitivity HLA-B*5701
Lancet 2002:359,727 & 1121; PNAS 2004:101,4180
z Indinavir
Jaundice
UGT-1A1
Atazanavir
PNAS 2001:98,12671; ICAAC 2002; JID 2005;192,1381
z NRTI
Lipoatrophy
TNF-α promoter, HFE
AIDS 2002:16,2013; AIDS 2003:17,121; JID 2008:197, 858
z Nevirapine
Hypersensitivity HLA-DRB1*0101, -Cw8, -B3505
Hepatotoxicity
ABCB1
Pharmacokinetics CYP2B6
AIDS 2005:19,97; Pharmacogenet Genom 2005;15,1; Clin Inf Dis 2006;43,779 & 783; AIDS 2006:20,1621; AIDS
2007;21,264; Pharmacogenet Genom 2009;19,139
From DH Haas, MD, at San Francisco, CA: April 20, 2009, IAS–USA.
Genetic Associations (continued)
Drug
z Efavirenz
Phenotype
Slide 28
Gene
CNS effects, Pharmacokinetics
CYP2B6
ABCB1, CYP2A6
Viral response, Resistance
Lancet 2002;359:30; AIDS 2004;18:2391; Pharmacogenet Genom 2005;15:1;
JID 2005;192:1931; CID 2006;42:401; CROI 2008; JID 2009;199:872
z Nelfinavir
Viral response, Pharmacokinetics CYP2C19
JID 2005;192:1931
z PIs
Dyslipidemia
APOC, RETN
JID 2005;191:1419; PLoS Med 2006;3:e52; AIDS 2008;22:1561.
z NRTIs
Peripheral neuropathy
AIDS 2005;19:1341, AIDS 2006;20:1503
z HAART
CD4 recovery
JID 2006;194:1098
From DH Haas, MD, at San Francisco, CA: April 20, 2009, IAS–USA.
Mitochondrial
haplogroup T,
HFE
Proliferation &
apoptosis
Genetic Associations (continued)
Drug
z Tenofovir
Slide 29
Phenotype
Gene
Renal toxicity
MRP2 (ABCC2)
JID 2006;94:1481
z Others…
z ?
z ?
z ?
z ?
z ?
z ?
z ?
From DH Haas, MD, at San Francisco, CA: April 20, 2009, IAS–USA.
Slide 30
Approved Studies with ACTG Human DNA from US
(A5128)
Project
Papers
NWCS 213 – efavirenz, nelfinavir PK & response ◄
2
NWCS 214 – efavirenz CNS toxicity and PK ◄
2
NWCS 215 – T cell turnover rates ◄
1
NWCS 224 – metabolic complications
1
NWCS 233 – CD4 increase on ART ◄
1
NWCS 237 – metabolic complications
*
NWCS 238 – peripheral neuropathy ◄
3
NWCS 239 – efavirenz resistance after Rx interruption ◄
1
NWCS 243 – HLA and viral evolution
*
NWCS 248 – efavirenz & lopinavir PK
1
NWCS 253 – efavirenz response ◄
NWCS 254 – efavirenz response ◄
NWCS 256 – peripheral neuropathy ◄
NWCS 259 – metabolic complications
NWCS 262 – innate immunity and responses to ART
NWCS 266 – treatment responses to ART
NWCS 268 – efavirenz PK ◄
NWCS 273 – peripheral neuropathy ◄
NWCS 275 – pharmacogenomics of HIV therapy ◄
NWCS 279 – immune control
NWCS 280 – lipoatrophy ◄
From DH Haas, MD, at San Francisco, CA: April 20, 2009, IAS–USA.
NWCS 291 – tenofovir renal toxicity ◄
DNA banked
on >10,000
individuals
Slide 31
Abacavir
hypersensitivity
&
HLA-B*5701
From DH Haas, MD, at San Francisco, CA: April 20, 2009, IAS–USA.
Frequency of HLA-B*5701
Slide 32
W. EUROPE 5-7%
US
Caucasian
~8%
US Asian
~1%
MEDITERRANEAN UK
1-2%
~8%
MIDDLE EAST 1-2%
(NB 5-7% Ashkenazi Jews)
INDIA 5-20%
CHINA 0%
(NB 2.5% N.E.
provinces)
US
AfricanAmerican
~2.5%
JAPAN 0%
US
Hispanic
~2%
AUSTRALIA
~8%
THAILAND
4-10%*
S. AMERICAN
Caucasian
5-7%
Subsaharan
AFRICA
<1%
*THAILAND B*57 carriage:
Urban Bangkok 3.6%
Thai Dai Lue (NE Thai) ~11%
Southern Thai Muslim 3%
Nolan et al J HIV Ther 2003;8:36
From DH Haas, MD, at San Francisco, CA: April 20, 2009, IAS–USA.
“PREDICT” Double-Blind Study Design
ABC-containing regimen
HSR monitoring according to
Standard of Care1
(control arm)
ABC-naïve
subjects
Randomise (1:1)
ABC-containing regimen
HSR monitoring according to
Standard of Care
plus HLA-B*5701 screening2
(screening arm)
• 6-Week Observation Period
1. retrospective high resolution typing
2. prospective high resolution typing
HLA-B*5701
positive
subjects excluded
HLA-B*5701
negative subjects
continued
Mallal et al; NEJM 2008.
Performance Characteristics of
HLA-B*5701 Screening for HSR
Clinically Suspected HSR1
HLA-B*5701
HSR
No HSR
Pos
Neg
30
19
36
762
Pos PV Neg PV
62%
1
Control Arm Data Only
96%
Sens 46%
Spec 98%
Immunologically Confirmed HSR1
HLA-B*5701
Pos
Neg
23
25
0
794
Sens 100%
Spec 97%
Pos PV Neg PV
48%
100%
Mallal et al; NEJM 2008
DHHS Panel Guidelines (12/07)
(http://aidsinfo.nih.gov)
“The Panel recommends HLA-B*5701 testing prior to
initiating abacavir therapy... HLA-B*5701-positive patients
positive
status should be recorded as an
abacavir allergy in the patient’s
medical record….”
should not be prescribed abacavir…,
From DH Haas, MD, at San Francisco, CA: April 20, 2009, IAS–USA.
Why TDM in HIV therapy?
Adapted from Acosta EP, et al AIDS Res Human Retro 2002
ART and the liver: Conclusions
z Liver-related morbidity and mortality are assuming an
increasing importance in HIV care
z Each class of antiretroviral agents may be associated
with hepatic toxicity
z Viral hepatitis co-infection increases the risk of drug-
induced liver injury; all co-infected patients must be
monitored carefully
z Data suggest that treatment of HIV slows progression
of fibrosis and reduces liver-related mortality