Epatotossicità da farmaci antiretrovirali: ruolo della farmacocinetica ... · 20-04-2009 ·...
Transcript of Epatotossicità da farmaci antiretrovirali: ruolo della farmacocinetica ... · 20-04-2009 ·...
Epatotossicità da farmaci antiretrovirali: ruolo della
farmacocinetica edella patologia epatica sottostante
Raffaele BrunoUniversità degli studi di Pavia
Liver injury in HIV-infected patients
Opportunistic diseases
Alcohol abuse/IVDU
HCV treatment
Immunereconstitution
Hepatitis viruses
HIV treatmentNRTIs, NNRTIs, PIs; OI Rx
Preexisting diseases
Fatty Liver Disease
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
Inci
denc
e/
100
pers
ons
How is hepatotoxicity defined?
Grade 3 toxicity
Grade 4 toxicity
Normal
Grade 1 or 2 toxicity
ALT or AST level (number of times ULN)
1
5
10
0
ULN →
“Severe hepatotoxicity”
Hepatotoxicity spectrum
Fulminant Hepatitis - Hepatic Failure
Reversible Clinical Drug-induced 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
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.
- Patterns of liver injury
Bruno et. Al. Am J Gastroenterol 2002
++ ++ + +Gamma glutamyl transpeptidase (GGT)
++ ++ + +Alkaline phosphatase
+ + ++ ++Aspartate aminotransferase (AST)
+ + ++ ++Alanine aminotransferase (ALT)
HepatocellularMixedCholestatic
Patterns of Hepatic Injury
Liver Disease and Antiretroviral Therapy
Lactic acidosis, steatosis? Impaired mitochondrial polymerase gamma
NNRTIs
Hepatocellular injury, steatosis
? Inhibition of retinoic binding proteinPIs
Eosinophilic hepatic injury? Immune-mediated hypersensitivity
Unconjugated hyperbilirubinemia
UDP-glucuronyl transferase competition
Lactic acidosis, steatosisImpaired mitochondrial polymerase gamma function
NRTIs
ManifestationsMechanismDrugClass
Probable Mechanisms of Antiretroviral-Induced Hepatotoxicity
Liver Disease and Antiretroviral Therapy
NRTI-related hepatotoxicitySyndrome 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
NRTIs inhibit DNA polymerase γ– Mitochondrial dysfunction– Cellular toxicity
High-risk drugs– Stavudine, didanosine, zalcitabine
Low-risk drugs– Abacavir, zidovudine, lamivudine, tenofovir
0.01 0.02 0.04
3.69 11 13
0.0010.010.1
110
100
Abacav
irZidovu
dineLam
ivudine
Stavidine
Didanosin
eZalc
itabine
FIAU
NRTIs: Inhibition of DNA polymerase γ
Martin JL, et al. Antimicrob Agents Chemother 1994;38:2743-9
Rel
ativ
e P
oten
cy o
f Inh
ibiti
on*
A: HepG2 Liver Cells
Birkus G, et al. Antimicrob Agents Chemother. 2002;46:716-723
1000
NRTI concentration (µmol/L)0.1 1 10 100
0
20
40
60
80
100
120
140
Rel
ativ
e m
tDN
A c
onte
nt (%
)
Tenofovir3TC
Abacavir
ZDV d4T
ddI ddC
0.1 1 10 100 10000
20
40
60
80
100
120
140
Tenofovir3TC
Abacavir
ZDV
d4T
NRTI concentration (µmol/L)
ddI ddC A B
B: Skeletal Muscle Cells
Effect of NRTIs on mtDNA Content in Liver and Muscle Cells
Mitochondria
Energy power-houses Have their own DNAMitochondrial DNA is replicated by a separate enzyme to nuclear DNA
Mitochondrion
Cell
mtDNA
Polymerase γ
mtDNA
Polymerase γ NRTI
function
dysfunction
mitochondrion
mtDNA mtDNA encoded protein
nDNA encoded protein
Inhibition of Mitochondrial DNA Synthesis
Compound IC50 (µ M) IC50 (µ M) mt DNA
virus3TC >200 0.7
ABC >100 5.3ZDV >100 0.01d4T 10 0.9ddC 0.002 0.5ddI not determined 3.9
Kakuda et al Clin Ther 2000
Progenitor cell showing heteroplasmy of mitochondria
Normal MitochondriaDysfunctionalMitochondria
At cell division, each daughter cell gets the same nDNA, but varying mtDNA
80% mutantDISEASE
60% mutantNORMAL
40% mutantNORMAL
100%NORMAL
Threshold70% mutant
Segregation of mitochondria during cell division
Neuromuscular:polyneuropathy ddC, ddI, d4Tmyopathy ZDV, ddIcardiomyopathy ZDV, ddC, ddI
Hepatic:steatosis, lactic acidosis ddI,d4T,ddC
gastro-intestinal:pancreatitis ddI, d4T
hematological:pancytopenias ZDV
nephrological:prox. renal tubular dysfunction adefovir
metaboliclipodystrophy d4T
Mitochondrial dysfunction due to NRTIs
Energy production in mitochondriaglucose
pyruvate + NADH
FFA triglycerides
Acetyl CoATCAcycleNADH
CO2 + H2O
NAD+
ketone bodiesNAD+
Resp chain
cytosol
mitochondrion
Lactic acidosisglucose
pyruvate + NADH lactate + NAD+
FFA triglycerides
Acetyl CoATCAcycleNADH
CO2 + H2O
NAD+
ketone bodiesNAD+
Resp chain
cytosol
mitochondrion
From Hyperlactatemia to Acidosis
Source: Medscape
NRTI-based liver toxicity:Clinical presentation
Non-specific symptoms– Abdominal pain, vomiting, anorexia, pain (right
upper quadrant), weight loss
Hepatomegaly
Mixed cholestatic/hepatocellular pattern of liver enzymes
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
US FDA Reporting System of HIV/HCV patients treated with IFN/RBV
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)
Fleischer R, et al. Clin Infect Dis 2004;38:e79-e80
DidanosineDidanosine
Didanosine +Didanosine +stavudinestavudine
StavudineStavudine
AbacavirAbacavir
LamivudineLamivudine
ZidovudineZidovudine0.01 0.1 1.0 10 1000.01 0.1 1.0 10 100
Odds Ratio (95% CI)Odds Ratio (95% CI)
RBV +RBV +
Mitochondrial ToxicityMitochondrial ToxicityRiskRisk
12.412.4
8.08.0
3.33.3
1.11.1
0.20.2
0.060.06
ROS
MITOCYPs
Fat deposits
Lipid peroxidation
Interactions between Mito and CYPs 450
Mitochondrial disfunction
ROS
TNF- α
Depletion of antioxidans
FAT
LipidPeroxidation
Vicious cycles involving ROS and Mitochondria
1
23
4
ROS
From ROS to steatohepatitis fibrosis
Lipid peroxidation productsCytokines
(IL-2, IFN-γ ,TNF-α, TGF-β, PDGF)
Kupffer cellKupffer cell
ActivationActivation
FIBROSISFIBROSIS
Cell killing
ApoptosiApoptosiss
Hepatocytes
TGFTGF--ββ
Hepatic stellate cellsHepatic stellate cells
Some ARV Pharmacogenetic Variants Abacavir HSR (HLA-B*5701)white > blackEfavirenz PK (CYP2B6) black > whiteNevirapine LFTs (ABCB1) black > whiteAtazanavir jaundice (UGT) white > blackAtazanavir PK (PXR?) white > blackNelfinavir (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.
Drug Phenotype GeneAbacavir Hypersensitivity HLA-B*5701Lancet 2002:359,727 & 1121; PNAS 2004:101,4180
Indinavir Jaundice UGT-1A1Atazanavir PNAS 2001:98,12671; ICAAC 2002; JID 2005;192,1381
NRTI Lipoatrophy TNF-α promoter, HFEAIDS 2002:16,2013; AIDS 2003:17,121; JID 2008:197, 858
Nevirapine Hypersensitivity HLA-DRB1*0101, -Cw8, -B3505Hepatotoxicity ABCB1Pharmacokinetics CYP2B6
AIDS 2005:19,97; Pharmacogenet Genom 2005;15,1; Clin Inf Dis 2006;43,779 & 783; AIDS 2006:20,1621; AIDS2007;21,264; Pharmacogenet Genom 2009;19,139
Associations Between Allelic Variants and HIV Treatment Response
From DH Haas, MD, at San Francisco, CA: April 20, 2009, IAS–USA.
Drug Phenotype GeneEfavirenz CNS effects, Pharmacokinetics CYP2B6
Viral response, Resistance ABCB1, CYP2A6Lancet 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
Nelfinavir Viral response, Pharmacokinetics CYP2C19JID 2005;192:1931
PIs Dyslipidemia APOC, RETNJID 2005;191:1419; PLoS Med 2006;3:e52; AIDS 2008;22:1561.
NRTIs Peripheral neuropathy Mitochondrial AIDS 2005;19:1341, AIDS 2006;20:1503 haplogroup T,
HFEHAART CD4 recovery Proliferation & JID 2006;194:1098 apoptosis
Genetic Associations (continued) Slide 28
From DH Haas, MD, at San Francisco, CA: April 20, 2009, IAS–USA.
Drug Phenotype GeneTenofovir Renal toxicity MRP2 (ABCC2)JID 2006;94:1481
Others…
?
?
?
?
?
?
?
Genetic Associations (continued) Slide 29
From DH Haas, MD, at San Francisco, CA: April 20, 2009, IAS–USA.
Approved Studies with ACTG Human DNA from US (A5128)
Project PapersNWCS 213 – efavirenz, nelfinavir PK & response ◄ 2NWCS 214 – efavirenz CNS toxicity and PK ◄ 2NWCS 215 – T cell turnover rates ◄ 1NWCS 224 – metabolic complications 1NWCS 233 – CD4 increase on ART ◄ 1NWCS 237 – metabolic complications *NWCS 238 – peripheral neuropathy ◄ 3NWCS 239 – efavirenz resistance after Rx interruption ◄ 1NWCS 243 – HLA and viral evolution *NWCS 248 – efavirenz & lopinavir PK 1NWCS 253 – efavirenz response ◄NWCS 254 – efavirenz response ◄NWCS 256 – peripheral neuropathy ◄NWCS 259 – metabolic complications NWCS 262 – innate immunity and responses to ARTNWCS 266 – treatment responses to ARTNWCS 268 – efavirenz PK ◄NWCS 273 – peripheral neuropathy ◄NWCS 275 – pharmacogenomics of HIV therapy ◄NWCS 279 – immune controlNWCS 280 – lipoatrophy ◄NWCS 291 – tenofovir renal toxicity ◄
DNA banked on >10,000 individuals
Slide 30
From DH Haas, MD, at San Francisco, CA: April 20, 2009, IAS–USA.
Abacavir hypersensitivity
&HLA-B*5701
Slide 31
From DH Haas, MD, at San Francisco, CA: April 20, 2009, IAS–USA.
Nolan et al J HIV Ther 2003;8:36
INDIA 5-20%
JAPAN 0%
CHINA 0%(NB 2.5% N.E. provinces)
UK ~8%
MIDDLE EAST 1-2% (NB 5-7% Ashkenazi Jews)
AUSTRALIA ~8%
US Caucasian
~8%US Asian
~1%
US African-
American ~2.5%
W. EUROPE 5-7%
THAILAND 4-10%*
*THAILAND B*57 carriage:Urban Bangkok 3.6%
Thai Dai Lue (NE Thai) ~11%Southern Thai Muslim 3%
MEDITERRANEAN 1-2%
S. AMERICAN Caucasian
5-7%
US Hispanic
~2%
Subsaharan AFRICA
<1%
Slide 32FrequencyFrequency of of HLAHLA--B*5701B*5701
From DH Haas, MD, at San Francisco, CA: April 20, 2009, IAS–USA.
• 6-Week Observation Period
ABC-naïve subjects ABC-containing regimen
HSR monitoring according toStandard of Care
plus HLA-B*5701 screening2
(screening arm)
ABC-containing regimen HSR monitoring according to
Standard of Care1
(control arm)
Randomise (1:1) HLA-B*5701positive
subjects excluded
HLA-B*5701 negative subjects
continued
1. retrospective high resolution typing2. prospective high resolution typing Mallal et al; NEJM 2008.
“PREDICT” Double-Blind Study Design
HSRNo HSR
Pos Neg
Immunologically Confirmed HSR1
HLA-B*5701
23 025 794
Pos PV
48%
Neg PV
100%
Sens 100%Spec 97%
Clinically Suspected HSR1
HLA-B*5701
Pos Neg
30 3619 762
Pos PV Neg PV
62% 96%
Sens 46%Spec 98%
1 Control Arm Data Only Mallal et al; NEJM 2008
Performance Characteristics ofHLA-B*5701 Screening for HSR
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
should not be prescribed abacavir…, positive status should be recorded as an abacavir allergy in the patient’s medical record….”
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
Liver-related morbidity and mortality are assuming an increasing importance in HIV care
Each class of antiretroviral agents may be associated with hepatic toxicity
Viral hepatitis co-infection increases the risk of drug-induced liver injury; all co-infected patients must be monitored carefully
Data suggest that treatment of HIV slows progression of fibrosis and reduces liver-related mortality