Download Hepatotoxicity of Antituberculosis Therapy

Hepatotoxicity of
Antituberculosis Therapy
Department of Pulmonary & Critical Care Medicine
R3 Yang BH
An Official ATS Statement
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Introduction
Methods
The Liver: Structure and Function
Drug-induced Liver Injury: General Concepts
DILI during Treatment of Latent TB Infection
Hepatotoxicity during Treatment of TB Disease
Recommendations regarding TB DILI
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Program Infrastructure
Provider Education and Resources
Pretreatment Clinical Evaluation
Patient Education
Medication Administration and Pharmacy
Treatment of LTBI
Treatment of TB Disease
Conclusions
Introduction
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Drug-induced liver injury (DILI)
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Liver : Drug metabolism & Detoxification
From hepatic adaptation to hepatocellular injury
Incomplete knowledge
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Metabolism of anti-TB medication
Mechanism of TB DILI
Available data regarding the incidence & severity of TB DILI →
prevention & management recommendation
Priorities for future study to develop safer treatments for LTBI and
TB disease
Methods
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Multidisciplinary symposium on Nov. 13-14, 2002
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Specialist in TB
Pharmacology
Hepatology
PubMed searches
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TB
Treatment
Hepatitis
Liver injury
Hepatotoxicity
Adverse events
Latent
Infection
THE LIVER: STRUCTURE AND FUNCTION
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Between the alimentary tract and the systemic circulation
→ to maximize processing of absorbed nutrients
→ to minimize exposure to toxins, foreign chemicals
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Hepatic drug metabolism: transporters, enzymes, excretion
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“First pass phenomenon”
Phase 1 pathway : oxidation, reduction, hydrolysis by cytochrome
P450 class of enzyme
Phase 2 pathway : glucuronidation, sulation, acetylation,
glutathione conjugation
Phase 3 pathway : excretion into bile or the systemic circulation by
celluar transporter protein
DILI : General concepts
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Definition : clinical diagnosis of exclusion
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Histologic specimen
Other causes such as acute viral hepatitis
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Rechallenge
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Dimension of the problem
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7 % of reported drug adverse effects
2 % of jaundice in hospitals
30 % of fulminant liver failure
> 700 drugs with hepatotoxicity in United States
Pathogenesis
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Direct toxicity of the primary compound, a metabolite
Immunological mediated response
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Hepatic enzyme measurement
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ALT is more specific.
AST also signify abnormality in m., heart, or kidney.
Normal range within 2 SD from healthy populations
Variation as much as 45 % on a single day
Elevation after exercise, hemolysis, muscle injury
Higher conc. in men and those with greater BMI
Lower conc. in children and older adults
Types of DILI
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Hepatic adaptation : survival gene→injury→hepatocyte proliferation
Drug-induced acute hepatitis or hepatocellular injury : phenytoin, MTX
Nonalcoholic fatty liver disease : obesity, ethanol, HAART
Granulomatous hepatitis : allopurinol, quinidine, sulfonamides, RZ
Cholestasis
Chemical cofactor : ethanol, calcium channel blocker
Preexisting liver disease : HIV, HCV
DILI DURING TREATMENT OF LTBI
Isoniazid (I)
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Metabolism mostly in liver
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Mechanism of injury : reactive metabolites of MAH
Histopathology
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Acetyl-isoniazid by NAT-2
→ mono-acetyl hydrazine (MAH) & di-acetyl hydrazine
Acetylator status : fast or slow acetylator
Non-specific changes resemble those of viral hepatitis with
nonzonal necrosis.
Drug interaction : phenytoin, carbamazepine↑by
Inhibition of cytochrome P450 2E and 2C
Hepatic adaptation : up to 20 %
Overall rate of hepatotoxicity 1~4 %
Timing : within weeks to months
Isoniazid (II)
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Age : age associated, more severe, highter mortality
Racial difference : Asian male (double risk) > white male
Sex : no sex-related difference
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Death : women, cirrhosis, older than 35 years
Cofactors
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Pregnant women in the 3rd trimester and in the 1st 3 months of
the postpartum period
Alcohol
Concomitant administration of other hepatotoxic drugs
; acetaminophen, methotrexate, sulfasalazine
HIV : same range
Hepatitis B and C, elevated baseline transaminases,
rifampin, malnutrition, prior INH related hepatotoxicity,
continued use of INH while symptomatic as a risk factor
Rifampin
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Mechanism of hepatotoxicity
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Conjugated hyperbilirubinemia by inhibiting the major bile salt exporter
pump
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Rare injury byHypersensitivity reaction
Drug interaction : induction of cytochromes
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warfarin, prednisone, digitoxin, quinidine, ketoconazole,
itraconazole, propranolol, clofibrate, sulfonylureas, phenytoin,
HIV protease inhibitors, and HIV nonnucleoside reverse
transcriptase inhibitors
Isoniazid and rifampin
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Intermittent isoniazid & rifampin = daily isoniazid in a canadian
study
2.25 % in a meta analysis , a higher incidence than in regimens
containing one or the other drug
Pyrazinamide
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Metabolism
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Mechanism of injury
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T1/2 :10 hrs → 15 hrs in preexisting hepatic disease
Pyrazinamide is de-aminated to pyrazinic acid
→5-hydroxy pyrazinic acid by xanthine oxidase, aldehyde oxydase,
xanthine dehydrogenase
Clearance by kidney
Dose-dependent hepatotoxicity
Idiosyncratic hepatotoxicity
Drug interaction : allopurinol
Fluoroquinolones
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Ciprofloxacin, Moxifloxacin ↔ Levofloxacin, Gatifloxacin
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Reversible transaminase elevation : 2~3 %
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0.9 % reported MFXN related liver injury: >1.5 times ULN
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LFXN : rate of the severe hepatotoxicity < 1 per 1,000,000
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Mechanism : hypersensitivity reaction, eosinophilia
DILI DURING TREATMENT OF TB DISEASE
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Age over 35
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TB DILI rate as age increased 2 → 8 %
22 ~ 33 % in >35 years V.S. 8 ~ 17 % in < 35 years
Children < 5 years
Sex : women
Cofactors : alcohol use
Abnormal baseline transaminase
Acetylator status : slow acetylator
Other factors : malnutrition, hypoalbuminemia, HLA-DQB1
Regimen : rifampin
HIV-infected individuals : slight overall influence
Hepatitis B : Increased severity in hepatitis B carrier
Hepatitis C : independent risk factor
DILI with second-line Anti-TB agents
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2 % in ethionamide, prothionamide
0.3 % in para-aminosalicylic acid
RECOMMENDATIONS REGARDING TB DILI
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Program Infrastructure
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Clear and recurring communications with patients in the preferred
language
Accurate medical evaluation, treatment, and monitoring
Convenient access to care and rapid responses to suspected drug
adverse events
Provider Education and Resources
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TB DILI policies and procedures should be included in clinic
manuals and in staff training.
Other health providers should be made aware of TB diagnosis and
treatment, as allowed.
Providers without TB treatment experience or infrastructure should
consider referral to a specialized clinic.
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Pretreatment Clinical Evaluation
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A standardized history form is recommended, which includes risk
factors for hepatotoxicity.
The physical examination should include evaluation for signs of liver
disease, such as liver tenderness, hepatosplenomegaly, jaundice, caput
medusa, spider angiomata, ascites, and edema.
Previous laboratory values should be reviewed when available.
Screening for viral hepatitis should be considered for individuals who
inject drugs; were born in endemic areas of Asia, Africa, the Pacific
Islands, Eastern Europe, or the Amazon Basin; are HIV infected; may
have had sexual or household contact with chronically infected
individuals; may have had occupational exposure to infected blood; are
chronic hemodialysis patients; are recipients of clotting factors before
1987; have undiagnosed liver disease; or arerecipients of blood or solid
organ transplants before 1992. Infants born to infected mothers should
also be considered for screening.
Voluntary HIV counseling and testing are recommended for all patients
with TB disease.
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Patient Education
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Printed instructions should include clinic telephone numbers,
include explicit instructions for after-hours care, and utilize
patient’s preferred language at a readable level.
Patients should be categorically told to immediately stop
medications for nausea, vomiting, abdominal discomfort, or
unexplained fatigue and to contact the clinic for further
evaluation.
Patients should attend clinic follow-up visits for monitoring and
reinforcement of education.
Patients should be warned about concomitant alcohol and
hepatotoxic over-the-counter, and alternative and prescription
medication use.
Patients should inform their health care providers of anti-TB
medications prescribed.
Treatment of Tb disease
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Rechallenge
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After ALT returns to less than two times the ULN, rifampin may be
restarted with or without ethambutol.
After 3 to 7 days, isoniazid may be reintroduced, subsequently
rechecking ALT.
If symptoms recur or ALT increases, the last drug added should be
stopped.
For those who have experienced prolonged or severe hepatotoxicity, but
tolerate reintroduction with rifampin and isoniazid, rechallenge with
pyrazinamide may be hazardous. In this circumstance, pyrazinamide
may be permanently discontinued, with treatment extended to 9 months.
Although pyrazinamide can be reintroduced in some milder cases of
hepatotoxicity (144), the benefit of a shorter treatment course likely
does not outweigh the risk of severe hepatotoxicity from pyrazinamide
rechallenge
Conclusion
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Many unanswered questions
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Nascent understanding of the basic mechanism and
genetic factors associated with TB DILI
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Identification of those most likely to suffer increased
and/or severity of DILI
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In the future, reexamination as new and available data