1. Hepatotoxicity of Antituberculosis Therapy Department of Pulmonary & Critical Care Medicine R3 Yang BH

2. An Official ATS Statement 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 Program Infrastructure Provider Education and Resources Pretreatment Clinical Evaluation Patient Education Medication Administration and Pharmacy Treatment of LTBI Treatment of TB Disease Conclusions

3. Introduction Drug-induced liver injury (DILI) Drug-induced liver injury (DILI) Liver : Drug metabolism & Detoxification Liver : Drug metabolism & Detoxification From hepatic adaptation to hepatocellular injury From hepatic adaptation to hepatocellular injury Incomplete knowledge Incomplete knowledge Metabolism of anti-TB medication Metabolism of anti-TB medication Mechanism of TB DILI Mechanism of TB DILI Available data regarding the incidence & severity of TB DILI → prevention & management recommendation 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 Priorities for future study to develop safer treatments for LTBI and TB disease

4. Methods Multidisciplinary symposium on Nov. 13-14, 2002 Multidisciplinary symposium on Nov. 13-14, 2002 Specialist in TB Specialist in TB Pharmacology Pharmacology Hepatology Hepatology PubMed searches PubMed searches TB TB Treatment Treatment Hepatitis Hepatitis Liver injury Liver injury Hepatotoxicity Hepatotoxicity Adverse events Adverse events Latent Latent Infection Infection

5. THE LIVER: STRUCTURE AND FUNCTION Between the alimentary tract and the systemic circulation → to maximize processing of absorbed nutrients → to minimize exposure to toxins, foreign chemicals Hepatic drug metabolism: transporters, enzymes, excretion Hepatic drug metabolism: transporters, enzymes, excretion “First pass phenomenon” “First pass phenomenon” Phase 1 pathway : oxidation, reduction, hydrolysis by cytochrome P450 class of enzyme Phase 1 pathway : oxidation, reduction, hydrolysis by cytochrome P450 class of enzyme Phase 2 pathway : glucuronidation, sulation, acetylation, glutathione conjugation Phase 2 pathway : glucuronidation, sulation, acetylation, glutathione conjugation Phase 3 pathway : excretion into bile or the systemic circulation by celluar transporter protein Phase 3 pathway : excretion into bile or the systemic circulation by celluar transporter protein

6. DILI : General concepts

7. Definition : clinical diagnosis of exclusion Definition : clinical diagnosis of exclusion Histologic specimen Histologic specimen Other causes such as acute viral hepatitis Other causes such as acute viral hepatitis Rechallenge Rechallenge Dimension of the problem Dimension of the problem 7 % of reported drug adverse effects 7 % of reported drug adverse effects 2 % of jaundice in hospitals 2 % of jaundice in hospitals 30 % of fulminant liver failure 30 % of fulminant liver failure > 700 drugs with hepatotoxicity in United States > 700 drugs with hepatotoxicity in United States Pathogenesis Pathogenesis Direct toxicity of the primary compound, a metabolite Direct toxicity of the primary compound, a metabolite Immunological mediated response Immunological mediated response

8. Hepatic enzyme measurement Hepatic enzyme measurement ALT is more specific. ALT is more specific. AST also signify abnormality in m., heart, or kidney. AST also signify abnormality in m., heart, or kidney. Normal range within 2 SD from healthy populations Normal range within 2 SD from healthy populations Variation as much as 45 % on a single day Variation as much as 45 % on a single day Elevation after exercise, hemolysis, muscle injury Elevation after exercise, hemolysis, muscle injury Higher conc. in men and those with greater BMI Higher conc. in men and those with greater BMI Lower conc. in children and older adults Lower conc. in children and older adults Types of DILI Types of DILI Hepatic adaptation : survival gene→injury→hepatocyte proliferation Hepatic adaptation : survival gene→injury→hepatocyte proliferation Drug-induced acute hepatitis or hepatocellular injury : phenytoin, MTX Drug-induced acute hepatitis or hepatocellular injury : phenytoin, MTX Nonalcoholic fatty liver disease : obesity, ethanol, HAART Nonalcoholic fatty liver disease : obesity, ethanol, HAART Granulomatous hepatitis : allopurinol, quinidine, sulfonamides, RZ Granulomatous hepatitis : allopurinol, quinidine, sulfonamides, RZ Cholestasis Cholestasis Chemical cofactor : ethanol, calcium channel blocker Chemical cofactor : ethanol, calcium channel blocker Preexisting liver disease : HIV, HCV Preexisting liver disease : HIV, HCV

9. DILI DURING TREATMENT OF LTBI

10. Isoniazid (I) Metabolism mostly in liver Metabolism mostly in liver Acetyl-isoniazid by NAT-2 Acetyl-isoniazid by NAT-2 → mono-acetyl hydrazine (MAH) & di-acetyl hydrazine Acetylator status : fast or slow acetylator Acetylator status : fast or slow acetylator Mechanism of injury : reactive metabolites of MAH Mechanism of injury : reactive metabolites of MAH Histopathology Histopathology Non-specific changes resemble those of viral hepatitis with nonzonal necrosis. Non-specific changes resemble those of viral hepatitis with nonzonal necrosis. Drug interaction : phenytoin, carbamazepine↑by Inhibition of cytochrome P450 2E and 2C Drug interaction : phenytoin, carbamazepine↑by Inhibition of cytochrome P450 2E and 2C Hepatic adaptation : up to 20 % Hepatic adaptation : up to 20 % Overall rate of hepatotoxicity 1~4 % Overall rate of hepatotoxicity 1~4 % Timing : within weeks to months Timing : within weeks to months

11. Isoniazid (II) Age : age associated, more severe, highter mortality Age : age associated, more severe, highter mortality Racial difference : Asian male (double risk) > white male Racial difference : Asian male (double risk) > white male Sex : no sex-related difference Sex : no sex-related difference Pregnant women in the 3 rd trimester and in the 1 st 3 months of the postpartum period Pregnant women in the 3 rd trimester and in the 1 st 3 months of the postpartum period Death : women, cirrhosis, older than 35 years Death : women, cirrhosis, older than 35 years Cofactors Cofactors Alcohol Alcohol Concomitant administration of other hepatotoxic drugs Concomitant administration of other hepatotoxic drugs ; acetaminophen, methotrexate, sulfasalazine HIV : same range 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 Hepatitis B and C, elevated baseline transaminases, rifampin, malnutrition, prior INH related hepatotoxicity, continued use of INH while symptomatic as a risk factor

12. Rifampin Mechanism of hepatotoxicity Mechanism of hepatotoxicity Conjugated hyperbilirubinemia by inhibiting the major bile salt exporter pump Conjugated hyperbilirubinemia by inhibiting the major bile salt exporter pump Rare injury byHypersensitivity reaction Rare injury byHypersensitivity reaction Drug interaction : induction of cytochromes Drug interaction : induction of cytochromes warfarin, prednisone, digitoxin, quinidine, ketoconazole, itraconazole, propranolol, clofibrate, sulfonylureas, phenytoin, HIV protease inhibitors, and HIV nonnucleoside reverse transcriptase inhibitors Isoniazid and rifampin Isoniazid and rifampin Intermittent isoniazid & rifampin = daily isoniazid in a canadian study 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 2.25 % in a meta analysis, a higher incidence than in regimens containing one or the other drug

13. Pyrazinamide Metabolism Metabolism T 1/2 :10 hrs → 15 hrs in preexisting hepatic disease T 1/2 :10 hrs → 15 hrs in preexisting hepatic disease Pyrazinamide is de-aminated to pyrazinic acid Pyrazinamide is de-aminated to pyrazinic acid →5-hydroxy pyrazinic acid by xanthine oxidase, aldehyde oxydase, xanthine dehydrogenase Clearance by kidney Clearance by kidney Mechanism of injury Mechanism of injury Dose-dependent hepatotoxicity Dose-dependent hepatotoxicity Idiosyncratic hepatotoxicity Idiosyncratic hepatotoxicity Drug interaction : allopurinol Drug interaction : allopurinol

14. Fluoroquinolones Ciprofloxacin, Moxifloxacin ↔ Levofloxacin, Gatifloxacin Ciprofloxacin, Moxifloxacin ↔ Levofloxacin, Gatifloxacin Reversible transaminase elevation : 2~3 % Reversible transaminase elevation : 2~3 % 0.9 % reported MFXN related liver injury: >1.5 times ULN 0.9 % reported MFXN related liver injury: >1.5 times ULN LFXN : rate of the severe hepatotoxicity < 1 per 1,000,000 LFXN : rate of the severe hepatotoxicity < 1 per 1,000,000 Mechanism : hypersensitivity reaction, eosinophilia Mechanism : hypersensitivity reaction, eosinophilia

15. DILI DURING TREATMENT OF TB DISEASE

16. Age over 35 Age over 35 TB DILI rate as age increased 2 → 8 % TB DILI rate as age increased 2 → 8 % 22 ~ 33 % in >35 years V.S. 8 ~ 17 % in 35 years V.S. 8 ~ 17 % in < 35 years Children < 5 years Children < 5 years Sex : women Sex : women Cofactors : alcohol use Cofactors : alcohol use Abnormal baseline transaminase Abnormal baseline transaminase Acetylator status : slow acetylator Acetylator status : slow acetylator Other factors : malnutrition, hypoalbuminemia, HLA-DQB1 Other factors : malnutrition, hypoalbuminemia, HLA-DQB1 Regimen : rifampin Regimen : rifampin HIV-infected individuals : slight overall influence HIV-infected individuals : slight overall influence Hepatitis B : Increased severity in hepatitis B carrier Hepatitis B : Increased severity in hepatitis B carrier Hepatitis C : independent risk factor Hepatitis C : independent risk factor DILI with second-line Anti-TB agents DILI with second-line Anti-TB agents 2 % in ethionamide, prothionamide 2 % in ethionamide, prothionamide 0.3 % in para-aminosalicylic acid 0.3 % in para-aminosalicylic acid

17. RECOMMENDATIONS REGARDING TB DILI

18. Program Infrastructure 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 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.

19. Pretreatment Clinical Evaluation 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.

20. Patient Education 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.

24. Treatment of Tb disease Rechallenge Rechallenge 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

25. Conclusion Many unanswered questions Many unanswered questions Nascent understanding of the basic mechanism and genetic factors associated with TB DILI Nascent understanding of the basic mechanism and genetic factors associated with TB DILI Identification of those most likely to suffer increased and/or severity of DILI Identification of those most likely to suffer increased and/or severity of DILI In the future, reexamination as new and available data In the future, reexamination as new and available data