Adverse reactions to antituberculosis agents

1. Boonthorn 14 Aug 2009

5. Epidemiology Tubercle and Lung Disease

6. Tubercle and Lung Disease

7. Most common in first 9 weeks Largely due to PZA Majority within 4 weeks Tubercle and Lung Disease

8. MJAFI 2006; 62 : 45-49 chronic HBV infection on ATT (9/24, 37.5%) patients given ATT who had no evidence of HBV infection (13/128,10.2%)

9. Pak J Med Sci January - March 2007 Vol. 23 No. 1 33-38

10. Risk Factors of Antituberculosis Drugs-Induced Hepatotoxicity in Thai patient S. Krittiyanunt et al./Thai J. Pharm. Sci. 26 (3-4): 121-128 (2002) retrospective-analytical research , collected between 1998 and 2000

11. S. Krittiyanunt et al./Thai J. Pharm. Sci. 26 (3-4): 121-128 (2002)

12. Studied MHC class II alleles and clinical risk factors for the development of hepatotoxicity in 346 North Indian pts. with TB. 56 patients developed drug-induced hepatotoxicity (DIH group), whereas the remaining 290 patients did not (non-DIH group). Sharma, Balamurugan, Saha, et al. : Hepatotoxicity and Antituberculosis Chemotherapy

13. Breen, Miller, Gorsuch, et al

14. International Union Against Tuberculosis and Lung Disease 2003

16. . 5. Treatment with other drugs. cytochrome P450 has been frequently associated with production of hepatotoxic reactive metabolites 6. Disseminated or advanced TB. consequence of malnutrition or liver deterioration attributable to the disease itself. 7. Patients previously subjected to antituberculous therapy. increased risk of damage attributable to rifampicin, which in turn is associated with hypersensitivity reactions that lead to the release of immune complexes. 8. Atopy. linked to the existence of other cases of adverse anti-TB drug reactions in family members; thus, the clinical history of the patient should be carefully evaluated before treatment is started. 9. Sex. Women are at a comparatively greater risk of developing druginduced liver reactions. 10. HIV infection. risk of such reactions increases with the degree of host immunosuppression. International Union Against Tuberculosis and Lung Disease 2003

17. Principle of drug metabolism HEPATOLOGY, Vol. 37, No. 4, 2003 Journal compilation © 2006 Asian Pacific Society of Respirology

24. Mechanisms of Drug-Induced Liver Injury The AAPS Journal 2006; 8 (1) Article 6

26. W.J. Pichler / Immunol Allergy Clin N Am 24 (2004) 373–397

27. W.J. Pichler / Immunol Allergy Clin N Am 24 (2004) 373–397 p-i concept

29. Liver Immunology:Principles and Practice model of the immune mechanisms of idiosyncratic DILI

32. Clin Liver Dis 10 (2006) 207–217

36. Recommendations for the use of ATT in cirrhosis Meta analysis Incidence of clinical hepatitis : INH (0.6%),INH wihtout R (1.6%),rifam without INH (1.1%),INH with rifam (2.5%) British study :INH (0.3%),Rifam (1.4%),PZA (1.25%) Hepatitis per mo. :PZA>Rifam (3 times),>INH (5 times) A meta-analysis. Chest 1991;99:465–71. Thorax 1994;45:403–8.

38. Lymphocytic Transformation test

39. DETECTION OF HYPERSENSITIVITY TO DRUGS BY LYMPHOCYTE CULTURES IN DRUG-INDUCED ALLERGIC HEPATITIS antituberculosis drugs (streptomycin: 7,INH: 5, PAS: 3, ethionamide :2, rifampicin: 1) Positive responses : 15 cases ( MI test ) and 49 cases ( lymphocyte transformation ) Clinical symptoms : cutaneous eruption (60%), fever (69 %) itching (73%),eosinophilia (50%) were seen in more than half of the patients . Gastroenterologia Japonica Vol. 10, No. 4.--1975--

40. Gastroenterologia Japonica Vol. 10, No. 4.--1975--

41. Lymphocyte transformation studies in drug hypersensitivity CMA JOURNAL/MAY 5, 1979/VOL. 120 8 pts. with INH -induced hepatitis, liver biopsy ( negative for H B sAg ) and rapid resolution of jaundice , abnormal LFT upon withdrawal of the drug 3 patients with MP rashes following INH therapy were assessed by LTT with INH . Substantial lymphocyte stimulation was demonstrated for 9/11 patients 19 control subjects - 8 pts(INH without adverse effects ), 6 healthy individuals and 5 patients who had recently discontinued isoniazid .

42. Diagnostic value of specific T cell reactivity to drugs in 95 cases of drug induced liver injury Gut 1997; 41: 534–540

43. Gut 1997; 41: 534–540 25(26%) 53(56%) clinical markers (rash,arthralgia,eosinophilia) absent about 70% pts. with demonstrable T cell reactivity to drugs challenges

46. Patch test