Antitubercular agents in TB patients with Chronic Liver disease (CLD). Brief review on how to initiate and maintan ATT IN CLD patients.

1. Using Antitubercular drugs for
Tuberculosis in patients with
Chronic Liver diseases
Pratap Sagar Tiwari, MD (Internal Medicine)
DM HEPATOLOGY, BIR HOSPITAL, NAMS, NEPAL

2. Introduction
• It is quite evident that more than 90 percent of tuberculosis are reactivation of
their latent form that usually present in patients with some level of
immunodeficient or immunosuppressed state.
• So, Cirrhosis being itself an immunodeficient state[1], it would be aggreable to
state that prevalence of tuberculosis is much higher in cirrhotic population when
compared to normal population.
• A study conducted in Western India showed that the prevalence rate was 15
times higher than in the general population[2].
• Another study from India showed that there is nearly five times higher
prevalence of TB in cirrhosis patients (8.1%) compared to the general population
(1.6%), with pulmonary TB being the commonest form[3].
1. Cho YJ, Lee SM, Yoo CG, Kim YW, Han SK, Shim YS, Yim JJ. Clinical characteristics of tuberculosis in patients with liver cirrhosis. Respirology. 2007;12:401–405.
2. Saigal S, Nandeesh HP, Agarwal SR, Misra A, Jain SK, Sarin SK. High prevalence and profile of tuberculosis in chronic liver disease patients. Gastroenterology. 1998;114:A38.
3. Baijal R, Praveenkumar HR, Amarapurkar DN, Nagaraj K, Jain M. Prevalence of tuberculosis in patients with cirrhosis of liver in western India. Trop Doct. 2010;40:163–164.

3. Drug induced hepatotoxicity: ATT
• Anti-TB chemotherapy containing isoniazid (H), rifampicin (R) and
pyrazinamide (Z) has proved to be highly effective but hepatotoxic and the
risk further increases when these drugs are combined.
• The development of DIH during chemotherapy for TB is one of the most
common reason leading to interruption of therapy.
• Wide variations have been found in the incidence of hepatotoxic reactions
from different countries, with the reported incidence being 3 % in the
USA[1], 4 % in the UK[1], 11 % in Germany[2], 13 % in HK[3], 36 % in
Japan[4], 26 % in Taiwan[4] and 8-36 % in India[5,6].
1. Ormerod LP, Skinner C, Wales J. Hepatotoxicity of antituberculosis drugs. Thorax 1996; 51 : 111-3.
2. Garg PK, Tandon RK. Antituberculosis treatment induced hepatotoxicity. In: Sharma SK, Mohan A, editors. Tuberculosis 2nd ed. New Delhi: Jaypee Brothers Medical Publishers;
2009.p. 783-95.
3. Lauterburg BH, Smith CV, Todd EL, Mitchell JR. Pharmacokinetics of the toxic hydrazino metabolites formed from isoniazid in humans. J Pharmacol Exp Ther 1985; 235 : 566-70.
4. Ellard GA, Mitchison DA, Girling DJ, Nunn AJ, Fox W. The hepatic toxicity of isoniazid among rapid and slow acetylators of the drug. Am Rev Respir Dis 1978; 118 : 628-9.
5. Parthasarthy R, Sarma GR, Janardhanam B, Ramachandran P, Santha T, Sivasubramania S, et al. Hepatic toxicity in south Indian patients during treatment of tuberculosis with short-
course regimens containing isoniazid, rifampicin and pyrazinamide. Tubercle 1986; 67 : 99-108.
6. Mehta S. Malnutrition and drugs: clinical implications. Dev Pharmacol Ther 1990; 15 : 159-65.

4. Risk Factors
• Why only some pts who receive anti-TB drugs develop hepatitis is not clear. Even
from the incidence datas, it can be derived that hepatotoxicity occurs more in
patients of Asian origin, so ethnicity and environment seems to play a role aswell.
• Several studies have searched for host factors, or genetic factors such as HLA
typing[1], cytochrome P450 2E1[2] or acetylator status[3].
RISK FACTORS
Advance age[4-10] Women [4,6,12,13] Extrapulmonary TB [10,11]
Greater disease severity on chest radiograph [10,14].
Poor nutritional status [9,10,15,16]. PEM[17], MAC < 20 cm and hypoalbuminaemia [10]
References are at the end of the slides
Now it is noteworthy to state that patients with cirrhosis already have some of these risk factors like advanced age, poor
nutritional status and hypoalbuminemia.

5. Studies on hepatotoxicity of ATT drugs in
combination therapy
References are at the end of the slides

6. Studies on hepatotoxicity of ATT drugs in
combination therapy
References are at the end of the slides

7. Risk Factors
• Treating a tuberculosis with drugs among which many are hepatotoxic, in
CLD patients who are already in immunodeficient state and moreover have
these risk factors poses a great challenge.
• Treatment of TB in decompensated cirrhosis is challenging because
treatment is a double-edged sword. Treatment may lead to hepatotoxicity
and progressive TB may lead to liver decompensation.
• However the real picture is not scary as I have just explained. Anti-
tubercular drugs can be safely used in these patients with CLD when some
appropriate measures are applied.

8. Principle of Safe ATT Therapy in CLD
1. Monitoring
2. Modification

9. Monitoring
• LFT should be carried out before initiating ATT, for baseline levels[1] as it has
been seen that pts with abnormal baseline ATs levels are at ↑ risk of
developing hepatic injury eventually.[2]
• These should be repeated twice weekly for the first 2 wks followed by wkly
monitoring till the end of 2 months and then monthly till the end of the RX.[3]
• If the serum AT is >3 X normal before the initiation of treatment,[4] the
modified regimens should be considered.
1. American Thoracic Society and Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med.
2000;161:S221–47.
2. Teleman MD, Chee CB, Earnest A , Wang YT . Hepatotoxicity of tuberculosis chemotherapy under general programme conditions in Singapore. Int J Tuberc Lung Dis.2002;6:699–705.
3. Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med.
2006;174:935–52.
1 Note that TB itself may involve the liver and cause abnormal liver function.

10. Modification:
• Two hepatotoxic drugs REGIME:
— 9 HRE
— 2 HRSE + 6 HR
— 6–9 ZRE
• One hepatotoxic drug REGIME:
— 2 SHE + 10 HE
• No hepatotoxic drugs REGIME:
— 18–24 SEO.
WHO 4th ed: TB treatment Guideline
Regimes without pyrazinamide (Z)
Regime without isoniazid (H)
2 HRE + 7 HR
1. American thoracic society, CDC, infectious disease society of America. Treatment of
tuberculosis. Morbidity and mortality weekly report: recommendations and
reports.2003;52(RR-11):1–77.
[1]
Most preferred regime
Most preferred regime

11. Modification:
1. Sonika U. Tuberculosis and liver disease: management issues. Tropical Gastroenterology 2012;33(2):102–106
However, in some situations like early CLD, the patient will obviously fall under CLASS A despite relatively
preserved function, so in such situations,it isn’t necessary to stick to CPA OR B, First line drugs HRZE can be
initiated with close monitoring. Moreover at times, it is better to deal case by case basis. For eg Though
Pyrazinamide is a weak bactericidal but its stong sterilizing properties may prove to be beneficial while
treating tb.

12. A study on hepatotoxic drug regime containing Z
• The regime containing H+Z+E+O for 2 months followed by H+E+O for 10 months
was found to be less hepatotoxic and better tolerated than rifampicin containing
regimes.[1]
• 26.6% pts on regimen (2 HRE + 7 HR ) developed hepatotoxicity as compared to
none on regimen B (2 HZEO + 10 HEO )(P = 0.043).[1] [N=31]
• Hepatotoxicity was diagnosed if ALT increased > 5X from the baseline or to > 400 IU/L, or if bilirubin increased by > 2.5
mg/dL from the baseline.
1. Saigal S, Agarwal SR, Nandeesh HP, Sarin SK. Safety of an ofloxacin-based antitubercular regimen for the treatment of
tubrculosis in patients with underlying chronic liver disease: a preliminary report. J Gastroenterol Hepatol.
2001;16:1028–32.
2 HZEO + 10 HEO

13. • The American Thoracic Society (ATS) guidelines advise the use of E+O+ cycloserine
+ capreomycin or aminoglycoside for 18-24 mo if the patient has liver cirrhosis
with encephalopathy[1].
Proposed regimens are: [2]
(1) REO ± Aminoglycoside for 9-12 mo
(2) HEO ± Aminoglycoside for 9-12 mo
(3) EO ± Aminoglycoside for 12-24 mo.
Note: Role of aminoglycosides may be limited due to ↓ renal reserve in these pts.
The role of streptomycin is slowly being eliminated and it is also not included in
proposed regime for future (see next slide).
1. American Thoracic Society. CDC; Infectious Diseases Society of America. Treatment of tuberculosis. MMWR
Recomm Rep. 2003;52:1–77.

14. Summary of the existing classifications of anti-tuberculosis drugs (1
and 2) and possible future evolutions based on recent evidence (3)

15. Summary of the existing classifications of anti-tuberculosis drugs (1
and 2) and possible future evolutions based on recent evidence (3)
Jose A. Caminero, Anna Scardigli. Classification of antituberculosis drugs: a new proposal based on the most recent
evidence.European Respiratory Journal 2015 46: 887-893

16. Summary of the existing classifications of anti-tuberculosis drugs (1
and 2) and possible future evolutions based on recent evidence (3)

17. Definition of hepatotoxicity
• The definition of hepatotoxicity in pts with liver diseases is controversial,
because of difficulty in defining the influence of the natural evolution of
the underlying liver disease.
• There is a need to define better the level of AST/ALT and serum bilirubin
at which to consider hepatotoxicity to avoid unnecessary treatment
withdrawal and to avoid dangerous continuation of antitubercular
therapy when hepatotoxicity has set in.
• Although it is generally recommended that therapy be interrupted when AT
levels ↑ to 3-5 X ULN, this limit has not been defined in pts with AT values
already elevated before starting therapy[1].
1. Lew W, Pai M, Oxlade O, Martin D, Menzies D. Initial drug resistance and tuberculosis treatment outcomes: systematic review and meta-analysis. Ann Intern Med 2008; 149: 123-
134

18. Definition of hepatotoxicity
• Schenker et al[1] reported that elevations in the ALT and/or AST levels to
50-100 IU/L more than the baseline levels might define toxicity.
• In a study by Saigal et al[2], hepatotoxicity was diagnosed if ALT/AST levels
↑ to >5X of the baseline level, or >400 IU/L, or if the bilirubin ↑ by 2.5
mg/dL after exclusion of superimposed acute hepatitis.
1. Schenker S, Martin RR, Hoyumpa AM. Antecedent liver disease and drug toxicity. J Hepatol 1999; 31: 1098-1105
2. Saigal S, Agarwal SR, Nandeesh HP, Sarin SK. Safety of an ofloxacin-based antitubercular regimen for the treatment of tuberculosis in patients with underlying chronic liver
disease: a preliminary report. J Gastroenterol Hepatol 2001; 16: 1028-1032

19. • All confounding factors like superimposed acute viral hepatitis and
recidivism towards alcohol should be investigated.
• Usually, transaminase elevation falls back to baseline after stopping the
drugs.
• When the initial antitubercular regimen has been interrupted due to
hepatotoxicity, it is reasonable to go either of the 2 ways a: modified
regime or b: reintroduction one at a time (BTS/ATS)
1. Schenker S, Martin RR, Hoyumpa AM. Antecedent liver disease and drug toxicity. J Hepatol 1999; 31: 1098-1105
2. Saigal S, Agarwal SR, Nandeesh HP, Sarin SK. Safety of an ofloxacin-based antitubercular regimen for the treatment of tuberculosis in patients with underlying chronic liver
disease: a preliminary report. J Gastroenterol Hepatol 2001; 16: 1028-1032

20. ATDT ESTABLISHED
Stoppage of all
hepatotoxic drugs
Continue 2-3 non
hepatotoxic drug
Wait for AST/ALT
and Bilirubin to
return to baseline
or < 2ULN
Complete full ATT
Stop temporary
drugs
Similarly introduce
Isoniazid if
required
Start/Continue 2-3
non hepatotoxic
drug
Increase by 150 mg
every 7-14 d till
full dose (450
mg/d)
Restart with 150
mg/d rifampicin
Development of nausea, vomiting,
abdominal pain, jaundice
LFT every 3-7 d
Rifampicin
tolerated

21. • If a second episode of ATDT occurs after full institution of antitubercular
therapy, all hepatotoxic drugs should be stopped and extended duration
antitubercular therapy with no potentially hepatotoxic drugs should be
provided OR the last drug added should be stopped.
• One advise is to start with R because it is less likely than H or Z to cause
hepatotoxicity and is the most effective agent [1,2].
• In pts who have experienced jaundice but tolerate the reintroduction of R
and H, it is advisable to avoid Z.
1. American Thoracic Society, CDC, Infectious Diseases Society of America. Treatment 7. of tuberculosis. Morbidity and Mortality Weekly Report: Recommendations and Reports,
2003,52(RR-11):1–77.
2. Saukkonen JJ et al. An official ATS statement: hepatotoxicity of antituberculosis 8. therapy. American Journal of Respiratory and Critical Care Medicine, 2006, 174:935–952.

22. Prevention of ATDH
• N-Acetyl cysteine (NAC) has been shown in one study to prevent ATT-induced
hepatotoxicity[1].
• In that RCT, 60 new TB pts aged ≥ 60 years were randomized into two groups. In
Group Ⅰ (n = 32), the drug regimen included daily doses of HRZE. Pts in Group Ⅱ
(n = 28) were treated with the same regimen and NAC.
• The mean values of AT were significantly higher in group Ⅰ than in group Ⅱ
(with NAC) after 1 and 2 wk of treatment[1]. Hepatotoxicity occurred in 12 pts with
(37.5%) group I and none in group II.
• This study proved that NAC protects against antitubercular-drug-induced
hepatotoxicity.
• A hepatoprotective effect of silymarin on ATDH has been shown in rats[2].
1. Baniasadi S, Eftekhari P, Tabarsi P, Fahimi F, Raoufy MR, Masjedi MR, Velayati AA. Protective effect of N-acetylcysteine on antituberculosis drug-induced hepatotoxicity. Eur J
Gastroenterol Hepatol 2010; 22: 1235-1238
2. Tasduq SA, Peerzada K, Koul S, Bhat R, Johri RK. Biochemical manifestations of anti-tuberculosis drugs induced hepatotoxicity and the effect of silymarin. Hepatol Res 2005; 31:132-
135

23. END OF SLIDES

24. References to slide: Studies on hepatotoxicity
61. Døssing M, Wilcke JT, Askgaard DS, Nybo B. Liver injury during antituberculosis treatment: an 11-year study. Tuber Lung Dis. 1996;77:335–340.
62. Ormerod LP, Horsfield N. Frequency and type of reactions to antituberculosis drugs: observations in routine treatment. Tuber Lung Dis. 1996;77:37–42.
63. Tost JR, Vidal R, Caylà J, Díaz-Cabanela D, Jiménez A, Broquetas JM. Severe hepatotoxicity due to anti-tuberculosis drugs in Spain. Int J Tuberc Lung Dis. 2005;9:534–540.
64. van Hest R, Baars H, Kik S, van Gerven P, Trompenaars MC, Kalisvaart N, Keizer S, Borgdorff M, Mensen M, Cobelens F. Hepatotoxicity of rifampin-pyrazinamide and isoniazid preventive therapy and tuberculosis treatment. Clin Infect Dis.
2004;39:488–496.
65. Teleman MD, Chee CB, Earnest A, Wang YT. Hepatotoxicity of tuberculosis chemotherapy under general programme conditions in Singapore. Int J Tuberc Lung Dis. 2002;6:699–705.
66. Fernández-Villar A, Sopeña B, Fernández-Villar J, Vázquez-Gallardo R, Ulloa F, Leiro V, Mosteiro M, Piñeiro L. The influence of risk factors on the severity of anti-tuberculosis drug-induced hepatotoxicity. Int J Tuberc Lung Dis. 2004;8:1499–1505.
67. Pukenyte E, Lescure FX, Rey D, Rabaud C, Hoen B, Chavanet P, Laiskonis AP, Schmit JL, May T, Mouton Y, et al. Incidence of and risk factors for severe liver toxicity in HIV-infected patients on anti-tuberculosis treatment. Int J Tuberc Lung Dis.
2007;11:78–84.
68. Schaberg T, Rebhan K, Lode H. Risk factors for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis. Eur Respir J. 1996;9:2026–2030.
69. Saigal S, Agarwal SR, Nandeesh HP, Sarin SK. Safety of an ofloxacin-based antitubercular regimen for the treatment of tuberculosis in patients with underlying chronic liver disease: a preliminary report. J Gastroenterol Hepatol. 2001;16:1028–
1032.
70. Breen RA, Miller RF, Gorsuch T, Smith CJ, Schwenk A, Holmes W, Ballinger J, Swaden L, Johnson MA, Cropley I, et al. Adverse events and treatment interruption in tuberculosis patients with and without HIV co-infection. Thorax. 2006;61:791–794.
71. Huang YS, Chern HD, Su WJ, Wu JC, Chang SC, Chiang CH, Chang FY, Lee SD. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology. 2003;37:924–930.
72. Sharma SK, Balamurugan A, Saha PK, Pandey RM, Mehra NK. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med. 2002;166:916–919.
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75. Pande JN, Singh SP, Khilnani GC, Khilnani S, Tandon RK. Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study. Thorax. 1996;51:132–136.
48. Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med. 2003;167:1472–1477.
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25. References to slide: RISK FACTORS
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Respir Crit Care Med 2002; 166 : 916-9.
2. Singh J, Arora A, Garg PK, Thakur VS, Pande JN, Tandon RK. Antituberculosis treatment-induced hepatotoxicity: role of predictive factors. Postgrad Med J 1995; 71 : 359-62
3. Garg PK, Tandon RK. Antituberculosis treatment induced hepatotoxicity. In: Sharma SK, Mohan A, editors. Tuberculosis 2nd ed. New Delhi: Jaypee Brothers Medical Publishers; 2009.p. 783-95.
4. Ormerod LP, Horsfield N. Frequency and type of reactions to antituberculosis drugs: observations in routine treatment. Tuber Lung Dis 1996; 77 : 37-42.
5. Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir
Crit Care Med 2003; 167 : 1472-7.
6. Dossing M, Wilcke JT, Askgaard DS, Nybo B. Liver injury during antituberculosis treatment: an 11-year study. Tuber Lung Dis 1996; 77 : 335-40.
7. Teleman MD, Chee CB, Earnest A, Wang YT. Hepatotoxicity of tuberculosis chemotherapy under general programme conditions in Singapore. Int J Tuberc Lung Dis 2002; 6 : 699-705.
8. Hwang SJ, Wu JC, Lee CN, Yen FS, Lu CL, Lin TP, et al. A prospective clinical study of isoniazid-rifampicinpyrazinamide-induced liver injury in an area endemic for hepatitis B. J Gastroenterol
Hepatol 1997; 12 : 87-91.
9. Ohkawa K, Hashiguchi M, Ohno K, Kiuchi C, Takahashi S, Kondo S, et al. Risk factors for antituberculous chemotherapyinduced hepatotoxicity in Japanese pediatric patients. Clin Pharmacol Ther
2002; 72 : 220-6.
10. Singla R. Evaluation of risk factors for antituberculosis treatment induced hepatotoxicity. Indian J Med Res 132, July 2010, pp 81-86
11. Anand AC, Seth AK, Paul M, Puri P. Risk factors of hepatotoxicity during anti-tuberculosis treatment. MJAFI 2006; 62 : 45-9.
12. [No authors listed]. Controlled clinical trial comparing a 6-month and a 12-month regimen in the treatment of pulmonary tuberculosis in the Algerian Sahara Algerian Working Group/British
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14. Pande JN, Singh SP, Khilnani GC, Khilnani S, Tandon RK. Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study. Thorax 1996; 51 : 132-6.
15. Singh J, Garg PK, Tandon RK. Hepatotoxicity due to antituberculosis therapy: clinical profile and reintroduction of therapy. J Clin Gastroenterol 1996; 22 : 211-4.
16. Krishnaswamy K, Prasad CE, Murthy KJ. Hepatic dysfunction in undernourished patients receiving isoniazid and rifampicin. Trop Geogr Med 1991; 43 : 156-60.
17. Buchanan N, Eyberg C, David MD. Isoniazid pharmacokinetics in kwashiorkor. S Afr Med J 1979; 56 : 299-300.