Antitubercular therapy in patients with cirrhosis: Challenges and options

Table 1 Incidence of hepatotoxicity of isoniazid and rifampicin individually, and in combination[49]

Drugs used	Total no. of patients	Patients with hepatotoxicity	Incidence of hepatotoxicity
INH	38257	210	0.6%
RIF	NA	NA	NA
INH + RIF	6155	168	2.73%
INH + other drugs	2053	33	1.6%
RIF + other drugs	1264	14	1.1%

INH: Isoniazid; RIF: Rifampicin.

Table 2 Studies on hepatotoxicity of antitubercular drugs in combination therapy

Ref.	Definition of hepatotoxicity	Incidence	Risk factors
Døssing et al[61] 1996	AST > 6 × ULN and confirmation by re-challenge	2.0	Female sex, advanced age
Ormerod et al[62] 1996	ALT > 5 × pre-treatment level	2.3	Advanced age
Tost et al[63] 2005	ALT/AST > 10 × ULN	2.6	Alcoholism, hepatitis B carrier state, other
			hepatotoxic drugs
Yee et al[48] 2003	ALT > 3 × ULN	3.0	Advanced age, female sex, Asian, HIV positive
Van Hest et al[64] 2004	ALT > 5 × ULN	3.4	Female gender
Teleman et al[65] 2002	ALT/AST > 3 × ULN	5.3	Abnormal baseline values, female sex, advanced age
Fernández-Villar et al[66] 2004	ALT/AST > 5 × ULN	8.1	Abnormal baseline liver function, low BMI,
			hepatitis B/C, other drugs
Pukenyte et al[67] 2007	ALT > 5 × ULN	10.7	Baseline CD4 < 100 cells/mL, bilirubin > 13 mmol/L or ALT > 51 U/L
Schaberg et al[68] 1996	ALT/AST > 3 × ULN	11.0	Advanced age, past history of hepatitis, female sex
Saigal et al[69] 2001	AST/ALT > 5ULN or > 400 IU/mL	12.9	Advanced child status
	Bilirubin rise > 2.5 mg/dL
Breen et al[70] 2006	ALT/AST > 5 × ULN	13.0	HIV infection, Asian
Huang et al[71] 2003	ALT > 3 × ULN	15.0	Advanced age, low BMI, slow acetylator
			status, CYP2E1 c1/c1 genotype
Sharma et al[72] 2002	ALT/AST > 5 × ULN, or any increase + symptoms	16.1	Advanced age
Park et al[38] 2010	ALT > 3 × ULN	17.0	Female sex, total no. of hepatotoxic drugs administered and baseline ALP levels
Ungo et al[73] 1998	ALT/AST > 3 × ULN	19.0	HIV or hepatitis C infection
Sharifzadeh et al[74] 2005	ALT > 3 × ULN with or > 5 × ULN without symptoms	27.7	No significant risk factors
Pande et al[75] 1996	AST > 3 × ULN	ND	Advanced age, high alcohol intake, slow acetylators

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; ULN: Upper limit of normal; BMI: Body mass index; HIV: Human immunodeficiency virus.

Table 3 Proposed treatment according to stage of liver disease

Child’s status	Treatment
A	Two hepatotoxic drugs can be used namely isoniazid and rifampicin with/without pyrazinamide (low dose). Duration 6-9 mo
B	Ideally one hepatotoxic drug is used in combination. Pyrazinamide generally avoided Duration generally 9-12 mo
C	No hepatotoxic drugs to be used. Can use second-line drugs like streptomycin, ethambutol, fluoroquinolones, amikacin, kanamycin for extended duration of 12 mo or more. Role of aminoglycosides may be limited due to reduced renal reserve in these patients