Prevention of hepatotoxicity due to anti tuberculosis treatment: A novel integrative approach

Table 1 Protocol for selection of patients for recruitment

Protocol for selection of patients for recruitment
Criteria for selection
Evidence of active pulmonary or extra-pulmonary tuberculosis
Age between 15 and 85 years
Readiness to comply with randomization, treatment and follow-up protocols
Patients giving written informed consent
Absence of diseases warranting treatment with systemic steroids, antimetabolites or warfarin
Concomitant conditions allowed
Patients with relapse, multiple relapse, treatment failure of DOTS regimen
Patients with hypertension, diabetes mellitus, COPD (chronic obstructive pulmonary disease) with continuation of required medications
Patients with asthma on inhalational steroid
Skin conditions requiring topical small area steroid application
Patients with HIV positivity but without symptoms suggestive of AIDS
Hepatitis B/C virus carrier
Criteria for rejection
Presumptive diagnosis or lack of evidence of active tuberculosis
Age < 15 or > 85
Patients taking other alternative therapies for tuberculosis
Patients declining to give consent or comply with protocol
Pregnant females
Heavy alcoholism history, > 80 g of alcohol/d for males and > 20 g of alcohol/d for females[50]
Concomitant conditions not allowed
Preexisting liver disease with AST, ALT raised > twice upper normal, evidence of portal hypertension.
Preexisting renal disease with S. Creatinine raised > twice upper normal
Sickle cell disease with history of crisis, anemia and jaundice
History of gout
Recent drop-outs from other TB centers due to complications and side effects
Patients on steroid and/or antimetabolite for other collagen, auto-immune or neoplastic diseases

Table 2 Chemical constituents of formulation

Chemical constituents of formulation with active principles
Chemical constituents of curcuma longa with active principles
Curcuminoids	Desmethoxycurcumin
	Bisdesmethoxycurcumin
	Curcumin
Turmerones	Ar-turmerone
	α-turmerone
	β-turmerone
Curcumenes	γ-Curcumene, ar-Curcumene, Dehydrocurcumene
	zingiberene
	β-bisabolene
	β-sesquiphellandrene
Miscellaneous	Terpinolene, P-Cymene, 1-8-Cineole, Curlone
Chemical constituents of Tinospora cordifolia with active principles
Alkaloids	Berberine, Palmatine,Tembetarine,
	Magnoflorine, Choline,Tinosporin,
	Isocolumbin, Tetrahydropalmatine
Glycosides	18-norclerodane glycoside,
	Furanoid diterpene glucoside,
	Tinocordiside,Tinocordifolioside,
	Syringin, Syringin-apiosylglycoside,
	Palmatosides C, PalmatosidesP
	Cordifolioside A, Cordifolioside B
	Cordifoliside- A, -B, -C, -D and -E
Diterpenoid Lactones	Furanolactone, Clerodane derivatives,
	Tinosporon, Tinosporides, Jateorine,
	Columbin
Steroids	β-sitosterol, δ-sitosterol, 20β-hydroxyecdysone
	Ecdysterone, Makisterone A, Giloinsterol.
Sesquiterpenoid	Tinocordifolin
Aliphatic compounds	Octacosanol, Heptacosanol, Nonacosan-15-one
Miscellaneous compounds	3, (α, 4-dihydroxy-3-methoxy-benzyl)-4-(4- hydroxy-3-methoxy-benzyl)- tetrahydrofuran,
	Jatrorrhizine, Tinosporidine, cordifol, cordifelone
	N-trans-feruloyl tyramine as diacetate, Giloin, Giloinin
	Tinosporic acid

Table 3 Baseline demographic and disease characteristics in the intention-to-treat population

Characteristics of patients	Control	Trial	P
Sex
Male (%)	104 (54)	169 (53)	0.934
Female (%)	88 (46)	147 (47)	0.927
Age-yr median(IQR 25th & 5th)	35 (23.75-45)	35 (27-45)	0.229
Weight (kg, mean ± SD)	37.61 ± 5.94	38.32 ± 6.08	0.199
Ethnicity (%)1
Tribals	171(89)	287(91)	0.883
Others	21(11)	29(9)	0.559
Habits (%)
Smoking	58 (30.2)	103 (32.6)	0.685
Alcohol	23 (12)	33 (10.4)	0.633
Both	26 (13.5)	53 (16.7)	0.403
Socio-Economic status (%)
Upper-Middle	20 (10.4)	40 (12.6)	0.499
Middle	30 (15.6)	52 (16.4)	0.833
Lower	142 (74)	224 (71)	0.763
Pulmonary (%)2
Open cases (sputum +ve)	67 (35)	137 (43.4)	0.214
Parenchymal	152 (79.2)	258 (81.6)	0.822
Cavitary	18 (9.4)	66 (21)	0.003
Effusion	9 (4.6)	20 (6.3)	0.464
Fibrosis	27 (14)	68 (21.5)	0.081
Extra pulmonary (%)2
Cervical lymph node	18 (9.4)	31 (9.8)	0.883
Abdominal	4 (2.1)	6 (2)	0.886
Laryngeal	7 (3.6)	11 (3.5)	0.925
Central nervous system	6 (3.1)	6 (2)	0.389
Bones/Joints	10 (5.2)	19 (6)	0.72
Skin	0	3 (1)	0.598
Genito-Urinary	2 (1.04)	1 (0.3)	0.304
Type of case (%)
New	140 (73)	195 (61.7)	0.245
Relapse	43 (22.4)	97 (30.7)	0.122
Chronic	9 (4.7)	24 (7.6)	0.225
Hematology
Hb (%)	8.84 ± 1.93	8.95 ± 1.95	0.808
Total leucocyte count/mm3	10 179 ± 4 680	9575 ± 4075	0.478
ESR	66.79 ± 30.64	70.49 ± 27.91	0.517
Liver Function (mean, 95%CI)
Serum bilirubin	1.07 (0.7-1.3)	1.09 (0.8-1.4)	0.952
AST	34.35 (17-63)	32.4 (11-61)	0.658
ALT	27.45 (9-57)	31.15 (6-52)	0.655
ALP	100 (50-260)	107 (50-260)	0.092

Unless stated otherwise, P values were calculated with the use of a two sided t-test with Welch’s modification (when unequal variance) for continuous data and a χ² test for categorical data.

¹Ethnic group was assessed by investigation on screening. Tribal consists of Chaudhari, Gamit, Vasava, Bhil, Valvi, Nayka and Halpati.

²Patients may belong to more than one category. ALP: Alkaline phosphatase.

Table 4 Effects of herbal formulation on incidence, onset, duration and severity of hepatitis

ATT induced hepatitis outcome (Table 2)	Control (n = 192)	Trial (n = 316)	P
Patients with raised AST (%)	27 (14)	2 (0.63)	< 0.0001
Patients with raised S bilirubin (%)	17/27 (63)	0	< 0.0001
Mean onset of hepatitis symptomatic	49.12 ± 17.22	-	< 0.0001
Mean onset of hepatitis asymptomatic	29.9 ± 17.63	39 ± 11.31	0.443
Mean onset of any hepatitis	42 ± 19.48	39 ± 11.31	0.776
Mean duration of raised AST	27.5 ± 7.25	21	< 0.0001
Hepatitis gradation
Grade-I	10	2	< 0.0001
Grade-II	9	0	< 0.0001
Grade-III	8	0	< 0.0001
Grade-IV	0	0
Reinstitution of ATT in patients (%)	22/27 (81.5)	NA

P calculated by χ² (categorical data) and two-sided Student’s t-test with Welch’s procedure (continuous data with unequal variance). NA: Not applicable.

Table 5 Comparison of liver enzymes and bilirubin in patients developing hepatitis

	Control (n = 27)	Trial (n = 2)	P
AST	195.93 ± 108.74	85 ± 4.24	< 0.0001
ALT	75.74 ± 26.54	41 ± 1.41	< 0.0001
AST/ALT	2.35 ± 0.74	2.08 ± 0.18	0.207
ALP	241.74 ± 140.96	147.5 ± 45.96	0.118
Serum bilirubin	5.4 ± 3.4	1.5 ± 0.42	< 0.0001

Two-sided Student’s t-test with Welch’s procedure for continuous data with unequal variance. ALP: Alkaline phosphatase.

Table 6 Effects of herbal formulation addition on disease outcome

Treatment outcome for ATT	Control	Trial	P
Number of sputum +ve case at start (%)	67/192 (35)	137/316 (43)	0.03
Number of sputum +ve case after 1-month of treatment (%)	10/67 (14.93)	4/137 (2.9)	0.0068
Poorly resolved parenchymal lesion (%)	9/152 (5.92)	2/258 (0.78)	0.0037
Failure to improve functional status (%)	19/192 (10)	6/316 (2)	0.00013
Treatment dropouts (%)	10/192 (5.2)	0	0.0001
Weight (kg)	39.17 ± 5.5	40.65 ± 6.22	0.0016
Hb (%)	10.92 ± 2.01	11.17 ± 1.97	0.176
ESR mm in 1st hour	45.96 ± 18.52	38.84 ± 22.37	0.0001

P calculated by χ² (categorical data) and two-sided Student’s t-test with Welch’s procedure (continuous data with unequal variance).