Isoniazid for preventing tuberculosis in non-HIV infected persons

 

Characteristics of included studies [ordered by study ID]

Comstock 1962

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Methods	Randomization by family unit.
Participants	7,333 Alaskan villagers in 28 villages and 2 boarding schools. Enrolled regardless of PPD status.
Interventions	Isoniazid 300 mg daily for 1 year.
Outcomes	1. Active tuberculosis
Notes	—

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Del Castillo 1965

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Methods	Randomization by family unit.
Participants	400 household contacts of index cases treated at Quezon Institute, Manila, Phillippines.
Interventions	Isoniazid 5-10 mg/kg for 1 year.
Outcomes	1. Active tuberculosis
Notes	—

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Egsmose 1965

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Methods	Randomization by household. Allocation by random numbers tables.
Participants	626 Kenyan rural villagers, contacts of index cases.
Interventions	Isoniazid 300-500 mg daily for 12-24 months.
Outcomes	1. Pulmonary tuberculosis (sputum microscopy or culture) 2. Deaths
Notes	—

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Falk 1978

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Methods	Individual randomization.
Participants	7,036 men in U.S. VA hospitals; abnormal chest x-ray. 98% men; mostly 30-50 years old. 77% white.
Interventions	Isoniazid 300 mg daily 1-2 years.
Outcomes	1. Active tuberculosis
Notes	Majority of this group had received previous TB medications and were excluded from analysis. 2,389 participants included.

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Ferebee 1962

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Methods	Randomization by family unit.
Participants	25,033 household contacts of newly diagnosed reported tuberculosis. 2/3 under 20 years old.
Interventions	Isoniazid 300 mg/kg or 5 mg/kg for one year.
Outcomes	1. Active tuberculosis 2. Extrapulmonary tuberculosis 3. Death
Notes	—

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Ferebee 1963

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Methods	Randomization by ward or building.
Participants	24,838 patients in 37 county institutions for chronic psychiatric or mentally retarded in Wisconsin, Georgia, and Massachusetts, U.S.A. PPD >5mm in 50%. Age 2-100, >85% white, mean age 48 (men) 54 (women).
Interventions	Isoniazid 300 mg daily for 12 months.
Outcomes	1. Active tuberculosis 2. Death
Notes	91% had normal chest x-ray, 9% abnormal at baseline.

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Girling 1992

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Methods	Inidividual randomization.
Participants	679 Chinese men with silicosis in Hong Kong. Most 45-64, 63% current smokers, 94% >10mm. Criteria: silicosis diagnosis, no history TB, no evidence TB, negative sputum microscopy and culture.
Interventions	INH 300 mg daily 6 months; Rifampin 600 mg daily 12 weeks; INH + Rif 12 weeks; placebo.
Outcomes	1. Active tuberculosis
Notes	All had abnormal chest x-rays. Only the INH and placebo arms included in this review (total 199).

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John 1994

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Methods	Individual randomization, random numbers table.
Participants	184 transplant or dialysis patients in India.
Interventions	Isoniazid 300 mg or placebo for one year. Low compliance.
Outcomes	1. Active tuberculosis 2. Hepatitis 3. Death
Notes	High rates of drop out and hepatitis in both groups.

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Mount 1962

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Methods	Randomization by family unit.
Participants	2,824 household contacts of known tuberculosis cases (prevalent cases) in USA. 1/3 children; 55% PPD< 5mm; 60% black.
Interventions	Isoniazid 300 mg daily for one year.
Outcomes	1. Active tuberculosis 2. Extrapulmonary tuberculosis 3. Deaths
Notes	—

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Thompson 1982

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Methods	Individual randomization.
Participants	28,000 adults in Eastern Europe: 115 clinics Czechoslovakia, Finland, German Democratic Republic, Hungary, Poland, Romania, Yugoslavia. Mean age 50 (20-65), attending chest clinic, abnormal chest x-ray, no previous treatment, no previous positive bacteriology. 1/3 were age 55-65. PPD>6mm.
Interventions	Isoniazid for 3, 6 or 12 months or placebo.
Outcomes	1. Active tuberculosis 2. Hepatitis
Notes	Only placebo, 6 and 12 month arms included in this analysis (total of 20,828).

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Veening 1968

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Methods	Individual randomization.
Participants	261 PPD positive contacts of active cases in Royal Netherlands Navy barracks.
Interventions	Isoniazid 600 mg for 4 months then 400 mg daily for total 1 years.
Outcomes	1. Active tuberculosis
Notes	Close follow-up and attention to compliance.

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Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Bush 1961	Only 1 year follow-up results. At one year: 5/1096 INH treated versus 6/1048 placebo treated original interpretation 8 vs 11. US PHS reinterpreted.
Chiba 1963	Included PAS with INH.
Clayson 1963	Co-intervention with PAS.
Comstock 1969	No placebo group.
Comstock 1972	No randomization.
Curry 1967	Non-randomized.
Dahlstrom 1960	No clinical end-point, follow-up less than 2 years.
Debre 1973	No placebo group, no randomization.
Dimond 1968	No placebo control, no randomization.
Dorken 1984	No randomization, co-intervention with ethambutol.
Dormer 1959	No randomization.
Dormer 1960	No randomization, no placebo.
Ferebee 1957	Primary tuberculosis in children.
Gordin HIV 1997	HIV positive population.
Groth-Peterson 1960	Inadequate dose: 400 mg twice weekly for two thirteen week periods. Follow-up numbers do not match original reports.
Grzybowski 1972	No randomization, concurrent use of PAS.
Hawken HIV 1997	HIV positive population.
Hsu 1974	Non-randomized.
Katz 1962	Non-random allocation, no use of placebo.
Katz 1965	Non-random allocation, no use of placebo.
Khoury 1969	No placebo group, no randomization.
Lotte 1964	Primary tuberculosis in children.
Mount 1961	Primary tuberculosis in children.
Mysakowska 1964	No placebo group, no randomization.
Narain 1970	No randomization, no placebo.
Nyboe 1963	One-year follow-up only, never published.
Pamra 1971	Incomplete follow-up and unclear measure of active tuberculosis.
Pape HIV 1993	HIV positive population.
Vandiviere 1973	INH and BCG co-interventions; INH for less than 6 months.
Whalen HIV 1997	HIV positive population.
Zorini 1958	Non-randomized, no placebo.
Zorini 1961	Non-randomized, no placebo.
Zorini 1963	Non-randomized, no placebo.

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Comparison 1. Isoniazid versus placebo

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Active tuberculosis	11	73375	Risk Ratio (M-H, Random, 95% CI)	0.40 [0.31, 0.52]
2 Extra-pulmonary tuberculosis	4	44636	Risk Ratio (M-H, Random, 95% CI)	0.34 [0.16, 0.71]
3 TB deaths	2	25714	Risk Ratio (M-H, Random, 95% CI)	0.29 [0.07, 1.18]
4 Hepatitis	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected
5 Hepatitis-related deaths	2	25714	Risk Ratio (M-H, Random, 95% CI)	4.13 [0.50, 34.39]
6 Total deaths	5	33716	Risk Ratio (M-H, Random, 95% CI)	1.10 [0.94, 1.28]

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Comparison 2. Isoniazid 6 vs 12 months

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Active tuberculosis	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected
2 Hepatitis	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected
3 Active tuberculosis in highly compliant	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

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Comparison 3. INH 6 months vs placebo

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Active tuberculosis	2	14145	Risk Ratio (M-H, Random, 95% CI)	0.44 [0.27, 0.73]

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Comparison 4. INH 12 months+ vs placebo

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Active tuberculosis	10	66257	Risk Ratio (M-H, Random, 95% CI)	0.38 [0.28, 0.50]

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Comparison 5. High compliance (>80%) INH vs placebo

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Active tuberculosis	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

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