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Treatment of latent tuberculosis infection in HIV infected persons

  1. Jimmy Volmink2,
  2. Sara Woldehanna1,*

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 7 OCT 2009

Assessed as up-to-date: 25 NOV 2003

DOI: 10.1002/14651858.CD000171.pub2

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Volmink J, Woldehanna S. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD000171. DOI: 10.1002/14651858.CD000171.pub2.

Author Information

  1. 1

    Academy for Educational Development, Center for Health Communication , Washington, DC, USA

  2. 2

    University of Stellenbosch, Faculty of Health Sciences, Tygerberg, South Africa

*Sara Woldehanna, Center for Health Communication , Academy for Educational Development, 1825 Connecticut Avenue NW, Washington, DC, 20009-5721, USA. swoldehanna@aed.org.

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  1. Publication Status: Unchanged
  2. Published Online: 7 OCT 2009

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Characteristics of included studies [ordered by study ID]
Fitzgerald 2001
Methods237 individuals "randomized"; blinding: providers unclear, participants unclear, assessors unclear. 54 (23%) lost to follow-up; intention to treat analysis.
ParticipantsHIV positive, PPD negative individuals living in Haiti. Inclusion criteria: Age >18 years; HIV symptom free (CDC category A); PPD < 5mm induration; informed consent; negative sputum examination results by smear and culture; negative chest x-ray; no history of TB. Exclusion Criteria: Positive sputum examination results by smear and culture; a history of TB; pregnant.
Interventions1) Control (placebo) plus pyridoxine (vitamin B6): 50 mg daily for 1 year.
2) INH 300 mg plus pyridoxine 50 mg daily for 1 year.
Outcomes1) Active TB: ATS definition- 2 of the following required a) clinical symptoms suggesting TB, b) AFB on Ziehl Nielsen stain or MTb cultured from sputum or biopsy sample, c) chest X-ray independently evaluated as highly suggestive of TB. If no microbiological confirmation, response to anti-TB meds required. 2) AIDS: CDC classification of HIV infection. 3) Death. -- Mean duration of follow-up 2.5 years.
NotesAll patients were treated for opportunistic infections but none were on ART. 91% had +ve reactions to candida + mumps.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear




Gordin 1997
Methods517 individuals, centralized randomisation, stratified by study unit, permuted blocks; blinding: providers yes, participants yes, assessors yes. 34 (7%) lost to follow-up; intention to treat analysis
ParticipantsHIV positive patients attending AIDS research clinics in the US. Inclusion criteria: Anergic (PPD less than 5mm induration AND less than 2mm induration to mumps antigen and tetanus toxoid); age >= 13+ years; no active TB; written consent. Exclusion Criteria: household TB contact in past year, on drugs with activity against TB, acute hepatitis, peripheral neuropathy, history of positive PPD, intolerance to study drug, treatment for >= 1 month with drug active against TB.
Interventions1) Control (Placebo) plus pyridoxine 50mg daily for 6months.
2) INH 300mg plus pyridoxine 50mg daily for 6months.
Outcomes1) Active TB (primary end point): positive culture from any source. 2) Probable TB: clinical features of TB plus a response to anti-TB drugs or autopsy evidence of granulomata containing AFB. 3) Progression of HIV disease: first occurrence of an AIDS-defining condition. 4) Death. 5) Adverse effects.-- Mean duration of follow-up 33.5 months.
NotesUse of ART 73.2% in control arm and 72.7% in INH arm.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate




Gordin 2000
Methods1583 individuals "randomized," stratified by clinic; blinding: providers no, participants no, assessors yes. 115 (7%) lost to follow-up; intention to treat analysis.
ParticipantsPatients attending HIV/AIDS clinics in US, Mexico, Haiti and Brazil. Inclusion criteria: HIV positives, age >= 13 years, >=5mm induration to 5 U PPD or documented history of positive test, informed consent. Exclusion Criteria: Active TB, current treatment with fluoroquinolones or history of >2 mo treatment with anti-TB drugs, intolerance to study drugs, acute hepatitis or peripheral neuropathy, pregnancy.
Interventions1) INH 300mg plus pyridoxine 50mg daily for 12 months.
2) RIF 600mg plus PZA 20mg/kg, daily for 2 months.
Outcomes1) Active TB: positive culture from any source. 2) Probable TB: clinical evidence from a physical examination. 3) Clinical progression of HIV disease: first occurrence of AIDS defining condition. 4) Death. 5) Adverse Effects. -- Mean duration of follow-up 37months.
NotesUse of ART at baseline 35.8% in INH arm and 36.8% in RIF/PZA arm. "Progression of HIV was not reliably diagnosed in Haiti."
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear




Halsey 1998
Methods784 individuals "randomized" with assignment in blocks of 4 or 6; sealed, sequentially numbered envelopes but not described as opaque; blinding: providers no, participants no, assessors yes. 85 (11%) lost to follow-up; 96% included in analysis.
ParticipantsHIV-1 positive individuals living in Haiti. Inclusion criteria: Adults 16 to 77 years, verbal consent, PPD >=5mm, HIV-1 positive (2 positive EIA or rapid test followed by positive EIA confirmed by Western blot). Exclusion Criteria: Evidence of TB, pregnant, negative or indeterminate western blot.
Interventions1) INH 600 mg plus pyridoxine 25mg twice weekly for 6 months.
2) RIF 450mg plus PZA1500mg twice weekly, for 2 months.
Outcomes1) Confirmed TB: positive culture with a compatible clinical illness. 2) Probable TB: positive smear or characteristic morphology and clinically compatible disease. 3) Possible TB: clinically compatible disease responding to anti-TB therapy. 4) Adverse reactions. -- Median duration of follow-up 2.5 years.
NotesReasons for exclusion from analysis: 23 HIV-1 neg or indeterminate on Western blot; 10 had a PPD <5mm; 1 had a abnormal CXR .
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear




Hawken 1997
Methods684 individuals randomized using computer generated random numbers, permuted blocks of 10; labelled tablet packs; blinding: providers yes, participants yes, assessors unclear. 151 (22%) lost to follow-up; 98% included in analysis.
ParticipantsHIV-1 positive commercial sex workers and patients attending STD clinics in Nairobi Kenya. Inclusion criteria: HIV-1 positive (two ELISA tests), local residents, age 14-65 years. Consent- not mentioned. Exclusion Criteria: Past history of TB, current TB suspected, abnormal liver enzymes, life threatening intercurrent illness, pregnant.
Interventions1) Control (Placebo) daily for 6 months.
2) INH 300mg daily for 6months.
Outcomes1) TB: symptoms plus either a) >= 1 positive culture or b) TB histology and no response to broad-spectrum antibiotics for 7 days, and a resolution of symptoms and X-ray findings on anti-TB treatment by 12 weeks. 2) Death. 3) Adverse effects. 4) HIV disease progression: decline in CD4 counts. -- Median duration of follow-up 1.83 years.
Notes12 patients were excluded after enrolment for the following reasons: TB within 30 days of enrolment (3), abnormal chest X ray at enrolment found on review (3), abnormal liver enzymes at enrolment (1), HIV-negative (4), needed hospital referral after enrolment (1).
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate




Johnson 2001
Methods2018 individuals "randomized" in blocks of 6; sequentially numbered, sealed opaque envelopes; blinding: providers no, participants no, assessors yes. 427 (21%) lost to follow up; intention to treat analysis.
ParticipantsAs in Whalen97.
InterventionsAs in Whalen97.
Outcomes1) Definite TB: Culture confirmed (from 3 sputum specimens for suspected cases). 2) Probable TB: Clinical illness consistent with TB based on at least 2 of the following: a) results of chest X ray; b) smear positive for AFB c) response to anti-TB therapy. 3) Possible TB. Not defined. 4) Drug resistance: Isolates tested for drug susceptibility against INH, RIF, PZA ethambutol and streptomycin using standard BACTEC radiometric methods. 5) Death. -- Mean duration of follow-up 2 years.
NotesLong-term follow up of Whalen97 study. Following the interim analysis, INH was offered to all participants in the placebo arm. Relative risks were adjusted for haemoglobin, body mass index and period of enrolment in a Cox proportional hazards model
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate




Johnson 2001 -anergy
Methods718 individuals "randomized" in blocks of 6. Sequentially numbered, sealed opaque envelopes; blinding: providers no, participants no, assessors blind. 103 (14.3%) lost to follow-up; intention to treat analysis.
ParticipantsAs in Whalen97anergy.
InterventionsAs in Whalen97anergy.
OutcomesAs in Johnson01. -- Mean duration of follow-up= 1.6 years.
NotesLong-term follow up of Whalen97anergy study. After interim analysis, INH was offered to participants in placebo arm. Relative risks were adjusted for haemoglobin, body mass index and period of enrolment in a Cox proportional hazards model
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate




Martinez 2001
Methods133 individuals assigned by "random number method"; blinding: providers no, participants no, assessors unclear. 30 (23%) lost to follow-up; intention to treat analysis.
ParticipantsHIV positive patients living in areas of high tuberculosis incidence in Spain. Inclusion criteria: HIV positive, PPD >=5mm or anergic (a negative PPD and induration <2 mm after 48 hours to 7 antigens Multitest IMC), Institut Merieux, Lyon, France), consent. Exclusion Criteria: Contraindications to the study drugs, liver disease, pregnant or lactating, on drugs that could interfere with RIF metabolism, active TB, previous TB prophylaxis.
Interventions1) INH 300 mg daily for 12 months. 2) RIF 600mg plus INH 300 mg daily for 3 months.
Outcomes1) Active TB: positive microscopy and confirmation by culture. 2) Adverse effects. -- Mean duration of follow-up= 17 months.
Notes
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear




Mwinga 1998
Methods1053 individuals assigned using computer generated random method and blocks of 30; serially numbered sealed envelopes not stated to be opaque; blinding: providers yes participants yes, assessors yes. 332 (32%) lost to follow-up; 98% included in analysis
ParticipantsHIV positive patients in Lusaka, Zambia. Inclusion criteria: HIV positive (2 positive ELISA tests); over 15 years of age; written consent. Exclusion Criteria: Previous history of treatment of TB; abnormal liver function tests; evidence of TB; pregnant; unable to attend study clinic.
Interventions1) Placebo twice a week for 6 months or 3 months.
2) INH 900 mg, twice a week, for 6 months. 3) RIF 600mg plus PZA 3500 mg twice a week for 3 months.
Outcomes1) Active TB (confirmed and presumed): includes a) Confirmed TB: positive smear or culture or positive histopathology; b) Presumed TB: abnormal X-ray and clinical symptoms responding to TB treatment in 2 months or pleural or pericardial effusion with a documented response to TB treatment within 2 months. 2) Probable tuberculosis. 3) Death. 4) Adverse events. -- Median duration of follow-up 1.8 years.
Notes27 individuals were excluded after enrolment because they did not meet inclusion criteria: 22 were HIV negative, 3 were duplicates, 1 revealed previous history of TB treatment and 1 subject was discovered to have a TB positive culture. The long-term results of this study are published in the Quigley01
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate




Pape 1993
Methods118 individuals randomized using computer generated numbers; blinding: providers no, participants no, assessors yes. No loss to follow up; intention to treat analysis.
ParticipantsHIV positive patients living in Haiti. Inclusion criteria: Adults 18 to 65 years, symptom free, newly diagnosed as HIV positive (ELISA confirmed by western blot). Consent - non mentioned. Exclusion Criteria: History of TB, abnormal chest X ray or liver function tests.
Interventions1) Pyridoxine 50 mg, daily for 12 months. 2) INH 300mg plus pyridoxine 50 mg daily for 12 months.
Outcomes1) Active TB: Clinical response to TB therapy and at least 2 of: a) TB symptoms 4 weeks b) positive smear, culture or histology; c) chest X-ray suggestive of TB. 2) HIV disease: CDC class II or IVA. 3) AIDS: CDC class IV. 4) Death. -- Mean duration of follow-up= 36 months.
NotesAfter 1989, control patients were offered INH- 21 of the 60 patients accepted.. Anergy screen included mumps, tricophyton and candida. The % of PPD+ in the INH plus pyridoxine group was significantly higher than the placebo group (66% vs. 38%).
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear




Quigley 1998
Methods1053 individuals using computer generated randomization and blocks of 30; serially numbered sealed envelopes not stated to be opaque; blinding: providers no (discontinued after initial phase), assessors yes. Awaiting data on patients lost to follow up.
ParticipantsAs in Mwinga 98
InterventionsAs in Mwinga 98
OutcomesAs in Mwinga 98. -- Mean duration of follow-up 3 years.
NotesLong-term follow up of Mwinga98 study. Placebo group was offered 6 mo of INH after initial analysis.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate




Rivero 2002
Methods319 individuals "randomized"; blinding: providers no, participants no, assessors unclear. 17 (5%) lost to follow-up; intention to treat analysis.
ParticipantsHIV positive anergy patients attending hospitals in Spain. Inclusion criteria: Confirmed HIV infection; age 18-65 yrs; anergy (defined as 0 mm induration after 48-72 hrs to 3 antigens applied by the Mantoux method: PPD, candida albicans and mumps antigens). Consent: none mentioned. Exclusion Criteria: Presence of active TB; previous treatment or chemoprohylaxis for TB; history of hypersensitivity to study drugs; Aspartate aminotransferase (ALT) > 4x normal values; Bilirubin > 2 mg/ml; Creatinine > 2 mg/ml; pregnancy.
Interventions1) Control (No treatment).
2) INH 5 mg/kg (max 300 mg) daily for 6 months. 3) RIF 10 mg/kg (max 600 mg) plus INH 5 mg/kg (max 300 mg) daily for 3 months. 4) RIF 10 mg/kg (max 600 mg) plus PZA 2000 mg daily for 2 months.
Outcomes1) Confirmed Tuberculosis: Confirmation by MTb culture. 2) Probable TB. 3) Death. 4) Adverse events. -- Mean duration of follow-up= 1.23 years.
NotesUnpublished data derived from conference poster.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear




Whalen 1997
Methods2018 individuals "randomized" in blocks of 6; sequentially numbered, sealed opaque envelopes; blinding: providers no, participants no, assessors yes. No loss to follow up; intention to treat analysis.
ParticipantsPPD+ adults attending clinics or counselling centres for persons with HIV-1 infection in Kampala, Uganda. Inclusion criteria: Adults (18 to 50 years) with HIV-1 infection (ELISA test), PPD >=5mm, Karnofsky performance score >50, verbal consent. Exclusion Criteria: Active TB, previous treatment for TB, use of antiviral drugs, anaemia, liver or kidney disease, pregnancy test, home >20km from project clinic, advanced HIV disease, serious medical illness not related to HIV.
Interventions1) Control (Placebo) 250mg ascorbic acid daily for 6 months.
2) INH 300mg daily for 6 months. 3) INH 300mg plus RIF 600mg daily for 3 months. 4) INH 300mg plus RIF 600mg plus PZA 2000mg, daily for 3months.
Outcomes1) Definite TB: Culture confirmed. 2) Probable TB: Clinical illness consistent with TB based on at least 2 of the following: a) results of chest X-ray; b) positive smear c) response to anti-TB therapy. 3) Adverse reactions. 4) Death. -- Mean duration of follow-up= 15 months.
NotesAfter interim analysis INH was offered to placebo group. The long-term results of this study are published in Johnson01.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate




Whalen 1997-anergy
Methods718 individuals "randomized" in blocks of 6. Sequentially numbered, sealed opaque envelopes; blinding: providers no, participants no, assessors yes. 103 (14%) lost to follow-up; intention to treat analysis.
ParticipantsAs in Whalen 97 except patients had to be anergic. Anergy was defined as 0mm induration in reaction to both PPD and candida antigens.
Interventions1) Control (placebo) Ascorbic acid 250mg daily for 6 months.
2) INH 300mg, daily for 6 months.
OutcomesAs in Whalen 97. -- Mean duration of follow-up 12 months.
NotesThe long-term results of this study are published in Johnson01anergy.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate


 
Characteristics of excluded studies [ordered by study ID]
StudyReason for exclusion
Fitzgerald 2000Only evaluated preventive therapy to reduce recurrence of TB in individuals who had previously had the disease, not to prevent occurence of 1st TB.
Garcia 1993Assessed drug tolerability rather than prevention of active TB
Matteelli 1998Assessed drug tolerability rather than prevention of active TB
Saenghirunvatta 1996Described only as "prospective, comparative"


 
Comparison 1. Any TB drug vs placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Incidence of active TB (confirmed, probable or possible)85664Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.51, 0.81]
    1.1 PPD+
42378Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.25, 0.57]
    1.2 PPD-
72822Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.58, 1.18]
    1.3 PPD unknown
2464Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.49, 1.34]
 2 Incidence of confirmed TB42573Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.49, 1.08]
    2.1 PPD+
1161Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.06, 1.57]
    2.2 PPD-
31353Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.38, 1.45]
    2.3 PPD unknown
21059Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.47, 1.32]
 3 Incidence of death (all cause)85664Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.85, 1.06]
    3.1 PPD+
42378Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.63, 1.02]
    3.2 PPD-
72822Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.89, 1.15]
    3.3 PPD unknown
2464Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.58, 1.24]
 4 Incidence of AIDS2355Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.60, 1.28]
    4.1 PPD+
163Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.15, 0.85]
    4.2 PPD-
2292Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.72, 1.69]
   4.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 5 Incidence of adverse events leading to stopping treatment75427Risk Ratio (M-H, Fixed, 95% CI)2.49 [1.64, 3.77]
7 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.1 PPD+
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.2 PPD-
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.3 PPD unknown
00Mean Difference (IV, Fixed, 95% CI)Not estimable
8 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)Not estimable
9 Mean time to death00Mean Difference (IV, Fixed, 95% CI)Not estimable
 10 Mean time to AIDS1118Mean Difference (IV, Fixed, 95% CI)7.80 [1.71, 13.89]
 
Comparison 2. Isoniazid vs placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Incidence of active TB (confirmed, probable or possible)84136Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.51, 0.87]
    1.1 PPD+
41311Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.22, 0.61]
    1.2 PPD-
72490Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.59, 1.26]
    1.3 PPD unknown
2335Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.48, 1.52]
 2 Incidence of confirmed TB42063Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.47, 1.11]
    2.1 PPD+
1112Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.32]
    2.2 PPD-
31021Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.36, 1.61]
    2.3 PPD unknown
2930Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.46, 1.36]
 3 Incidence of death (all cause)84136Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.85, 1.06]
    3.1 PPD+
41311Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.55, 1.00]
    3.2 PPD-
72490Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.90, 1.16]
    3.3 PPD unknown
2335Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.52, 1.27]
 4 Incidence of AIDS2355Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.60, 1.28]
    4.1 PPD+
163Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.15, 0.85]
    4.2 PPD-
2292Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.72, 1.69]
   4.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 5 Incidence of adverse events leading to stopping treatment73899Risk Ratio (M-H, Fixed, 95% CI)1.66 [1.09, 2.51]
7 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.1 PPD+
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.2 PPD-
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.3 PPD unknown
00Mean Difference (IV, Fixed, 95% CI)Not estimable
8 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)Not estimable
9 Mean time to death00Mean Difference (IV, Fixed, 95% CI)Not estimable
 10 Mean time to AIDS1118Mean Difference (IV, Fixed, 95% CI)7.80 [1.71, 13.89]
 
Comparison 3. Isoniazid + rifampicin vs placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Incidence of active TB (confirmed, probable or possible)21179Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.21, 0.81]
    1.1 PPD+
11020Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.17, 0.77]
    1.2 PPD-
1159Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.16, 3.05]
   1.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 2 Incidence of confirmed TB1159Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.16, 3.05]
   2.1 PPD+
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    2.2 PPD-
1159Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.16, 3.05]
   2.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 3 Incidence of death (all cause)21179Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.50, 0.95]
    3.1 PPD+
11020Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.53, 1.04]
    3.2 PPD-
1159Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.11, 1.03]
   3.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
4 Incidence of AIDS00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.1 PPD+
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.2 PPD-
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 5 Incidence of adverse events leading to stopping treatment21179Risk Ratio (M-H, Fixed, 95% CI)16.72 [3.29, 84.89]
7 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.1 PPD+
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.2 PPD-
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.3 PPD unknown
00Mean Difference (IV, Fixed, 95% CI)Not estimable
8 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)Not estimable
9 Mean time to death00Mean Difference (IV, Fixed, 95% CI)Not estimable
10 Mean time to AIDS00Mean Difference (IV, Fixed, 95% CI)Not estimable
 
Comparison 4. Rifampicin + pyrazinimide vs placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Incidence of active TB (confirmed, probable or possible)2855Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.34, 0.86]
    1.1 PPD+
1109Risk Ratio (M-H, Fixed, 95% CI)0.22 [0.05, 0.96]
    1.2 PPD-
2493Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.34, 1.23]
    1.3 PPD unknown
1253Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.28, 1.27]
 2 Incidence of confirmed TB2855Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.34, 1.38]
    2.1 PPD+
1109Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.12, 3.20]
    2.2 PPD-
2493Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.28, 2.01]
    2.3 PPD unknown
1253Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.19, 2.22]
 3 Incidence of death (all cause)2855Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.77, 1.41]
    3.1 PPD+
1109Risk Ratio (M-H, Fixed, 95% CI)2.76 [0.90, 8.41]
    3.2 PPD-
2493Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.68, 1.52]
    3.3 PPD unknown
1253Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.51, 1.41]
4 Incidence of AIDS00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.1 PPD+
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.2 PPD-
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 5 Incidence of adverse events leading to stopping treatment2855Risk Ratio (M-H, Fixed, 95% CI)7.84 [2.60, 23.67]
7 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.1 PPD+
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.2 PPD-
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.3 PPD unknown
00Mean Difference (IV, Fixed, 95% CI)Not estimable
8 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)Not estimable
9 Mean time to death00Mean Difference (IV, Fixed, 95% CI)Not estimable
10 Mean time to AIDS00Mean Difference (IV, Fixed, 95% CI)Not estimable
 
Comparison 5. Isoniazid + rifampicin + pyrazinamid vs placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Incidence of active TB (confirmed, probable or possible)1926Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.23, 1.00]
    1.1 PPD+
1926Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.23, 1.00]
   1.2 PPD-
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   1.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
2 Incidence of confirmed TB00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   2.1 PPD+
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   2.2 PPD-
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   2.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 3 Incidence of death (all cause)1926Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.65, 1.27]
    3.1 PPD+
1926Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.65, 1.27]
   3.2 PPD-
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   3.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
4 Incidence of AIDS00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.1 PPD+
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.2 PPD-
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 5 Incidence of adverse events leading to stopping treatment1926Risk Ratio (M-H, Fixed, 95% CI)26.11 [3.56, 191.63]
7 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.1 PPD+
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.2 PPD-
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.3 PPD unknown
00Mean Difference (IV, Fixed, 95% CI)Not estimable
8 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)Not estimable
9 Mean time to death00Mean Difference (IV, Fixed, 95% CI)Not estimable
10 Mean time to AIDS00Mean Difference (IV, Fixed, 95% CI)Not estimable
 
Comparison 6. Isoniazid vs rifampicin + pyrazinimide
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Incidence of active TB (confirmed, probable or possible)43196Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.73, 1.38]
    1.1 PPD+
32434Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.65, 1.43]
    1.2 PPD-
2511Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.59, 2.32]
    1.3 PPD unknown
1251Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.40, 2.26]
 2 Incidence of confirmed TB43196Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.67, 1.55]
    2.1 PPD+
32434Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.62, 1.63]
    2.2 PPD-
2511Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.47, 3.28]
    2.3 PPD unknown
1251Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.18, 3.47]
 3 Incidence of death (all cause)43137Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.89, 1.19]
    3.1 PPD+
32434Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.93, 1.29]
    3.2 PPD-
2452Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.54, 1.17]
    3.3 PPD unknown
1251Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.50, 1.52]
4 Incidence of AIDS00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.1 PPD+
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.2 PPD-
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 5 Incidence of adverse events leading to stopping treatment43196Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.48, 0.86]
7 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.1 PPD+
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.2 PPD-
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.3 PPD unknown
00Mean Difference (IV, Fixed, 95% CI)Not estimable
8 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)Not estimable
9 Mean time to death00Mean Difference (IV, Fixed, 95% CI)Not estimable
10 Mean time to AIDS00Mean Difference (IV, Fixed, 95% CI)Not estimable
 
Comparison 7. Isoniazid vs isoniazid + rifampicin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Incidence of active TB (confirmed, probable or possible)31390Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.51, 2.17]
    1.1 PPD+
21139Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.46, 2.53]
    1.2 PPD-
2251Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.25, 3.87]
   1.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 2 Incidence of confirmed TB2298Risk Ratio (M-H, Fixed, 95% CI)1.49 [0.49, 4.50]
    2.1 PPD+
147Risk Ratio (M-H, Fixed, 95% CI)3.71 [0.42, 33.15]
    2.2 PPD-
2251Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.25, 3.87]
   2.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 3 Incidence of death (all cause)31385Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.80, 1.50]
    3.1 PPD+
21134Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.75, 1.49]
    3.2 PPD-
2251Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.59, 2.84]
   3.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
4 Incidence of AIDS00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.1 PPD+
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.2 PPD-
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 5 Incidence of adverse events leading to stopping treatment31390Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.46, 1.24]
7 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.1 PPD+
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.2 PPD-
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.3 PPD unknown
00Mean Difference (IV, Fixed, 95% CI)Not estimable
8 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)Not estimable
9 Mean time to death00Mean Difference (IV, Fixed, 95% CI)Not estimable
10 Mean time to AIDS00Mean Difference (IV, Fixed, 95% CI)Not estimable
 
Comparison 8. Isoniazid + rifampicine vs Rifampicin + Pyrazinimide
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Incidence of active TB (confirmed, probable or possible)1159Risk Ratio (M-H, Fixed, 95% CI)2.82 [0.30, 26.51]
   1.1 PPD+
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    1.2 PPD-
1159Risk Ratio (M-H, Fixed, 95% CI)2.82 [0.30, 26.51]
   1.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 2 Incidence of confirmed TB1159Risk Ratio (M-H, Fixed, 95% CI)2.82 [0.30, 26.51]
   2.1 PPD+
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    2.2 PPD-
1159Risk Ratio (M-H, Fixed, 95% CI)2.82 [0.30, 26.51]
   2.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 3 Incidence of death (all cause)1159Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.21, 2.70]
   3.1 PPD+
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    3.2 PPD-
1159Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.21, 2.70]
   3.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
4 Incidence of AIDS00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.1 PPD+
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.2 PPD-
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 5 Incidence of adverse events leading to stopping treatment1159Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.55, 2.13]
7 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.1 PPD+
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.2 PPD-
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.3 PPD unknown
00Mean Difference (IV, Fixed, 95% CI)Not estimable
8 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)Not estimable
9 Mean time to death00Mean Difference (IV, Fixed, 95% CI)Not estimable
10 Mean time to AIDS00Mean Difference (IV, Fixed, 95% CI)Not estimable
 
Comparison 9. Isoniazid vs isoniazid + rifampicin + Pyrazinamide
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Incidence of active TB (confirmed, probable or possible)1998Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.23, 1.57]
    1.1 PPD+
1998Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.23, 1.57]
   1.2 PPD-
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   1.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
2 Incidence of confirmed TB00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   2.1 PPD+
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   2.2 PPD-
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   2.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 3 Incidence of death (all cause)1998Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.61, 1.21]
    3.1 PPD+
1998Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.61, 1.21]
   3.2 PPD-
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   3.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
4 Incidence of AIDS00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.1 PPD+
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.2 PPD-
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 5 Incidence of adverse events leading to stopping treatment1998Risk Ratio (M-H, Fixed, 95% CI)0.10 [0.03, 0.33]
7 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.1 PPD+
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.2 PPD-
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.3 PPD unknown
00Mean Difference (IV, Fixed, 95% CI)Not estimable
8 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)Not estimable
9 Mean time to death00Mean Difference (IV, Fixed, 95% CI)Not estimable
10 Mean time to AIDS00Mean Difference (IV, Fixed, 95% CI)Not estimable
 
Comparison 10. Isoniazid + rifampicin vs isoniazid + rifampicin + Pyrazinamide
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Incidence of active TB (confirmed, probable or possible)11018Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.31, 1.82]
    1.1 PPD+
11018Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.31, 1.82]
   1.2 PPD-
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   1.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
2 Incidence of confirmed TB00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   2.1 PPD+
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   2.2 PPD-
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   2.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 3 Incidence of death (all cause)11018Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.58, 1.15]
    3.1 PPD+
11018Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.58, 1.15]
   3.2 PPD-
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   3.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
4 Incidence of AIDS00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.1 PPD+
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.2 PPD-
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
   4.3 PPD unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 5 Incidence of adverse events leading to stopping treatment11018Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.22, 0.80]
7 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.1 PPD+
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.2 PPD-
00Mean Difference (IV, Fixed, 95% CI)Not estimable
   7.3 PPD unknown
00Mean Difference (IV, Fixed, 95% CI)Not estimable
8 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)Not estimable
9 Mean time to death00Mean Difference (IV, Fixed, 95% CI)Not estimable
10 Mean time to AIDS00Mean Difference (IV, Fixed, 95% CI)Not estimable
 
Comparison 22. Isoniazid vs placebo (stratified by AIDS status at baseline)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 2 Incidence of confirmed TB1517Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.15, 1.90]
    2.1 AIDS
1120Risk Ratio (M-H, Fixed, 95% CI)3.42 [0.14, 82.33]
    2.2 NO AIDS
1397Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.06, 1.54]
 3 Incidence of death (all cause)1520Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.87, 1.22]
    3.1 AIDS
1120Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.79, 1.17]
    3.2 NO AIDS
1400Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.84, 1.35]
 
Comparison 26. Isoniazid vs rifampicin + pyrazinimide (stratified by AIDS status at baseline)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 2 Incidence of confirmed TB11583Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.74, 2.36]
    2.1 AIDS
1112Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.28, 3.43]
    2.2 NO AIDS
11471Risk Ratio (M-H, Fixed, 95% CI)1.42 [0.74, 2.74]
 3 Incidence of death (all cause)11583Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.90, 1.35]
    3.1 AIDS
1112Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.69, 1.41]
    3.2 NO AIDS
11471Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.90, 1.43]
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